Diagnosis and

Management of
Testicular Cancer

The European
Point of View

Susanne Krege
Editor

123
Diagnosis and Management of Testicular
Cancer
Susanne Krege
Editor

Diagnosis and
Management of Testicular
Cancer
The European Point of View
Editor
Susanne Krege
Kliniken Essen-Mitte
Klinik für Urologie
Essen
Germany

ISBN 978-3-319-17466-2 ISBN 978-3-319-17467-9 (eBook)

DOI 10.1007/978-3-319-17467-9

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Contents

Part I Overview of the Latest Recommendations

of the European Germ Cell Cancer Group

1 Latest Recommendations of the European

Germ Cell Cancer Group on Diagnosis and
Treatment of Germ Cell Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Susanne Krege

Part II Special Topics About Controversial Aspects,

New Results from Studies, Which Might Change
Treatment Recommendations and Long-Term-Survivorship

2 Is There Still an Indication for Radiotherapy

in Seminoma Clinical Stages I–IIA/B? . . . . . . . . . . . . . . . . . . . . . . . . 19
Sophie Dorothea Fosså and Klaus-Peter Dieckmann
3 How Should We Treat Clinical Stage I (CSI) Nonseminoma . . . . . . 25
Torgrim Tandstad
4 Is There Still an Indication for Primary RPLND
in Clinical Stage I Non-seminoma? . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Nicola Nicolai and Alessandro Crestani
5 Metastatic Germ Cell Cancer:
The Intermediate-Prognosis Risk Category . . . . . . . . . . . . . . . . . . . . 55
Carsten Bokemeyer and Christoph Seidel
6 Poor-Prognosis Germ Cell Tumours . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Karim Fizazi and Stephane Culine
7 How Should Patients with Recurrent Disease
Be Treated Actually? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Anja Lorch

v
vi Contents

8 Prognostic Factors at Initial Presentation

and in Recurrent Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Jörg Beyer
9 Postchemotherapy Retroperitoneal Lymph
Node Dissection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Axel Heidenreich
10 What Are the Recent Recommendations
for Follow-Up in Testicular Cancer? . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Richard Cathomas and Michael Hartmann
11 What Are the Long-Term Toxicities to
Be Controlled and Treated? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
J. Oldenburg, H.S. Haugnes, and S.D. Fosså
12 Consequences of the Disease and Its
Treatment Concerning Sexuality and Fertility. . . . . . . . . . . . . . . . . . 127
Sabine Kliesch
Contributors

Jörg Beyer Department of Oncology, University Hospital Zürich, Zürich,

Switzerland
Carsten Bokemeyer Department of Oncology, Hematology and Bone Marrow
Transplantation with Section Pneumology, University Hospital Hamburg-Eppendorf,
Hamburg, Germany
Richard Cathomas Department of Internal Medicine/ Section Oncology,
Kantonsspital Graubünden, Chur, Switzerland
Alessandro Crestani Department of Urology/ Testis Surgery Unit, Fondazione
IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
Stephane Culine Department of Medical Oncology, Hospital Saint Louis,
University of Paris VII, Paris, France
R. de Wit Erasmus University Medical Center/ Cancer Institute, Rotterdam,
The Netherlands
Klaus-Peter Dieckmann Department of Urology, Albertinen-Krankenhaus,
Hamburg, Germany
Karim Fizazi, MD, PhD Department of Cancer Medicine, University of Paris
Sud, Institut Gustave Roussy, Villejuif, France
Sophie Dorothea Fosså Oslo University Hospital, The Norwegian Radium
Hospital, National Advisory Unit for Late Effects after Cancer Therapy, Oslo,
Norway
Michael Hartmann Department of Oncology/ Interdisciplinary Testis Cancer Unit,
University Hospital Hamburg-Eppendorf, Hamburg, Germany
H.S. Haugnes Department of Oncology, University Hospital of North Norway,
Tromso, Norway
Axel Heidenreich Department of Urology, University Hospital Aachen, Aachen,
Germany

vii
viii Contributors

Sabine Kliesch Department of Clinical Andrology, Center of Reproductive

Medicine and Andrology WHO Collaboration Center, EAA Training Center,
University Hospital Münster, Münster, Germany
Susanne Krege Klinik für Urologie, Kliniken Essen-Mitte, Essen, Germany
Anja Lorch Genitourinary Medical Oncology/ Department of Urology, University
Hospital Düsseldorf, Düsseldorf, Germany
Nicola Nicolai Department of Urology/ Testis Surgery Unit, Fondazione IRCCS,
Istituto Nazionale dei Tumori, Milan, Italy
Jan Oldenburg Department of Oncology, Akershus University Hospital,
Lorenskog and Oslo University Hospital, Lorenskog, Norway
Christoph Seidel Department of Oncology, Hematology and Bone Marrow
Transplantation with Section Pneumology, University Hospital Hamburg-
Eppendorf, Hamburg, Germany
Torgrim Tandstad, MD, PhD Department of Oncology, St. Olavs University
Hospital, Trondheim, Norway
 Part I
Overview of the Latest Recommendations of
the European Germ Cell Cancer Group
Latest Recommendations
of the European Germ Cell Cancer 1
Group on Diagnosis and Treatment
of Germ Cell Cancer

Susanne Krege

Contents
1.1 Diagnosis........................................................................................................................ 3
1.2 Treatment of the Primary Tumour ................................................................................. 4
1.3 Contralateral TIN ........................................................................................................... 4
1.4 Staging ........................................................................................................................... 4
1.5 Treatment of Patients with Seminoma CSI .................................................................... 9
1.6 Treatment of Patients with Non-seminoma CSI ............................................................ 9
1.7 First-Line Treatment of Metastatic Disease ................................................................... 10
1.8 Residual Tumour Resection ........................................................................................... 11
1.9 Salvage Treatment .......................................................................................................... 11
1.10 Late Relapse ................................................................................................................... 12
1.11 Follow-Up ...................................................................................................................... 12
1.12 Long-Term Survivorship ................................................................................................ 13
References ............................................................................................................................... 13

1.1 Diagnosis

The majority of germ cell tumours present in the testis as a painless swollen mass.
Mandatory diagnostic examinations of a suspicious testis include palpation, ultraso-
nography with a >7.5-MHz transducer and determination of the tumour markers
alpha-fetoprotein (AFP), human choriongonadotropin (hCG) and lactic dehydroge-
nase (LDH). The diagnosis is confirmed by surgical exploration of the testis using
an inguinal incision. Only in case of life-threatening metastatic disease and unequiv-
ocal diagnosis, surgery of the testis should be postponed until completion of
chemotherapy.

S. Krege
Klinik für Urologie, Kliniken Essen-Mitte, Essen, Germany
e-mail: [email protected]

© Springer International Publishing Switzerland 2015 3

S. Krege (ed.), Diagnosis and Management of Testicular Cancer: The European
Point of View, DOI 10.1007/978-3-319-17467-9_1
4 S. Krege

In a minority germ cell cancer presents as a primary extragonadal cancer, prefer-

ably in the retroperitoneum or mediastinum. Back pain can be the first symptom.
Diagnosis is confirmed by elevated tumour markers or biopsy of the mass.

1.2 Treatment of the Primary Tumour

Standard treatment of the tumour-bearing testicle is orchiectomy along with the

resection of the spermatic cord at the level of the internal inguinal ring. Some testis
tumours might be benign. Therefore, in case of negative tumour markers and a small
testicular lesion a frozen section should be performed to allow organ-preserving
surgery in case of a benign histology [5]. Organ-preserving surgery in case of tes-
ticular cancer can be performed in patients with synchronous bilateral tumours, a
metachronous contralateral tumour or a solitary testicle with normal preoperative
testosterone level [6]. A testicular intraepithelial neoplasia (TIN) which is regularly
found around the tumour is managed by local radiation with 20 Gy, but may be
delayed in patients who wish to father children.

1.3 Contralateral TIN

Nine per cent of patients with germ cell cancer of the testis harbour TIN within the
contralateral testicle. Especially patients younger than 40 years and with a testicu-
lar volume <12 ml are at risk. To detect TIN contralateral biopsies at two sides,
preferably at the time of resection of the tumour-bearing testicle, can be performed
[7]. The biopsies should be preserved in Bouin’s solution, not formalin. TIN can
be managed by orchiectomy or local radiotherapy with 20 Gy as definitive treat-
ment options or surveillance in case of patients who still want to father children
[8]. Patients who need chemotherapy for their definitive cancer have a chance of
about 66 % that TIN will be eradicated by chemotherapy. Another biopsy to con-
firm this should not be performed earlier than 2 years after completion of chemo-
therapy [9].

1.4 Staging

Table 1.1 gives an overview about mandatory information of the histopathological

report.
Table 1.2 shows the different types of germ cell tumours according to the WHO
classification.
1 Latest Recommendations of the European Germ Cell Cancer 5

Table 1.1 Requests concerning the histopathological report

Localization of the tumour
Size
Multiplicity
Extension of the tumour (pT category according to UICC)
Histopathological type (WHO)
In seminoma: presence of syncytiotrophoblasts
In spermatocytic seminoma: any sarcomatous elements
In pluriform tumours: description and percentage of each individual component
Presence of TIN
Immunohistochemistry: AFP and hCG for detection of yolk sac tumour and choriocarcinoma
CD31/FVIII for vascular invasion (pluripotency-related markers such as OCT4, NANOG,
LIN28, AP-2 gamma for TIN, seminoma, embryonal cell carcinoma)

The clinical stage is defined by the UICC TNM classification (Table 1.3). Patients
with metastatic disease are classified according to the classification of the

Table 1.2 WHO classification of germ-cell tumours of the testis [10]

Histological type ICD-O-M
Intratubular germ cell neoplasia, unclassified 9064/2
Others
Tumours of one histological type (pure forms)
Seminoma 9061/3
(Subtype) Seminoma with syncytiotrophoblastic cells
Spermatocytic seminoma 9063/3
(Subtype) Spermatocytic seminoma with sarcoma
Embryonal carcinoma 9070/3
Yolk sac tumour 9071/3
Trophoblastic tumours
Choriocarcinoma 9100/3
Trophoblastic neoplasms other than choriocarcinoma
Monophasic choriocarcinoma
Placental site trophoblastic tumour 9104/1
Teratoma 9080/3
Dermoid cyst 9084/0
Monodermal teratoma
Teratoma with somatic type malignancies 9084/3
Tumours of more than one histological type (mixed forms)
Mixed embryonal carcinoma and teratoma 9081/3
Mixed teratoma and seminoma 9085/3
Choriocarcinoma and teratoma/embryonal carcinoma 9101/3
Others
WHO World Health Organization

International Germ Cell Cancer Collaborative Group (IGCCCG), which also pays
regard to the elevation of tumour markers (Table 1.4).
Spiral computerized tomography (CT) scans of the thorax, abdomen and pelvis
remain the staging procedures of choice. Magnetic resonance tomography (MRT)
 6

Table 1.3 TNM classification – UICC 2009 [11]

pT Primary tumour
pTX Primary tumour cannot be assessed
pT0 No evidence of primary tumour (e.g. histological scar in testis)
pTis Intratubular germ cell neoplasia (carcinoma in situ)
pT1 Tumour limited to testis and epididymis without vascular/lymphatic invasion: tumour may invade tunica albuginea
but not tunica vaginalis
pT2 Tumour limited to testis and epididymis with vascular/lymphatic invasion, or tumour extending through tunica
albuginea with involvement of tunica vaginalis
pT3 Tumour invades spermatic cord with or without vascular/lymphatic invasion
pT4 Tumour invades scrotum with or without vascular/lymphatic invasion
N Regional lymph nodes clinical
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis with a lymph node mass 2 cm or less in greatest dimension or multiple lymph nodes, none more than 2 cm
in greatest dimension
N2 Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph
nodes, any one mass more than 2 cm but not more than 5 cm in greatest dimension
N3 Metastasis with a lymph node mass more than 5 cm in greatest dimension
pN Pathological
pNX Regional lymph nodes cannot be assessed
pN0 No regional lymph node metastasis
pN1 Metastasis with a lymph node mass 2 cm or less in greatest dimension and 5 or fewer positive nodes, none more than
2 cm in greatest dimension
pN2 Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or more than 5
nodes positive, none more than 5 cm; or evidence or extranodal extension of tumour
pN3 Metastasis with a lymph node mass more than 5 cm in greatest dimension
M Distant metastasis
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
S. Krege
 1

M1a Non-regional lymph nodes(s) or lung

M1b Other sites
S Serum tumour markers
Sx Serum marker studies not available or not performed
S0 Serum marker study levels within normal limits
LDH (U/l) hCG (mlU/ml) AFP (ng/ml)
S1 <1.5 × N and <5,000 and <1,000
S2 1.5–10 × N or 5,000–50,000 or 1,000–10,000
S3 >10 × N or >50,000 or >10,000
N indicates the upper limit of normal for the LDH assay
Except for pTis and pT4, where radical orchiectomy is not always necessary for classification purposes, the extent of the primary tumour is classified after
radical orchiectomy; see pT in other circumstances. TX is used if no radical orchiectomy has been performed
According to the 2002 TNM classification, stage I testicular cancer includes the following substages:
Stage IA pT1 NO MO S0
Stage IB pT2, pT3, or pT4 NO MO S0
Stage IS Any pT/TX NO MO S1–3
AFP alpha-fetoprotein, hCG human gonadotropin, LDH lactate dehydrogenase, UICC International Union Against Cancer
Latest Recommendations of the European Germ Cell Cancer
7
 8

Table 1.4 IGCCCG prognostic grouping classification [12]

Prognosis 5-year survival Non-seminoma Seminoma
Good 90 % Testis or primary extragonadal retroperitoneal tumour Any primary localization
No non-pulmonary visceral metastases No non-pulmonary visceral metastases
Low markers Any marker level
AFP <1,000 ng/ml
ß-hCG <1,000 ng/ml (<5,000 IU/l)
LDH <1.5 × normal level
Intermediate 75 % Testis or primary extragonadal retroperitoneal tumour Any primary localization
No presence of non-pulmonary visceral metastases Presence of non-pulmonary visceral metastases (liver,
CNS, bone, intestinum)
Intermediate markers Any marker level
AFP 1,000–10,000 ng/ml and/or
ß-hCG 1,000–10,000 ng/ml (5,000–50,000 IU/l) and/or
LDH 1.5–10 × normal level
Poor 50 % Primary mediastinal germ cell tumour with or without –
testis or
Primary retroperitoneal tumour and
Presence of non-pulmonary visceral metastases (liver,
CNS, bone, intestinum) and/or
High markers
AFP >10,000 ng/ml and/or
ß-hCG >10,000 ng/ml (50,000 IU/l) and/or
LDH >10 × normal level
AFP a-fetoprotein, ß-hCG human chorionic gonadotropin, CNS central nervous system, IGCCCG International Germ Cell Cancer Collaborative Group, LDH
lactic dehydrogenase
S. Krege
1 Latest Recommendations of the European Germ Cell Cancer 9

can be an alternative, but should be done only at institutions with special expertise
in evaluating testis cancer patients [13]. Positron electron tomography (PET) has no
role as a staging procedure [14, 15]. Imaging of brain or bones only is mandatory in
patients with visceral metastases or in case of symptoms.
AFP, hCG and LDH should be performed before and after orchiectomy. To
define a clinical stage I, marker normalization is mandatory. Therefore in case of
still elevated markers post-orchiectomy several marker controls might be necessary
before finally to define the clinical stage. If markers do not normalize, it is declared
as stage IS disease. In patients with metastatic disease, pre-chemotherapy markers
instead of pre-orchiectomy markers should be used to allocate the IGCCCG cate-
gory [12, 16].
Because further treatment might influence the hormonal status and fertility of the
patient a baseline assessment including testosterone, luteinising hormone (LH),
follicle-stimulating hormone (FSH) and, if possible, a semen analysis should be
performed.
Patients should also be informed about cryoconservation.

1.5 Treatment of Patients with Seminoma CSI

Rete testis infiltration and tumour size >4 cm have been recognized as risk factors
for occult retroperitoneal lymph node metastases in a retrospective analysis [17].
A metaanalysis of patients managed by surveillance showed a 5-year relapse rate
of 12 % in patients without any risk factor, a relapse rate of 16 % in case of one
risk factor and of 32 % in patients with both risk factors. Based on these data, a
risk-adapted strategy was recommended with surveillance for patients without
any risk factors and adjuvant treatment in those with one or two risk factors.
Options for adjuvant therapy are a single course of carboplatin (AUC 7) or para-
aortal/paracaval radiation with 20 Gy. Recent data about the induction of second-
ary malignancies after adjuvant radiotherapy reduced the choice of this strategy
[18–20]. Since the latest prospective series from the Canadian Group could not
validate the rete testis infiltration and tumour size >4 cm as risk factors, many
physicians already favour surveillance independent of any risk factor [21]. On the
other hand, a prospective Spanish trial could at least confirm the negative predic-
tive value of these factors [22]. Therefore, no definitive recommendation can be
given.

1.6 Treatment of Patients with Non-seminoma CSI

In non-seminoma patients, CSI vascular invasion is the strongest prospectively eval-

uated risk factor for occult retroperitoneal metastases. High-risk patients will
relapse in about 50 % compared with 14 % in low-risk patients. Therefore surveil-
lance is the favoured strategy for low-risk patients, while in case of high-risk patients
adjuvant BEP chemotherapy is recommended. While at first two cycles of BEP
10 S. Krege

were given, the recently published data from the SWENOTECA showed no differ-
ence in the relapse rate after one or two cycles [23]. Therefore, a single course of
BEP is favoured now. Nevertheless 50 % of high-risk patients would not need adju-
vant chemotherapy and might suffer from acute and late toxicity unnecessarily.
Therefore, some physicians will choose surveillance for all non-seminoma patients
irrespective of vascular invasion.
While primary RPLND became less important during the last years, a minority
of panelists during the European Consensus favoured surgery considering the late
toxicity of adjuvant chemotherapy, especially the metabolic syndrome, on one side
and the very low retroperitoneal relapse rate, also simplifying follow-up, on the
other side [24].
Thus, the optimal management of clinical stage I seminoma and non-seminoma
is still under discussion. Therefore, Chaps. 2, 3 and 4 will elucidate some facts
around this debate.

1.7 First-Line Treatment of Metastatic Disease

Treatment of seminoma CS IIA/B remains a matter of debate. Being aware of the

induction of secondary malignancies and a relapse rate of 10–15 % in stage
IIA/B radiotherapy, so far the standard option for these stages, loses importance
and is replaced by chemotherapy with three cycles of BEP or 4 × EP [25]. Though
especially for patients with stage IIA the treatment burden of 3 × BEP with its
acute and late toxicity might not be justified. Here the Swiss and German
Testicular Study Group have initiated a trial combining involved node radio-
therapy plus one course of carboplatin. The technique chosen for radiation should
minimize side effects, while carboplatin should destroy micrometastases outside
the radiation field.
Another problematic constellation is non-seminoma patients with normal mark-
ers and retroperitoneal lymph nodes slightly larger than 1 cm. As it is unclear if this
is stage IIA disease or a false-positive CT scan with indeed pathological stage I,
there are two options: surveillance, performing another CT scan 6 weeks later, or a
staging RPLND.
All other patients with metastatic disease are classified according to the IGCCCG
classification and receive three cycles of BEP or, if bleomycin is contraindicated,
four cycles of EP in case of good prognosis [26, 27] as well as 4 × BEP in case of
intermediate or poor prognosis [28, 29]. If patients in the intermediate or poor
prognosis group should not receive bleomycin, 4 × PEI is the most favoured
alternative.
Based on two studies, one from the United States and one from Europe, high-
dose chemotherapy was not superior compared to standard chemotherapy in patients
with poor prognosis [30, 31]. Nevertheless cure rates with 75 % for intermediate
and 50 % for poor prognosis are not satisfying.
In Chap. 5 the question how to improve the outcome of patients with intermedi-
ate prognosis is discussed, especially concerning the recent results of a Phase III
1 Latest Recommendations of the European Germ Cell Cancer 11

study by the EORTC comparing BEP versus T-BEP (a combination of BEP plus
paclitaxel).
Chapter 6 deals with the same question for poor prognosis patients. In the centre
of the discussion are the results of a prospective randomized study from the French
GETUG group comparing standard BEP with a dose-intensified chemotherapy, the
latter chosen for those patients with a delayed marker decline after one cycle of BEP.

1.8 Residual Tumour Resection

More than 90 % of residual tumour in seminoma patients reveals necrosis. For this
reason lesion <3 cm should only be observed. Lesions >3 cm can be evaluated by
PET-CT, performed not earlier than 8 weeks after completion of chemotherapy
because of a high false-positive rate of PET results [32, 33]. Even a positive PET
scan at this time might be questionable. In these cases the examination should be
repeated after 6–8 weeks, a biopsy should be taken or the patient should only undergo
close observation, because of the high morbidity of surgery in seminoma patients.
In non-seminoma, a residual tumour resection (RTR) should be performed in all
patients with residual disease ≥1 cm within 4–6 weeks after completion of chemo-
therapy [34, 35]. Though recent data from a metaanalysis with 588 patients with
residual disease <1 cm, who underwent surgery, revealed teratoma in up to 25 %
and carcinoma in about 4 %, the pooled estimate of relapse in 455 men, who under-
went surveillance, was 5 %,with a relapse rate in the retroperitoneum of only 3 %
[36]. Therefore in these cases surveillance is justified. Concerning the boundaries of
resection, the European consensus recommends to resect the left or right template
according to the side of the primary tumour plus all other areas of initial tumour.
Histology of residual retroperitoneal and lung disease is different in up to 25 %.
Therefore, residual lesions >1 cm within the lung should also be resected indepen-
dent of the histology of the retroperitoneal mass. Different histologies between the
two lung wings are described in 5–20 % [37, 38]; therefore, experts could not reach
a consensus, if both lung wings should be operated.
The question, if patients showing cancer within the histology of RTR should
receive adjuvant chemotherapy is not yet answered. Retrospective data favour an
adjuvant therapy in case of more than 10 % viable malignant tumour cells or posi-
tive surgical margins [39].
Several open questions concerning RTR are discussed in Chap. 9.

1.9 Salvage Treatment

Patients who relapse after surveillance for stage I disease should receive three or
four cycles of BEP according to their prognosis group. The same is recommended
for patients with stage I disease, who show a recurrence after adjuvant chemother-
apy or radiotherapy, though the optimal management of these patients is not yet
defined.
12 S. Krege

The procedure how to treat patients, who relapse after full cisplatin-based con-
ventional-dose chemotherapy, was a matter of debate considering high-dose chemo-
therapy for none of the patients or all of them or only for patients with risk factors.
Also after salvage chemotherapy surgery of all residual disease is an essential
part for the success. This kind of surgery should only be performed at centres of
excellence [40].
While Chap. 7 tries to find the best management for patients with recurrent dis-
ease, Chap. 8 discusses the importance of prognostic factors for selecting the best
treatment in primary as well as recurrent disease.

1.10 Late Relapse

The European experts voted for a new definition of late relapse, which should
exclude all those patients, who relapse later than 2 years after surveillance or adju-
vant therapy. They are cured by standard chemotherapy. On risk are patients after
full cisplatin-based chemotherapy. This subgroup does not respond to chemotherapy
the way we know it. Histology shows a high percentage of teratoma or non–germ
cell cancer elements. These patients should undergo surgery whenever a R0-resection
seems possible independent of serum marker levels. In case of marker normalization
after surgery, even no adjuvant chemotherapy seems necessary [41, 42].

1.11 Follow-Up

During the last years, several data about the related risk of radiation-induced sec-
ondary tumours have been published. The fact that one CT scan exposes the patient
to 10 mSv underscores the demand to reduce the number of CT scans [43].
There are few prospective data about minimizing imaging, though the MRC trial
could show that 2 versus 5 CTs during the first 2 years of follow-up in high-risk
stage I non-seminoma patients did not deteriorate the prognosis of the patients [44].
The issue of replacing CT by MRI was a matter of debate, but most of the experts
considered the general use as not feasible, because MRI is not available at every
location or by time. Also the majority of radiologists are not so familiar with the
evaluation of MRI results in testis cancer patients.
Agreement consisted that follow-up protocols should take into account the
patient’s treatment and the resulting probability of recurrence at different
locations.
Follow-up examinations should also consider late toxicities as well as secondary
malignancies.
The German and Swiss Testicular Study Group have published recent recom-
mendations for follow-up of testis cancer patients. Detailed information can be
found in Chap. 10.
1 Latest Recommendations of the European Germ Cell Cancer 13

1.12 Long-Term Survivorship

Long-term survivorship is a topic of interest in testis cancer. This includes late tox-
icities, reproductive health and quality of life. Chapters 11 and 12 inform about
these topics in detail.

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19. Horwich A, Fossa SD, Huddart R, et al. Second cancer risk and mortality in men treated with
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for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC
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 Part II
Special Topics About Controversial Aspects,
New Results from Studies, Which Might
Change Treatment Recommendations
and Long-Term-Survivorship
Is There Still an Indication
for Radiotherapy in Seminoma Clinical 2
Stages I–IIA/B?

Sophie Dorothea Fosså and Klaus-Peter Dieckmann

Contents
2.1 Stage I ............................................................................................................................ 19
2.2 Stage IIA/B .................................................................................................................... 22
2.3 Conclusion ..................................................................................................................... 22
References ............................................................................................................................... 23

Testicular seminoma is one of the most radiosensitive malignancies, and target

doses of 20 Gy are sufficient to eradicate microscopic tumor foci. This radiobiologi-
cal background explains why radiotherapy to the retroperitoneal lymph nodes with
or without the ipsilateral pelvic nodes has been a well-recognized treatment in
patients with early seminoma since about 1930 [1].

2.1 Stage I

In the 1980s and 1990s, randomized trials have shown that a para-aortic target field
combined with a target dose of 20 Gy should be the treatment of choice if radio-
therapy is a therapeutic option in a patient with seminoma stage 1 [2, 3]. The radia-
tion-related mild–moderate acute side effects (nausea, vomiting, lethargy) usually
last for 2–3 weeks after treatment completion [4, 5]. Follow-up of irradiated patients

S.D. Fosså (*)

Oslo University Hospital, The Norwegian Radium Hospital, National Advisory Unit for Late
Effects after Cancer Therapy, P.O. Box 4953, Oslo Nydalen, NO-0424, Norway
e-mail: [email protected]
K.-P. Dieckmann
Department of Urology, Albertinen-Krankenhaus,
Süntelstrasse 11a, Hamburg 22457, Germany
e-mail: [email protected]

© Springer International Publishing Switzerland 2015 19

S. Krege (ed.), Diagnosis and Management of Testicular Cancer: The European
Point of View, DOI 10.1007/978-3-319-17467-9_2
20 S.D. Fosså and K.-P. Dieckmann

is relatively easy with no need of regular CTs after para-aortic pelvic irradiation.
However, regular pelvic CT examinations during the first 5 years are mandatory to
diagnose an eventual pelvic relapse if radiotherapy is restricted to the para-aortic
region. Post-radiotherapy recurrences occur in 4–5 % of these cases mostly outside
the target field [5–7]. Though most recurrences are diagnosed within the first 3 years
after radiotherapy, relapses may occasionally occur after 5 years or more [8]. As
recurrent seminoma is highly sensitive to cisplatin-based chemotherapy, cause-spe-
cific survival rates range between 99.4 and 100 % [5].
During the last 25 years, the role of routine radiotherapy for seminoma CSI has
increasingly been questioned based on the growing understanding of the tumor biol-
ogy of this malignancy, the growing recognition of late post-radiotherapy adverse
effects, and the appreciation of new management strategies [9]. Adjuvant chemo-
therapy with one course of carboplatin (AUC7) [4] and active surveillance [10] have
become therapeutic alternatives. Acute toxicity is rather modest and short-lasting
after one cycle of carboplatin (3–5 days). In a series of 200 patients receiving one or
two cycles of carboplatin monotherapy, no excess of second cancer incidence nor
excess mortality due to cardiovascular disease had been noted [11]. The relapse rate
after adjuvant carboplatin therapy is around 5 %, and the overall and cause-specific
survival is very similar to that after radiotherapy [6, 12].
In patients managed by surveillance, approximately 20 % relapses have to be
expected [12–14]. Cure can be achieved by three cycles of BEP or four cycles of EP
or in select cases with radiotherapy [15].
Surveillance strategies require periodic reexaminations to detect eventual relapses
as early as possible. Unfortunely, seminomas usually do not express the classical
tumor markers, e.g., beta-hCG or alpha-fetoprotein. Thus control examinations are
largely based on imaging procedures. As cumulative diagnostic radiation exposure
may result in a small but well-recognized excess risk of second cancer [16–18], appli-
cation of computed tomography should be restricted to no more than four abdomino-
pelvic CTs during the first 2 years of follow-up to be followed by ultrasonographic
examinations thereafter [19] with MR as an (resource-requiring) alternative [20].
The key problem in surveillance strategies is the compliance of patients [21]. In
the USA, compliance of patients with germ cell cancer to adhere to the schedule of
CT examinations was only 70 % in the first year of follow-up with a continuous
decline in the following years [22]. In Germany, a very similar failure rate was
found [23]. So, if surveillance is employed in a given patient, any effort must be
made to keep the patient adhering to the follow-up schedule.
Carboplatin monotherapy and surveillance have gained increasing acceptance
among oncologists and urologists during the past decades [17, 24]. Conversely, the
use of radiotherapy has dropped accordingly. The most important rationale to reduce
the use of radiotherapy has been the evidence of life- threatening long-term compli-
cations in irradiated testicular cancer patients, in particular second cancer within the
irradiated body site [25–28]. Currently, only 3 % of seminoma CS1 patients undergo
radiotherapy in Germany [29], and the same is true in Sweden and Norway [13].
Noteworthy, radiotherapy is still the first choice in about two thirds of seminoma
2 Is There Still an Indication for Radiotherapy in Seminoma Clinical Stages I–IIA/B? 21

Table 2.1 Use of single-modality treatment options for stage I seminoma in the USAa and Europe
Treatment option USA (N:261)a (%) Europe (N:969) (%)
RAD 62b 19
Chemotherapy 3b 21
Surveillance 21b 18
Several options 42
Vossen et al. [32]
Arvold et al. [31]
a
Compliance rate, 53 %; unknown for Europe
b
“Always/usually”

patients in the USA [30, 31], whereas it is used in approximately 20 % of the patients
in Europe [32] (Table 2.1).
Importantly, experience with active surveillance has proven that about 80 % of
patients with seminoma stage 1 are rendered tumor-free by orchiectomy alone.
Thus, any adjuvant treatment strategy must be considered critically [14]. While
adjuvant treatment strategies have been compared to each other by several con-
trolled trials [4, 6], no formal randomized trial has been performed comparing sur-
veillance with adjuvant therapy in seminoma patients stage 1. Nevertheless, today’s
principal question is whether surveillance should be offered to all patients with
seminoma CS1 or only to those with an elevated risk of recurrence based on recog-
nized risk factors.
In the pooled analysis by Warde et al. [33], primary tumor size >4 cm and rete
testis invasion have been associated with subsequent recurrence in patients follow-
ing the surveillance strategy. The Spanish Germ Cell Cancer Group has developed
a risk-adapted treatment policy based on these risk factors [34]. In the largest study
on surveillance comprising of 1,954 patients with seminoma stage 1, the Danish
group recently confirmed tumor size to be associated with risk of relapse [14]. In
addition, vascular invasion and epididymal invasion were found to predispose to
progression if patients are put on surveillance. Although these results were gener-
ated in a (nonrandomized) single-arm study, the results appear to be quite mature
because of the huge sample size of the study and because of the consistency with
previous results.
Accordingly, a majority of European experts favor the use of adjuvant carbopla-
tin in patients with one or two risk factors [35]. As many as 48 % of the experts
attending the Third European Consensus Conference in November 2011 selected
surveillance as the treatment of choice for patients with low-risk seminoma stage 1
but preferred adjuvant therapy for those with two high-risk features. Novel molecu-
lar biomarkers that have been proposed recently may help indicate microscopically
metastasized disease in the near future. But, clearly, these novel tools need confir-
mation in further studies [36, 37].
In summary, two therapeutic strategies exist for patients with stage 1 semi-
noma: active surveillance or adjuvant therapy with chemotherapy. Radiotherapy is
no longer considered a part of routine treatment. It may however still be
22 S.D. Fosså and K.-P. Dieckmann

considered in the very few selected patients for whom surveillance appears inap-
propriate and chemotherapy is contraindicated. Any post-orchiectomy therapy if
applied to unselected patients represents “overtreatment” in 80 % of all patients.
Adjuvant chemotherapy with carboplatin appears justified in the cases with the
currently known risk factors, though unequivocal evidence for the usefulness of
these factors is still lacking.

2.2 Stage IIA/B

Radiotherapy is still a valid option in patients with limited spread to the retroperito-
neal lymph nodes [15]. At the Third European Consensus Conference, approxi-
mately 70 % of the experts viewed three cycles of BEP or four cycles of EP as an
equally effective or even preferred option in patients with CSIIA (lymph node size
<2 cm). This percentage increased to 94 % in patients with stage CSIIB (lymph
node size 2–5 cm) [35]. If radiotherapy is applied, the target field should comprise
the para-aortic and the ipsilateral pelvic lymph nodes, with the target dose being
30 Gy and additional 10 Gy to the involved lymph node area. The relapse rate is
approximately 10 %, and most recurrences are located above the diaphragm [38]. In
a series published after 2001, cause-specific survival was reported to be between
97.5 and 100 % [5]. On the other hand, treatment with cisplatin-based chemother-
apy considerably reduces the relapse rate in patients with early metastatic semi-
noma: according to the Swedish-Norwegian Testicular Cancer Group, no relapse
was observed after three cycles of BEP in 73 patients with CSIIA after 5 years of
follow-up [13].
Neither was there a relapse among 26 Spanish patients with CSIIA treated with
BEP chemotherapy [39]. In Kollmansberger et al.’s experience, only 1 of 65 patients
relapsed whose initial treatment consisted of chemotherapy due to early CSII [40].
A third alternative, the combination of one to two cycles of carboplatin prior to
radiotherapy, has been shown to lower the risk of relapse in seminoma stage II with
limited extent [41]. Recently, the Swiss Testicular Cancer Study Group initiated a
study for stage IIA/B disease combining one course of carboplatin and node
radiation.
In summary, three cycles of BEP chemotherapy or four cycles of EP should be
the routine treatment for early metastatic seminoma. Radiotherapy, eventually com-
bined with carboplatin, should represent the exception in case of expected intoler-
ability of BEP chemotherapy.

2.3 Conclusion

Radiotherapy is no longer a part of the routine treatment of stage 1 seminoma. In

patients with early stage II, radiotherapy may exceptionally be used after thorough
counseling about the particular pros and cons of this treatment modality when com-
pared to chemotherapy.
2 Is There Still an Indication for Radiotherapy in Seminoma Clinical Stages I–IIA/B? 23

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How Should We Treat Clinical Stage I
(CSI) Nonseminoma 3
Torgrim Tandstad

Contents
3.1 Surveillance .................................................................................................................... 25
3.2 Adjuvant BEP Chemotherapy ........................................................................................ 26
3.3 Risk-Adapted Treatment ................................................................................................ 26
3.4 Discussion ...................................................................................................................... 27
References ............................................................................................................................... 28

Second to CSI seminoma, CSI nonseminoma constitutes the second largest group of
patients with testicular cancer, and the management of CSI nonseminoma has long
been controversial. The argument in the testicular cancer community have been
between a strategy of surveillance for all patients or the use of adjuvant therapy,
particularly in patients with a high risk of relapse.
In contrast to CSI seminoma, we have a robust prognostic factor for occult
metastasis in CSI nonseminoma. From large patient series, we know that patients
with lymphovascular invasion in the primary tumor (LVI+) have a 50 % chance of
relapse without adjuvant treatment, while patients without lymphovascular invasion
(LVI−) have a 15 % chance of relapse [1–4].

3.1 Surveillance

Large, modern patient series have shown surveillance to be a safe strategy following
orchiectomy. In an unselected population of CSI nonseminoma patients, the relapse
rate is expected to be 25 % [1–3]. In the case of relapse, almost every patient is expected
to be cured using cisplatin-based chemotherapy and postchemotherapy surgery.

T. Tandstad, MD, PhD

Department of Oncology, St. Olavs University Hospital, Trondheim, Norway
e-mail: [email protected]
© Springer International Publishing Switzerland 2015 25
S. Krege (ed.), Diagnosis and Management of Testicular Cancer: The European
Point of View, DOI 10.1007/978-3-319-17467-9_3
26 T. Tandstad

The advantage of surveillance is that no patient is treated unnecessary, resulting in

75 % of patients not requiring treatment beyond an orchiectomy. Looking at this patient
population in such an unselected way is however insufficient. One must appreciate the
fact that for LVI+ patients, only 50 % of patients are cured by orchiectomy alone, with
50 % of patients requiring salvage chemotherapy in the form of minimum three courses
of BEP (Bleomycin, etoposide, cisplatin) at relapse. We known salvage therapy
increase the risk or serious late effects.
Surveillance demands compliant patients and frequent follow-up in order to
detect relapses as early as possible.

3.2 Adjuvant BEP Chemotherapy

The first large publication on adjuvant chemotherapy in high-risk CSI nonsemi-

noma, published in 1996, used two courses of BEP [5]. Two courses of BEP have
since been an adjuvant treatment option to these patients. The difference in treat-
ment burden between good prognosis metastatic disease (i.e. three courses of BEP)
and two courses of adjuvant BEP have by many clinicians been considered to small
to justify adjuvant treatment. Several groups initiated protocols to explore a lesser
adjuvant treatment burden by reducing the number of adjuvant BEP courses to one.
The German Testicular Cancer Study group published in 2008 a randomized phase III
trial comparing RPLND and one course of adjuvant BEP to an unselected CSI popula-
tion (42 % LVI+, 57 LVI− and 1 % pT3) [6]. A total of 191 patients received one course
of adjuvant BEP. At 4.7 years of follow-up, the results favoured one course of adjuvant
BEP over RPLND Retroperitoneal lymph node dissection with two vs. fifteen relapses.
In 2009, the SWENOTECA group reported results of a risk-adapted protocol
implementing surveillance and one course of adjuvant BEP; the expanded and
updated results were published in 2014 [4, 7]. With a median follow-up of 7.9 years,
517 patients received one course of adjuvant BEP (50 % LVI+, 49 % LVI−). The
relapse rates at 5 years were 3.2 % in LVI+ patients and 1.6 % in LVI− patients. The
latest relapse was reported 3.6 years after orchiectomy.
One course of adjuvant BEP effectively prevents 90–95 % of relapses compared
to surveillance alone. Furthermore, a large proportion of relapses following one
course of adjuvant BEP are marker negative. These patients should be treated with
RPLND as the histology most often shows teratoma. Consequently, only a very
small proportion of patients are exposed to the burden of salvage chemotherapy.
Side effects of one course of adjuvant BEP are as expected moderate haemato-
logical toxicity with neutropenia. Very few patients experience neutropenic infec-
tion, and no treatment-related deaths have so far been reported [4, 6].

3.3 Risk-Adapted Treatment

The rationale for a risk-adapted approach to adjuvant treatment is the fact that there
are two clearly defined risk groups in CSI nonseminoma. The high-risk group consti-
tutes of LVI+ patient representing about 1/3 of patients with a 50 % chance of relapse,
while the remaining 2/3 of patients is LVI− patients with a 15 % chance of relapse.
3 How Should We Treat Clinical Stage I (CSI) Nonseminoma 27

Table 3.1 Assumed burden of chemotherapy, different treatment strategies

Alla LVI + LVI −
Treatment Surveillanceb BEP × 1c Surveillanceb BEP × 1c Surveillanceb BEP × 1c
Number of 1,000 1,000 1,000 1,000 1,000 1,000
patients
Relapses 250 21 500 32 150 16
Total number of 735 1,030 1,470 1,072 441 1,012
chemotherapy
courses given
Patients exposed 245 (24.5 %) 10 (1 %) 490 (49 %) 23 147 (14.7 %) 4
to salvage (2.3 %) (0.4 %)
therapy, i.e. ≥ 3
courses of
chemotherapy
a
Assuming: 1/3 of patients with lymphovascular invasion (LVI) and 2/3 of patients without LVI
b
Based on a risk of relapse of 50 % in patients with LVI, 15 % in patients without LVI and 25 % in
an unselected population
c
Based on treatment results, where only 25 % of relapsing patients without LVI and 75 % of
patients with LVI required salvage chemotherapy [7]

To many, a risk-adapted approach represents the best balance between minimizing

the risk of relapse and thereby late toxicity while at the same time exposing patients
with a low risk of relapse unnecessary treatment. See Table 3.1 for a comparison of
the treatment burden between surveillance for all, BEP × 1 for all or a risk-adapted
approach with surveillance for LVI− patients and BEP × 1 for LVI+ patients.

3.4 Discussion

Both surveillance and adjuvant BEP result in short-term survival rates close to
100 %. Today, the aim of the treatment in these patients is to minimize the risk of
long-term toxicity. The data on one course of adjuvant BEP is now solid and mature
with long-term results on over 700 patients reported. Two courses of adjuvant BEP
now represent overtreatment in CSI nonseminoma and should no longer be used.
Salvage treatment is associated with serious long-term toxicity such as cardiovascu-
lar disease and secondary cancers as well as pulmonary toxicity, nephrotoxicity, neuro-
toxicity, hypogonadism, infertility, ototoxicity and psychological sequelae [8]. Short
adjuvant chemotherapy seems not to increase the risk of neurotoxicity, infertility, hypo-
gonadism or cognition. Data on the risk of secondary cancers and cardiovascular dis-
ease is still lacking. Until data is presented, one must assume that one course of adjuvant
may increase the risk of serious late toxicities. However, the risk of long-term toxicity
is highly dose dependant [8], indicating that an increased risk will be small.
With this in mind, the rationale must be to expose as few patients as possible to
unnecessary treatment and the risk of long-term toxicities.
Many experienced clinicians have advocated surveillance as the preferred
approach in CSI nonseminoma [9]. Surveillance results in excellent outcomes,
particularly in LVI− patients where 85 % of patients are spared the burden of any
treatment following orchiectomy. However, surveillance for LVI+ patients is not
28 T. Tandstad

uncomplicated. In LVI+ patients, the choice is either to expose 50 % of patients

to one course of adjuvant BEP unnecessary or to expose 50 % of patients to a
minimum of three courses of BEP unnecessary.
If the argument is to reduce the treatment burden in patients by as much as possible,
the rational solution is to recommend surveillance to LVI− and one course of adjuvant
BEP LVI+ patients. There may be situations where LVI− patients may opt for adjuvant
treatment based on personal preferences or where LVI+ patients choose surveillance.
There is no universal “truth” to which management option to choose in CSI non-
seminoma, and the management of CSI nonseminoma will most likely remain con-
troversial in the future. However, both physicians and patients now have good
clinical data at hand before deciding between surveillance and one course of adju-
vant BEP. The decision on which management to choose should not be based on the
personal preference of the individual physician, but should be respectful of patient’s
autonomy. Patients should be presented with unbiased information on the short- and
long-term risk of surveillance, adjuvant treatment and possible salvage treatment
before deciding management of CSI nonseminoma.

References
1. Daugaard G, Petersen PM, Rorth M. Surveillance in stage I testicular cancer. APMIS.
2003;111(1):76–83; discussion −5.
2. Sturgeon JF, Moore MJ, Kakiashvili DM, Duran I, Anson-Cartwright LC, Berthold DR, et al.
Non-risk-adapted surveillance in clinical stage I nonseminomatous germ cell tumors: the
Princess Margaret Hospital’s experience. Eur Urol. 2011;59:556–62.
3. Kollmannsberger C, Moore C, Chi KN, Murray N, Daneshmand S, Gleave M, et al. Non-risk-
adapted surveillance for patients with stage I nonseminomatous testicular germ-cell tumors:
diminishing treatment-related morbidity while maintaining efficacy. Ann Oncol. 2010;21(6):
1296–301.
4. Tandstad T, Dahl O, Cohn-Cedermark G, Cavallin-Stahl E, Stierner U, Solberg A, et al. Risk-
adapted treatment in clinical stage I nonseminomatous germ cell testicular cancer: the
SWENOTECA management program. J Clin Oncol. 2009;27(13):2122–8.
5. Cullen MH, Stenning SP, Parkinson MC, Fossa SD, Kaye SB, Horwich AH, et al. Short-course
adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: a
Medical Research Council report. J Clin Oncol. 1996;14(4):1106–13.
6. Albers P, Siener R, Krege S, Schmelz H-U, Dieckmann K-P, Heidenreich A, et al. Randomized
phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin
and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I non-
seminomatous testicular germ cell tumors: AUO trial AH 01/94 by the German Testicular
Cancer Study Group. J Clin Oncol. 2008;26:2966–72. JCO.2007.12.0899.
7. Tandstad T, Ståhl O, Håkansson U, Dahl O, Haugnes HS, Klepp OH, et al. One course of adju-
vant BEP in clinical stage I nonseminoma mature and expanded results from the SWENOTECA
group. Ann Oncol. 2014;25:2167–72.
8. Haugnes HS, Bosl GJ, Boer H, Gietema JA, Brydoy M, Oldenburg J, et al. Long-term and late
effects of germ cell testicular cancer treatment and implications for follow-up. J Clin Oncol.
2012;30(30):3752–63.
9. Nichols CR, Roth B, Albers P, Einhorn LH, Foster R, Daneshmand S, et al. Active surveillance is
the preferred approach to clinical stage I testicular cancer. J Clin Oncol. 2013;31(28):3490–3.
Is There Still an Indication for Primary
RPLND in Clinical Stage I 4
Non-seminoma?

Nicola Nicolai and Alessandro Crestani

Contents
4.1 Introduction .................................................................................................................... 30
4.2 Evolution of RPLND and Dissection Templates ........................................................... 30
4.2.1 The Rationale of Template Dissections .............................................................. 30
4.2.2 Evolution of Modified Template Dissection ....................................................... 31
4.3 Efficacy of RPLND ........................................................................................................ 34
4.3.1 Theoretical Advantages of Retroperitoneal Lymph Node Dissection ................ 34
4.3.2 Actual Results According to Pathologic Stage and
Recourse to Adjuvant Chemotherapy ................................................................. 35
4.4 Morbidity ....................................................................................................................... 36
4.4.1 General Morbidity .............................................................................................. 36
4.4.2 Preservation of Antegrade Ejaculation ............................................................... 37
4.5 Does RPLND Associate with a High Regional Efficacy? The Issue of
In-field Recurrences ....................................................................................................... 39
4.6 Does RPLND Limit Long-Term Side Effects of Treatment? The Theoretical
Long-Term Advantages in Comparison with Other Alternatives ................................... 40
4.7 RPLND and Prognostic Factors of Recurrence ............................................................. 42
4.8 Randomised Trials and RPLND..................................................................................... 44
4.9 Mini-invasive RPLND ................................................................................................... 44
4.10 Primary RPLND and Guidelines ................................................................................... 48
4.11 Current Approach in the Treatment Delivery in Stage I Non-seminoma ...................... 49
4.12 Conclusions .................................................................................................................... 49
References ............................................................................................................................... 50

N. Nicolai (*) • A. Crestani

Department of Urology/ Testis Surgery Unit, Fondazione IRCCS,
Istituto Nazionale dei Tumori, Milan 20133, Italy
e-mail: [email protected]

© Springer International Publishing Switzerland 2015 29

S. Krege (ed.), Diagnosis and Management of Testicular Cancer: The European
Point of View, DOI 10.1007/978-3-319-17467-9_4
30 N. Nicolai and A. Crestani

4.1 Introduction

Retroperitoneal lymph node dissection (RPLND) represented the only effective

treatment for non-seminomatous germ cell tumours up to the 1970s [1]. A propor-
tion of patients with nodal metastases from testicular tumours could have a long-
term benefit from this surgery.
The history of germ cell tumours, and probably of the oncology itself, was upset
by the introduction of cisplatin at the end of 1970s, when an effective chemotherapy
radically changed the prognosis of this disease [2]. Etoposide, which was intro-
duced soon after cisplatin [3], was the definitive milestone for the success of com-
bination chemotherapy.
This revolution deeply modified the role of RPLND, whose indications were
split in two settings: as a primary treatment, in early stage non-seminoma, and fol-
lowing completion of chemotherapy in case of residual retroperitoneal masses.
In this chapter, it is examined how primary RPLND evolved up to the present days.
It has both taken into account all the considerations that gradually have contributed to
shelve primary RPLND according to many opinions and underscored and reinter-
preted – under the perspective of a modern scenario – all the potential and effective
advantages that RPLND can still offer in the case of stage I non-seminoma.

4.2 Evolution of RPLND and Dissection Templates

4.2.1 The Rationale of Template Dissections

The study of the anatomy of the human retroperitoneum as well as of the lymphatic
drainage of the testis and the pathology of tumour spread had provided an evolution
of template RPLND in non-seminomatous germ cell tumours (NSGCTs).
Nowadays, the superior boundary for RPLND is the plane passing through the
renal arteries. A wider RPLND that also includes super-hilar dissection has been
abandoned in staging RPLND. The Indiana University experience demonstrated
that the super-hilar dissection was not curative alone when disease was present in
this area and suprarenal hilar involvement was occasionally present only in locally
advanced stage IIB or IIC disease [4].
Furthermore, this series posed the bases of the concept of the first landing zone
for nodal metastasis. The hypothesised landing zones were identified as the intera-
ortocaval and precaval nodes followed by pre-aortic nodes from right-sided (93 %)
tumours and the para-aortic (88 %) nodes and then pre-aortic and interaortocaval
node for left-sided tumours [5].
A support of this evidence was given by a large series published by Weissbach,
which supported this hypothesis showing as positive nodes were almost always ipsi-
lateral to the testis in pathologic N1 patients [6].
4 Is There Still an Indication for Primary RPLND in Clinical Stage I Non-seminoma? 31

In the series published by Pizzocaro, 61 patients, with no intraoperative evidence

of lymph node involvement, underwent unilateral RPLND. The 3-year progression-
free survival was 96.4 % for pathological stage I disease confirming the safety of
unilateral dissection [7].
On the other hand, the hypothesis of a rigid landing zone has been criti-
cised at Memorial Sloan Kettering Cancer Center (MSKCC), as a para-aortic
crossover, especially occurring in multiple nodes positive disease, has been
reported [ 8 ].

4.2.2 Evolution of Modified Template Dissection

We can generally distinguish two different approaches, featuring two different

schools of thought.
Staging RPLND as proposed by referral centres in the United States is usually
bilateral, and it is different from staging RPLND following the evolution of the
template dissection that has taken place in Europe and that has led to perform more
frequently an unilateral RPLND.
Based on the newfound understanding of the retroperitoneal sympathetic neu-
roanatomy and pathologic data from anatomic mapping studies, two paradigms
were developed with the goal of achieving more favourable antegrade ejaculation
rates. The first one relies on a less extensive “modified” template, which has been
proposed with the intent of avoiding dissection and resection of essential neural
structures. This is most easily accomplished by eliminating their respective
regions from the surgical template. This theory is at the basis of the concept of
the modified templates of dissection. The second one relies on the selective iden-
tification, and on the bilateral preservation, of postganglionic anterior fibres of
nerves originating from the thoracic and lumbar sympathetic ganglia, in order to
maintain a wider retroperitoneal dissection without compromising antegrade
ejaculation. This is the conceptual benchmark of the prospective nerve-sparing
techniques. Actually, both concepts and respective applications merge in the
common practice.
The Indiana University proposed a model starting from a bilateral RPLND,
as initial template (Fig. 4.1a). The boundaries recommended for right-sided
tumours were limited to include the paracaval, precaval, inter-aortocaval, pre-
aortic, right iliac nodes and right gonadal vessels (Fig. 4.1b). The template for
left-sided tumours included the para-aortic, pre-aortic, inter-aortocaval, left
iliac and left gonadal vessels (Fig. 4.1b). Ultimately, Indiana’s modified tem-
plates eliminated dissection of the contralateral tissue below a plane passing
through the inferior mesenteric artery, thereby sparing the contralateral lower
sympathetic nerves, superior hypogastric nerves and hypogastric sympathetic
plexus (Fig. 4.1c) [4].
32 N. Nicolai and A. Crestani

Fig. 4.1 Boundaries of template RPLND according to schools. (a) Original full bilateral RPLND.
(b) Modified template dissections (right and left) as proposed at Indiana University. (c) Reduced
modified template dissections (right and left) as proposed at Indiana University. (d) Template dis-
sections (right and left) as proposed at Memorial Sloan Kettering Cancer Centre. (e) Modified
template dissection (left) as proposed by Weissbach and Bodefeld. (f) Modified template dissec-
tions (right and left) as proposed by Pizzocaro
4 Is There Still an Indication for Primary RPLND in Clinical Stage I Non-seminoma? 33

Fig. 4.1 (continued)

34 N. Nicolai and A. Crestani

The MSKCC model brought a slight modification to the bilateral dissection tem-
plate, as only the common iliac contralateral nodes were excluded from the dissec-
tion (Fig. 4.1d) [5].
In 1987, Weissbach and Boedefeld proposed, in a large series, a modified RPLND
within ipsilateral areas to the side of the tumour as a staging operation for clinical
stage I disease. The proposed template was nearly identical to Indiana’s for right-
sided tumours; for left-sided tumours, the template was further minimised to elimi-
nate interaortocaval and ipsilateral iliac regions (Fig. 4.1e) [6]. In the same period,
Pizzocaro adopted a unilateral template, excluding interaortocaval nodes for left-
side tumours, demonstrating that unilateral RPLND was able to offer better func-
tional outcomes without compromising long-term efficacy in patients with stage I
NSGCTs (Fig. 4.1f) [7].

4.3 Efficacy of RPLND

4.3.1 Theoretical Advantages of Retroperitoneal Lymph Node

Dissection

4.3.1.1 Staging
The traditional purpose of primary RPLND is the accurate staging of retroperitoneal
lymph nodes. The historical figures reported that 30 % of patients with clinical stage
I non-seminoma and normal markers had metastatic deposits in retroperitoneal
lymph nodes [4]. In more recent series, based on CT scans of the modern generation,
the rate of patients with metastatic deposits reduced to about 20 % [9], as a reason-
able consequence of clinical staging improvement. Actually, none of the available
clinical surgical examinations is able to improve the capability of RPLND. Magnetic
resonance imaging (MRI) was never proved to replace or improve computed tomog-
raphy (CT) scans performance. 18-Fluoro-deoxyglucose positron emission tomogra-
phy (FDG-PET) has been evaluated in two distinct multicentric and prospective
studies conducted by German centres [10] and by the Medical Research Council
[11]. Both studies aimed at increasing the negative predictive value of standard stag-
ing with CT scans from about 70–90 % with the use of FDG-PET. The German study
included patients at clinical stage I and II-A, who were candidate to primary
RPLND. The study was closed when only 72 out of a total of 169 planned patients
were accrued before than the accrual was completed, and the achieved negative pre-
dictive value was 78 %, with no chance of reaching the expected 90 % rate. The
Medical Research Council study provided FDG-PET following CT scans in patients
at high risk of recurrence due to the presence of peri-tumoural vascular invasion. One
hundred patients with negative PET should have been recruited to rule out a recur-
rence-free survival (RFS) inferior to 80 % at 2 years. This study too failed its objec-
tive and was closed by the internal ethical committee following the accrual of 88
patients, as at 1 year the recurrence-free rate was 65 % only (90 % CI 53–74 %), and
the best achievable 2-years RFR could have not be better than 70 %.
4 Is There Still an Indication for Primary RPLND in Clinical Stage I Non-seminoma? 35

4.3.1.2 Eradication of Chemo-Resistant and Chemo-Insensitive Germ

Cell Tumours
Small deposits in retroperitoneal nodes can contain teratomatous elements, which
cannot be eradicated by adjuvant or therapeutic chemotherapy. Moreover, the neces-
sary time until teratomatous component become clinically evident is potentially
very long, implementing the risk of late and advanced relapse. About 21–22 % of
patients in the series from Indiana and from MSKCC [12, 13] had teratomatous ele-
ments in the resected metastatic lymph nodes following primary RPLND.

4.3.1.3 Simplification of Follow-Up

Following RPLND, relapses usually do not occur in the abdomen and are diagnosed
within 24 months since the intervention. In a series from Istituto Nazionale dei
Tumori of Milan, less than 2 % of the recurrences were abdominal and only 1.2 %
of the relapses occurred beyond the 2nd year of observation [14]. Following surveil-
lance only, the vast majority of relapses occur in the retroperitoneum, a site that
conventionally needs CT scan examination, and a not negligible proportion of
relapses occur after the 2nd year, especially among patients with no vascular inva-
sion: in a recent multi-institutional series, about 10 % of all recurrences recorded
among patients at low risk occurred after the 2nd year [15].
In case of adjuvant chemotherapy, few relapses occur, but also in this setting,
these may occur after the first 2 years and almost all are in the retroperitoneum,
leading to the need of use of CT scans and prolonged follow-up [16, 17].

4.3.2 Actual Results According to Pathologic Stage

and Recourse to Adjuvant Chemotherapy

When RPLND is used as a staging procedure only, adjuvant chemotherapy could be

suggested in case of the presence of nodal metastases at definitive pathology.
Actually, an intuitive advantage in recurrence rate is given by adjuvant platinum-
based chemotherapy, and the randomised trial published by Williams et al. in 1987
showed a superiority of adjuvant chemotherapy (cisplatin, etoposide and bleomycin
(BEP)) versus surveillance alone [18].
One argument in this field was the number of courses to be recommended as
adjuvant therapy. Two courses of cisplatin-based chemotherapy became the stan-
dard policy, once that this option resulted better tolerated than 3 courses of BEP or
4 courses of EP in case of recurrence, with no difference in terms of recurrences in
a randomised German trial [19]. Omission of bleomycin was subsequently demon-
strated to be safe, as no difference in preventing recurrences was documented, when
4 × EP was given [20].
On the other hand, controversy still exists concerning the opportunity of adjunc-
tive platinum-based chemotherapy following RPLND in patients with regional
nodal involvement as only a proportion of patients with pathological stage II disease
experience a recurrence, especially in case of low-volume disease, following a
36 N. Nicolai and A. Crestani

RPLND with curative intent. A risk-adapted strategy could be adopted according to

the extent of nodal disease at definitive pathology, unless the patient is not compli-
ant for a surveillance protocol. According to the American Joint Committee on
Cancer (AJCC), the probability of relapse for patients with pathologic N1 disease is
one third or less, and therefore, observation in compliant patients is considered pref-
erable [21, 22]. For patients with a more advanced stage (pathologic N2), adjuvant
chemotherapy is suggested because more than half of these patients will relapse
following observation alone [14, 23].
It is a matter of fact that primary RPLND had demonstrated a good capability
on cancer control, as demonstrated in a long period experience at Indiana
University. Out of a total of 378 with clinical stage I non-seminoma patients, the
recurrence rate was 12 and 34 % for pathological stage I and pathological stage II,
respectively [24]. Another series by Testicular Cancer Centre Intergroup Study
demonstrated a recurrence rate of 10.2 % in pathological stage I patients [25].
These data were confirmed several years later in a large mono-institutional series
published by Nicolai et al. that showed a recurrence rate of 12 % in pathological
stage I patients and of 32 % in pathological stage II patients following RPLND
alone with no adjuvant chemotherapy [26]. The Indiana University experience
demonstrated a 35 % recurrence rate in case of pathological stage II disease fol-
lowing RPLND in clinical stage II non-seminoma patients who were followed up
only [25]. If we consider only patients with low-volume disease (pathologic N1
according to 1997 TNM classification), the recurrence rate drops out to about
20 % [27].
It has been underscored that as the majority of recurrence occurs within 24
months after surgery, a simplification of follow-up schedule among patients who
remain relapse-free following 2 years of surveillance is possible, safe and then
advisable.
On the other hand, a European randomised trial published in 2008 showed a
significant difference (7.6 %: 95 % CI, 3.1–12.1 %) in terms of recurrence rate in
favour of one course of chemotherapy BEP versus RPLND followed by two courses
of BEP in case of ascertained nodal metastases [28].

4.4 Morbidity

4.4.1 General Morbidity

Although rare, the possible complications after RPLND include bowel obstruction,
lymphocele and chylous ascites, urinary complications (consequent to ureteral dam-
age) and wound infection. The frequency of complications is low in patients under-
going primary nerve-sparing RPLND for clinical stage I non-seminoma in respect
of the case of a post-chemotherapy RPLND.
The experience of the German Testicular Cancer Study Group [29] reported on
wound infection in 5.4 %, chylous ascites in 2.1 %, bowel obstruction in 2.1 %,
urinary complications in 2.5 % and repeat bleeding in 0.8 % of cases. The incidence
4 Is There Still an Indication for Primary RPLND in Clinical Stage I Non-seminoma? 37

of complications in this series did not basically differ from the series of the 1980–
1990s [30].
In most recent experiences, including data of the 2000s, the complication rate
reduced, but the recorded rate of 7 % still remains quite relevant [31, 32].
Laparoscopic RPLND was introduced in 2000s and represented a minimal inva-
sive approach with the intent of providing a reduced morbidity, a shorter hospital
stay and a faster recovery of normal function (see further paragraph). Laparoscopic
approach reduces the risk of bowel obstruction, wound infection and bleeding;
however chylous leak due to lymphatic interruption is one of the most common
complications also for this approach, and this is reported in up to 6.6 % of patients
following laparoscopic RPLND [33]. In a systematic review of 2008, Rasswailer
et al. reported on an overall complication rate of 15.6 % for laparoscopic approach
compared to 33 % for open approach [34]. Chylous ascites is a relatively frequent
event and may be preventable. A prophylactic low-fat diet has been associated
with reduction in incidence of chylous ascites. The Innsbruck group uses a low-
fat diet starting 2 weeks before surgery and continuing for 3 weeks following
surgery [33].

4.4.2 Preservation of Antegrade Ejaculation

As reported in the previous paragraphs, the preservation of antegrade ejaculation is

due to the saving of the anterior postganglionic fibres of the thoracic and lumbar
sympathetic chains, which can be obtained with the modification of the template as
well as with prospective nerve-sparing techniques.
The retroperitoneal neurologic structures, which transmit the impulse for
antegrade ejaculation, include the two paravertebral sympathetic trunks and the
postganglionic sympathetic fibres, which travel dorsal to the inferior vena cava
and cross ventrally to the aorta. These fibres converge as a trunk, the hypogastric
nerve, in the hypogastric plexus on the anterior aorta just caudal to the origin of
the inferior mesenteric artery [35]. The elegant studies by Colleselli et al. dem-
onstrated the association between specific post-ganglionic fibres preservation
and the chance of maintaining antegrade ejaculation following RPLND, where
fibres originating from L3 ganglia represented the most important ones (Fig. 4.2)
[36, 37].
Nerve-sparing RPLND was firstly described by Jewett in 1987 [38] and soon
after by Donohue [39] and represented the culmination of efforts to reduce the mor-
bidity of classic RPLND in patients with testicular cancer. Nerve-sparing RPLND
preserves ejaculatory function in “virtually” 100 % of patients with low-stage dis-
ease and in selected patients with more advanced disease. As discussed before, cru-
cial help to maintain antegrade ejaculation is given not only by nerve-sparing
procedure but also by the development of modified templates. Jewett described the
feasibility and effectiveness of the nerve-sparing technique previously described for
preservation of antegrade ejaculation. They reported a series of 20 nerve-sparing
procedures. The antegrade ejaculation rate was 90 % without a significant impact on
38 N. Nicolai and A. Crestani

a b

Fig. 4.2 (a) The right sympathetic trunk is located dorsal to inferior vena cava and the left sympa-
thetic trunk is located dorsal and lateral to aorta. (b) L3 ganglion is visible postero-laterally to aorta.
(c) Right and left fibers interconnect 2-3 cm caudally to inferior mesenteric artery (IMA) anteriorly
to aorta (IVC and aorta are severed 1 cm above IMA) (Reproduced from Colleselli et al. [36])
4 Is There Still an Indication for Primary RPLND in Clinical Stage I Non-seminoma? 39

the oncological control [40]. Donohue, at Indiana University, demonstrated 100 %

preservation of antegrade ejaculation, utilising a similar nerve-sparing approach in
a series of 75 patients with a recurrence rate of 28.5 % and 0 % in pathologic stage
II and stage I patients respectively [39].
Nonetheless, the preservation of antegrade ejaculation may be eventually guar-
anteed by the bilateral preservation of postganglionic sympathetic fibres, but a uni-
lateral sparing of these structures is enough to maintain this function. The final
common theme in the modified templates was the avoidance of dissection in the
region of the contralateral sympathetic trunk and the elimination of contralateral
dissection below the inferior mesenteric artery. Since 1981, Indiana University
experience began employing modified unilateral RPLND templates for patients
with clinical stage I disease (see previous paragraph) [4].
Thanks to the experience of Weissbach [6] and Pizzocaro [7], modified templates
were proposed in Europe, providing support to spare the dissection in the interaor-
tocaval and ipsilateral iliac regions for left-sided tumours. In Pizzocaro’s study, the
para-aortic region for right-sided tumours and the interaortocaval, precaval and
paracaval regions for left-sided tumours were excluded [7].
Richie proposed a full bilateral dissection above the inferior mesenteric artery
with only a unilateral dissection inferior to the inferior mesenteric artery.
Antegrade ejaculation was maintained in 94 % of the patients undergoing this
dissection [41].
Following the introduction of modern concept of nerve-sparing techniques that
include both sparing by exclusion and prospective preservation of the retroperito-
neal nerves, we documented a 99 % of antegrade ejaculation in patients undergoing
unilateral RPLND and in about 95 % of those undergoing bilateral dissection since
the 1990s.

4.5 Does RPLND Associate with a High Regional Efficacy?

The Issue of In-field Recurrences

As previously discussed, staging RPLND provides good staging results and also a
curative potential for low-volume disease. The data that are available in literature
are published by referral centres, commonly recognised because of a high number
of patients seen per year. The rate of in-field recurrences (i.e. within the boundar-
ies of template dissection) is an important parameter to evaluate the quality of
surgery [42].
The study of United States Testicular Cancer Intergroup showed a retroperito-
neal recurrence rate of 2.6 % in patients with pathological stage I disease versus
7.5 % of distant recurrences (lung). The Indiana University experience showed only
one in-field recurrence in 559 cases (0.19 %) [25].
Low in-field recurrence rate are also reported in European experience as pub-
lished by Nicolai et al. in 2010. They reported an overall 1.86 % recurrence rate in
retroperitoneum and 1.24 % within 2 years from surgery [26].
40 N. Nicolai and A. Crestani

The relatively high in-field recurrence rate (3.6 %) reported by Albers et al. as
the result of a multicentric randomised trial of German Testicular Cancer Study
Group [25] confirms that retroperitoneal surgery for NSGCT should be limited to
high-volume centres.

4.6 Does RPLND Limit Long-Term Side Effects of Treatment?

The Theoretical Long-Term Advantages in Comparison
with Other Alternatives

As was seen, RPLND, when performed in the appropriate setting and in experi-
enced hands, is associated with a definite morbidity; a low rate of recurrence, in
particular of abdominal recurrences, usually occurring within 2 years of follow-up;
and a very high chance of preserving antegrade ejaculation.
Could these advantages be better achieved following an initially nonsurgical
approach in clinical stage I non-seminoma? Do we have evident disadvantages fol-
lowing the alternative options of a surveillance programme and of adjuvant
chemotherapy?
In the case of active surveillance, a proportion of patients, about 15–20 % in case
of low-risk patients and about 30 % in case of a non-risk-adapted strategy, will
recur. The vast majority of these relapses, up to near 90 % of cases, will recur in the
retroperitoneum [17]. This implies the need of examinations that permit an adequate
exploration of the retroperitoneum, which is essentially based on CT scans. In an
old series with active surveillance of ours, we recorded that retroperitoneal metasta-
ses were larger and occurred significantly later than lung relapses did [43]. This
observation is not disavowed in more recent data, as recurrence later than 2 years
have been reported in 3 % of series of 223 north-American patients, whose follow-
up was just 52 months and having a proportion of 22 % who had not yet reached 2
years of follow-up [44].
Adjuvant chemotherapy as a primary choice associates with a lower risk of
recurrence. In the first series, however, the few patients who experienced a relapse
(not exceeding 3 %) were difficult to rescue, arising the suspect of a drug resistance
induced by chemotherapy. This unfavourable outcome was not fortunately met
among the patients recruited by the Swedish and Norwegian Testicular Cancer
group, which recently reported on 512 patients undergoing one course of BEP,
whose 5-year overall survival is 100 % [16].
One emerging problem with chemotherapy is a growing body of direct and indi-
rect evidence of long-term toxicities. Second cancer, cardiovascular diseases, meta-
bolic syndrome and other effects have been recently addressed.
Second cancer following a first diagnosis of a germ cell tumour has been repre-
sented a major concern following a large population study published in 2005 by
Travis et al. [45]. Although they reported on an increased 1.8-fold risk of solid
4 Is There Still an Indication for Primary RPLND in Clinical Stage I Non-seminoma? 41

tumours after chemotherapy among 10-year survivors, the population included

many patients treated as far as in 1943 (i.e. in a period when cisplatin was not admin-
istered), the site-specific risks of solid cancers were not reported, and the study
essentially focused on long-term effects of radiation therapy. Recently, Fung et al.
[46] evaluated the risk of second solid tumour in a target population of 12,691
patients with non-seminoma identified in 16 SEER databases as having received or
not having received chemotherapy and who had not undergone radiation therapy
between 1980 and 2008. Standard incidence ratio (SIR) was calculated for each
subpopulation considering cancer incidence rates in the general population. No
increased risk (SIR, 0.93) was recorded following surgery alone, whereas signifi-
cantly increased 40 % excess (SIR, 1.43) was recorded after chemotherapy.
Specifically, median time to second cancer was 12.5 years, and significantly
increased 3–7-fold risks of cancers of the kidney (SIR, 3.37), thyroid (SIR, 4.40) and
soft tissue tumours (SIR, 7.49) were recorded. Although the absolute excess of a
second tumour risk was only 6.47 per 10,000 person-years, this finding arises con-
cerns in delivering chemotherapy in patients who could be managed without chemo-
therapy, as those presenting as clinical stage I non-seminoma (in the study population,
about 30 % of those undergoing chemotherapy had an organ-confined disease).
In general, not specifically addressing the case of stage I disease, treatment
with BEP alone had a 5.7-fold higher risk for coronary artery disease compared
with surgery only and a 3.1-fold higher risk for myocardial infarction compared
with general population, by analysing a series of 990 men treated for testicular
cancer between 1980 and 1994 [47]. Increased risks (HR 2.6) for atherosclerotic
disease were observed following chemotherapy alone in comparison with surgery
alone, while the prevalence of antihypertensive medication was significantly
higher following any form of cytotoxic treatment in comparison with surgery
alone.
Survivors following a testicular neoplasm treated with cisplatin-based chemo-
therapy showed an increased risk of developing metabolic syndrome compared with
patients treated with surgery alone among 1135 patients aged up to 60 [48]. Although
the maximal detrimental effects were observed among patients who received higher
dose of cisplatin (>850 mg), this effect was recorded also in those receiving lower
doses, and a cumulative dose-event association was documented for cisplatin, eto-
poside and bleomycin.
Moreover, other long-term side effects have been recently detected among
patients undergoing chemotherapy. Fertility is severely impaired by chemotherapy,
which, as well as radiation therapy, can significantly compromise the DNA integrity
and quality of sperm after treatment [49]. Essentially, infertility following RPLND
alone is almost due to the loss of antegrade ejaculation, which currently occurs in a
marginal proportion of patients undergoing primary RPLND.
Lauritsen et al. [50] found out that renal function invariably worsens following
chemotherapy in patients with metastatic germ cell tumours, and this is usually
42 N. Nicolai and A. Crestani

underestimated with the use of formulae surrogating the direct glomerular filtrate
measure with ethylene-diamine-tetra-acetic acid (EDTA).
On the other hand, primary active surveillance still poses questions regarding
duration, intensity and modality of follow-up regimen. We do not have a uniform
schedule of follow-up, as different respectable plans have been proposed. Three
main issues lay under the surveillance strategy. The first is type and number of
examinations in the real common practice. In a recent survey performed among
Australian medical oncologists, the number of abdominal CT scans, chest CT
scans and chest-X rays in a period of 5 years in case of stage I non-seminoma
varied from 1 to 15, 0 to 14 and 0 to 27, respectively [51]. The number of abdomi-
nal CT scans delivered in the two distinct academic north-American centres expe-
riencing non-risk-adapted active surveillance in stage I non-seminoma deeply
differed [44], as one centre doubled (14) the number of CT scans of the other one
(7). The second issue is adherence to protocol. Recent data on stage I seminoma
reports on a 14 % drop-off at 2 years and of a 38 % at 5 years [52]. We can only
hypothesise that in case of non-seminoma, the situation could be better than what
we experienced in the past [43]. The third issue regards toxicity of diagnostic
radiations. We have evidence that diagnostic radiation doses exceeding
50–100 mSv associate with an increased risk of second cancer [53]. The risk of
second cancer increases for each single CT scans delivered and it is greater in
younger individuals [54, 55].
Finally, we can address the long-term oncologic efficacy but without any
evidence-based answer. As the prognosis of clinical stage I disease is fortunately
compressed towards the 100 % of cure rate, it is almost impossible to appreciate any
difference in terms of efficacy among the different options. In a large population-
based study, RPLND emerged as a favourable risk factor for patients with non-
seminoma, giving a 7-fold greater chance of surviving cancer in respect of those not
receiving surgery [56]. This datum is importantly hampered by the nature of the
study, but it underscores the therapeutic impact of retroperitoneal surgery in this
disease.

4.7 RPLND and Prognostic Factors of Recurrence

RPLND has been proposed both as risk-adapted choice and as exclusive treatment
independently of risk factors. Following RPLND, we may have an impact on the
risk of recurrence, which could still drive further decision.
The simpler risk stratification after RPLND is based on nodal status. Patients
with nodal metastases found in the resected specimen may undergo adjuvant treat-
ment as discussed before, usually represented by two courses of PEB. This policy
followed the real experience of some decades ago, when the proportion of patients
with nodal metastases was greater as also many patients with clinical stage II under-
went RPLND and because of a lower clinical staging accuracy.
4 Is There Still an Indication for Primary RPLND in Clinical Stage I Non-seminoma? 43

As a whole, the risk of recurrence in case of nodal disease was about 30 % in

the case of pathologic stage II-A/II-B, and it was greater when the burden of retro-
peritoneal disease was greater. The first dichotomisation in case of nodal metasta-
ses has been represented by considering nodal disease extent and proposing
adjuvant chemotherapy in case of pathological nodal status pN ≥ 1. The role
adjuvant chemotherapy and the evolution of this issue are illustrated in the previ-
ous paragraph.
Further clinical researches have been exploring prediction of relapse following
RPLND according to more parameters. Evaluation of characteristics of metastatic
lymph nodes was intuitive. Number of metastases, presence of extranodal exten-
sion, positive nodes ratio and histology of metastases were evaluated by different
authors. Beck et al. at Indiana University sequentially evaluated nodal metastases
features as predictors of recurrence in 118 patients with nodal stage B1 disease
following RPLND. Neither the number of positive lymph nodes (continuous or
categorical) nor the ratio of the number of positive lymph nodes to the total number
removed (continuous or categorical) predicted recurrence [12]. Similarly, disease-
free survival was not statistically different according to each of the solitary histo-
logical subtypes (embryonal carcinoma, yolk sac tumour, seminoma and teratoma)
or according to embryonal carcinoma presence (pure vs mixed vs absent) [57].
Finally, these authors were unable to detect any prognostic significance of extrano-
dal extension (present vs absent) in a series of 80 patients with nodal metastases
[12]. Similar conclusions were reached at MSKCC after the evaluation of 90
patients with nodal metastases at RPLND who did not receive adjuvant treatment.
Number of metastatic nodes, embryonal carcinoma predominance, extranodal
extension, presence of necrosis and diameter of node did not represent significant
predictors of recurrence [58]. A countertrend experience found out that both less
than 3 metastatic lymph nodes and a node positive ratio <9 % significantly predict
a <10 % risk of recurrence at 2 years, leading to consider that patients with small
nodal burden of retroperitoneal disease clinically may behave as patients with neg-
ative nodes [59].
Another hypothesis is the integration of pathologic parameters of primary
tumour with information regarding the nodal status at RPLND. Vascular invasion,
pT category and percentage of embryonal carcinoma component in the primary
tumour (as well as nodal metastases at definitive pathology) still remain significant
predictors of relapse following RPLND, although the clinical usefulness of such
information is limited [8]. Eventually, the proportion of patients still having a clini-
cally relevant risk of recurrence after RPLND is small. In a series of 322 patients
undergoing RPLND alone, only 9 % of patients had an individual risk exceeding
30 % of further recurrence (i.e. a risk equal to the pretest probability of recurrence
in clinical stage I population) and only 3 % had a risk exceeding 50 % [26]. These
proportions limit the usefulness of such predictive information in the clinical prac-
tice and underscore the ability of RPLND in modifying the aggressiveness of the
disease.
44 N. Nicolai and A. Crestani

4.8 Randomised Trials and RPLND

Primary RPLND was compared with one single course of PEB in a nationwide
prospective randomised trial in Germany [28]. A total of 382 patients were ran-
domly allocated and eventually 173 underwent RPLND and 174 one course of PEB
between 1996 and 2005. RPLND template provided unilateral ipsilateral or modi-
fied dissection. Patients with nodal metastases at RPLND had to receive two courses
of adjuvant BEP chemotherapy, while those with negative nodes were followed.
Pathological features at diagnoses were centrally reviewed and about 42 % of
patients in each group presented vascular invasion.
Following RPLND, 19.5 % of patients had nodal metastases and received adjuvant
treatment. The aim of the study to test performance of both treatments in a commu-
nity-based acceptance in primary care hospitals was achieved, as actually 61 centres
were involved, although 12 centres recruited two thirds of the patients. After a median
of 4.7 years, two relapses have been reported following one course of adjuvant BEP
and 13 relapses have occurred after RPLND. This was statistically significant in
favour of adjuvant PEB with a hazard ratio of 7.94 (95 % CI, 1.81–34.48). None of the
patients undergoing adjuvant chemotherapy following RPLND relapsed. Interestingly,
7 of the 13 patients who relapsed after RPLND recurred in the retroperitoneum.
This study became one of the most important cornerstones in support of one
course of PEB in clinical stage I non-seminoma both in risk-adapted and in non-
risk-adapted policies. Further data from SWENOTECA indicated the feasibility and
the excellent results of one course of PEB in a community-based strategy in this
setting [16]. On the other hand, the German trial [28] unequivocally demonstrated
that RPLND is an extremely operator-depending procedure, which is very difficult
to reproduce at high performance on a large scale. Primary adjuvant chemotherapy
as well as active surveillance requires experience in this setting in order to achieve
the best performance and the outstanding results that one usually expects in the case
of stage I germ cell tumours. Attention to clinical data (e.g. checking the normalisa-
tion of serum tumour markers after orchiectomy) and a shared evaluation of radio-
logical imaging to assess the absence of retroperitoneal nodes are needed prior to
deliver any choice. Actually, RPLND requires a greater technical experience. The
most important result from the German randomised trial is that RPLND, with any
indication, must be offered in the context of very experienced surgeons and in high-
volume referral centres only.

4.9 Mini-invasive RPLND

Solid data are available about efficacy and safety of open-RPLND as a primary
treatment in early stage non-seminoma and in particular in clinical stage I disease.
Nonetheless, open-RPLND remains a major abdominal surgery, and also in the
most recent experiences, morbidity of open-RPLND is not negligible [31, 34].
Postoperative pain, length of stay and recovery are strict consequences of the lapa-
rotomy approach. As in other surgical settings, the recourse to a mini-invasive
4 Is There Still an Indication for Primary RPLND in Clinical Stage I Non-seminoma? 45

approach represented a natural evolution in order to overcome these problems also

in the case of RPLND.
The main questions regarding the use of laparoscopic RPLND concern technical
feasibility, actual effectiveness in reducing morbidity, length of hospital stay and
postoperative recovery, equivalence with open counterpart in terms of oncologic
efficacy and safety.
The issue of cost-effectiveness is a sensible one, but it is clearly a consequence
of the favourable or unfavourable balance of the previously mentioned clinical
issues.
Since the 1990s, about one thousand of laparoscopic (Lap) RPLND have been
published in the literature. This procedure, however, probably reached its maturity
in the most recent years, once that its use as therapeutic device in cases of metastatic
patients has been experienced and proved. As far as in 2008, a European review
compared the series published since 2000 of primary Lap-RPLND and open-
RPLND performed according to a bilateral modified template in order to answer the
most important questions up for discussion [32]. A total of 557 Lap-RPLND and of
761 open-RPLND have been analysed. Although this report was not performed with
the criteria of a meta-analysis or a pool analysis, and we do not have statistical com-
parisons regarding the evaluated items, the essential message is that of a reduced
morbidity and a maintained oncologic efficacy of Lap-RPLND when compared
with open-RPLND. In the domain of operative data, patients undergoing Lap-
RPLND showed advantages in length of stay, complication rate (about half the
cases), re-intervention rate, analgesics duration and a disadvantage in terms of oper-
ative time (a median of 204 min vs 186 min) and in the number of retrieved nodes
(14 Vs 19). In the domain of the oncologic efficacy, the numbers do not differ in
retroperitoneal as well as in-field relapse, in the need of secondary retroperitoneal
surgery and in biochemical recurrence following similar follow-ups. Apparently,
the rate of distant relapse was twice greater following open-RPLND, and this may
be due to different selection in the two groups.
One of the most important critical aspects in treating patients with Lap-RPLND
regards the risk of transcoelomatic spread of disease in case of metastatic nodes,
which may be due to inappropriate manipulation of nodes or an excess or an uncon-
trolled intra-abdominal CO2 pressure. Some of these cases have been reported in the
literature [60]. This unexpected spread of disease usually allocates the patient in a
worse prognostic category, but we do not have enough data to assess if the reported
cases needed more than one therapeutic rescue line and if they eventually had a poor
outcome.
Taking into account more sizeable and recent data, Table 4.1 reports on the larg-
est series undergoing primary Lap-RPLND in clinical stage I [61–63] and includes
also the unpublished series from the Istituto Nazionale dei Tumori in Milan. These
experiences show that Lap-RPLND may be applied in these patients with a very
high proportion of them avoiding further chemotherapy, while observed complica-
tions were mild. One important aspect regards indication and recourse to adjuvant
treatment. Almost all the cases that had nodal metastases underwent adjuvant che-
motherapy, actually obscuring the therapeutic potential, if any, of Lap-RPLND.
46 N. Nicolai and A. Crestani

Table 4.1 Lap-RPLND most important series

A – Operative data
OT Intraoperative Postoperative LAE
Series No min Conversions complications complications LOS (%)
Hyams 91 NR 4 (4.3) 4 (4.3) 9 (10) Mean 4 (4.3)
et al. Clavien I–II: 7 2.1 days
2012 [61] Clavien III–IV:
2 (2.2)
Gardner 46 291 3/59 (5.1)a NR 5 (8.5 %)a 2 10/45
et al. (22)b
2011 [62]
Basiri 55 237 2/55 7 (18 %)c 3.6 23/38d
et al. (61)
2013 [63]
INT 225 200 17/225 (7.5)e 10 Clavien III: 5 4 4 (1.7)
series (2.2)
B – Outcomes considering definitive pathology
Adjuvant chemo Follow-up (median
Series pN+ for pN+ or mean) Recurrences
Hyams et al. 2012 [61] 28/91 14 (50 %) 38 5 (all pN0)
Gardner et al. 2011 [62] 18/46 13 (72.2 %) 21.3 0
Basiri et al. 2013 [63] 14/55 14 (100 %) 56 0
INT series 29/225 6 (21 %) 78 8/169 pN0
6/23 pN+ no
adjuvant
0/7 pN+ adjuvant
a
All 59 patients of the series including post-chemo RPLND
b
10 of 45 evaluable (out of 59 patients)
c
No distinction between intraoperative and perioperative complications
d
23 of 38 evaluable (out of 55 patients)
e
6/122 (4.9 %) since 2007

Table 4.2 Data on pN+ undergoing surveillance only following Lap-RPLND

Series No Follow-up (median or mean) (months) Relapses
Hyams et al. 2012 [61] 14 38 0
Gardner et al. 2011 [62] 5 21.3 0
Nielsen 2007 et al. [67] 10 55 2 (20 %)
INT series 23 78 6 (26 %)
Totals 52 – 8 (15 %)

Nonetheless, 52 cases from recent series [61, 62, 64, plus the our one], with nodal
metastases at definitive pathology underwent observation only, and the relative fig-
ure is a relapse rate <30 % (Table 4.2), mirroring what we have historically observed
following open-RPLND. Unfortunately, the total number of these patients (includ-
ing ours) is small, and it is not possible to draw a definitive conclusion and to give
strong indication on the basis of a limited sample. In our experience with
4 Is There Still an Indication for Primary RPLND in Clinical Stage I Non-seminoma? 47

Lap-RPLND, we changed selection criteria and indications to adjuvant chemother-

apy over the time. In the most prudent time frame, we proposed Lap-RPLND in
low-risk clinical stage I patients, and we recommended adjuvant chemotherapy in
case of nodal metastases at definitive pathology. Currently, we do not use restric-
tions according to risk category and we do not recommend adjuvant chemotherapy
as primary choice in case of nodal metastases unless metastatic nodal density
exceeds 0.25.
One criticism moved to Lap-RPLND regards the template of dissection,
which is usually unilateral and not fully bilateral. Some north-American
researchers pose the issue of properness for this limited dissection. By a techni-
cal point of view, bilateral RPLND is possible but usually requires patient repo-
sitioning and, as a consequence, a longer operative time. Steiner et al. reported
of a mean operative duration of 323 min (range 240–420) in a series of bilateral
dissection including both primary and post-chemotherapy interventions [54].
The arguments against unilateral dissection rely on the risk of missing nodal
metastases, and they bring in support that the higher is the number of removed
nodes the higher is the proportion of patients with metastatic nodes [54].
Thompson et al. analysed a series of 255 patients undergoing open-RPLND and
found that total node count (p = 0.045) was significantly associated with finding
positive nodes on multivariate analysis together with clinical stage [65]. The
probability of finding positive nodes varied from 23 % if the retrieved nodes
were ≤40–31 % if 41–60 and 48 % >60, respectively. All these criticisms could
be logical, and we do not have enough number in the setting of metastatic cases
not undergoing chemotherapy to support a sufficient demonstration of apparent
non-inferiority of Lap-RPLND in respect of open RPLND. On the other hand,
the high number of patients with negative nodes at definitive pathology did not
develop an excess of recurrences when compared cases with those patients oper-
ated conventionally (Table 4.1). This is quite consistent with the hypothesis that
Lap-RPLND would not leave un-staged lymph nodes in the retroperitoneal
space.
Another aspect concerning mini-invasive RPLND is the emerging role of robot-
assisted laparoscopic surgery in almost all the mini-invasive applications. In gen-
eral, robotic surgery is easier to perform than laparoscopic counterparts in many
contexts, and this may facilitate its employ in this setting too [66]. One potential
advantage of robotic-assisted Lap-RPLND regards feasibility of bilateral dissection
without the need of repositioning the patient in the surgical theatre, although one
should equipoise the theoretical advantages of a bilateral dissection without reposi-
tioning with the higher costs of robotic surgery. Nonetheless, few published data are
available in this setting and it is not possible to currently state that robotic RPLND
is equivalent to Lap-RPLND.
In conclusion, despite we are not able to undeniably support that mini-invasive
Lap-RPLND could replace open surgery in clinical stage I non-seminoma, it seems
that Lap-RPLND, when performed in high-volume centres and mainly when there
is a specific expertise in testicular cancer, associate with sufficient data of efficiency
and safety to be proposed.
48 N. Nicolai and A. Crestani

4.10 Primary RPLND and Guidelines

There is not a substantial agreement between recommendations we find in the most

important guidelines approved by international societies and agencies regarding the
role of primary RPLND in clinical stage I non-seminoma.
As far as in 2009, the International Consultation on Urologic Diseases and
Société Internationale d’Urologie (SIU/ICUD) consensus expressed grade B rec-
ommendations (consistent level II or III evidence or “majority evidence” from
Randomised Clinical Trials) in clinical stage I non-seminoma and proposed a risk-
adapted treatment based on the presence or absence of vascular invasion [68]. The
SIU/ICUD panellists recommended surveillance as the first choice in low-risk stage
I non-seminoma and considered 2 courses of BEP as an alternative in those who
cannot undergo surveillance. For high-risk patients, active surveillance, RPLND
and primary chemotherapy with 2 cycles of BEP or EP have been considered all
acceptable treatment options that should be pursued according to patient preference
and hospital resources and expertise. Actually, the SIU/ICUD consensus recom-
mended that patients should be made aware of all treatments (i.e., surveillance,
chemotherapy and RPLND), potential short- and long-term treatment-related toxic-
ity and the risk and nature of any additional treatments.
The National Comprehensive Cancer Network Clinical Practice Guidelines in
Oncology provides recommendations according to 4 category levels [69]. They rec-
ommend primary RPLND as a category 2A (uniform consensus based on a lower
level of evidence) option both in low- and in high-risk clinical stage I non-seminoma.
In low-risk cases, surveillance remains the preferred alternative, while in high-risk
patients, RPLND equals surveillance and adjuvant chemotherapy with 2 courses of
PEB, while one course of PEB is regarded as a category 2B option (not uniform
consensus based on lower level of evidence). The 2015 Testis Cancer European
Urology Association guideline edition [66] will consider as a first alternative sur-
veillance in all patients versus the risk-adapted treatment according to presence/
absence of vascular invasion. In the latter case, the primary choice in low-risk
patients should be active surveillance, while one course of BEP would represent an
alternative option. In high-risk patients, one course of BEP is the recommended
option and surveillance should follow as a second option. Only when one course of
BEP and surveillance, in the sequence provided for each risk category, cannot be
delivered, RPLND could be considered under the condition that this intervention
must be performed in centres of experience. However, in the context of clinical
stage I germ cell cancer, also EAU guidelines anticipate any recommendation with
an explicit invitation to take a decision based on “a thorough discussion with the
patient, taking into account the described advantages and disadvantages, as well as
the individual situation of the patient…”. This significant premise means that
patients must be informed about the alternatives, they should be empowered in the
decisional process and, finally, they have the right of choosing the option which bet-
ter comply with.
There is a common awareness among the physicians involved in this field. Patient’s
need and perspective must be important components of the decisional process. Such
4 Is There Still an Indication for Primary RPLND in Clinical Stage I Non-seminoma? 49

cognisance mirrors the international consensus statement following the meeting on

testicular tumours held in Berlin in 2011 [70], which concluded that “the risks and
benefits of each strategy must be discussed with a patient in respect to its immediate
and long-term impact, and the patient actively involved in the final decision”.

4.11 Current Approach in the Treatment Delivery in Stage

I Non-seminoma

Definitely, any decision in these patients needs experience, knowledge of the disease
and accurate assessment of all the pieces of information. As some recommendations
report or suggest [68, 70], we may need a reliable histological examination that may
require a pathology review of the specimen to reassess histologic components and
the presence of vascular invasion, and we should pretend that CT images are reviewed
together by radiologists and physicians in order to adequately assess the stage of
disease. As recent as the middle 2000s, half of histological reports from primary care
hospitals did not report the information regarding the presence of vascular invasion,
and when this is reported, a 20–30 % discrepancy between first and reviewed diag-
nosis was observed [71]. These steps are necessary for surveillance, adjuvant chemo-
therapy as well as for RPLND. It is a matter of fact that RPLND also requires a high
technical expertise, which does not make this intervention so easy to reproduce in a
community hospital-based policy as surveillance or chemotherapy actually can be.
As we have seen, any of the possible strategies associate with a series of advan-
tages and limitations, and many of these limitations probably depend more on phy-
sician perspective than on individual patient point of view. Patient should be
en-powered in the decisional process and become an active part in sharing the strat-
egy. Once we have ruled out the issue of oncologic efficacy – which is excellent,
fortunately – what could be optimal for a part (physician) could not be ideal for the
other (patient). Nowadays, a deliberative approach must be considered for patients
presenting with a favourable disease where more options are possible [72]. We have
increasing evidence that specially young and well-educated patients are the ideal
candidates for a shared decision or an active role [73]. All the patients with testis
cancer are young and most of them present with a high education level. There are
not better patients than these individuals for this modern treatment delivery. In such
a context, a patient has the right to know which are the advantages and limitations
of primary RPLND and have the right to choose RPLND, if this option better com-
plies with his own expectations. Physicians have the duty of full information and of
permitting that any choice is performed under the best conditions.

4.12 Conclusions

Primary RPLND has lost most of its role in stage I non-seminoma, as a consequence
of the extraordinary efficacy of combined chemotherapy. Chemotherapy permits to
delay treatment until an initial progression is evident without compromising the
50 N. Nicolai and A. Crestani

prognosis and, more recently, has showed to be effective in preventing metastases

even if administered at a very low intensity, thus limiting most of the common associ-
ated early side effects. This theoretical construct reinforced following the evidence
that RPLND is a highly technical demanding procedure, whose best performances
are achieved only when delivered in referral, high-volume centres, while chemo-
therapy is an easy to perform choice even in community-based health-care policy.
Does this automatically mean that RPLND should not be ever suggested in any
case of stage I non-seminoma?
An increasing body of evidence seems to indicate that long-term toxicities of
chemotherapy in these young patients are probably cumulative, and this is now a
reason of major concern. Primary RPLND is not only a staging procedure, as its
curative intent has been demonstrated. RPLND has evolved as a safe procedure
whose side effects have decreased.
Moreover, we are assisting at an evolution of the concepts of therapy delivery in
early phases of the oncological diseases. Patient’s will and perspective have become
the cornerstone at the centre of the therapeutic proposals. In such a context, RPLND,
in its most modern capacities – that includes the mini-invasive approach – may
again represent a viable option. If patients have the right to know what each option
can offer and which are the associated risks, the physicians community should have
the duty to maintain RPLND as an opportunity for those patients who do not want
undergo chemotherapy for a very initial and very favourable disease.

Intellectual Acknowledgements The history of retroperitoneal lymph node dissection has been
changed in the past four to five decades due to very special physicians who dedicated their best
efforts in the cure of patients with testis cancer and were able to leave a mark in those who came
after them, by transmitting the enthusiasm and the sensibility needed to manage these patients.
Among these distinguished people, a particular thought is due to John P. Donohue and a personal
gratitude is due to Giorgio Pizzocaro.
We thank Dr. Mario Catanzaro and Dr. Davide Biasoni for their contribution.

References
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Metastatic Germ Cell Cancer:
The Intermediate-Prognosis Risk 5
Category

Carsten Bokemeyer and Christoph Seidel

Contents
5.1 Introduction .................................................................................................................... 56
5.2 Clinical Trials Testing Novel Treatment Strategies for Advanced
Germ Cell Tumor Exclusively with Intermediate Prognosis ......................................... 57
5.2.1 BEP Versus VIP .................................................................................................. 57
5.2.2 Bleomycin, Etoposide, and Cisplatin (BEP)
Versus BEP with Paclitaxel (T-BEP).................................................................. 57
5.3 Clinical Trials Testing Novel Treatment Strategies for Advanced Germ
Cell Tumor Including Intermediate- and Poor-Risk Prognosis Patients ........................ 58
5.3.1 Paclitaxel, Ifosfamide, and Cisplatin (TIP) Efficacy for
First-Line Treatment of Patients with Intermediate- or Poor-Risk
Germ Cell Tumors .............................................................................................. 58
5.3.2 Comparing BEP with Alternating Cisplatin/Cyclophosphamide/
Doxorubicin and Vinblastine/Bleomycin Regimens .......................................... 58
5.3.3 Conventional-Dose Versus High-Dose Chemotherapy and
Autologous Stem Cell Transplantation .............................................................. 59
5.4 In Addition to Randomized Clinical Trials: Patient
Population-Based Data Analyses ................................................................................... 60
5.4.1 A Retrospective Analysis of Patients with Intermediate-Risk Germ
Cell Tumor Treated at Indiana University from 2000 to 2010 ........................... 60
5.5 Further Analyses Concerning the Intermediate-Prognosis Group ................................. 60
5.6 Conclusion ..................................................................................................................... 61
References ............................................................................................................................... 64

C. Bokemeyer (*) • C. Seidel

Department of Oncology, Hematology and Bone Marrow Transplantation with Section
Pneumology, University Hospital Hamburg-Eppendorf,
Martinistraße 52, 20246 Hamburg, Germany
e-mail: [email protected]
© Springer International Publishing Switzerland 2015 55
S. Krege (ed.), Diagnosis and Management of Testicular Cancer: The European
Point of View, DOI 10.1007/978-3-319-17467-9_5
56 C. Bokemeyer and C. Seidel

5.1 Introduction

On the basis of a patient cohort analysis performed by the International Germ

Cell Cancer Collaborative Group (IGCCCG), a prognostic scoring system was
introduced in 1997. With the identification of several patient characteristics
with prognostic impact, this scoring system predicts the chance of survival for
patients with metastatic germ cell tumors (GCT). Hereby, patients were strati-
fied into good-, intermediate-, and poor-risk categories, associated with 5-year
overall survival (OS) rates of 91, 79, and 48 %, respectively [1]. In the whole
cohort of 5,202 nonseminoma and 660 seminoma patients, 26 % were consid-
ered to be of intermediate prognosis. Patients with seminoma were declared of
intermediate prognosis independent of the tumor marker constellation in case of
visceral metastases such as liver, bone, brain, etc. but not with lung metastases
or lymph node metastases only. Patients with a nonseminomatous histology
were categorized as intermediate prognosis when they either had a serum level
concentration prior to chemotherapy of alpha-fetoprotein (AFP) between 1,000
and 10,000 ng/m, ß-human chorionic gonadotropin (hCG) concentration of
5,000–50,000 mU/ml, or lactate dehydrogenase (LDH) between 1.5 and 10
higher of the normal limit and no visceral metastases except for pulmonary
lesions. The detailed patient characteristics that define the intermediate-risk cat-
egory are demonstrated in Table 5.1. On the basis of these characteristics, fur-
ther treatment planning was then stratified. Therapy for the intermediate-prognosis
category consists of the application of four cycles of cisplatin, etoposide and
bleomycin (BEP) or cisplatin, etoposide and ifosfamide (VIP) alternatively for
patients with an impaired lung function in order to avoid bleomycin. The aim of
this chapter is to present and discuss the available data for the intermediate-
prognosis category focusing on clinical trials performed for these patients after
the implementation of the ICCCGC risk stratification.

Table 5.1 Definition of the ICGCCC intermediate-risk prognosis for seminoma and nonsemi-
noma patients [1]
Criteria for intermediate-risk patients by IGCCCG criteria
Status Seminoma Nonseminoma
Intermediate risk Nonpulmonary visceral AFP 1,000–10,000 ng/mL
metastases present
Any hCG hCG 5,000–50,000 mU/mL
Any LDH LDH 3–10.0 upper limit of normal
Any primary site Nonpulmonary visceral metastases
absent
Gonadal or retroperitoneal primary
site
5 Metastatic Germ Cell Cancer: The Intermediate-Prognosis Risk Category 57

5.2 Clinical Trials Testing Novel Treatment Strategies

for Advanced Germ Cell Tumor Exclusively
with Intermediate Prognosis

5.2.1 BEP Versus VIP

This trial performed by de Wit and colleagues published in 1998 tested the BEP versus
the VIP regimen in 84 GCT patients with intermediate prognosis [2]. The VIP regimen
provides another standard for first-line treatment specifically for GCT patients with
impaired lung function. After the application of four cycles of chemotherapy, the frac-
tion of complete responses (CR) was similar with 74 % for VIP and 79 % for BEP
(p = 0.62), respectively. After a median follow-up of 7.7 years, no differences concern-
ing the relapse rates, disease-free survival (DFS), and OS were detected. The 5-year
progression-free survival (PFS) was 85 % (95 % CI 74–96 %) in the VIP arm and 83 %
(95 % CI 71–96 %) in the BEP arm. The results demonstrate that the treatment out-
come for both regimens has improved compared to the initially presented data by the
IGCCCG in 1997. Under VIP, however, the bone marrow function was significantly
more impaired. Therefore, with a leak of evidence for its superiority to BEP, VIP is not
recommended to be the first choice, but with its equal activity to BEP, it represents a
robust alternative for first-line treatment of intermediate-prognosis GCT patients.

5.2.2 Bleomycin, Etoposide, and Cisplatin (BEP)

Versus BEP with Paclitaxel (T-BEP)

Two clinical trials by de Wit and colleagues intended to improve the treatment options
for intermediate-risk patients by testing the efficacy of an escalated regimen consist-
ing of four cycles of BEP with paclitaxel (T-BEP). Prior to this, paclitaxel had already
demonstrated activity in patients with cisplatin-refractory germ cell cancer [3]. Within
a phase I/II study published in 1999, the investigators tested the feasibility of the addi-
tion of paclitaxel to BEP (T-BEP) with filgrastim (granulocyte colony-stimulating
factor) in patients with intermediate- and poor-prognosis GCT. In this trial, 14 patients
with intermediate- (n = 7) and poor (n = 7)-prognosis germ cell cancer received treat-
ment, and all of the evaluable patients achieved a complete response [4].
Due to these positive results, a randomized phase II/III study testing T-BEP ver-
sus BEP was initiated subsequently by the EORTC for patients with intermediate
prognosis. This study was designed to show a 10 % improvement in a 3-year
progression-free survival (PFS), but instead of the initially planned 498 patients,
only 337 patients were recruited and 7.7 % of the patients were ineligible. A total of
169 patients received BEP and 168 patients received T-BEP. No differences in terms
of the PFS after 3 years were seen in the T-BEP group versus the BEP group
(p = 0.153). The analysis of all eligible patients, however, demonstrated a 12 %
58 C. Bokemeyer and C. Seidel

superior 3-year PFS with T-BEP, which was statistically significant (p = 0.03). There
were no differences concerning the response rate. In the intent-to-treat analyses,
n = 84 patients treated with BEP received complete response, and n = 11 were free of
disease after chemotherapy and surgery compared to n = 100 and n = 8 patients
treated with T-BEP, respectively (p = 0.1482) [5].
The results of this trial have been discussed very controversially in the commu-
nity of physicians treating GCT. While the more intense regimen may lead to a
reduction of relapses, this does not result in a clear overall survival benefit, most
likely due to effective salvage strategies. Thus, T-BEP has not been adapted as a
standard regimen for intermediate-risk patients [5].

5.3 Clinical Trials Testing Novel Treatment Strategies

for Advanced Germ Cell Tumor Including Intermediate-
and Poor-Risk Prognosis Patients

5.3.1 Paclitaxel, Ifosfamide, and Cisplatin (TIP) Efficacy for First-

Line Treatment of Patients with Intermediate- or Poor-Risk
Germ Cell Tumors

This clinical trial tested the activity of the TIP regimen as first-line treatment of meta-
static GCT with intermediate- and poor-risk prognosis with a multicenter phase II
study. In total, 44 treatment-naïve intermediate prognosis n = 15 and poor-risk progno-
sis n = 29 patients received four cycles of TIP consisting of paclitaxel, ifosfamide, and
cisplatin, followed by G-CSF and levofloxacin for neutropenic fever prophylaxis. The
primary endpoint was the complete response (CR) rate, and secondary endpoints
included the PFS and safety. Of the 41 evaluable patients, 28 achieved a CR (57 % of
them with intermediate prognosis and 74 % with poor-risk prognosis), and 6 patients
achieved a partial response with negative markers (36 % intermediate prognosis and
4 % poor-risk prognosis). With a median follow-up of 2.2 years, the estimated 3-year
PFS was 87 % for intermediate-prognosis patients compared to 76 % for poor-risk
patients. The 3-year OS reached 98 % (100 % for intermediate prognosis and 97 % for
poor-risk prognosis). No treatment-related deaths were reported.
In conclusion, the TIP regimen demonstrated a promising efficacy and was well
tolerated [6]. Therefore, a randomized phase II trial to test TIP versus BEP as first-
line therapy in patients with intermediate and poor prognosis has been initiated, but
results are not yet available (NCT01873326).

5.3.2 Comparing BEP with Alternating Cisplatin/

Cyclophosphamide/Doxorubicin and Vinblastine/
Bleomycin Regimens

This trial performed by the French Federation of Cancer tested two chemotherapy
regimens for intermediate- and poor-risk metastatic nonseminomatous GCT for
5 Metastatic Germ Cell Cancer: The Intermediate-Prognosis Risk Category 59

efficacy and toxicity. From February 1994 to February 2000, 190 patients were
randomly assigned on either four cycles of BEP or four to six alternating cycles
of CISCA/VB (cyclophosphamide, doxorubicin, cisplatin, vinblastine, and bleo-
mycin). Among the 185 assessable patients (60 patients were of intermediate
prognosis), favorable responses did not differ statistically between these two
arms. However, the CISCA/VB regimen induced more significant hematologic
and mucous toxicities compared with the BEP arm. The 5-year event-free survival
rates were 37 and 47 % in the CISCA/VB and BEP arms, respectively (p = 0.15).
With a median follow-up of 7.8 years, the 5-year overall survival rates were 59
and 69 % in the CISCA/VB and BEP arms, respectively (p = 0.24). Of the 185
patients, n = 30 and n = 31 intermediate-risk patients received treatment with
CISCA/VB and BEP, respectively. There was no difference for the event-free and
overall survival for the intermediate-risk patients treated with CISCA/VB versus
BEP (p = 0.31 and p = 0.65, respectively). Separate results for the intermediate
group were not reported.
This trial represents a study that could not confirm that an alternative multi-
drug regimen is superior to the standard BEP treatment. Because of equivalent
efficacy and lesser toxicity, treatment for patients with intermediate- and poor-
risk metastatic nonseminomatous germ cell tumors remained four cycles of
BEP [7].

5.3.3 Conventional-Dose Versus High-Dose Chemotherapy

and Autologous Stem Cell Transplantation

This clinical trial performed by Motzer and colleagues aimed to investigate the role
of high-dose chemotherapy with stem cell support in the first-line treatment of high-
risk GCT. Hereby, investigators analyzed previously untreated patients with inter-
mediate- and poor-risk GCT treated with either four cycles of BEP alone or two
cycles of BEP followed by two cycles of high-dose chemotherapy (HDCT) contain-
ing carboplatin, etoposide, and cyclophosphamide supported with hematopoietic
stem cell rescue. Altogether, 219 patients could be randomly assigned with 108
patients (n = 87 poor risk versus 24 intermediate risk) to BEP with HDCT and 111
patients (n = 87 poor risk versus 21 intermediate risk) to BEP alone.
The 1-year durable complete response rate was 52 % after BEP with HDCT and
48 % after BEP alone (p = 0.53). Secondary data analyses investigated the potential
relation between tumor marker decline and the outcome. The investigators could
demonstrate that patients with slow serum tumor marker decline during the first two
cycles of chemotherapy had a shorter PFS and OS compared with patients with a
satisfactory marker decline (p = 0.02 and p = 0.03, respectively). Among the 67
patients with unsatisfactory marker decline, the 1-year durable complete response
proportion was 61 % for patients who received HDCT versus 34 % for patients
receiving BEP alone (p = 0.03). A separate report for the outcome of the intermediate-
prognosis patients was not available. The general inclusion of HDCT in first-line
treatment for intermediate- and poor-prognosis GCT patients, however, did not
60 C. Bokemeyer and C. Seidel

improve the treatment outcome. Frequent serum marker determinations to estimate

marker decline during the first two cycles of BEP chemotherapy provide a clinically
useful estimate of outcome and potentially identify the patients who can benefit
from the high-dose chemotherapy approach [8].

5.4 In Addition to Randomized Clinical Trials: Patient

Population-Based Data Analyses

5.4.1 A Retrospective Analysis of Patients with Intermediate-

Risk Germ Cell Tumor Treated at Indiana University
from 2000 to 2010

This group analyzed all the GCT patients with intermediate prognosis treated
between the years 2000 and 2010 at Indiana University. Of the 84 patients, 45
received either four cycles of BEP, four cycles of VIP, or two cycles of BEP fol-
lowed by two cycles of HDCT. Thirty-nine patients had received three cycles of
BEP or three times BEP plus one additive cycle of etoposide and carboplatin.
Treatment decisions were based on clinical characteristics and marker levels. Within
this cohort, 93 % of the patients had a nonseminomatous histology.
The overall 1- and 2-year Kaplan-Meier estimates were 93 and 87 % for PFS
(p = 0.6) and 98 and 92 % for OS (p = 0.86). The results from these analyses showed
that the outcome of intermediate-risk GCT patients treated at Indiana University is
superior to the IGCCCG results of patients treated from 1975 to 1990. The authors
therefore concluded that a routine administration of four cycles of BEP probably
may represent an overtreatment for a proportion of intermediate-prognosis GCT
patients [9].

5.5 Further Analyses Concerning the Intermediate-

Prognosis Group

A population-based trial published in 2011 by the Swedish-Norwegian Testicular

Cancer Group with 603 adult patients from Sweden and Norway with metastatic
testicular nonseminomatous GCT was performed to study a treatment guided by
tumor marker decline [10]. All patients received two courses of standard BEP and a
weekly tumor marker analysis. Good marker response was defined as a half-life
(t1/2) for AFP of ≤7 days and/or for HCG of ≤3 days. Patients with a prolonged
marker decline received treatment intensification with the addition of ifosfamide
(BEP-if/PEI). If the poor marker decline continued, treatment was intensified with
HDCT and stem cell rescue as a further intensification. Overall, seventy-seven per-
cent of the patients were treated with BEP alone; 18 % received the intensification
with additional ifosfamide, and 5 % received the dose intensification with
5 Metastatic Germ Cell Cancer: The Intermediate-Prognosis Risk Category 61

HDCT. The 10-year OS was 94.7 % in good-prognosis patients (n = 395), 90.0 % in

intermediate-prognosis patients (n = 114), and 67.4 % in poor-prognosis patients
(n = 94) in this trial. The survival of intermediate-prognosis patients was remarkable
in this trial and close to that of good-prognosis patients and clearly better compared
to historical data from the IGCCCG patients treated from 1975 to 1990.

5.6 Conclusion

In this book chapter, data retrieved from several clinical trials performed and ana-
lyzed over the past years focusing on treatment strategies for intermediate-prognosis
GCT patients are presented. Often these trials tested the treatment standard consist-
ing of four cycles of BEP with a more intense regimen to improve the outcome
concerning PFS, OS, or complete response rate. Hereby, the application of high-
dose chemotherapy or the CISCA/VB regimen revealed that dose-escalated regi-
mens did not lead to additional benefit compared to BEP.
The application of T-BEP compared to BEP could reveal some benefit when
ineligible patients were excluded, and the study by Feldman and colleagues also
demonstrated promising activity for the TIP regimen as the first-line treatment with
a 3-year OS of 98 %. Data to compare the efficacy of TIP versus BEP is not yet
available.
Regardless of that, almost every trial demonstrated that the patients’ outcome has
improved compared to the data presented by the IGCCCG trial. Hereby, a gain of
experience of the therapists over the past decades but also the advancement of sup-
portive care measures such as the application of novel antiemetics may have led to
improved conditions which resulted in a better treatment outcome.
With an improved prognosis, Albany et al. hypothesized that some intermediate-
prognosis patients are potentially overtreated. However, there are no randomized
clinical trials available to prove this conclusion, e.g., three versus four cycles of
BEP in these patients.
As described in the trials by Motzer and Olofsson, the therapy-induced decrease
of tumor markers resembles a strong prognostic marker. Olofsson and colleagues
applied the course of tumor markers to individualize the treatment strategy. With
this strategy where treatment was intensified when the marker decline was not ade-
quate, the authors reached a 10-year OS of 90.0 % for intermediate-prognosis
patients. These results are excellent and may indicate that even among the interme-
diate category, there are differences in patients’ outcome with many patients with
excellent prognosis and some patients who will need a more intense treatment. In
summary, we come to the conclusion that the treatment results for intermediate-risk
GCT patients have developed satisfactorily over the past years even without the
implementation of novel treatment regimens. The course of tumor marker decline
under treatment may be a decent strategy to regulate the treatment intensivity, while
4 × BEP remains the standard for most patients in this risk category (Table 5.2).
Table 5.2 Summary of the literature discussed in the text
62

Title Author Published Description Patients treated Results Summary

Four cycles of BEP vs. four cycles of de Wit et al. [2] Br J Cancer Phase III trial 337 pat. Similar fraction VIP not superior
VIP in patients with intermediate- 1998 4 × BEP versus randomly of complete to BEP; VIP:
prognosis metastatic testicular 4 × VIP assigned (26 response 74 % impaired bone
nonseminoma: a randomized study of the ineligible pts.) for VIP and marrow function
EORTC Genitourinary Tract Cancer n = 311 79 % for BEP
Cooperative Group intermediate risk (p = 0.62)
pts. analyzed
Phase III randomized trial of Motzer et al. [8] JCO 2007 Phase III trial BEP n = 111 pts 1-year durable No difference
conventional-dose chemotherapy with or 4 × BEP versus versus complete concerning the
without high-dose chemotherapy and 2 × BEP + 2 × HDCT BEP + HDCT response rate complete response
autologous hematopoietic stem-cell n = 108 pts. 52 % after BEP rate
rescue as first-line treatment for patients (Altogether with HDCT and
with poor-prognosis metastatic germ cell n = 174 poor risk 48 % after BEP
tumors and n = 45 alone (p = 0.53)
intermediate risk
patients)
Randomized trial comparing bleomycin/ Culine et al. [7] JCO 2008 Randomized trial Of 185 pts. Intermediate risk No difference
etoposide/cisplatin with alternating testing BEP versus n = 30 and n = 31 pts. event free concerning
cisplatin/cyclophosphamide/doxorubicin CISCA VB intermediate risk and overall survival rates
and vinblastine/bleomycin regimens of pts. were treated survival CISCA/
chemotherapy for patients with with CISCA/VB VB versus BEP
intermediate- and poor-risk metastatic and BEP, p = 0.31 and
nonseminomatous germ cell tumors: respectively p = 0.65,
Genito-Urinary Group of the French respectively
Federation of Cancer Centers Trial
T93MP.
C. Bokemeyer and C. Seidel
 5

Population-based study of treatment Olofsson et al. JCO 2011 Population based Of n = 603 pts. 10-year OS was Survival of
guided by tumor marker decline in [10] analyses testing n = 114 were 94.7 % for good, intermediate
patients with metastatic treatment intensity intermediate 90 % for prognosis patients
nonseminomatous germ cell tumor: a with BEP, ifBEP risk, n = 395 intermediate and is remarkable and
report from the Swedish-Norwegian and HDCT good and n = 94 67.4 % for poor dose to that of
Testicular Cancer Group. according marker poor risk risk prognosis good-prognosis
decline patients
Randomized phase III study comparing de Wit et al. [5] JCO 2012 Randomized trial n = 84 PFS at 3 years No difference
paclitaxel-bleomycin, etoposide, and testing 4 × BEP intermediate 79.4 mo. T-BEP concerning PFS
cisplatin (T-BEP) to standard BEP in versus 4 × T-BEP prognosis pts. versus 71.1 BEP and OS; 12 %
intermediate-prognosis germ-cell cancer: (p = 0.153); no superior 3-year
intergroup study EORTC 30983. difference in OS PFS for T- BEP
when ineligible
patients excluded
A retrospective analysis of patients with Albany et al. [9] JCO 2012 Retrospective n = 84 Overall 1 and The authors
intermediate-risk germ cell tumor (abstr 4534) patients cohort intermediate 2 year Kaplan- conclude
(IRGCT) treated at Indiana University analyses prognosis pts. Meier estimates overtreatment for
from 2000 to 2010. were 93 % and some patients due
87 % for PFS to positive results
(p = 0.6) and
98 % and 92 %
for OS (p = 0.86)
Paclitaxel, ifosfamide, and cisplatin Feldmam et al. [6] J Clin Activity of TIP in 44 pts. (n = 15 Favorable 3 year PFS of
(TIP) efficacy for first-line treatment of Oncol 2013 the first line intermediate; response 79 % and 3 year
patients (pts) with Intermediate- or (suppl; abstr n = 29 poor (CR + PR- 93 % OS of 98 %
poor-risk germ cell tumors (GCT). 4501) prognosis) intermediate and (100 % OS for
Metastatic Germ Cell Cancer: The Intermediate-Prognosis Risk Category

97 % poor risk) intermediate

prognosis and
97 % for poor risk
prognosis)
63
64 C. Bokemeyer and C. Seidel

References
1. International Germ Cell Consensus Classification: a prognostic factor-based staging system
for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin
Oncol. 1997;15(2):594–603.
2. de Wit R, Stoter G, Sleijfer DT, Neijt JP, ten Bokkel Huinink WW, de Prijck L, Collette L,
Sylvester R. Four cycles of BEP vs four cycles of VIP in patients with intermediate-prognosis
metastatic testicular non-seminoma: a randomized study of the EORTC Genitourinary Tract
Cancer Cooperative Group. European Organization for Research and Treatment of Cancer. Br
J Cancer. 1998;78(6):828–32.
3. Bokemeyer C, Beyer J, Metzner B, Ruther U, Harstrick A, Weissbach L, Kohrmann U, Verbeek
W, Schmoll HJ. Phase II study of paclitaxel in patients with relapsed or cisplatin refractory
testicular cancer. Ann Oncol. 1996;7:31–40.
4. de Wit R, Louwerens M, de Mulder PH, Verweij J, Rodenhuis S, Schornagel J. Management
of intermediate-prognosis germ-cell cancer: results of a phase I/II study of Taxol-BEP. Int J
Cancer. 1999;83(6):831–3.
5. de Wit R, Skoneczna I, Daugaard G, De Santis M, Garin A, Aass N, Witjes AJ, Albers P, White
JD, Germa-Lluch JR, Marreaud S, Collette L. Randomized phase III study comparing
paclitaxel-bleomycin, etoposide, and cisplatin (BEP) to standard BEP in intermediate-
prognosis germ-cell cancer: intergroup study EORTC 30983. J Clin Oncol. 2012;30(8):792–9.
doi:10.1200/JCO.2011.37.0171.
5. Oldenburg J, Fosså SD, Nuver J, Heidenreich A, Schmoll HJ, Bokemeyer C, Horwich A,
Beyer J, Kataja V, ESMO Guidelines Working Group. Testicular seminoma and non-seminoma:
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol.
2013;24 Suppl 6:vi125–32. doi:10.1093/annonc/mdt304. No abstract available.
6. Feldman DR, Hu J, Dorff TB, Patil S, Van Alstine LJ, Momen L, Carousso M, Hughes A,
Snively-Solomon J, Ketchens C, Sheinfeld J, Bains MS, Bajorin DF, Bosl GJ, Motzer RJ,
Quinn DI. Paclitaxel, ifosfamide, and cisplatin (TIP) efficacy for first-line treatment of patients
(pts) with intermediate- or poor-risk germ cell tumors (GCT). J Clin Oncol. 2013;31 (suppl;
abstr 4501).
7. Culine S, Kramar A, Théodore C, Geoffrois L, Chevreau C, Biron P, Nguyen BB, Héron JF,
Kerbrat P, Caty A, Delva R, Fargeot P, Fizazi K, Bouzy J, Droz JP, Genito-Urinary Group of
the French Federation of Cancer Centers Trial T93MP. Randomized trial comparing bleomy-
cin/etoposide/cisplatin with alternating cisplatin/cyclophosphamide/doxorubicin and vinblas-
tine/bleomycin regimens of chemotherapy for patients with intermediate- and poor-risk
metastatic nonseminomatous germ cell tumors: Genito-Urinary Group of the French Federation
of Cancer Centers Trial T93MP. J Clin Oncol. 2008;26(3):421–7. doi:10.1200/
JCO.2007.13.8461.
8. Motzer RJ, Nichols CJ, Margolin KA, Bacik J, Richardson PG, Vogelzang NJ, Bajorin DF,
Lara Jr PN, Einhorn L, Mazumdar M, Bosl GJ. Phase III randomized trial of conventional-dose
chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-
cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors.
J Clin Oncol. 2007;25(3):247–56.
9. Albany C, Satpute SR, Brames MJ, Suleiman Y, Al Nasrallah N, Perkins SM, Hanna NH,
Einhorn LH. A retrospective analysis of patients with intermediate-risk germ cell tumor
(IRGCT) treated at Indiana University from 2000 to 2010. J Clin Oncol. 2012;30 (suppl; abstr
4534).
10. Olofsson SE, Tandstad T, Jerkeman M, Dahl O, Ståhl O, Klepp O, Bremnes RM, Cohn-
Cedermark G, Langberg CW, Laurell A, Solberg A, Stierner U, Wahlqvist R, Wijkström H,
Anderson H, Cavallin-Ståhl E. Population-based study of treatment guided by tumor marker
decline in patients with metastatic nonseminomatous germ cell tumor: a report from the
Swedish-Norwegian Testicular Cancer Group. J Clin Oncol. 2011;29(15):2032–9. doi:10.1200/
JCO.2010.29.1278.
Poor-Prognosis Germ Cell Tumours
6
Karim Fizazi and Stephane Culine

Contents
6.1 Definition of Poor-Prognosis Germ Cell Tumours ........................................................ 65
6.2 1987–2014: How 4 BEP Became the Standard Treatment and
Has Not Been Superseded for over 25 Years ................................................................. 66
6.3 Tumour Marker Decline Is a Prognostic Factor
in Poor-Risk GCT .......................................................................................................... 66
6.4 2014: Individualising Chemotherapy Based on Early Tumour Marker Decline
Assessment Becomes the New Standard Treatment for Poor-Risk GCT ...................... 68
6.5 Towards Systematic Centralisation of Patients with Poor-Risk NSGCT ....................... 69
6.6 Conclusion ..................................................................................................................... 69
References ............................................................................................................................... 69

6.1 Definition of Poor-Prognosis Germ Cell Tumours

Approximately 80 % of disseminated non-seminomatous germ cell tumours

(NSGCT) are cured with cisplatin-based chemotherapy and surgery [1]. In the
International Germ Cell Consensus Classification Group (IGCCCG) classification,
a poor-risk group is defined as either having a mediastinal primary NSGCT, extra-
pulmonary visceral metastases or very high serum tumour marker levels
(hCG > 50,000 UI/L, AFP > 10,000 ng/mL and/or LDH > 10 times the upper limit
value). This subgroup of patients comprises approximately 10 % of patients with
advanced NSGCT. Their progression-free survival (PFS) rate is 41 % with only half
of them achieving long-term overall survival (OS) [2].

K. Fizazi, MD, PhD (*)

Department of Cancer Medicine, University of Paris Sud, Institut Gustave Roussy,
114 rue Edouard Vaillant, Villejuif 94800, France
e-mail: [email protected]
S. Culine
Department of Medical Oncology, Hospital Saint Louis, University of Paris VII, Paris, France

© Springer International Publishing Switzerland 2015 65

S. Krege (ed.), Diagnosis and Management of Testicular Cancer: The European
Point of View, DOI 10.1007/978-3-319-17467-9_6
66 K. Fizazi and S. Culine

6.2 1987–2014: How 4 BEP Became the Standard Treatment

and Has Not Been Superseded for over 25 Years

Four cycles of the BEP regimen [cisplatin (20 mg/m2/day × 5 days), etoposide
(100 mg/m2/day × 5 days) and bleomycin (30 mg/week)], followed by resection of
residual masses, became the standard regimen for this group in 1987 after a ran-
domised trial found that survival was superior with cisplatin, vinblastine and bleo-
mycin [3]. BEP was also associated with less haematotoxicity and less neurotoxicity
and became the standard of care for the next quarter of a century. Indeed, all attempts
to improve the results of BEP that focused on increasing the peak dose intensity
[4, 5], high-dose chemotherapy with stem cell support [6–8], incorporating
ifosfamide [9] and developing alternating regimens [10, 11] have failed, perhaps
partly because the planned accrual could not be completed in some trials (Table 6.1).
On the other hand, replacing bleomycin by ifosfamide (4 BEP instead of 4 VIP) is
considered a possible option, specifically for patients at risk for bleomycin-induced
lung toxicity, based on similar results obtained with the two regimens [9].

6.3 Tumour Marker Decline Is a Prognostic Factor

in Poor-Risk GCT

Investigators have studied whether a slow decline in hCG and AFP during chemo-
therapy could single out patients likely to fail conventional therapy [7, 12–14]. A
subgroup of patients with poor-prognosis NSGCT with a better outcome was identi-
fied based on a tumour marker decline assessed 3 weeks after the start of chemo-
therapy [14]. Baseline and days 18–21 tumour marker values are introduced into a
logarithmic formula, which defines a favourable and an unfavourable decline pat-
tern in serum tumour markers. A decline is defined as favourable only if both AFP
and hCG declines are considered favourable by the formula. The calculator tool is
available online at http://www.gustaveroussy.fr/calculation-tumor/NSGCT.html.
Using this method, patients with an unfavourable decrease and those with a favour-
able decrease had a 3-year PFS rate of 46 and 73 % (p = 0.01) and an overall survival
(OS) rate of 59 % and 81 % (p = 0.02), respectively [14]. These data were prospec-
tively confirmed in a separate set: 48 % [95 %CI: 38; 59 %] versus 70 % [95 %CI:
57–81 %] for 3-year PFS (p = 0.01) and 65 % [95 %CI: 55–75 %] versus 84 %
[95 %CI: 71–92 %] for OS (p = 0.02) in patients with poor-risk NSGCT and an
unfavourable and a favourable decline, respectively [15].
One major advantage of the method used to calculate a tumour marker decline is
that it is based exclusively on two values (at baseline and at 3 weeks), which allows
physicians to switch patients to more active therapies early on during treatment,
unlike other methods [7, 8, 12, 13]. A post hoc analysis of the intergroup US phase
III trial suggested a better outcome for patients with an unfavourable decline treated
with intensive chemotherapy, although treatment was not allocated according to
tumour marker decline and patients with intermediate-prognosis GCT were also
included [7]. Tumour marker decline assessed during salvage treatment was also
Table 6.1 Phase III trials in poor-risk NSGCT testing new strategies versus 4 BEP
Classification Number of Favourable response Progression-free
6

Chemotherapy system patients rates (%) survival (%) Conclusion First author
BEP × 4 Indiana 159 73 61 Double-dose cisplatin not Nichols
v University superior and more toxic
BEP200 × 4 68 63
BEP × 4 Indiana 299 60 57 Substitution of ifosfamide for Nichols
v University bleomycin not superior and
VIP × 4 63 56 more toxic
BEP × 4 EORTC 250 76 NR Alternating regimen not de Wit
v superior and more toxic
BEP/PVeB × 4 72 NR
BEP × 4/EP × 2 MRC/EORTC 380 57 55 Dose-dense alternating regimen Kaye
v not superior and more toxic
BOP/VIP-B 54 53
Poor-Prognosis Germ Cell Tumours

BEP × 4 Institut Gustave 190 61 47 Alternating regimen not Culine

v Roussy superior and more toxic
CISCA/VeB 54 37
P200VeBE × ¾ Institut Gustave 115 75 54 High-dose chemotherapy not Droz
v Roussy superior and more toxic
P200VeBE × 2 + P200EC 67 47
BEP × 4 IGCCCG 219 55 48 High-dose chemotherapy not Motzer
v superior and more toxic
BEP × 3 + CaEC 56 52
BEP × 4 IGCCCG 137 33 45 High-dose chemotherapy not Daugaard
v superior and more toxic
VIP × 1 + HD-VIP × 3 45 58
BEP × 4 IGCCCG 263 30 48 Personalised chemotherapy Fizazi
v improves PFS in patients with
BEP × 1 + T-BEP-Ox × 2 + BIP × 2 in 40 59 unfavourable tumour marker
patients with unfavourable tumour decline after 1 BEP
marker decline
B bleomycin, E or V etoposide, P cisplatin (100 mg/m2/cycle), P200 cisplatin (200 mg/m2/cycle), I ifosfamide, Ve vinblastine, O vincristine, C cyclophospha-
67

mide, A doxorubicin, Ca carboplatin, MRC Medical Research Council, EORTC European Organisation for Research and Treatment of Cancer, IGCCCG
International Germ Cell Cancer Collaborative Group, NR not reported
68 K. Fizazi and S. Culine

recently shown to have an independent prognostic value in patients with GCT who
relapse or progress after chemotherapy [16].

6.4 2014: Individualising Chemotherapy Based on Early

Tumour Marker Decline Assessment Becomes the New
Standard Treatment for Poor-Risk GCT

We hypothesised that incorporating new drugs into an intensified regimen would

improve current therapeutic results in patients with slowly decreasing tumour mark-
ers [15]. The dose-dense regimen used in the GETUG 13 international phase III trial
(NCT00104676; EU-20502) was designed to improve the results obtained with
BEP in various ways: using six drugs, individual bleomycin adjustment, increased
dose density, increased cisplatin and oxaliplatin exposure, limiting the cumulative
etoposide doses to try to prevent secondary leukaemia and selecting patients consid-
ered unlikely to achieve cure based on a tumour marker decline. In this trial, once
patients with IGCCCG poor-prognosis NSGCT had received one cycle of the BEP
regimen, AFP and hCG were assessed between days 18 and 21: (1) patients with a
favourable decline continued BEP (Fav-BEP) and (2) patients with an unfavourable
decline were randomised to receive either BEP (Unfav-BEP) or a dose-dense regi-
men (Unfav-dose-dense), consisting of paclitaxel (175 mg/m2 day 1)-BEP plus
oxaliplatin (130 mg/m2 day 10) (2 cycles), followed by cisplatin (100 mg/m2 day 1),
ifosfamide (2 g/m2 on days 10, 12, 14 + mesna) and bleomycin (25 units/day, by
continuous infusion × 5 days on days 10–14) (2 cycles), with G-CSF support. The
primary endpoint was progression-free survival (PFS), and the efficacy analysis was
conducted on an intention-to-treat basis. The planned trial accrual was completed in
May 2012: 263 patients were enrolled and 203 had an unfavourable tumour marker
decline. The primary endpoint, namely, PFS in patients with an unfavourable tumour
marker decline receiving dose-dense chemotherapy, was improved: 59 % [95 %
confidence interval (CI): 49–68] versus 48 % [95 % CI: 38–59] (p = 0.05; HR: 0.66
[0.44–1.00]). Patients with a primary mediastinal NSGCT may benefit less from
this strategy, which is consistent with findings indicating that this tumour is a dis-
tinct biological entity [17].
The incidence of neutropenic fever (17 % in each arm) and that of toxicity-
related deaths (1 % in each arm) was similar, although the dose-dense regimen was
associated with more side effects unrelated to neutropenia, especially peripheral
neuropathy and auditory toxicity [15]. Patients tended to recover from peripheral
neuropathy at 2 years. The rigorous use of lung function assessment in the GETUG
13 trial made it possible to continue bleomycin beyond the classic 300 mg cumula-
tive dose in selected patients randomised to the dose-dense regimen arm, without an
increased incidence of lung failure, and this may have contributed to treatment effi-
cacy. This emphasises the need for centralisation of care in expert centres for opti-
mal management of patients with poor-risk NSGCT [18].
Importantly, fewer patients in the dose-dense arm required salvage high-dose
chemotherapy plus a stem cell transplant (6 % vs. 16 %; p = 0.015). Attempting to
cure patients with poor-risk disease with first-line treatment is exceedingly
6 Poor-Prognosis Germ Cell Tumours 69

relevant given the well-known high toxicity of salvage therapies, including toxic
deaths [19].

6.5 Towards Systematic Centralisation of Patients

with Poor-Risk NSGCT

More and more data support the need to centralise the care of patients with poor-risk
NSGCT, and some countries like Denmark or the UK have already implemented
this policy at national level. Investigators from the EORTC retrospectively assessed
whether the experience of the treating institution had an impact on the outcome of
patients with poor-risk NSGCT included in a phase III trial: they found that patients
treated at institutions who enrolled fewer than five patients in the trial had signifi-
cantly worse overall survival than those treated in institutions that enrolled more
than five patients (p = 0.01; HR: 1.85 [1.16–3.03]) [18].
Another example is that of rare patients with multiple lung metastases and high
hCG levels who fulfilled the criteria for the risk of acute respiratory distress syndrome
(dyspnoea or pO2 < 80 mmHg at presentation) during the first days of chemotherapy:
early clinical management by an experienced team with chemotherapy dose reduction
(using, e.g. cisplatin and etoposide for only 2–3 days, without initial bleomycin) dur-
ing the first 2 weeks of chemotherapy seems to avoid the risk of early death [20].
Systematic and immediate referral of patients with poor-risk NSGCT is now
strongly recommended [1].

6.6 Conclusion

Poor-risk NSGCT is responsible for most of the deaths due to GCT. After a period
of 25 years during which all attempts to improve the results of BEP in patients with
poor-risk NSGCT failed [4–11], the paradigm changed in 2014 with the use of per-
sonalised chemotherapy based on tumour marker decline [15]. The overall probabil-
ity of curing patients with poor-risk NSGCT managed according to this algorithm
(BEP for patients with a favourable decline and dose-dense chemotherapy for
patients with an unfavourable decline) now exceeds 75 %. For these reasons, we
believe that the results of GETUG 13 are practice-changing and that patients with
poor-risk NSGCT should benefit from treatment intensification in case of unfavour-
able tumour marker kinetics during therapy with BEP.

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18. Collette L, Sylvester RJ, Stenning SP, et al. Impact of the treating institution on survival of
patients with “poor-prognosis” metastatic nonseminoma. J Natl Cancer Inst. 1999;91:
839–46.
6 Poor-Prognosis Germ Cell Tumours 71

19. Lorch A, Kleinhans A, Kramar A, et al. Sequential versus single high-dose chemotherapy in
patients with relapsed or refractory germ cell tumors: long-term results of a prospective ran-
domized trial. J Clin Oncol. 2012;30:800–5.
20. Massard C, Plantade A, Gross-Goupil M, et al. Poor prognosis nonseminomatous germ-cell
tumours (NSGCTs): should chemotherapy doses be reduced at first cycle to prevent acute
respiratory distress syndrome in patients with multiple lung metastases? Ann Oncol.
2010;21:1585–8.
How Should Patients with Recurrent
Disease Be Treated Actually? 7
Anja Lorch

Contents
7.1 Introduction .................................................................................................................... 73
7.2 High-Dose Chemotherapy in Relapsed Germ Cell Cancer............................................ 74
7.3 Prognostic Factors That Predict Treatment Response
Abschnitt evt. Weglassen ............................................................................................... 76
7.4 Conventional-Dose Chemotherapy Versus High-Dose
Chemotherapy at First Relapse ...................................................................................... 77
7.5 High-Dose Salvage Chemotherapy in Patients with a Second or
Subsequent Relapse ....................................................................................................... 78
7.6 Palliative Chemotherapy Regimens ............................................................................... 78
7.7 Conclusions for Clinical Practice................................................................................... 78
References ............................................................................................................................... 79

7.1 Introduction

Germ cell cancer is the most common type of cancer found in males aged 15–45 and
is increasing in incidence. Over the past 25 years, the use of well-validated, guide-
line- based treatment concepts has resulted in consistent successes and high cure
rates [11].
Approximately 5–10 % of patients with germ cell tumors and approximately
30 % of patients with metastatic disease at first presentation will nevertheless expe-
rience progression or recurrence during the course of their disease and will require
treatment for relapse.

A. Lorch
Genitourinary Medical Oncology/ Department of Urology, University Hospital Düsseldorf,
Moorenstrasse 5, 40255 Düsseldorf, Germany
e-mail: [email protected]

© Springer International Publishing Switzerland 2015 73

S. Krege (ed.), Diagnosis and Management of Testicular Cancer: The European
Point of View, DOI 10.1007/978-3-319-17467-9_7
74 A. Lorch

When compared with primary treatment, treatment for relapse (salvage therapy)
is considerably more intensive in nature. The fact that it is also more complex and
less well validated by clinical data is due not only to its rarity of occurrence but also
due to the heterogeneity of the patient group affected.
Conventional chemotherapeutic regimens achieve long-term remission in only
approximately 15–60 % of patients with recurrence. The most successful regimens
comprise a combination of cisplatin and ifosfamide with either etoposide (VIP), vin-
blastine (VeIP), or paclitaxel (TIP), with none clearly superior to the others [5, 8].
The unsatisfactory results obtained with conventional-dose chemotherapy, par-
ticularly in patients with unfavorable risk profiles at relapse and/or with multiple
relapses, led to the introduction of high-dose chemotherapy (HDCT) combined with
the reinfusion of autologous hematopoietic stem cells [16]. Even today, the com-
bined use of carboplatin and etoposide (CE) remains the mainstay of HDCT. In the
past, a number of studies investigated treatment modifications that included dose
increases or the addition of other substances. While none delivered clinical evidence
of improved efficacy, many revealed evidence of a significant increase in adverse
effects. It was improvements in supportive care and the use of autologous peripheral
blood stem cells (PBSCs) that led to a significant reduction in the time to hemato-
poietic recovery and thus a reduction in the high initial treatment-related mortality
rate from more than 10 % to approximately 3 % [3, 7, 10].
The use of HDCT has resulted in long-term remission being achieved even in
patients with unfavorable prognoses or multiple relapses.
What remains controversial, however, is the exact role of HDCT as first-line sal-
vage therapy in relapsed patients with favorable risk profiles. In an attempt to avoid
overtreatment, the use of HDCT outside of clinical studies has so far often been
limited to mainly patients presenting with relapsed disease and unfavorable prognos-
tic factors, as well as patients with a second or subsequent relapse [2, 4, 6, 8, 17].
Recent years have also seen a recognition of the role of prognostic factors in the
process of selecting appropriate therapy and predicting treatment success. In addi-
tion to identifying simple clinical prognostic factors, these efforts have led to the
development of an internationally accepted prognostic score for patients with
relapsed disease (Table 7.2) [1] (see also Chap. 7).

7.2 High-Dose Chemotherapy in Relapsed Germ Cell Cancer

In 1989, Nichols et al. first reported on a combination of high-dose carboplatin and

etoposide achieving a response rate of 44 % and long-term remission of more than
12 months in patients with refractory germ cell tumor who either had not responded
to conventional-dose chemotherapy with cisplatin or had shown a suboptimal
response [16]. Many working groups from the United States and Europe were able
to reproduce these results over the next few years [6, 9, 12]. Results from these stud-
ies showed that successful treatment outcomes and long-term remission were
achieved both in patients with first recurrence and with multiple recurrences. Even
today, the combination of carboplatin and etoposide (CE) remains the mainstay
of all high-dose chemotherapy regimens. In many cases, therapy regimens were
7 How Should Patients with Recurrent Disease Be Treated Actually? 75

altered by further increasing the doses involved and by adding ifosfamide, cyclo-
phosphamide, or thiotepa to the drug combination. While these treatment modifica-
tions were not usually associated with better efficacy, they were also associated with
a marked increase in adverse events. In Germany, the Interdisciplinary Testicular
Cancer Working Group (Interdisziplinäre Arbeitsgruppe Hodentumoren) therefore
carried out a large prospective, randomized, multicenter trial to address the question
of what constitutes the optimal HDCT regimen [12]. A total of 216 patients with
relapsed and/or refractory testicular cancer were randomized either to treatment arm
A and one cycle of conventional-dose chemotherapy with cisplatin, etoposide, and
ifosfamide (VIP) followed by three cycles of high-dose carboplatin and etoposide
(CE) or to treatment arm B and three cycles of conventional-dose VIP followed by
one cycle of high-dose carboplatin, etoposide, and cyclophosphamide (CEC). In
terms of efficacy, both treatment regimens produced similar results. Progression-
free survival after 2 years was reported as 52 and 47 % for the two treatment arms
involved, with overall survival after 2 years of 58 and 50 %, respectively. However,
the trial had to be terminated early due to treatment-related excess mortality in treat-
ment arm B, which involved the administration of one cycle of high-dose CEC. The
recently published results on the long-term follow-up of the patients in this study
confirmed these results showing treatment-dependent mortality to be lower for
sequential HDCT, resulting in a 50 % increase in overall survival in the sequential
HDCT arm versus a 40 % overall survival in the single HDCT arm [13]. As a result,
nearly all of the treatment centers worldwide deliver HDCT as a sequential regimen
that includes two to three high-dose cycles of carboplatin and etoposide (see
Table 7.1) [6, 7]. Improvements in supportive care and, in particular, the use of
peripheral blood stem cells have led to what constitutes a high initial

Table 7.1 Salvage chemotherapy

Conventional-dose chemotherapy (CDCT)
VIP
Cisplatin 20 mg/m2 Days 1–5 4 cycles
Ifosfamide 1.2 g/m2 Days 1–5
Etoposide 75 mg/m2 Days 1–5
TIP
Cisplatin 20 mg/m2 Days 1–5 4 cycles
Ifosfamide 1.2 g/m2 Days 1–5
Paclitaxel 250 mg Day 1
VeIP
Cisplatin 20 mg/m2 Days 1−5 4 cycles
Ifosfamide 1.2 g/m2 Days 1−5
Vinblastine 0.11 mg/kg Days 1 + 2
High-dose chemotherapy (HDCT) [9, 14, 16]
Carboplatin 500 mg/m2 Days 1−3 3 cycles
Etoposide 500 mg/m2 Days 1−3
Carboplatin AUC 8 Days 1−3 3 cycles
Etoposide 400 mg/m2 Days 1−3
Carboplatin 700 mg/m2 Days 1−3 2 cycles
Etoposide 750 mg/m2 Days 1−3
76 A. Lorch

Table 7.2 Prognostic factors at first relapse [1]

Histology in patients with refractory disease or at first relapse following first-line chemotherapy
Favorable Unfavorable
Histology Seminoma Nonseminoma
Primary tumor All, except primary mediastinal Primary mediastinal nonseminomas
location nonseminomas
Response to CR or PR with negative tumor PR with positive markers or even
first-line therapy markers worse
Progression-free More than 3 months after the end Less than 3 months after the end of
interval of first-line therapy first-line therapy
Metastases at Only lymphatic or pulmonary Extrapulmonary organ metastases
relapse metastases (liver, bone, CNS)
Tumor markers at AFP low (≤1,000 ng/mL) AFP high (>1,000 ng/mL)
relapse HCG low (≤1,000 U/L) HCG high (>1,000 U/L)
CR complete remission, PR partial remission, CNS central nervous system, AFP alpha-fetoprotein
in serum, HCG human chorionic gonadotropin in serum

treatment-related mortality rate following HDCT being reduced from more than
10 % to about 3 % of all patients treated.

7.3 Prognostic Factors That Predict Treatment Response

Abschnitt evt. Weglassen

The concept of therapy selection being guided by prognostic factors has been
proven successful in first-line therapy and is now also being implemented in sal-
vage therapy [10, 18]. However, the process of identifying prognostic factors in
patients with relapsed and refractory tumors is being rendered more difficult by
the fact that the data available are far more heterogeneous. While a range of prog-
nostic factors have been known for some years, their wider acceptance and the
introduction of a validated prognostic score have been rather recent developments
(Table 7.2).
Two years ago, an article was published that reported on the retrospective analy-
sis of data collected on nearly 1,600 patients worldwide who presented with relapsed
or refractory disease and who had received either CDCT or HDCT as initial salvage
therapy. The research was able to identify seven independent variables with a sig-
nificant impact on progression-free survival (PFS) and overall survival (OS) as well
as being successful in developing a prognostic scoring system. A total of five prog-
nostic categories were defined based on these variables. The 2-year PFS, estimated
using the Kaplan-Meier method, was 75 % for patients in the very-low-risk group,
51 % for patients in the low-risk group, 40 % for patients in the intermediate-risk
group, 26 % for patients in the high-risk group, and 6 % for patients in the very-
high-risk group [1]. Patients with pure seminoma represented a separate subgroup
among the five prognostic categories.
7 How Should Patients with Recurrent Disease Be Treated Actually? 77

7.4 Conventional-Dose Chemotherapy Versus High-Dose

Chemotherapy at First Relapse

When used as part of conventional chemotherapeutic measures and in combination

with cisplatin, etoposide, ifosfamide, and the newer substances paclitaxel, gem-
citabine, and oxaliplatin, it can achieve remission in patients who show no response
or only a limited response to conventional cisplatin-based therapy [5, 8].
However, at 50–70 %, the percentage of patients who show a favorable long-term
response to chemotherapy for relapsed GCT is lower than that for first-line therapy.
Long-term remission varies widely between individual studies, with percentages
reported ranging from 15 to 60 %. While no single conventional-dose chemotherapy
regimen has been shown to be clearly superior (see Table 7.1), it is becoming obvi-
ous that any such treatment comparisons must include patients with comparable
prognostic factors in order to allow a meaningful interpretation of results.
The routine use of HDCT in all patients requiring first-line salvage therapy
remains controversial and is the subject of ongoing discussion. In a carefully exe-
cuted matched-pair analysis that took into consideration all of the prognostic factors
known in clinical practice at the time, Beyer et al. were able to show that the use of
HDCT as part of salvage therapy produced a significant benefit of approximately
10 % in terms of both event-free survival and overall survival [4]. Pico et al. pub-
lished the results of the “IT94” study, a multicenter, randomized, prospective clini-
cal trial involving 263 patients who presented with progressive or relapsed disease
after first-line therapy with cisplatin and who had favorable prognostic criteria. As
part of the study, patients received either four cycles of conventional-dose salvage
therapy with cisplatin, etoposide and vinblastine, or ifosfamide or three cycles of
the same treatment and one cycle of HDCT. The IT94 study was unable to show a
clear benefit in relation to the use of HDCT as an early first-line salvage therapy in
patients with favorable prognostic factors [17]. However, the results obtained may
have been affected by the fact that patients with further relapse after the second
cycle of conventional chemotherapy also received HDCT.
Other working groups have suggested that HDCT is superior to CDCT at first
relapse. In a retrospective analysis of 135 patients at first relapse, which was carried
out at Indiana University, Einhorn at al. showed that long-term survival following
sequential HDCT was approximately 70 % [6]. A prospective study of 81 patients
at first relapse, which was carried out at MSKCC (Memorial Sloan Kettering Cancer
Center), showed that an initial treatment with two cycles of conventional chemo-
therapy with paclitaxel and ifosfamide followed by three cycles of CE (TI-CE) pro-
duced a 5-year survival rate of approximately 50 % [15].
A recent article reported on a subgroup analysis of approximately 1,600 sets of
patient data retrospectively collected by the International Prognostic Factors Study
Group, which compared the efficacy of HDCT with that of CDCT alone in the treat-
ment of patients at first relapse, with separate analyses for the five newly defined
prognostic categories described above.
High-dose chemotherapy produced better results than conventional-dose che-
motherapy in terms of both PFS and OS. The overall benefit observed was between
78 A. Lorch

10 and 15 % and applied both to the entire cohort of patients and to the individual
prognostic groups. These results are to be validated in a prospective, worldwide,
randomized phase 3 trial (TIGER) comparing conventional-dose paclitaxel-based
salvage therapy (TIP) with sequential high-dose chemotherapy (CE). While results
are not yet available, currently available data would suggest that the use of HDCT
even at first relapse is justified both when treating patients in higher-risk categories
and when treating patients in the lower-risk categories. When dealing with patients
in the very-low-risk category, the decision as to which treatment modality to use
should be made on a case-by-case basis. Here, conventional-dose paclitaxel-based
chemotherapy (TIP) and HDCT appear to produce equivalent results [12].

7.5 High-Dose Salvage Chemotherapy in Patients

with a Second or Subsequent Relapse

Even in the absence of relevant randomized trial data on the use of HDCT in patients
with a second or subsequent relapse, nobody had ever challenged the truthfulness of
such an assumption [6]. Only very little was known regarding the issue of whether
HDCT might prove as beneficial in patients with germ cell tumors in second or subse-
quent relapse as it did in patients at first relapse. Until now, this specific group of
patients has never been subjected to separate analysis. Recently, however, a retrospec-
tive study of 49 patients who received HDCT at second or subsequent relapse was able
to show that while this treatment still represented a curative treatment option, long-
term survival rates were reduced to under 20 % [14]. Unless contraindicated, HDCT is
recommended even in patients who have undergone multiple previous treatments,
regardless of the fact that survival rates in this patient group are markedly lower than
those achieved in patients who receive HDCT as a first-line salvage therapy [12].

7.6 Palliative Chemotherapy Regimens

In addition to paclitaxel, chemotherapeutic agents like oxaliplatin and gemcitabine

have shown activity even in patients after HDCT and are used either as monother-
apy or in various combinations. As a very successful treatment combination, GOP
was identified consisting of oxaliplatin, gemcitabine, and paclitaxel [5]. Long-term
remissions could be achieved with this regimen. Another effective agent in the pal-
liative setting is the application of oral etoposide.

7.7 Conclusions for Clinical Practice

As a whole, it would appear that current data support the view that HDCT plays a
significant role in the treatment of patients with relapsed germ cell tumors. The data
also appear to emphasize the importance of relevant experience in those who deliver
therapy and the need for close cooperation with centers that have accumulated spe-
cialist expertise in dealing with this group of patients.
7 How Should Patients with Recurrent Disease Be Treated Actually? 79

References
1. Anonymous. Prognostic factors in patients with metastatic germ cell tumors who experienced
treatment failure with cisplatin-based first-line chemotherapy. J Clin Oncol.
2010;28:4906–11.
2. Beyer J, Albers P, Altena R, et al. Maintaining success, reducing treatment burden, focusing on
survivorship: highlights from the third European consensus conference on diagnosis and treat-
ment of germ-cell cancer. Ann Oncol. 2013;24:878–88.
3. Beyer J, Schwella N, Zingsem J, et al. Hematopoietic rescue after high-dose chemotherapy
using autologous peripheral-blood progenitor cells or bone marrow: a randomized compari-
son. J Clin Oncol. 1995;13:1328–35.
4. Beyer J, Stenning S, Gerl A, et al. High-dose versus conventional-dose chemotherapy as first-
salvage treatment in patients with non-seminomatous germ-cell tumors: a matched-pair analy-
sis. Ann Oncol. 2002;13:599–605.
5. Bokemeyer C, Oechsle K, Honecker F, et al. Combination chemotherapy with gemcitabine,
oxaliplatin, and paclitaxel in patients with cisplatin-refractory or multiply relapsed germ-cell
tumors: a study of the German Testicular Cancer Study Group. Ann Oncol. 2008;19:448–53.
6. Einhorn LH, Williams SD, Chamness A, et al. High-dose chemotherapy and stem-cell rescue
for metastatic germ-cell tumors. N Engl J Med. 2007;357:340–8.
7. Feldman DR, Bosl GJ, Sheinfeld J, et al. Medical treatment of advanced testicular cancer.
JAMA. 2008;299:672–84.
8. Kondagunta GV, Bacik J, Donadio A, et al. Combination of paclitaxel, ifosfamide, and cispla-
tin is an effective second-line therapy for patients with relapsed testicular germ cell tumors.
J Clin Oncol. 2005;23:6549–55.
9. Kondagunta GV, Bacik J, Sheinfeld J, et al. Paclitaxel plus Ifosfamide followed by high-dose
carboplatin plus etoposide in previously treated germ cell tumors. J Clin Oncol.
2007;25:85–90.
10. Kondagunta GV, Motzer RJ. Chemotherapy for advanced germ cell tumors. J Clin Oncol.
2006;24:5493–502.
11. Kondagunta V, Galsky MD, Sonpavde G. Germ-cell tumors. N Engl J Med. 2007;357:1773;
author reply 1773–4.
12. Lorch A, Bascoul-Mollevi C, Kramar A, et al. Conventional-dose versus high-dose chemo-
therapy as first salvage treatment in male patients with metastatic germ cell tumors: evidence
from a large international database. J Clin Oncol. 2011;29:2178–84.
13. Lorch A, Kleinhans A, Kramar A, et al. Sequential versus single high-dose chemotherapy in
patients with relapsed or refractory germ cell tumors: long-term results of a prospective ran-
domized trial. J Clin Oncol. 2012;30:800–5.
14. Lorch A, Neubauer A, Hackenthal M, et al. High-dose chemotherapy (HDCT) as second-
salvage treatment in patients with multiple relapsed or refractory germ-cell tumors. Ann
Oncol. 2010;21:820–5.
15. Motzer RJ, Mazumdar M, Sheinfeld J, et al. Sequential dose-intensive paclitaxel, ifosfamide,
carboplatin, and etoposide salvage therapy for germ cell tumor patients. J Clin Oncol.
2000;18:1173–80.
16. Nichols CR, Tricot G, Williams SD, et al. Dose-intensive chemotherapy in refractory germ cell
cancer–a phase I/II trial of high-dose carboplatin and etoposide with autologous bone marrow
transplantation. J Clin Oncol. 1989;7:932–9.
17. Pico JL, Rosti G, Kramar A, et al. A randomised trial of high-dose chemotherapy in the sal-
vage treatment of patients failing first-line platinum chemotherapy for advanced germ cell
tumours. Ann Oncol. 2005;16:1152–9.
18. Sammler C, Beyer J, Bokemeyer C, et al. Risk factors in germ cell tumour patients with relapse
or progressive disease after first-line chemotherapy: evaluation of a prognostic score for sur-
vival after high-dose chemotherapy. Eur J Cancer. 2008;44:237–43.
Prognostic Factors at Initial Presentation
and in Recurrent Disease 8
Jörg Beyer

Contents
8.1 Introduction .................................................................................................................... 81
8.2 Prognostic Factors at Initial Presentation....................................................................... 82
8.3 Early Identification of Unfavorable Response to First-Line Treatment ......................... 83
8.4 Prognostic Factors in Recurrent Disease ....................................................................... 84
8.5 Early Identification of Unfavorable Response to Salvage Treatment ............................ 87
8.6 Rare Scenarios................................................................................................................ 87
8.7 Summary ........................................................................................................................ 87
References ............................................................................................................................... 88

8.1 Introduction

Prognostic factors in germ-cell cancer reflect tumor biology and extent of disease
in any given patient and can be used to guide treatment decisions as well as to
compare treatment results across different institutions. The issue of prognostic fac-
tors can be divided into two broad categories. One focuses on the use of prognostic
factors in clinical stage I seminoma and non-seminoma in order to assess a patient’s
risk of having occult metastatic disease. This discussion has been presented in the
previous chapters of this book. The other one will be presented here and focuses on
the much more pressing question of survival probabilities in patients with meta-
static disease.

J. Beyer
Department of Oncology, University Hospital Zürich, Zürich, Switzerland
e-mail: [email protected]

© Springer International Publishing Switzerland 2015 81

S. Krege (ed.), Diagnosis and Management of Testicular Cancer: The European
Point of View, DOI 10.1007/978-3-319-17467-9_8
82 J. Beyer

8.2 Prognostic Factors at Initial Presentation

Historically, the prognosis of patients with metastatic germ-cell cancer has been
assessed according to local risk classifications at major institutions worldwide. The
ones most commonly used were those from Indiana University, the MD Anderson
Cancer Center, the Memorial Sloane Kettering Cancer Center, and the Royal
Marsden Hospital [1–4]. Whereas these classifications were instrumental to assess
an individual patient’s risk of progressing and possibly even dying from germ-cell
cancer, the heterogeneity of classification systems did now allow comparison of
treatment results across institutions and clinical trials.
A major step forward was the effort of the International Germ Cell Cancer
Collaborative Group (IGCCCG) to create a common database on more than 5,000
patients that allowed a robust multivariate statistical analysis. The results of the
analysis have been published in 1997 and have become the reference prognostic
classification system for all metastatic germ-cell cancer ever since [5]. The IGCCCG
classification system is based on following four prognostic variables: histology
(seminoma vs. non-seminoma), primary site (primary mediastinal non-seminoma
vs. all other primary locations), metastatic sites (extrapulmonary visceral metasta-
ses vs. other metastatic sites), and the serum levels of alpha-fetoprotein (AFP),
human chorionic gonadotropin (HCG), and lactate dehydrogenase (LDH). The

Table 8.1 IGCCCG prognostic classification (Ref. [6]) evt. weglassen, taucht schon an anderer
Stelle im Buch auf
“Good risk” (about 56 % of patients) >90 % survival probability
Clinical presentation Low marker profile
Non-seminoma Gonadal or retroperitoneal primary tumor AFP < 1,000 ng/ml
and HCG < 5,000 U/l
No extrapulmonary visceral metastases LDH < 1.5 × normal
Seminoma Any primary tumor location
and
No extrapulmonary visceral metastases
Intermediate risk (about 28 % of patients) ~78 % survival probability
Clinical presentation Intermediate marker profile
Non-seminoma Gonadal or retroperitoneal primary tumor AFP 1,000–10,000 ng/ml
and HCG 5,000–50,000 U/l
No extrapulmonary visceral metastases LDH 1.5–10 × normal
Seminoma Any primary tumor location
plus
Extrapulmonary visceral metastases
Intermediate risk (about 16 % of patients) ~45 % survival probability
Clinical presentation Intermediate marker profile
Non-seminoma Mediastinal primary tumor AFP > 10,000 ng/ml
or HCG > 50,000 U/l
Extrapulmonary visceral metastases LDH > 10 × normal
AFP alpha-fetoprotein, HCG human chorionic gonadotropin, IGCCCG International Germ Cell
Classification Cooperative Group
8 Prognostic Factors at Initial Presentation and in Recurrent Disease 83

categories obtained were those of “good risk,” “intermediate risk,” and “poor risk”
in respect to progression or survival (Table 8.1) [5]. The idea of having only three
categories was to identify patients who would be similar in respect to progression or
survival probabilities within a prognostic group but significantly different to patients
from another one. In the following decades and until now, the IGCCCG classifica-
tion determines the treatment intensity and duration in routine first-line treatment as
well as the risk stratification in all clinical trials that have been performed since its
first publication.
However, despite its undisputable merits, the IGCCCG classification has several
problems that require an updated classification system in the near future. First, the
IGCCCG classification is mainly based on treatments that have been performed
prior to 1990, which would no longer be considered acceptable today. In actual fact,
in the IGCCCG database, not all patients even had received cisplatin, and only a
fraction of patients had received etoposide as part of their first-line treatments.
Second, many improvements in diagnostic staging procedures have resulted in stage
migration. Third, better supportive care has led to significant improvements in over-
all survival probabilities across all risk categories [6]. Fourth, and most importantly,
several analyses have shown that the intermediate-risk and the poor-risk categories
comprise of quite heterogeneous subsets of patients. Particularly patients with liver,
bone, and brain metastases at initial diagnosis as well as patients with primary
mediastinal non-seminoma have a significantly worse prognosis compared to
patients classified as having “poor-risk” disease based on serum tumor marker ele-
vations alone [7].

8.3 Early Identification of Unfavorable Response

to First-Line Treatment

Over almost two decades, the prognostic impact of the decline of serum tumor
markers after initiation of chemotherapy has been subject to considerable debate [8,
9]. However, only recently, it could be shown that the rate of decline of the serum
tumor markers AFP and HCG according to their estimated serum half-lives can be
used to further subdivide the groups of intermediate- and poor-risk patients. In a
prospective intergroup phase III trial in the United States that randomized
intermediate-risk and poor-risk patients to conventional-dose and high-dose first-
line chemotherapy, it showed that those patients with a slow marker decline beyond
the estimated marker half-life of AFP and HCG had inferior survival probabilities
and profited more from treatment intensification compared to patients with marker
declines according to their estimated marker half-lives [10]. This observation was
recently confirmed in a randomized trial from the French Testicular Cancer Study
Group that prospectively stratified patients according to their decline of serum AFP
and HCG after an initial cycle of chemotherapy [11]. In this trial, patients with a
slow marker decline had an inferior survival probabilities that could be significantly
improved by early treatment intensification (see also Chap. 5). The German
84 J. Beyer

Poor risk patients

Contact reference center

Decision

One cycle conventional-dose

chemotherapy
Adverse risk criteria
• PMNS
• Brain metastases Adequate marker decline
• Liver metastases
• Bone metastases ↓

↓ No Yes

Recommendation ↓

Upfront sequential high-dose Continue with thee more

chemotherapy cycles of conventional-dose
chemotherapy

PMNS=Primary mediastinal non-seminoma

Fig. 8.1 Algorithm for first-line treatment according to marker decline. PMNS primary mediasti-
nal non-seminoma

Testicular Cancer Study Group uses this information for an integrated, rational
approach for first-line treatment of poor-risk patients (Fig. 8.1). An unresolved
question, however, is the optimal calculation method of marker decline, which dif-
fered in the abovementioned trials and resulted in conflicting results depending on
the algorithm used [12].

8.4 Prognostic Factors in Recurrent Disease

Prognostic factors have long been recognized to impact strongly on the results of
first-salvage chemotherapy and have been the focus of several retrospective analy-
ses [13–15]. In the first-salvage setting, the importance of prognostic factors is even
greater as compared to initial diagnosis.
Although consistent prognostic variables have been identified, previous analy-
ses suffered from substantial limitations. All have been too small to identify but a
few variables reliably; some databases contained only incomplete information and
were without source data verification; often external or internal validation of the
8 Prognostic Factors at Initial Presentation and in Recurrent Disease 85

Table 8.2 Prognostic factors for survival after first-salvage treatment of seminoma and non-
seminoma patients (Ref. [15])
Score points
0 1 2 3 Score
Primary site Gonadal Extragonadal – Mediastinal
Non-seminoma
Prior response CR/PRm− PRm+/SD PD –
PFI >3 months ≤3 months – –
AFP salvage Normal ≤1,000 >1,000 –
HCG salvage ≤1,000 >1,000 – –
LBB No Yes – –
Score sum (values from 0 to 10)
Regroup score sum into categories: (0), 0; (1 or 2), 1; (3 or 4), 2; (5 or more), 3
Add histology score points: pure seminoma, −1; non-seminoma or mixed tumors, 0

Final prognostic score (−1 = very low risk, 0 = low risk, 1 = intermediate risk, 2 = high risk,
3 = very high risk)
PFI progression-free interval, AFP alpha-fetoprotein, HCG human chorionic gonadotropin, LDH
lactate dehydrogenase, LBB liver, bone, brain metastases, CR complete remission, PRm− partial
remission, negative markers, PRm+ partial remission, positive markers, SD stable disease, PD
progressive disease, TS total sum of score points

results was missing; many analyses were based on outdated treatments that would
no longer be considered standard today. Many of these obstacles have been over-
come by the recent large collaboration of the International Prognostic Factor Study
Group that included more than 1,500 patients in an analysis of prognostic factors
for first-salvage treatment [15]. Seminoma histology was identified as a favorable
prognostic factor. Adverse prognostic factors were (1) extragonadal primary
tumors, in particular primary mediastinal non-seminomas; (2) less than complete
remission or less than tumor-marker-negative partial remission to first-line treat-
ment; (3) a progression-free interval of three months or less; (4) elevations of AFP
at salvage, particularly if more than 1,000 ng/ml; (5) elevation of HCG at salvage
to more than 1,000 U/l; and (6) the presence of liver, bone, or brain metastases
(Table 8.2).
The results of the analysis confirmed the large variation in survival in patients
relapsing after at least three cycles of cisplatin-based first-line treatment [15].
Whereas patients relapsing with seminoma and no other risk factors had a projected
progression-free survival rate of more than 75 % at 2 years, patients relapsing with
seminoma or non-seminoma and one or several of the abovementioned risk factors
had an increasingly dismal prognosis with a progression-free survival probability of
less than 10 % at 2 years in the most unfavorable risk group (Fig. 8.2).
The challenge will be to exploit these results in clinical practice, in particular to
use them to adjust the intensity of the salvage strategy according to the risk of fail-
ure. However, the availability of the robust analysis from the International Prognostic
Factor Study Group makes this a timely enterprise. International efforts are now
86 J. Beyer

Overall survival

1.00

0.75
Probability

0.50

0.25

0.00
0 1 2 3 4 5
Years
V Low Low Interm High V High

Fig. 8.2 Overall survival probability after first-salvage treatment according to prognostic factors
(Ref. [15])

Patients
with relapse or progression
after chemotherapy

Indication for salvage surgery?

- Progression mature teratoma
- Late relapse > 2 years
- Resectable relapse after HDCT

Risk factors
Without With
risk factors risk factors - Extragonadal primary tumor
- No CR / PRm-after first-line
- Early relapse
- Extrapulmonary metastases
Conventional High - High AFP or HCG levels
dose treatment dose treatment - Any second or subsequent
relapse

Fig. 8.3 Algorithm for first-salvage treatment according to prognostic factors

8 Prognostic Factors at Initial Presentation and in Recurrent Disease 87

needed to study risk-adapted salvage strategies prospectively [16]. Meanwhile, the

German Testicular Cancer Study Group uses all available information for an inte-
grated, rational approach for first-line salvage treatment (Fig. 8.3).

8.5 Early Identification of Unfavorable Response to

Salvage Treatment

Similar to the situation in first-line treatment, the subgroup of patients who relapse
and receive first-salvage chemotherapy can also be further subdivided based on
the decline of their serum AFP and HCG values. According to a retrospective
analysis of trial data from France and Germany, patients with a slow marker
decline have an inferior prognosis as compared to patients with a decline accord-
ing to the expected serum half-lives [17]. In contrast to first-line treatment, how-
ever, no data exists if a change in the treatment strategy, e.g., switch from
conventional-dose treatment to high-dose treatment, will change the unfavorable
prognosis of such patients.

8.6 Rare Scenarios

Patients who suffer multiple relapses or progress despite adequate salvage che-
motherapy have a poor prognosis [18, 19]. Although cures can still be achieved
in individual patients in the second or subsequent salvage setting, the long-term
survival probabilities are well below 20 % overall. Although no formal analyses
have been performed to identify prognostic factors in the second or subsequent
salvage setting, it is likely that similar prognostic factors apply as for first-salvage
treatment.
Similarly, rare patients who suffer late relapses more than 2 years after adequate
cisplatin-based treatment also have an inferior prognosis compared to patients with
earlier relapses [20–23]. Although the number of patients in available analyses has
been small, patients with multifocal relapses that cannot completely be resected as
well as those with rapidly rising makers and/or HCG elevations have an inferior
survival probability as compared to patients without these adverse prognostic
factors.

8.7 Summary

Prognostic factors are a reflection of individual disease biology and extent and play
a major role in treatment decisions in metastatic germ-cell cancer. Apart from
allowing a judgement and best estimate about the survival probabilities prior to
initiation of treatment in an individual patient, prognostic factors help to stratify
treatment intensity and duration and allow a comparison of treatment outcomes
across different institutions and clinical trials.
88 J. Beyer

However, despite these classic prognostic factors, patient volume and availability
of an experienced interdisciplinary team have been shown to be additional strong
independent factors for survival particularly in poor-risk metastatic patients at ini-
tial presentation and in all patients with relapsed germ-cell cancer [24]. Therefore,
all patients in these high-risk scenarios must be referred to and treated at one of the
national reference centers.

References
1. Samuels ML, Holoye PY, Johnson DE. Bleomycin combination chemotherapy in the manage-
ment of testicular neoplasia. Cancer. 1975;36:318–26.
2. Bosl GJ, Geller NL, Cirrincione C, et al. Multivariate analysis of prognostic variables in
patients with metastatic testicular cancer. Cancer Res. 1983;43:3403–7.
3. Birch R, Williams S, Cone A, et al. Prognostic factors for favorable outcome in disseminated
germ-cell tumors. J Clin Oncol. 1986;4:400–7.
4. Medical Research Council Working Party on Testicular Tumors: prognostic factors in advanced
non-seminomatous testicular tumors: results of a Multicenter Study. Lancet. 1985;1:8–11.
5. International Germ Cell Consensus Classification: a prognostic factor-based staging system
for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin
Oncol. 1997;15:594–603.
6. Sonneveld DJA, Hoekstra HJ, van der Graaf WTA, et al. Improved long term survival of
patients with metastatic nonseminomatous testicular germ cell carcinoma in relation to prog-
nostic classification systems during the cisplatin era. Cancer. 2001;91:1304–15.
7. Kollmannsberger C, Nichols C, Meisner C, et al. Identification of prognostic subgroups among
patients with metastatic “IGCCCG poor prognosis” germ-cell cancer: an explorative analysis
using cart modeling. Ann Oncol. 2000;11:1115–20.
8. Toner GC, Geller NL, Tan C, et al. Serum tumor marker half-life during chemotherapy allows
early prediction of complete response and survival in nonseminomatous germ cell tumors.
Cancer Res. 1990;50:5904–10.
9. Fizazi K, Culine S, Kramar A, et al. Early predicted time to normalization of tumor markers
predicts outcome in poor-prognosis nonseminomatous germ cell tumors. J Clin Oncol.
2004;22:3868–76.
10. Motzer RJ, Nichols CJ, Margolin KA, et al. Phase III randomized trial of conventional-dose
chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-
cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors.
J Clin Oncol. 2007;25:247–56.
11. Fiazi K, Pagliaro L, Laplanche A, et al. Personalized chemotherapy based on tumor marker
decline in poor-prognosis germ-cell tumors (GCT): results of GETUG 13. Lancet Oncol.
Lancet Oncol 2014;15:1442–50.
12. Lorch A. A step forward, but is it likely to be practice-changing? Lancet Oncol. Lancet Oncol
2014;15:1409–10.
13. Beyer J, Kramar A, Mandanas R, Linkesch W, Greinix A, Droz JP, Pico JL, Diehl A,
Bokemeyer C, Schmoll HJ, et al. High-dose chemotherapy as salvage treatment in germ cell
tumours: a multivariate analysis of prognostic variables. J Clin Oncol. 1996;14:2638–45.
14. Einhorn LH, Williams SD, Chamness A, et al. High-dose chemotherapy and stem-cell rescue
for metastatic germ-cell tumours. N Engl J Med. 2007;357:340–8.
15. The International Prognostic Factors Study Group. Prognostic factors in patients with meta-
static germ cell tumors who experienced treatment failure with cisplatin-based first-line che-
motherapy. J Clin Oncol. 2010;28:4906–11.
16. Powles T, Kollmannsberger C, Feldman D. The conundrum of clinical trials in adult germ-cell
tumours. Lancet Oncol. 2013;14:14–5.
8 Prognostic Factors at Initial Presentation and in Recurrent Disease 89

17. Massard C, Kramar A, Beyer J, et al. Tumor marker kinetics predict outcome in patients with
relapsed disseminated non-seminomatous germ-cell tumors. Ann Oncol. 2013;24:322–8.
18. Bokemeyer C, Oechsle K, Honecker F, et al. Combination chemotherapy with gemcitabine,
oxaliplatin, and paclitaxel in patients with cisplatin-refractory or multiply relapsed germ-cell
tumors: a study of the German Testicular Cancer Study Group. Ann Oncol. 2008;19:448–53.
19. Lorch A, Neubauer A, Hackenthal M, et al. High-dose chemotherapy (HDCT) as second-
salvage treatment in patients with multiple relapsed or refractory germ-cell tumors. Ann
Oncol. 2010;21:821–5.
20. Baniel J, Foster RS, Gonin R, et al. Late relapse of testicular cancer. J Clin Oncol.
1995;13:1170–6.
21. Shahidi M, Norman AR, Dearnaley DP, et al. Late recurrence in 1263 men with testicular germ
cell tumours. Multivariate analysis of risk factors and implications for management. Cancer.
2002;95:520–30.
22. Oldenburg J, Alfsen GC, Waehre H, et al. Late recurrences of germ cell malignancies: a
population-based experience over three decades. Br J Cancer. 2006;94:820–7.
23. Lorch A, Rick O, Wündisch T, et al. High dose chemotherapy as salvage treatment for unre-
sectable late relapse germ cell tumors. J Urol. 2010;184:168–73.
24. Collette L, Sylvester R, Stenning S, et al. Impact of the treating institution on survival of
patients with “poor-prognosis” metastatic nonseminoma. J Natl Cancer Inst. 1999;91:
839–41.
Postchemotherapy Retroperitoneal
Lymph Node Dissection 9
Axel Heidenreich

Contents
9.1 Introduction .................................................................................................................... 91
9.2 PC-RPLND in Small Residual Lesions ......................................................................... 92
9.3 Resection of Extraretroperitoneal Disease ..................................................................... 93
9.3.1 Considerations for the Most Appropriate Surgical Strategy ............................... 93
9.3.2 Special Preoperative Imaging Studies ................................................................ 94
9.4 Timing of PC-RPLND ................................................................................................... 94
9.4.1 Extent of PC-RPLND ......................................................................................... 94
9.5 PC-RPLND After Salvage Chemotherapy or Previous Retroperitoneal Surgery .......... 96
9.6 Desperation PC-RPLND ................................................................................................ 96
References ............................................................................................................................... 97

9.1 Introduction

Surgical resection of postchemotherapy residual retroperitoneal lymph nodes or

residual visceral metastatic deposits represents an integral part of the multimodal
treatment of patients with advanced testicular cancer [1–3]. The rationale for
PC-RPLND is to remove persistent disease that may contain mature teratoma in
approximately 30–40 % and vital cancer in about 10–20 % of the patients. In non-
seminomatous germ cell tumours (NSGCT), PC-RPLND is generally indicated in
men with normalised or plateauing serum tumour markers and residual disease.

9.2 PC-RPLND in Small Residual Lesions

In patients with residual lesions <1 cm, the role of PC-RPLND is discussed contro-
versially based on the finding that up to 20 and 8 % of patients will harbour mature

A. Heidenreich
Department of Urology, University Hospital Aachen, Pauwelsstr. 30, Aachen 52074, Germany
e-mail: [email protected]

© Springer International Publishing Switzerland 2015 91

S. Krege (ed.), Diagnosis and Management of Testicular Cancer: The European
Point of View, DOI 10.1007/978-3-319-17467-9_9
92 A. Heidenreich

teratoma and vital cancer. However, this approach has been challenged by recent
retrospective studies from three groups. Kollmannsberger et al. [4] analysed 276
patients who underwent systemic chemotherapy for metastatic NSGCT. One hun-
dred sixty-one (58.3 %) achieved a complete remission (residual lesions <1 cm),
and all patients were followed without surgical resection. After a mean follow-up of
40 (2–128) months, relapses were observed in 6 %, and none of them died after
appropriate salvage therapy. Ninety-four percent of the patients belonged to the
IGCCCG good prognosis group. Ehrlich et al. [5] evaluated 141 patients who were
observed after systemic chemotherapy and had residual lesions <1 cm. After a mean
follow-up of up to 15 years, 9 % of the patients relapsed and 3 % of the patients died
due to testis cancer. IGCCCG risk group classification predicted the outcome best:
recurrence-free survival and cancer-specific survival were 95 and 99 %, respec-
tively, in men who belonged to the good risk group, whereas it dropped to 91 and
73 % in the intermediate and poor risk group. The German Testicular Cancer Study
Group (GTCSG) analysed the outcome of 392 patients who underwent PC-RPLND
for residual lesions of any size [6]. 9.4 and 21.8 % of the men with residual lesions
<1 cm harboured vital cancer and mature teratoma, respectively. These numbers
increased to 21 and 25 % in patients with residual lesions of 1–1.5 cm and to 36 and
42 % in men with lesions larger than 1.5 cm.
Based on these data, PC-RPLND for small residual masses might only be indi-
cated in patients with (1) intermediate or poor prognosis at initiation of chemo-
therapy and/or (2) >50 % teratoma in the orchiectomy specimen. The remainder can
be managed conservatively with close follow-up.

9.3 Resection of Extraretroperitoneal Disease

In patients with residual masses at multiple sites, an individual decision should be

made regarding the number and extension of resections based on the risk of relapse
and on quality-of-life issues [1–3]. Resection of residual tumours outside the abdo-
men or lung should also be considered on an individual basis, since discordant his-
tology is found in 35–50 % of patients. Pulmonary or mediastinal residual masses
harbour necrosis/fibrosis in 90 % if the retroperitoneal masses did not contain
mature teratoma or viable cancer [7, 8]. Management of liver lesions by postchemo-
therapy retroperitoneal lymph node dissection must be individualised. Observation
may be warranted for liver lesions requiring complicated hepatic surgery regardless
of retroperitoneal pathology [9]. The concordance between retroperitoneal and liver
histology was 49 % overall, including 94 % for necrosis, 26 % for teratoma and
36 % for cancer. Liver necrosis alone was found in 94, 70 and 50 % of patients with
retroperitoneal necrosis, teratoma and cancer, respectively.

9.3.1 Considerations for the Most Appropriate Surgical Strategy

PC-RPLND requires detailed knowledge of the retroperitoneal anatomy, familiarity

with surgical techniques of the vascular and intestinal structures, as well as
9 Postchemotherapy Retroperitoneal Lymph Node Dissection 93

profound experience in the management of patients with testicular cancer [2, 3].
Depending on the size and the extent of the residual lesions, the surgeon has to
modify his surgical approach to the retroperitoneal space. An abdominal midline
incision can be used in most patients with unilateral and infrahilar disease, whereas
a Chevron incision might be more suitable in those men with bilateral and suprahi-
lar disease. Retrocrural disease is best approached by a thoracoabdominal incision.

9.3.2 Special Preoperative Imaging Studies

Imaging studies should allow an adequate assessment of the large retroperitoneal

vascular structures since involvement of the inferior vena cava (IVC) and the
abdominal aorta can be expected in about 6–10 % and 2 %, respectively [2, 3, 10].
Magnetic resonance imaging represents the most appropriate imaging technique to
predict infiltrations of the vessel wall and the presence of an intracaval tumour
thrombus. Infiltrations of the IVC wall or IVC thrombi should be completely
resected since about two thirds of the patients harbour vital cancer or mature tera-
toma in the infiltrating masses. The necessity for aortic replacement is rare and
usually accompanied by large residual masses involving additional adjacent struc-
tures and making additional surgical procedures necessary (Fig. 9.1).

9.4 Timing of PC-RPLND

PC-RPLND should be initiated within 6–12 weeks after chemotherapy. Hendry

et al. retrospectively analysed the outcome of 443 patients undergoing either imme-
diate or elective PC-RPLND once progression of the residual masses was demon-
strated [11]. A significant benefit with regard to progression-free survival (83 %
versus 62 %, p = 0.001) and cancer-specific survival (89 % versus 56 %, p = 0.001)
was identified for the immediate surgical approach.

9.4.1 Extent of PC-RPLND

Early retrospective and single-centre studies indicate that a modified PC-RPLND

might be a safe approach in men with limited retroperitoneal disease and right/left
primary tumours with no evidence of teratoma or viable cancer on frozen section
analysis [2, 3]. However, application of the modified unilateral template to
PC-RPLND still is discussed controversially based on the 3–8 % incidence of
mature teratoma or viable cancer in the contralateral landing zone. Two experienced
groups reported their experience on modified unilateral template PC-RPLND. The
group at Indiana University has performed a limited PC-RPLND in 100 men with
low-volume retroperitoneal disease (<5 cm) confined to the primary landing zone of
the primary tumour [12]. After a mean follow-up of 32 months, only four patients
relapsed, all outside the boundaries of the modified and even of the bilateral tem-
plate. The 2- and 5-year disease-free survival was 95 %.
94 A. Heidenreich

b c

Fig. 9.1 (a) Encasement of the infrarenal aorta by mature teratoma (b) extensive and meticulous
preparation of the major retroperitoneal vessel: the left renal vein is marked with a blue vessel
loop, the renal arteries are prepared and the infrarenal aorta is marked with a red vessel loop.
(c) infrarenal aorta has been resected and replaced by an aortic graft

The GTCSG assessed the oncological necessity of full bilateral retroperitoneal

PC-RPLND in 152 patients [13]. If patients exhibited a well-defined lesion ≤2 cm,
modified PC-RPLND was performed; lesions >5 cm were always treated by a full
bilateral PC-RPLND (Fig. 9.2). Lesions 2–5 cm in diameter were approached
dependent on the site of the primary lesion and the location of the mass: interaor-
tocaval residuals were always approached with a full bilateral PC-RPLND,
whereas para-aortic and paracaval lesions were treated by a modified PC-RPLND
if the metastatic site corresponded to the site of the primary lesion. There was a
significant difference with regard to postoperative morbidity with more complica-
tions in patients undergoing extended surgery (p < 0.001). Antegrade ejaculation
9 Postchemotherapy Retroperitoneal Lymph Node Dissection 95

a b

Fig. 9.2 (a) Large retroperitoneal mass encased both the aorta and the IVC. The ureter (yellow),
the suprahilar inferior vena cava and both renal veins (blue) are marked with vessel loops.
(b) Intraoperative situs following a complete bilateral template resection. (c) Nerve sparing
PC-RPLND within a modified template due a small residual mass in the primary landing zone of
the left testis
96 A. Heidenreich

was preserved in 85 % of patients undergoing modified PC-RPLND, whereas it

could not be preserved in 75 % of the cases undergoing full bilateral
PC-RPLND. Eight (5.2 %) recurrences were observed after a mean follow-up of
39 (6–105) months: one in-field relapse following modified PC-RPLND and seven
recurrences even outside the boundaries of full bilateral PC-RPLND. The two-
year disease-free survival was 78.6 and 92.8 % for bilateral and modified
PC-RPLND, respectively.
The so-called Heidenreich criteria have been validated recently in a cohort of 59
patients who underwent PC-RPLND with a modified or a bilateral template [14]. In
the study cohort, median age at time of RPLND was 31 years. The 2-year disease-
free survival was 90 and 96 % for the bilateral and the unilateral RPLND patients,
respectively. Overall, eight (14 %) relapses were observed after a median follow-up
of 54 months. Of these, six were outside of the resection field and two were in-field.
Of the 23 patients with indication for a modified RPLND, one patient relapsed in the
contralateral testis and one inside the modified RPLND template. No relapse was
observed outside the modified RPLND field and inside the untouched contralateral
RPLND field. The Heidenreich criteria did therefore not misclassify a single patient.
The Heidenreich criteria for the selection of candidates for unilateral RPLND for
residual masses after chemotherapy allow a highly reliable selection of patients.
The application of the Heidenreich criteria can help reduce co-morbidity and inva-
siveness of RPLND.

9.5 PC-RPLND After Salvage Chemotherapy or Previous

Retroperitoneal Surgery

Patients who have undergone salvage chemotherapy, prior to primary or

PC-RPLND, those judged to be unresectable and those with disease progression
prior to retroperitoneal surgery are at high risk for both a poor therapeutic out-
come and an increased frequency of surgery-associated complications. The pres-
ence of anyone of these poor prognostic parameters increases the risk of relapse
from 12 to 45 %.
Repeat RPLND itself represents a poor risk factor associated with a significantly
lower 5-year survival rate of only 55 % as compared to 86 % in the group of patients
undergoing adequate PC-RPLND [15–17]. Whereas the cure rate for those with mature
teratoma only approaches 100 %, it decreases significantly to 44 and 20 % in the pres-
ence of viable cancer and teratoma with malignant transformation, respectively.

9.6 Desperation PC-RPLND

According to the data of various groups, the 5-year overall survival is 54 to 67 % so

that surgery might be indicated in well-selected subset cohort of patients [18, 19].
Increasing preoperative ß-hCG, elevated AFP, redo RPLND and incomplete resec-
tion have been identified as negative risk factors associated with a poor survival.
Despite elevated serum tumour markers, about 45–50 % of all patients harbour
9 Postchemotherapy Retroperitoneal Lymph Node Dissection 97

mature teratoma or necrosis/fibrosis in the surgical specimen resulting in a high cure

rate. If patients undergo desperation surgery, all residual masses should be com-
pletely resected; it will be necessary to resect adjacent visceral and vascular struc-
tures in 25–30 % of the cases.

References
1. Oldenburg J, Fosså SD, Nuver J, Heidenreich A, Schmoll HJ, Bokemeyer C, Horwich A,
Beyer J, Kataja V, ESMO Guidelines Working Group. Testicular seminoma and non- semi-
noma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol.
2013;24 Suppl 6:vi125–32.
2. Daneshmand S, Albers P, Fosså SD, Heidenreich A, Kollmannsberger C, Krege S, Nichols C,
Oldenburg J, Wood L. Contemporary management of postchemotherapy testis cancer. Eur
Urol. 2012;62(5):867–76.
3. Heidenreich A. Residual tumor resection following inductive chemotherapy in advanced tes-
ticular cancer. Eur Urol. 2007;51:299–301.
4. Kollmannsberger C, Daneshmand S, So A, Chi KN, Murray N, Moore C, Hayes-Lattin B,
Nichols C. Management of disseminated nonseminomatous germ cell tumors with risk-based
chemotherapy followed by response-guided postchemotherapy surgery. J Clin Oncol.
2010;28(4):537–42.
5. Ehrlich Y, Brames MJ, Beck SD, Foster RS, Einhorn LH. Long-term follow-up of Cisplatin
combination chemotherapy in patients with disseminated nonseminomatous germ cell tumors:
is a postchemotherapy retroperitoneal lymph node dissection needed after complete remis-
sion? J Clin Oncol. 2010;28(4):531–6.
6. Pfister D, Busch J, Winter C, Albers P, Schrader M, Dieckmann KP, Krege S, Schmelz H,
Heidenreich A. Pathohistological findings in patients with nonseminomatous germ cell
tumours who undergo postchemotherapy retroperitoneal lymph node dissection for small
residual lesions. J Urol. 2011;185:e334.
7. Besse B, Grunenwald D, Fléchon A, Caty A, Chevreau C, Culine S, Théodore C, Fizazi
K. Nonseminomatous germ cell tumors: assessing the need for postchemotherapy contralateral
pulmonary resection in patients with ipsilateral complete necrosis. J Thorac Cardiovasc Surg.
2009;137(2):448–52.
8. Schirren J, Trainer S, Eberlein M, Lorch A, Beyer J, Bölükbas S. The role of residual tumor
resection in the management of nonseminomatous germ cell cancer of testicular origin. Thorac
Cardiovasc Surg. 2012;60(6):405–12.
9. Jacobsen NE, Beck SD, Jacobson LE, Bihrle R, Einhorn LH, Foster RS. Is retroperitoneal
histology predictive of liver histology at concurrent post-chemotherapy retroperitoneal lymph
node dissection and hepatic resection? J Urol. 2010;184(3):949–53.
10. Winter C, Pfister D, Busch J, Bingöl C, Ranft U, Schrader M, Dieckmann KP, Heidenreich A,
Albers P. Residual tumor size and IGCCCG risk classification predict additional vascular pro-
cedures in patients with germ cell tumors and residual tumor resection: a multicenter analysis
of the German Testicular Cancer Study Group. Eur Urol. 2012;61(2):403–9.
11. Hendry WF, Norman AR, Dearnaley DP, Fisher C, Nicholls J, Huddart RA, Horwich
A. Metastatic nonseminomatous germ cell tumors of the testis: results of elective and salvage
surgery for patients with residual retroperitoneal masses. Cancer. 2002;94:1668–76.
12. Beck SD, Foster RS, Bihrle R, Donohue JP, Einhorn LH. Is full bilateral retroperitoneal lymph
node dissection always necessary for postchemotherapy residual tumor ? Cancer.
2007;110:1235–40.
13. Heidenreich A, Pfister D, Witthuhn R, Thüer D, Albers P. Postchemotherapy retroperitoneal
lymph node dissection in advanced testicular cancer: radical or modified template resection.
Eur Urol. 2009;55(1):217–24.
98 A. Heidenreich

14. Vallier C, Savoie PH, Delpero JR, Bladou F, Gravis G, Salem N, Rossi D, Walz J. External
validation of the Heidenreich criteria for patient selection for unilateral or bilateral retroperito-
neal lymph node dissection for post-chemotherapy residual masses of testicular cancer. World
J Urol. 2014;32(6):1573–8.
15. Heidenreich A, Ohlmann C, Hegele A, Beyer J. Repeat retroperitoneal lymphadenectomy in
advanced testicular cancer. Eur Urol. 2005;47(1):64–71.
16. McKiernan JM, Motzer RJ, Bajorin DF, Bacik J, Bosl GJ, Sheinfeld J. Reoperative retroperi-
toneal surgery for nonseminomatous germ cell tumor: clinical presentation, patterns of recur-
rence, and outcome. Urology. 2003;62(4):732–6.
17. Sexton WJ, Wood CG, Kim R, Pisters LL. Repeat retroperitoneal lymph node dissection for
metastatic testis cancer. J Urol. 2003;169(4):1353–6.
18. Albers P, Ganz A, Hannig E, Miersch WD, Müller SC. Salvage surgery of chemorefractory
germ cell tumors with elevated tumor markers. J Urol. 2000;164(2):381–4.
19. Beck SD, Foster RS, Bihrle R, Einhorn LH, Donohue JP. Outcome analysis for patients with
elevated serum tumor markers at postchemotherapy retroperitoneal lymph node dissection. J
Clin Oncol. 2005;23(25):6149–56.
What Are the Recent Recommendations
for Follow-Up in Testicular Cancer? 10
Richard Cathomas and Michael Hartmann

Contents
10.1 Introduction .................................................................................................................. 100
10.2 Modalities of Follow-Up .............................................................................................. 101
10.2.1 General Recommendations............................................................................. 101
10.2.2 Choice and Extent of Imaging Modality ........................................................ 102
10.2.3 Ultrasound of the Remaining Testis ............................................................... 103
10.2.4 Follow-Up for Long-Term Toxicity................................................................ 104
10.3 Risks Associated with Ionizing Radiation ................................................................... 104
10.4 Active Surveillance for Stage I Testis Cancer .............................................................. 106
10.4.1 Active Surveillance for Patients with Seminomatous
Germ Cell Tumor............................................................................................ 106
10.4.2 Active Surveillance for Patients with
Nonseminomatous Germ Cell Tumor............................................................. 107
10.5 Follow-Up After Adjuvant or Curative Treatment for
Advanced Stage Testis Cancer ..................................................................................... 108
10.6 Conclusions .................................................................................................................. 110
References ............................................................................................................................... 110

Conflict of interest: The authors have no conflict of interest to declare.

R. Cathomas, MD (*)
Department of Internal Medicine/ Section Oncology, Kantonsspital Graubünden,
Loestrasse 170, Chur CH-7000, Switzerland
e-mail: [email protected]
M. Hartmann, MD (*)
Department of Oncology/ Interdisciplinary Testis Cancer Unit,
University Hospital Hamburg-Eppendorf, Hamburg GER-20246, Germany
e-mail: [email protected]

© Springer International Publishing Switzerland 2015 99

S. Krege (ed.), Diagnosis and Management of Testicular Cancer: The European
Point of View, DOI 10.1007/978-3-319-17467-9_10
100 R. Cathomas and M. Hartmann

10.1 Introduction

The follow-up of patients with testicular cancer, either in an active surveillance

program for stage I patients or after successful initial treatment (adjuvant therapy or
curative treatment of advanced disease), is an important part of the management of
this disease. The primary aim of follow-up is the timely diagnosis of recurrent dis-
ease in order to be able to treat the patient with curative intent with the least aggres-
sive therapy [1]. An adequate follow-up relies on the profound knowledge about
testicular cancer with regard to histology, stage, primary treatment, and treatment
success. The follow-up has to be tailored to each individual patient, and the sched-
ule has to be acceptable for the patient, the physician, as well as the health-care
system [2]. The interval of follow-up visits and the tests to be performed at each
visit depend on the risk of relapse in general and on the likely site of relapse in par-
ticular [2, 3].
Very few prospective and even less randomized data are available regarding the
implication of different follow-up schedules and the respective use of imaging and
tumor markers. All published guidelines regarding follow-up therefore rely on
information from case series (mainly retrospective with some notable exception
such as the data from the SWENOTECA group) or therapeutic trials. For many
years, the recommendations for follow-up of testis cancer patients varied widely
depending on the faculty and the continent where the guidelines were published
(urology vs. medical oncology and Europe vs. North America). Most recommenda-
tions mandated tight schedules with extensive imaging including multiple computed
tomography (CT) scans [4, 5]. More recently, the risk of ionizing radiation associ-
ated with repeated CT scanning has been recognized [6]. While there still is no
international consensus available, most guidelines have reduced the number of vis-
its and more importantly also the number of CT scans over the past few years. This
applies to the recommendations of the European Association of Urology (EAU) [7]
as well as the European Society of Medical Oncology (ESMO) [8] and to some
lesser extent also to the US-based NCCN guidelines [9].
After 5 years, the primary goal of follow-up shifts from the diagnosis of recur-
rence to an early identification and treatment of late side effects of the cancer diag-
nosis and treatment including lifestyle counseling [10]. The long-term side effects
of chemotherapy and radiotherapy include but are not limited to hypogonadism,
metabolic syndrome, and cardiovascular disease as well as secondary malignancies
[10–13]. Especially patients who underwent chemotherapy as well as radiotherapy
have an excessive risk for cardiovascular events and secondary tumors [14].
Moreover, psychological and social support may be required over time. If neces-
sary, the patient should be referred for special counseling to improve psychosocial
health and maintain personal integrity and working ability [15].
Based on these recent guidelines, it can be concluded that some progress has
been made and a general consensus has been reached in the sense that experts in the
field agree to the following [7–9]: the frequency of follow-up and the use of imaging
modalities should be based on the likelihood of recurrence as well as recurrence
pattern, and patients can be grouped into different risk categories. Table 10.1 sum-
marizes the possible clinical situations according to histology, stage, and treatment
10 What Are the Recent Recommendations for Follow-Up in Testicular Cancer? 101

Table 10.1 Overview of relapse rate depending on initial stage, histology, and treatment
Relapse
Relapse rate Main area
Histology Initial stage Therapy rate (%) >2 years of relapse Reference
Seminoma I Surveillance 12–31 3–5 % Abdomen [16–18]
1%
>3 years
Seminoma I Adj. carboplatin 5 1% Abdomen [19, 20]
Seminoma I Adj. RT 20 Gy 4 1% Outside [21]
RT field
Seminoma IIA/B RT 30/36Gy 5–15 2% Outside [22]
RT field
Seminoma IIC–III, 3xBEP/4xEP 8–12 <2 % Abdomen, [23, 24]
good lung
prognosis
Nonseminoma I, low risk Surveillance 15 1% Abdomen, [17, 25]
lung
Nonseminoma I, high risk Surveillance 45–50 <2 % Abdomen, [17]
lung
Nonseminoma I Adj. RPLND 8–10 <2 % Lung [26]
Nonseminoma I, high risk Adj. 1xBEP 3–4 <1 % Abdomen, [27]
lung
Nonseminoma IIA–III, 3xBEP/4xEP 8–12 <2 % Abdomen, [23, 24]
good lung
prognosis

together with the respective risk of recurrence. The broadest distinction to be made
is between patients with stage I germ cell tumors treated with active surveillance
and all other patients that either received adjuvant treatment for stage I or curative
treatment for good-prognosis advanced stage.
It is important to note that patients diagnosed with either intermediate- or poor-
prognosis disease according to IGCCCG [28] or patients who did never reach a
complete remission are not eligible for standard follow-up as will be outlined in the
following paragraphs. These patients should receive individualized care under the
lead of an experienced high-volume center.
This chapter reviews the recent recommendations for the follow-up of patients
with testicular cancer and discusses the risk associated with ionizing radiation.

10.2 Modalities of Follow-Up

10.2.1 General Recommendations

The follow-up of testis cancer patients should be performed by a physician who has
profound knowledge of this type of rare cancer and experience in its treatment.
A complete medical history and examination is the cornerstone of each follow-
up visit. Changes in weight, increased fatigue, new onset of pain (especially in the
abdomen or back), cough, dyspnea, as well as erectile function and libido should be
102 R. Cathomas and M. Hartmann

assessed specifically [10, 29, 30]. The clinical exam includes measurement of height
and weight (or waist circumference), blood pressure, auscultation of the lungs, pal-
pation of supra- and infradiaphragmal regional lymph node regions (cervical, supra-
clavicular, axillary, inguinal), and palpation of the remaining testis [2, 29, 30].
Measurement of the serum tumor markers AFP (alpha-fetoprotein), β-hCG
(β-human chorionic gonadotropin), and LDH (lactate dehydrogenase) is central in
the follow-up of testis cancer patients [2, 29, 30]. If possible, the tumor markers
should always be checked in the same qualified laboratory. AFP is only elevated in
patients with nonseminomatous germ cell tumors, whereas β-hCG can also be
increased in up to 20 % of patients with seminoma [30]. The initial presentation
does not predict whether the patient will have elevated markers at relapse: initially,
marker-positive tumors can have a marker-negative relapse and vice versa [30].
Therefore, to control all tumor markers is the standard of care also in patients with
marker-negative tumors at diagnosis. The role of LDH in the follow-up schedule is
debatable. It has limited sensitivity and specificity, and a high rate of false-positive
tests is found. However, some publications show that it can contribute to identify
recurrence especially in advanced cases [31]. Cautious interpretation of LDH is
however necessary.

10.2.2 Choice and Extent of Imaging Modality

There is general consensus that all patients have to be staged with a CT scan of the
thorax, abdomen, and pelvis at the initial diagnosis of testis cancer [7–9, 30]. In case
of poor-prognosis metastatic disease or presence of neurological symptoms, a mag-
netic resonance imaging (MRI) of the brain should be performed [30]. A bone scin-
tigraphy is reasonable in case of specific bone pain, but bone metastases are very
rare.
In contrast to the consensus at initial diagnosis, the choice, the extent, and the
frequency of imaging in the follow-up setting are less clearly defined. For many
years, repeated CT scanning with up to >20 CT scans during follow-up of a testis
cancer patient was standard practice. Over the recent years, the risks of ionizing
radiation associated with CT scans have been recognized and have changed the
approach and attitude toward the use of CT scans in the follow-up setting. The risks
of ionizing radiation will be discussed in Sect. 10.2.3.
Only very few publications have focused on the modalities of imaging in the
follow-up of testis cancer. Retrospective studies looked at the usefulness of regular
CT scans of the pelvis or the chest [32, 33], and some studies evaluated the neces-
sity of regular chest x-rays [34, 35]. With regard to CT of the pelvis, only a small
group of patients is at increased risk of recurrence in the pelvis only: this includes
patients with bulky abdominal disease (>5 cm), previous history of maldescent of
the testis or orchidopexy, history of previous scrotal surgery, and invasion of the
carcinoma into the tunica vaginalis of the testis [32]. Moreover, patients who have
been treated for seminoma stage I with para-aortic radiotherapy can present with
isolated pelvic recurrence. Only in these particular cases should a CT of the pelvis
10 What Are the Recent Recommendations for Follow-Up in Testicular Cancer? 103

be included in the follow-up schedule [32]. Regarding the CT of the thorax, a retro-
spective analysis in patients with stage I nonseminoma revealed that all recurrences
were diagnosed with elevated tumor markers, abdominal disease, or lesions visible
on a conventional chest x-ray [33]. It is generally accepted that regular CT of the
thorax is not necessary in the follow-up of testis cancer patients. The necessity of
regular chest x-rays has also been debated in some publications [34, 35]. In contrast
to a chest CT, the conventional chest x-ray (especially if performed only as postero-
anterior image) applies a very low amount of ionizing radiation (0.02 mSv), is eas-
ily performed, and is cheap. Based on these considerations, the use of regular chest
x-rays has been reduced in recent recommendations but not abandoned. There is
clear consensus that positron emission tomography (PET) CT is not indicated in the
follow-up of testis cancer patients and should not be used.
Instead of using CT for abdominal imaging, magnetic resonance imaging (MRI)
of the abdomen can be a suitable replacement. Some experts, namely, the
SWENOTECA group, have replaced abdominal CT by abdominal MRI [36]. MRI
does not carry any risk of ionizing radiation and can be performed in patients with
allergic reactions to iodine contrast agents used with CT scans. Limited resources
and the lack of experience in interpreting the MRI scan currently restrict its use. In
experienced centers with enough resources and expertise, the abdominal MRI can
replace the CT.
The German Testicular Cancer Study Group (GTCSG) included the use of
abdominal ultrasound in addition to the recommended scanning with CT in their
recommendations [2, 3]. Abdominal ultrasound is highly dependent on the experi-
ence of the examiner and the anatomy and preparation of the patient. Ultrasound is
therefore not recommended in case of obese patients or if performed by not appro-
priately trained physicians. In a small study, ultrasound appeared to have similar
sensitivity and specificity for the detection of retroperitoneal metastases in patients
with testicular cancer when compared to a CT of the abdomen [37]. The ultrasound
should not replace all CT scans planned in the schedule but can be helpful in the
long-term follow-up after 5 years to detect slow-growing teratoma and in cases
where the patient requests a more intense follow-up schedule.

10.2.3 Ultrasound of the Remaining Testis

The use of regular ultrasound of the remaining testis is a subject of controversial

discussion. Patients under the age of 40 years with a low testis volume (<12 ml) are
at higher risk of developing a contralateral tumor. Biopsy should be offered in these
cases [30]. In case of contralateral testis biopsy without evidence of carcinoma in
situ (CIS, also known as intratubular germ cell neoplasia) or after radiotherapy for
CIS, the risk of a contralateral tumor is much lower but not eliminated. Some guide-
lines recommend an annual ultrasound of the testis for 10 years, especially if no
biopsy was performed [2]. Regular self-examination by the patient should be highly
encouraged, and the remaining testis should be palpated by the physician at every
visit. An ultrasound should be performed in case of any suspicious findings.
104 R. Cathomas and M. Hartmann

10.2.4 Follow-Up for Long-Term Toxicity

Patients who have been cured with chemotherapy or radiotherapy may develop late
toxicity. This includes cardiovascular disease, metabolic syndrome (arterial hyper-
tension, impaired glucose tolerance, hyperlipidemia, obesity), impaired renal func-
tion, ototoxicity, neuropathy, Reynaud’s phenomenon, as well as hypogonadism and
secondary malignancies [10–14]. Regular checkup of blood pressure, weight, body
mass index, or waist circumference as well as blood lipids (total cholesterol, LDL-
cholesterol, triglycerides) is recommended at baseline and annually afterward.
Patients should be followed for hormonal imbalances (total testosterone, LH, FSH)
1 year after diagnosis and then regularly every 1–2 years. In case of pathological
findings or a suggestive history of hypogonadism (e.g., missing morning erection),
the hormonal status should be determined repeatedly on an individual basis. In case
of symptomatic testosterone deficiency, substitution has to be discussed.
Testis cancer survivors should regularly be advised to adapt to a healthier life-
style in order to control additional risk factors (e.g., nonsmoking, weight control,
regular physical exercise).
An extensive review of the current literature on long-term toxicities and survi-
vorship issues can be found in Chap. 11.

10.3 Risks Associated with Ionizing Radiation

In the recent decades, a rapid increase in the use of medical imaging with ionizing
radiation has been noted. Over the last 30 years, the annual per capita effective
dose has increased about sixfold (from 0.5 mSv in 1980 to 3.0 mSv in 2006) [38].
The radiation dose from medical sources now exceeds the natural background
radiation (background radiation approximately 2.4 mSv). Computed tomography
and nuclear imaging are responsible for over 75 % of ionizing radiation adminis-
tered [39]. Of these, CT scans of the abdomen, the pelvis, and the chest account
for 18.3, 12.2, and 7.5 % of the total effective dose from all medicinal imaging
procedures, respectively. The effective dose administered per exam differs from
one procedure to another [39, 40]. Typically, the average effective dose from an
abdominal CT is around 8 mSv per exam which is comparable to the natural back-
ground radiation for 3 years [40]. Table 10.2 shows the average effective doses for

Table 10.2 Effective doses from various CT scans in mSv

Values reported in literature
Examination Average effective dose (mSv) (mSv)
Head 2 0.9–4.0
Chest 7 4.0–18.0
Abdomen 8 3.5–25.0
Pelvis 6 3.3–10.0
Adapted from Ref. [40]
10 What Are the Recent Recommendations for Follow-Up in Testicular Cancer? 105

different CT scans. In comparison, a chest x-ray (posteroanterior) applies only

0.02 mSv of ionizing radiation [39]. It is important to note that there is inhomo-
geneous distribution in different organs and that, hence, the amount of radiation
and risk for certain organs can differ [6, 41]. With the evolution of more modern
CT scanners, the average effective dose per examination has increased over the
last decades [42]. On the other hand, radiation reduction strategies have been
tested in recent years including the use of lower radiation dose, lower voltage, and
smaller volumes. Some of these improvements have however not been imple-
mented in all radiology departments and others remain experimental. Therefore,
the mean effective dose for each type of CT can vary considerably (up to 13-fold
higher doses) at different sites [43].
The excessive risks of radiation exposure due to a single or repeated computed
tomography (CT) have been calculated [6, 41]. These calculations are based on
stochastic risk calculations representing the statistical risk of genetic damage
occurring with radiation exposure. The stochastic risk is calculated from informa-
tion based on cohort studies from atomic-bomb survivors [44]. The radiation expo-
sure of each CT carries a small carcinogenic risk which is higher the younger the
patient is. Moreover, repeated CTs lead to an increased cumulative risk [6].
Calculations have been published showing that a single CT of the abdomen per-
formed in a 20-year-old male can lead to a radiation-induced cancer in 1 of 660
cases [43]. For one chest CT, this number is 1 in 1,020 men [43]. While these cal-
culations are discussed controversially, the FDA clearly states that there is a life-
time risk of cancer attributed to ionizing radiation with a particular risk for younger
patients [45].
A research group at Stanford University estimated the risk of developing can-
cer due to ionizing radiation from imaging for patients with stage I testis cancer
undergoing surveillance according to the NCCN protocol with up to 16 scans:
the lifetime cancer risk induced by CT scans for follow-up purposes ranged from
1.2 % in a 40-year- old to 1.9 % in an 18-year-old patient and increased to 2.6 %
if chest CT was included [46]. These numbers outweigh the benefit of surveil-
lance where the overall survival from testis cancer is nearly 100 %. In contrast,
a Canadian group looked at the association of secondary malignancies in patients
with testis cancer who had a median of 10 abdominopelvic CT scans during their
follow-up [47]. They could not find any increased risk for second abdominopel-
vic malignancies. However, this study has been heavily criticized due to the
fact that the medium follow-up was only 11 years, while it is clearly recognized
that radiation-induced malignancies only develop 30–40 years after exposure
[13, 14].
Minimizing the amount of ionizing radiation remains an important goal in the
management of patients with testis cancer who are often young and therefore more
vulnerable. Methods to reduce the radiation burden include technical improve-
ments, reducing the scanned volume, reducing the frequency of scanning, and
moreover a switch from CT scans to other imaging modalities such as MRI or
ultrasound.
106 R. Cathomas and M. Hartmann

10.4 Active Surveillance for Stage I Testis Cancer

Most patients with testicular cancer are diagnosed with stage I disease localized in
the testis: 80 % of seminoma and 60 % of nonseminoma patients present with stage
I [48]. The optimal management of stage I disease is undergoing constant change:
In recent years, there has been a shift toward increased use of active surveillance in
stage I disease for seminoma and nonseminoma [49]. Several reports have shown
that active surveillance is safe for patients and associated with excellent outcomes
[16, 17, 25, 36]. Data from the United States report that active surveillance is now
the preferred mode of treatment for stage I testis cancer [50]. The basis for success-
ful active surveillance is early detection of recurrence while minimizing ionizing
radiation and overall treatment burden. The optimal adherence of the patient and the
physician to a proposed schedule is essential for the success of active surveillance.
Because seminomatous and nonseminomatous stage I germ cell tumors differ
considerably with regard to time and site of recurrence, these two entities will be
discussed separately in the following.

10.4.1 Active Surveillance for Patients with Seminomatous

Germ Cell Tumor

For stage I seminomas, the recurrence risk after orchiectomy is around 15–20 %.
Adjuvant treatment with para-aortic radiotherapy or chemotherapy with single-dose
carboplatin reduces the risk of recurrence to 4–5 % [19–21]. Active surveillance and
adjuvant treatment are equal treatment options regarding overall outcome according to
published guidelines [7–9]. The advantage of active surveillance lies in the fact that
80–85 % of patients can avoid unnecessary treatment. There is an ongoing debate as to
whether seminoma stage I patients can be grouped into different risk categories: a ret-
rospective analysis suggested that patients with tumors >4 cm in size and with invasion
of the rete testis had a significantly increased relapse rate of up to 32 % [18]. However,
a prospective analysis from the same group as well as results from the SWENOTECA
group could not confirm these risk categories [36, 51]. Large prospective cohorts of
seminoma stage I patients treated with active surveillance have been reported [16, 36]:
they show that 75 % of patients relapse within 2 years, but a further 15–20 % relapse in
year 3. With regard to the whole population, < 1 % of patients relapse after 3 years [16].
The large majority of relapses occur in the abdomen and are detected on abdominal
imaging; a minority of patients are primarily diagnosed with elevated tumor markers.
Due to this pattern of recurrence, some authors have suggested that regular measure-
ment of tumor markers or chest x-rays is unnecessary in active surveillance of semi-
noma [34, 52]. All recommendations however continue to advise regular use of tumor
markers and x-rays, also in an attempt to maintain patient adherence. The major con-
troversy in stage I seminoma concerns the interval and modality of abdominal imaging.
A trial addressing this very important question is being performed in the United
Kingdom and will soon complete accrual (TRISST) [53]: in this 4-arm trial, 3 vs. 7
scans and CT vs. MRI are evaluated. Currently, most groups advise 4–6 CT scans
within the first 3 years. Further regular imaging after 3 years is debated due to the very
10 What Are the Recent Recommendations for Follow-Up in Testicular Cancer? 107

Table 10.3 Comparison of different recommendations for active surveillance in seminomatous

germ cell tumor stage I
Year 1 Year 2 Years 3–5
N tests per year N tests per year N tests per year
Modality EAU NCCN GTCSG EAU NCCN GTCSG EAU NCCN GTCSG
Exam 3 3–4 4 3 3–4 4 1 1–2a 2
Markers 3 3–4 4 3 3–4 4 1 1–2a 2
CXR 2 0 2 2 0 2 0 0 1–2
CT abdo 2 2 2 2 2 2 1 1–2a 0b
CXR chest x-ray, CT abdo CT abdomen, EAU European Association of Urology 2011 (Ref. [7]),
NCCN National Comprehensive Cancer Network 2014 (Ref. [9]), GTCSG German Testis Cancer
Study Group 2011 (Refs. [2, 3])
a
Lower number applies to year 5
b
No regular CT but ultrasound of the abdomen twice in year 3 and then annually

low risk of recurrence. Table 10.3 lists the recommendations of three different organi-
zations for patients with seminoma stage I undergoing active surveillance.

10.4.2 Active Surveillance for Patients with Nonseminomatous

Germ Cell Tumor

Stage I nonseminomatous germ cell tumors can be divided into a low-risk group with
a recurrence risk of approximately 15 % and a high-risk group with a recurrence risk
of 40–50 %. This distinction is made by the presence of lymphovascular invasion
(LVI) in the primary tumor which has become the most important and widely
accepted risk factor for relapse [54, 55]. A risk-adapted treatment strategy has been
proposed for nonseminoma stage I: surveillance is recommended for low-risk (LVI
negative) stage, whereas high-risk patients (LVI positive) are offered adjuvant che-
motherapy with BEP (bleomycine, etoposide, cisplatin) [7–9, 30]. Recent data show
that one cycle of BEP is sufficient with a risk reduction from 50 % to approximately
3–4 % [27]. Active surveillance remains an option for high-risk patients who are not
willing to undergo adjuvant chemotherapy [30]. Active surveillance can spare unnec-
essary chemotherapy to a significant proportion of patients. However, careful follow-
up is needed to ensure that recurrence is diagnosed while the patient is still in a
good-prognosis group situation in order to maintain the excellent outcome of nearly
100 % disease-specific survival for the whole population. Several large reports are
available on cohorts of nonseminoma stage I treated with active surveillance: they
show that 90–95 % of relapses occur within 2 years after diagnosis [17, 25]. With
regard to the whole population, less than 1 % of patients have a relapse after 3 years.
Due to different biology, relapse of nonseminoma develops more rapidly than semi-
noma such that shorter intervals are required. Around 60 % of cases are primarily
diagnosed due to elevated tumor markers; however, 20–25 % have no elevated tumor
markers so that imaging remains essential [17].
A prospective randomized trial looked at the frequency of CT scans performed
during active surveillance for nonseminoma stage I [56]. It showed that 2 CT scans
108 R. Cathomas and M. Hartmann

Table 10.4 Comparison of different recommendations for active surveillance in nonseminoma-

tous germ cell tumor stage I
Year 1 Year 2 Years 3–5
N tests per year N tests per year N tests per year
Modality EAU NCCN GTCSG EAU NCCN GTCSG EAU NCCN GTCSG
Exam 4 6–12 6 4 6 6 1 2–4b 2–4b
Markers 4 6–12 6 4 6 6 1 2–4b 2–4b
CXR 2 6–12 6 0 6 6 0 2–4b 2–4b
CT abdo 2a 3–4 2c 0 2–3 0d 0 1–2b 0d
CXR Chest x-ray, CT abdo CT abdomen, EAU European Association of Urology 2011 (Ref. [7]),
NCCN National Comprehensive Cancer Network 2014 (Ref. [9]), GTCSG German Testis Cancer
Study Group 2011 (Refs. [2, 3])
a
CT at 3 and 12 months (in patients with low-risk nonseminoma stage I)
b
Higher number applies to year 3
c
If low risk, CT at 3 and 12 months; if high risk, 5 CTs in the first two years
d
No regular CT but ultrasound of the abdomen annually

were not inferior to 5 CT scans performed within the first 2 years. This trial has been
criticized for being underpowered and including only 10 % of high-risk patients.
However, for the low-risk group, it clearly demonstrated that 2 CT scans (at 3 and
12 months) are sufficient to avoid an excess of patients relapsing with metastatic
disease in intermediate- or poor-risk group according to IGCCCG classification.
Some guidelines therefore recommend only 2 CT scans for patients with low-risk
nonseminoma. Due to the very low risk of recurrence, imaging after 2 years can be
safely omitted as proposed by most guidelines. Table 10.4 lists the recommenda-
tions of different organizations for the follow-up of patients with nonseminomatous
germ cell tumor on active surveillance.

10.5 Follow-Up After Adjuvant or Curative Treatment

for Advanced Stage Testis Cancer

It is important to note that only patients after adjuvant treatment for stage I or patients
with good-prognosis metastatic disease (according to IGCCCG) and a complete remis-
sion after treatment will be discussed in the following. Complete remission in nonsemi-
noma is defined as no evidence of disease after chemotherapy and eventual additional
resection of residual disease. Resection of residual disease in nonseminoma is recom-
mended for lesions >1 cm after chemotherapy. For seminoma, residual masses up to
3 cm or in case of masses > 3 cm with a negative PET/CT scan (performed a minimum
of 8 weeks post-chemotherapy) are considered as remission, and these patients can be
followed according to the outlined schedules. All patients with intermediate- or high-
risk metastatic disease according to IGCCCG classification or patients with refractory
disease should undergo individual follow-up at specialized centers.
As shown in Table 10.1, the risk of relapse and the main area of relapse in testis
cancer depend on the histology, the initial stage, and the chosen treatment. Generally,
10 What Are the Recent Recommendations for Follow-Up in Testicular Cancer? 109

Table 10.5 Comparison of different recommendations for follow-up after adjuvant treatment or
complete remission for advanced disease
Year 1 Year 2 Years 3–5
N tests per year N tests per year N tests per year
Modality EAU NCCN GTCSG EAU NCCN GTCSG EAU NCCN GTCSG
Exam 4 4–6 4 4 4–6 4 2 1–4d 2
Markers 4 4–6 4 4 4–6 4 2 1–4d 2
CXR 4 4–6 2 4 4–6 2 2 1–4d 1
CT abdo 2 2c 1–2a 2 1–2 1 b
1 0
CXR chest x-ray, CT abdo CT abdomen, EAU European Association of Urology 2011 (Ref. [7]),
NCCN National Comprehensive Cancer Network 2014 (Ref. [9]), GTCSG German Testis Cancer
Study Group 2011 (Refs. [2, 3])
a
2 CTs in year 1 if patient did not receive treatment to the retroperitoneum; include pelvis if para-
aortic RT was performed
b
As clinically indicated
c
No CT of the abdomen after RPLND (applies to nonseminoma); in case of seminoma, CT or PET/
CT is advised as clinically indicated
d
Decreasing intensity each year

the overall risk of relapse after adjuvant therapy or curative treatment is around
5–10 % [19–24, 26, 27]. Two years after treatment, the recurrence risk is reduced to
1–2 %, and hence, the intensity of follow-up can be reduced. The main area of
relapse is the retroperitoneum. However, if patients have received local treatment of
the retroperitoneum such as radiotherapy or retroperitoneal lymph node dissection
(RPLND), recurrences occur mainly outside the retroperitoneum. This should be
taken into account when planning follow-up for an individual patient.
Table 10.5 summarizes the proposed follow-up schedules for patients after adju-
vant treatment or curative treatment of advanced disease. Due to the similarity of the
relapse rate and the main site of relapse, this simple follow-up schedule can serve as
backbone for all these different situations. In view of the very low risk of recurrence
after 2 years, regular imaging with CT scans can be omitted beyond this timepoint.
The impact of chest x-rays has been debated [35], but for reasons outlined above,
most guidelines continue to recommend regular chest x-rays though at a low rate.
Some specific points have to be discussed:

• In patients with seminoma treated with radiotherapy, relapses occur outside (or
just at the edge) of the radiation field. The main site of recurrence is therefore in
the pelvis in case of para-aortic RT [21] and in the lungs, mediastinum, and neck
in the case of dogleg radiotherapy [22]. CT scan of these areas has to be consid-
ered in these cases.
• Patients who have undergone a RPLND have a very low risk of recurrence in the
retroperitoneum, but relapses can occur at the edge of the operating field and in
the lungs and mediastinum [26]. After RPLND, the imaging of the retroperito-
neum can be reduced.
• Patients diagnosed with mature teratoma or viable tumor in the RPLND histology
should undergo regular imaging of the retroperitoneum on an individual basis.
110 R. Cathomas and M. Hartmann

Follow-up for early detection of relapse is mandated for 5 years. After this time,
the risk of relapse is <1 %, and according to most guidelines, follow-up with tumor
markers or imaging can be omitted. It is however recommended that patients are
controlled annually for detection of late side effects of treatment on a long-term
basis or for at least 10 years [1]. Moreover, the patient should be evaluated for social
or psychological support, and lifestyle recommendations should be addressed.

10.6 Conclusions

The follow-up of patients with testicular cancer is an important part in the manage-
ment of these patients. Over the last few years, improved follow-up schedules have
been developed in order to increase adherence of both the patients and the treating
physicians. The risks of ionizing radiation have been taken into account with much
reduced frequency of CT scans while maintaining safety of the follow-up. With the
help of these proposed simplified schedules, it should be possible to improve the qual-
ity of surveillance for testis cancer patients since community-based studies showed
poor acceptance of the previous more intense and complicated schedules [57]. The
main factor for a successful follow-up remains a good patient-physician relationship,
and the proposed schedules should help to achieve and maintain this goal.

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What Are the Long-Term Toxicities
to Be Controlled and Treated? 11
J. Oldenburg, H.S. Haugnes, and S.D. Fosså

Contents
11.1 Introduction .................................................................................................................. 116
11.2 Second Malignant Neoplasms ...................................................................................... 116
11.3 Pulmonary Toxicity ...................................................................................................... 117
11.4 Cardiovascular Disease ................................................................................................ 117
11.5 Raynaud-Like Phenomena ........................................................................................... 118
11.6 Neurotoxicity................................................................................................................ 119
11.7 Ototoxicity ................................................................................................................... 120
11.8 Nephrotoxicity.............................................................................................................. 120
11.9 Hypogonadism ............................................................................................................. 121
11.10 Fatigue .......................................................................................................................... 121
11.11 Implications for Follow-Up.......................................................................................... 122
11.12 Conclusions .................................................................................................................. 122
References ............................................................................................................................... 122

J. Oldenburg, MD, PhD (*)

Department of Oncology, Akershus University Hospital,
Lorenskog and Oslo University Hospital, Lørenskog, Norway
e-mail: [email protected]
H.S. Haugnes
Department of Oncology, University Hospital of North Norway, Tromso, Norway
S.D. Fosså
Department of Oncology, Oslo University Hospital, Oslo, Norway

© Springer International Publishing Switzerland 2015 115

S. Krege (ed.), Diagnosis and Management of Testicular Cancer: The European
Point of View, DOI 10.1007/978-3-319-17467-9_11
116 J. Oldenburg et al.

11.1 Introduction

The combination of young age at diagnosis, high survival rate, and rising inci-
dence increases the cohort of TC survivors (TCS). Although TCS have an esti-
mated normal life expectancy, mortality rates among TCS may exceed rates
among the general population [1, 2]. In addition to an increased risk of dying
from recurrent TC or a second cancer, TCS have a 6 % increased risk of mortality
from non-cancer causes, including infections, cardiovascular disease (CVD), and
respiratory disease after cisplatin-based chemotherapy compared with the gen-
eral population [2].
The aim of this review is to present common long-term toxicities and identify
risk factors. We will focus on risk factors which should be controlled and are ame-
nable to interventions.

11.2 Second Malignant Neoplasms

Second malignant neoplasms (SMN) represent, in addition to CVD, the most seri-
ous toxicities after cancer treatment. It is relatively well established that TCS have
a significantly increased risk of a second cancer. Available data estimate a 1.7- to
3.5-fold increased risk compared with the general population [3–10].
Due to common etiologic factors, about 3–5 % of TC patients develop a contra-
lateral TC [11], but this is not regarded as a late effect from treatment and is not
further commented herein.
Second hematological malignancies, of which acute leukemia is the most com-
mon, generally occur within 10 years after the initial cancer treatment, and increased
risks are associated with both RT and chemotherapy [12, 13]. In particular, high
etoposide doses confer an increased risk for acute myeloid leukemia, although the
absolute risk is small. The observed/expected (O/E) ratio for leukemia in TCSs was
2.6 (95 % CI 2.1–3.2) in a large study by Howard et al. [13].
Treatment-induced solid SMN on the other hand generally occur first after more
than 10 years. The risk for solid SMN remains significantly elevated for at least
35 years, and the cumulative risk at any given attained age increases with decreasing
age at the TC diagnosis and with increasing follow-up time [6]. The increased risk
has been attributed to both RT and chemotherapy [3, 4, 6–8]. RT-related SMN are
primarily localized within or close to the RT field (the colon, stomach, pancreas,
bladder, and urinary tract) [4–10, 14] A recent publication by Fung et al. was the
first study to demonstrate a significantly increased risk of SMN after modern-era
chemotherapy for testicular non-seminoma patients treated since 1980, with no
excess risk among patients treated with surgery alone. They found that modern
cisplatin-based chemotherapy was associated with a 40 % increased risk of a solid
SMN [15].
Previous studies evaluating the risk of SMN have not provided details as type of
chemotherapy and cumulative doses. Thus, apart from treatment type, knowledge
regarding individual risks for developing a second malignancy is lacking.
11 What Are the Long-Term Toxicities to Be Controlled and Treated? 117

11.3 Pulmonary Toxicity

Bleomycin-induced pneumonitis (BIP) may occur during or after administration of

chemotherapy [16] and may develop into interstitial pulmonary fibrosis, which in
some cases may be fatal. Multivariate analyses have shown an increased risk of BIP
in patients with reduced renal function (GFR <80 ml/min, HR 3.3), age >40 years (HR
2.3), stage IV disease (HR 2.6), and cumulative bleomycin dose >300,000 IE [17].
Estimates of the current incidence of bleomycin-induced pulmonary fibrosis vary
between 0 and 2 % after up to 270 IE and between 6 and 18 % in patients who received
doses higher than 360 IE [18–21]. While bleomycin is an essential component in treat-
ing intermediate or poor-risk metastatic TC, its role for the treatment of good-risk TC
has been questioned due to concerns about pulmonary toxicity. However, omitting
bleomycin in good-risk TC patients did not significantly reduce pulmonary com-
plaints in 270 good-risk TC patients randomized to either 4 courses of EP or 3 courses
of BEP, with numerically better survival after BEP [22]. Among 1,049 Norwegian
TCS, those treated with large cumulative cisplatin doses and/or pulmonary surgery
had decreased spirometry parameters median 11 years after treatment compared with
men treated with surgery only [23]. Restrictive lung disease was observed in 8 % of
the survivors, with the highest proportion found after high cumulative cisplatin doses
and combined cisplatin/pulmonary surgery. In multivariate analyses including cumu-
lative bleomycin, etoposide, and vinblastine doses, only cisplatin dose (p = 0.007) and
age (p = 0.008) were significantly positively associated with prevalent restrictive lung
disease. Intriguingly, the impact of large cumulative cisplatin doses was equivalent to
the 2–4-fold effect of smoking [23]. Population-based epidemiologic studies have
shown an association between pulmonary function and all-cause mortality and sug-
gest that pulmonary function could be used as a predictor for overall survival [24, 25].
Furthermore, TCSs cured by chemotherapy have a 2.5-fold risk of dying of respi-
ratory disease as compared to the normal population [2].

11.4 Cardiovascular Disease

Mortality from CVD is higher in TCSs than in the general population [1, 2]. An
increased incidence of CVD, both fatal and nonfatal, has been observed in men previ-
ously treated with cisplatin-based chemotherapy in comparison to men treated with
surgery only [26, 27]. Treatment with cisplatin, vinblastine, and bleomycin (CVB)
was significantly associated with a 1.9-fold increased risk of myocardial infarction
(MI), while cisplatin, etoposide, and bleomycin (BEP) gave a nonsignificantly
increased risk for MI at 1.2 in comparison to surgery only treated men [27]. This dif-
ference may, however, rely on a longer observation time of CVB-exposed TCSs as
compared to those who received the contemporary BEP. A recent Norwegian study
reported a significantly increased risk of CAD after contemporary treatment with BEP
in comparison to age-matched controls, but this publication did not report mortality
[28]. Mediastinal irradiation increases the risk of MI nearly fourfold as compared to
surgery only [27]. Several studies have also reported an increased risk of CVD after
118 J. Oldenburg et al.

infradiaphragmatic irradiation [26, 29], but results are conflicting [27]. Coronary
artery disease (CAD) and peripheral atherosclerotic disease as well as stroke are parts
of CVD which is the most common cause of death in the general population [30].
CAD includes myocardial infarction (MI) and angina pectoris, and several risk factors
for CAD have been identified. Of note, the majority of these risk factors are modifi-
able and include smoking, hypertension, obesity, abnormal lipids, diabetes, unhealthy
diet, and inactivity [31]. The mechanisms behind the increased risk of CVD in TCS
may comprise direct endothelial damage by RT and/or chemotherapy and worsening
of common risk factors like those comprising the metabolic syndrome.
Cisplatin-based chemotherapy increases the risks of obesity and hypertension
[26, 32]. In a large Norwegian study, a higher proportion of TCS required antihyper-
tensive medication after chemotherapy with or without RT as compared to those
cured by surgery alone after 20 years of observation time [29]. Diabetes is, with a
prevalence rate at 10 %, more common at 20 years after RT than in healthy controls
or those treated with surgery [29, 31]. Several studies have also reported an increased
risk for hypercholesterolemia after cisplatin-based chemotherapy [10, 33–35], with
reported rates at 67–84 %. The clustering of CVD risk factors into the metabolic
syndrome [36] might be a link between cytotoxic treatment and later development
of CVD. The prevalence of the metabolic syndrome is higher among patients treated
with cisplatin-based chemotherapy than among controls or other treatment groups
[33, 34, 37], with prevalence rates ranging between 17 and 34 % several years after
cisplatin-based chemotherapy [29, 33, 37].
Inflammation and endothelial dysfunction promote the pathogenesis of atheroscle-
rosis [38]. A direct vascular damage from cytotoxic treatment may stimulate the endo-
thelium, possibly ultimately inducing the atherosclerotic process. A Dutch study
reported that the intima-media thickness of the carotid artery as well as plasma levels
of von Willebrand factor (vWF), which is a marker of endothelial function, increased
significantly shortly after cisplatin-based chemotherapy [39]. Both cisplatin and
bleomycin have been reported to induce upregulation of intracellular adhesion
molecule −1 (ICAM-1), tissue-type plasminogen activator (tPA), and plasminogen
activator inhibitor type 1 (PAI-1) in endothelial cells in vitro, suggesting an endothe-
lial activation shortly after chemotherapy administration [40]. In cisplatin-treated
TCSs, the endothelial markers vWF, tPA, and PAI-1 are increased compared with
healthy controls [41]. Further, increased levels of ICAM-1 and circulating endothelial
cells as well as impaired flow-mediated dilatation of the brachial artery after cisplatin-
based chemotherapy compared with chemotherapy-naïve survivors were reported by
Vaughn and coworkers [42]. These findings of endothelial dysfunction may lead to an
accelerated atherosclerotic process, possibly ultimately resulting in CVD.

11.5 Raynaud-Like Phenomena

Chemotherapy-related Raynaud-like phenomena (Fig. 11.1) were reported prior to

the introduction of cisplatin and are usually ascribed to bleomycin [32, 33]. Bolus
infusion of bleomycin as opposed to its continuous infusion was associated with a
higher incidence of Raynaud’s phenomenon, and importantly, all 7 out of 90 TC
11 What Are the Long-Term Toxicities to Be Controlled and Treated? 119

Fig. 11.1 Cold-induced Raynaud phenomenon of the fingers in a cisplatin-treated TCSs

patients with hypertension prior to chemotherapy developed this symptom [34].

Cisplatin is believed to contribute to cold-induced vasospasms as the incidence of
Raynaud’s phenomenon after CVB was approximately twice the rate reported after
vinblastine and bleomycin (41 % vs. 21 %) [35]. Chemotherapy-induced Raynaud’s
phenomenon may be associated with erectile dysfunction [36]. Avoidance of cold
is the most effective management of Raynaud-like phenomena. Norwegian health
authorities reimburse TCSs’ expenses for heat-generating gloves and shoes – and
these remedies appear to be superior to pharmaceutical interventions.

11.6 Neurotoxicity

Determination of neurotoxicity is a complex task and most precisely performed by

neurophysiologic examinations, which are time and cost consuming. A short 6-item
questionnaire, called SCIN (scale for chemotherapy-induced long-term
120 J. Oldenburg et al.

neurotoxicity), covers paresthesias and Raynaud’s phenomena in the hands and feet,
as well as ototoxicity, i.e., tinnitus and hearing impairment, and might help to quantify
these complications [37]. Using this scale, paresthesias were stated by 29 % of
cisplatin-treated TCSs as opposed to 10 % after surgery only [38]. Application of five
or more cycles increases the proportion of those bothered by paresthesias to 46 %. The
observed large interindividual variations of neurotoxicity may partly rely on polymor-
phisms of the detoxifying enzyme glutathione S-transferase P1 (GST-P1) [39].
Platinum is measurable in the serum of TCSs many years after its application, and the
intensity of paresthesias is more strongly associated with these serum levels than with
the cumulative dose of cisplatin [40]. Intriguingly, the association between serum
platinum levels measured 10 years after application was strongly associated with sub-
sequent self-reported paresthesias 20 years after treatment than with concomitantly
reported paresthesias, indicating an ongoing neuronal damage. Unfortunately, the
growing insights into the pathophysiology have not yielded preventive or palliative
treatments. Particularly vulnerable TCSs, who do not benefit sufficiently from anti-
convulsant drugs like pregabalin, may require morphine for pain relief. A Cochrane
Database review concluded that the use of neuroprotective agents, such as acetylcys-
teine, amifostine, calcium and magnesium, diethyldithiocarbamate, glutathione, Org
2766, oxcarbazepine, or vitamin E, could not be recommended since no substance had
prevented or limited neurotoxicity of platinum drugs [41].

11.7 Ototoxicity

Cisplatin-induced ototoxicity is a distinct side effect of cisplatin and presumably

caused by selective damage to the outer hair cells [42]. Cisplatin-induced ototoxicity,
i.e., tinnitus and hearing impairment, shows large interindividual variations [43].
Hearing ability of high frequencies of 4,000 Hz and above is typically affected, and
these changes persist for many years [44]. Some TCS are not very bothered by the
typical loss of high-frequency hearing which is similar to the aging-related presbycu-
sis, since language communication is based on lower frequencies. Hearing impair-
ment and tinnitus are probably rather caused by cisplatin’s peak concentration than of
its cumulative dose since application of 50 mg/m2 cisplatin over 2 days as compared
to 20 mg/m2 over 5 days resulted in ORs of 5.1 and 7.3, respectively [38]. Unfortunately,
there is no remedy for the prevention of cisplatin-induced ototoxicity, leaving no room
for more specific recommendations than to avoid noise and loud music.

11.8 Nephrotoxicity

Both radiotherapy and cisplatin-based chemotherapy lead to a reduced renal func-

tion in 20–30 % of TCSs [44–47], and a decreased GFR is measured in up to 30 %
of asymptomatic TCSs [46]. Hypomagnesemia may be observed after cisplatin
application [48], but its long-term persistence and potential clinical implications are
not unequivocally established [49]. Impaired renal function is considered an
11 What Are the Long-Term Toxicities to Be Controlled and Treated? 121

important complication since even moderate deteriorations have an adverse impact

on CVD and all-cause mortality in the general population [50]. In testicular cancer
patients, reduced renal elimination of cisplatin and bleomycin might increase the
risk of other toxicities, e.g., bleomycin-related pneumonitis [51, 52].

11.9 Hypogonadism

Testicular endocrine dysfunction comprises insufficient testosterone (T) production

and/or compensatory increased luteinizing hormone (LH) levels. Subnormal testos-
terone levels have been reported in TCS treated with chemotherapy compared with
surgery only or the general population [29, 53]. Furthermore, low testosterone lev-
els are associated with increased risks for the metabolic syndrome and CVD [29, 33,
34, 37], as well as decreased pulmonary function in TCS [20]. Of note, low testos-
terone levels are also associated with increased prevalence of the metabolic syn-
drome and an increased risk for CVD mortality [54, 55], reduction of spirometry
variables [56], and increased risk of respiratory disease mortality [57] in epidemio-
logic studies. Testosterone treatment has been shown to improve lipid profiles and
insulin resistance in men with diabetes or the metabolic syndrome [58, 59].
Testosterone substitution might not only not prevent CVD – a review revealed an
increased risk of subsequent CVD [60]. However, most clinicians agree that men
with endocrine hypogonadism and symptoms as reduced libido or loss of energy
should be offered testosterone treatment unless there are contraindications.

11.10 Fatigue

Chronic fatigue (CF) is described as a subjective feeling of emotional, physical,

and/or cognitive tiredness that is not relieved by rest, persisting for more than
6 months. The general male population in Norway previously reported a CF rate of
10 %, with a slight increase with age [61]. CF has repeatedly been reported to be
associated with anxiety and depression in the literature, and associations with
comorbidity, low educational level, not living in a relationship, being female, and
increasing age have also been described [61, 62]. Significantly higher levels of
C-reactive protein and interleukin-1 receptor antagonist have been reported to occur
more frequent for TCSs with CF, indicating a possible association between CF and
a low-grade inflammatory response [63]. Also, a significantly higher frequency of
CF (16 %) was reported in a cross-sectional Norwegian study of long-term TCSs
median 12 years after treatment for TC when compared with the age-matched
Norwegian population [62]. Of note, the prevalence of CF increased from 15 to
27 % from one to two decades after treatment, respectively [64]. Two decades after
TC treatment, the risk for CF was increased 5-fold for high levels of neuropathy and
2–3-fold for high levels of Raynaud’s phenomenon, physical inactivity, cardiac dis-
ease, and having testosterone levels in the lowest quartile. Furthermore, combina-
tion of these risk factors increased the likelihood of CF considerably.
122 J. Oldenburg et al.

11.11 Implications for Follow-Up

Risk factors for CVD like obesity, hypertension, hypercholesterolemia, and diabetes are
more prevalent in TCS treated with cytotoxic treatment than in those treated with sur-
gery only. However, this treatment burden of life-saving chemotherapy for metastatic
TC has to be accepted. For these young men, it is essential to improve unfavorable life-
style factors like obesity, hypertension, hypercholesterolemia, and possibly hypogonad-
ism. Consequently, TCSs should be informed of the importance of maintaining a healthy
lifestyle to reduce the risk of future CVD events. Preventive measures such as smoking
cessation, keeping a healthy diet, and an active lifestyle may play an important role in
reducing the potential risk of CVD from cytotoxic treatment in TCS [65]. Smoking ces-
sation is also important in order to avoid a declining pulmonary function. Since the
incidence of many cancers is related to an unhealthy lifestyle, promotion of a healthy
lifestyle is probably important also in order to prevent SMN, although not tested
in any randomized study among TCS. The diagnosis of cancer might represent a
window of opportunity with regard to promoting lifestyle changes [66].
Awareness about the possibility of second cancers and CVD among TCS as well
as their healthcare providers is important, and in case of symptoms, prompt diag-
nostic workup should be initiated.

11.12 Conclusions

Cure from cancer by chemotherapy comes at a prize in form of toxicities. The aim
to keep this prize as low as possible dictates adherence to international guidelines.
Whereas treatment of metastatic TC is quite homogenous worldwide, the role of
adjuvant chemotherapy for stage I TC as opposed to active surveillance is contro-
versial and depends, in light of excellent survival rates, on the potentially different
long-term toxicities between both approaches. TC patients should be informed
about acute and long-term toxicities before treatment and should be provided with
a survivorship care plan after follow-up. An example of a one-page summary of TC
treatment, inherent risks, and recommendations is available at www.swenoteca.org.

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Consequences of the Disease and Its
Treatment Concerning Sexuality 12
and Fertility

Sabine Kliesch

Contents
12.1 Fertility Problems in Testicular Cancer Patients .......................................................... 127
12.2 Fertility Preservation in Testicular Cancer Patients ..................................................... 129
12.3 Hypogonadism ............................................................................................................. 130
12.4 Metabolic Syndrome (MBS) ........................................................................................ 131
12.5 Sexual Dysfunction ...................................................................................................... 132
12.5.1 Ejaculatory Disorders ..................................................................................... 132
12.5.2 Disorders of Erectile Function and Libido ..................................................... 132
12.6 Summary ...................................................................................................................... 133
References ............................................................................................................................... 133

As germ cell cancer is the most common cancer in young adults with excellent cure
rates, late effects will affect quality of life. Fertility and sexuality are two main
issues that determine man’s quality of life. Whenever possible, preventive strategies
should be implemented in patient management and treatment be offered, if
possible.

12.1 Fertility Problems in Testicular Cancer Patients

Fertility problems very often precede the diagnosis of testicular germ cell cancer
(TGCC), and infertility itself is an accepted risk factor for TGCC. One out of 200
infertile men is diagnosed with a TGCC. As TGCC is a primary disease of the germ
cell, it impairs spermatogenesis. The tumour derives from the premalignant

S. Kliesch
Department of Clinical Andrology, Center of Reproductive Medicine and Andrology WHO
Collaboration Center, EAA Training Center, University Hospital Münster,
Münster 48149, Germany
e-mail: [email protected]

© Springer International Publishing Switzerland 2015 127

S. Krege (ed.), Diagnosis and Management of Testicular Cancer: The European
Point of View, DOI 10.1007/978-3-319-17467-9_12
128 S. Kliesch

Table 12.1 Semen parameters in patients with testicular cancer compared to Hodgkin lympho-
mas at time of diagnosis
Semen parameter Testicular cancer patients Patients with Hodgkin
(according to [1]) (n = 563) [2] lymphoma (n = 474) [3]
Normozoospermia 25 % 41 %
Oligozoospermia 56 % 56 %
Azoospermia 14 % 3%
Anejaculation 5% n.a.
Modified according to Kliesch [2]
n.a. no information available

precursor, the intraepithelial neoplasia (TIN), and disturbs the normal regulation of
spermatogenesis resulting in reduced semen quality (Table 12.1) [2, 3]. The impair-
ment of spermatogenesis in TGCC is much more pronounced compared to other
malignancies which may also affect spermatogenesis by systemic effects. Compared
with lymphoma patients, TGCC patients have significantly more often azoospermia
at the time of diagnosis (14 vs. 3 %, respectively). While 41 % of Hodgkin patients
reveal normozoospermia, only 25 % of testicular cancer patients have normal semen
parameters at the time of diagnosis (Table 12.1) [2, 3].
Patients with bilateral TGCC or unilateral cancer with contralateral TIN will
have worse results in semen analysis, and the rate of azoospermia may drastically
rise [4, 5].
Finally, impaired spermatogenesis results in reduced paternity rates in testicular
cancer patients. Prior to any further treatment, about 40 % of men are proven fathers
at the time of diagnosis. Of course, due to young age at diagnosis, testicular cancer
patients very often do not have yet finalised family planning and are therefore child-
less. However, paternity rates in long-term survivors of testicular cancer remain also
reduced (about 30 % lower) in comparison to the normal male population. A median
time interval of about 7 years goes by until pregnancies are induced. But even 12
years after end of treatment, recovery of fertility may be observed. In 3,005 long-
term survivors of TGCC, 1,460 (49 %) achieved paternity after a median follow-up
between 5 and 12 years [6] (Table 12.2). Negative prognostic parameters are the
application of radiotherapy and a treatment period before 1990. FSH may help to
indicate recovery of spermatogenesis, but is not reliable. Pregnancies are more often
reported in patients with normal FSH serum levels and antegrade ejaculation com-
pared to those with elevated FSH. Inhibin B does not improve prediction of fertility
and is thus only recommended in clinical studies and not for routine analysis.
However, in prediction of persistent posttreatment azoospermia, it may be of some
value [15]. For testicular cancer patients no increased risk for malformations in
offspring is reported [11].
Recovery of spermatogenesis and thus fertility cannot be safely predicted for
individual patients prior to treatment. Brydoy et al. [13] published data on 100 %
paternity in men after two cycles PEB treatment – however, even severely reduced
spermatogenesis may be observed after one cycle of carboplatin treatment. Thus the
individual susceptibility to the gonadotoxic agents cannot be foreseen and make
12 Consequences of the Disease and Its Treatment Concerning Sexuality and Fertility 129

Table 12.2 Paternity rates in testicular cancer survivors

Patient Median FU Paternity Paternity (with
numbers (years) (spontaneous) (%) ART) (%) Reference
246 73 (29.7 %) k.A. [7]
88 7 52 (59.0 %) 7 (13.5 %) [8]
164 8 110 (67.1 %) n.a. [9]
207 ≥5 159 (81.7 %) 10 (6 %) [10]
552 11 325 (65.5 %) 36 (10 %) [11]
1,359 5 513 (37.6 %) 14 (1.0 %) [12]
143 12 85 (59.4 %) n.a. [13]
246 83 (33.7 %) n.a. [14]
3,005 1,393 (46.4) 67 (2.6 %) Total numbers
published until 2010
Modified according to Kliesch [6]
ART assisted reproductive techniques, n.a. not available, FU follow-up

counselling of patients difficult. Most data on fertility issues are retrospectively

obtained. Recently, a cohort of 213 patients with TGCC with a mean follow-up of
48 months was analysed. They had cryopreserved their semen prior to treatment
[17]. Altogether, 18.8 % of these men revealed persistent azoospermia during fol-
low-up; another 4 % had cryptozoospermia with sperm counts <0.1 mill/ml and thus
no chance for spontaneous pregnancy induction. Seventy-seven percent of men
recovered with either oligozoospermia or normozoospermia. There was no differ-
ence in patients with seminomas or non-seminomas. Radiotherapy was associated
with higher rates of azoospermia (34 % compared to 12.5 % without radiotherapy).
Moreover, a clear association could be determined between initial semen quality
and potential for recovery: the lower the sperm concentration prior to treatment, the
higher the rate of posttreatment azoospermia [17].

12.2 Fertility Preservation in Testicular Cancer Patients

Due to the known negative long-term effects of TGCC and its treatment on fertility
aspects, counselling of patients in respect to fertility preservation is mandatory. Apart
from the medical indication, there exists a legal indication to inform the patients at
the time of diagnosis of the different aspects of fertility impairment and to offer fer-
tility preservation. The standard procedure comprises the cryopreservation of semen
[5]. Semen samples can be easily cryopreserved in small straws with acceptable sur-
vival rates of spermatozoa if handled according to standardised protocols as described
in detail in the WHO laboratory manual [18]. The cryopreserved spermatozoa can
later be used for assisted reproduction, namely, intracytoplasmic sperm injection
technique (ICSI). If patients are adequately informed, about 50 % of men will cryo-
preserve spermatozoa [12]. About 20 % of men will not be able to cryopreserve
semen with spermatozoa, either due to anejaculation or azoospermia. In these cases,
alternatively a surgical testicular sperm extraction (TESE) can be offered [5]. The
130 S. Kliesch

best method nowadays is the microsurgical approach, but also a multifocal approach
is still an accepted standard in case of non-obstructive azoospermia [19]. TESE can
be successfully performed if spermatogenic foci within the testicular parenchyma
can be isolated. The testicular spermatozoa can be cryopreserved for later use in
assisted reproduction (ICSI). TESE procedures in testicular cancer patients with azo-
ospermia can be successful in 61 % of patients [2]. Especially patients with bilateral
tumour manifestations (TGCC or TIN) will benefit from additional TESE options
prior to (functional) anorchia.
In general, semen cryopreservation should be offered prior to primary treatment
including inguinal orchiectomy. Results of semen analysis will be better in quality
and quantity before surgery is performed. Moreover, semen analysis prior to orchi-
ectomy will easily detect patients with azoospermia that will need additional TESE
for fertility preservation. Thus, treatment schedule can be optimised, and primary
surgery can immediately be combined with testicular sperm extraction. In summary,
patient counselling in respect to fertility issues as well as cryopreservation of sper-
matozoa improves quality of life and should be an accepted standard [5].

12.3 Hypogonadism

Testosterone is the central male hormone with numerous positive effects on male
physical and mental well-being. Testosterone deficiency may result in pathological
effects. Values above the accepted lower normal range of 12.1 nmol/l total testoster-
one can be expected in healthy men. Testosterone levels <12 nmol/l and the exis-
tence of clinical symptoms of testosterone deficiency result in serious changes in
body composition, reduced muscle strength, increase in fat mass and osteopenia
[19]. Very often hypogonadism is accompanied by insulin resistance and disturbed
lipid metabolism [20]. There exist several studies that revealed hypogonadism to be
a relevant late effect of TGCC treatment. Depending on treatment intensity, the
incidence varies between 11 and 33 % ([21], Table 12.2). In up to 34 % of men, a
compensated Leydig cell insufficiency with high LH and low normal testosterone
levels could be demonstrated in recent studies [10, 22]. There exist no relevant dif-
ferences between seminomatous and non-seminomatous tumours (Fig. 12.1) [21].
Irrespective of treatment modalities hypogonadism may develop (Table 12.3) [21],
although an association between decrease of testosterone levels and intensity of
treatment was shown [22]. A recent prospective follow-up study revealed an inci-
dence of 40 % in patients with manifest or testosterone-treated hypogonadism [23].
Several potential risk factors predictive for hypogonadism could be evaluated:
reduced testicular volume (<12 ml), microlithiasis of the testis, >2 cycles of poly-
chemotherapy and pre-existing low testosterone serum levels [21, 24]. However,
these findings are inconsistent and may vary between different study populations.
In case of hypogonadism defined by low testosterone serum levels and clinical
symptoms, testosterone substitution is indicated if contraindications are excluded.
Testosterone treatment is accepted as safe and can be effectively performed by either
transdermal or intramuscular application according to the current guidelines [25].
12 Consequences of the Disease and Its Treatment Concerning Sexuality and Fertility 131

70 50
testosterone testosterone
60 (nmol/l) seminoma (nmol/l) non-seminoma
40
hypogonadal hypogonadal
Testosteron (nmol/l)

Testosteron (nmol/l)
50 23.9% (17/71 pat) 26.2% (16/61 pat)
40 30

30 20
20
10
10

0 0
-1 0 1 2 3 4 5 6 -1 0 1 2 3 4 5 6
time (years) time (years)
age 37 +/- 8.2 years age 31.2 +/- 9.1 years

Fig. 12.1 Testosterone deficiency in testicular cancer patients 4.8 years after therapy (Modified
according to Pühse et al. [21])

In case of bilateral TGCC and anorchia, testosterone substitution has to be initi-

ated immediately after surgery. In case of unilateral TGCC and contralateral TIN or
bilateral TGCC with organ-sparing surgery, testosterone substitution can be delayed
if serum levels still remain in the normal range without symptoms of androgen
deficiency.

12.4 Metabolic Syndrome (MBS)

The components of the metabolic syndrome can significantly more often be observed
in patients after TGCC than in controls: overweight in 24–50 %, hypercholesterin-
emia in 24 % and high blood pressure in 30 % of men are present after 1–5 years
after diagnosis of TGCC. The MBS can be observed in about 25 % of men with
TGCC and increases up to 35 % at the age of 40–60 years [26, 23].
Recently, the close interaction between hypogonadism and metabolic syndrome
was shown. In case of testicular cancer patients, the young age may result in worse
results and possibly add to the increased cardiovascular risk factors documented as
late effects in long-term survivors and thus increase morbidity [26–28] [23]. From
endocrinological studies we learned that the treatment of hypogonadism may result
in normalised mortality rates comparable with eugonadal men, while untreated
hypogonadal men die earlier [29]. To what extent the early detection and treatment
of hypogonadism will positively influence the development of the metabolic syn-
drome and its late effects, especially on the cardiovascular system, cannot be
judged by now. Data from different patient populations suggest synergistic positive
effects by testosterone substitution on metabolism and thus morbidity and mortal-
ity rates [29].
132 S. Kliesch

12.5 Sexual Dysfunction

12.5.1 Ejaculatory Disorders

Ejaculatory disorders mainly result as a consequence of retroperitoneal lymph node

dissection (RPLND). The risk for retrograde or complete loss of ejaculation varies
depending on the surgical procedure: modified RPLND will result in about 90 %
antegrade ejaculations as mainly applied in non-seminomatous TGCC clinical stage
I [30]. However, indications for primary modified RPLND are rare by now as adju-
vant chemotherapy with one cycle of PEB is superior for disease control [31].
In case of post-chemotherapeutic resection of residual mass, the risk for retro-
grade ejaculation varies between 50 and 100 %. Antegrade ejaculation was reported
in 50 % of patients after nerve-sparing post-chemotherapeutic RPLND [32, 33]. For
successful nerve sparing, a right-sided tumour and a residual mass >5 cm are nega-
tive predictors [34]. In 341 patients dedicated for nerve-sparing residual tumour
resection, the nerve-sparing procedure could successfully be applied in 136 cases
only. Finally, 107 patients maintained antegrade ejaculation (31 %) [34].

12.5.2 Disorders of Erectile Function and Libido

In recent years several studies reported on a variable and significant proportion of

testicular cancer survivors with reduced sexuality [35]. A prospective follow-up
study showed a high proportion of men with several symptoms [36]: reduced libido
in 35 % of patients, reduced sexual activity in 42 %, erectile dysfunction in 32 %
and reduced intensity of orgasm in 32 %. Ejaculatory disorders including reduced
seminal volume were high in 85 % of patients. Most recent studies confirmed higher
incidences of sexual dysfunction [37, 38], while few previous data negotiated a dif-
ference between patients and controls [39]. Erectile dysfunction shows no associa-
tion with treatment strategies for TGCC [38]. Moreover, changes with body image
may contribute to sexual dysfunction [38, 40]. Thus sexual disorders are signifi-
cantly associated with chronic testicular pain or the presence of the phantom tes-
ticular syndrome [36, 40]. The phantom testicular syndrome was first described in
125 of 248 patients with unilateral TGCC. The presence of the phantom testicular
syndrome increases the rate of complaints concerning sexual function and seems
to be significantly associated with pain [40]. Thus adequate perioperative pain

Table 12.3 Testosterone deficiency in follow-up investigations of 160 men with either seminoma
or non-seminoma (mean follow-up of 4.8 years)
Seminoma patients with Non-seminoma patients with
testosterone deficiency (%) testosterone deficiency (%)
Surgery only 11.1 25.0
Radiotherapy 33.3 n.a.
Carboplatin monotherapy 24.0 n.a.
Polychemotherapy (PEB/PEI) 18.8 26.4
Modified according to Pühse et al. [21]
12 Consequences of the Disease and Its Treatment Concerning Sexuality and Fertility 133

management in testicular cancer could be a preventive strategy. Overall, most long-

term survivors of TGCC with erectile dysfunction seem to respond adequately to
phosphodiesterase inhibitors (88 %) [41].
Moreover, partner satisfaction seems to be lower in patients with a partnership
that evolved after the diagnosis of TGCC [42]. Psychosexual factors may play a
certain but not well-investigated role. Some studies revealed an increased incidence
of depressive mood in TGCC [43]. Also lifestyle factors seem to have some rele-
vance: smoking and alcohol intake are more often observed in testicular cancer
patients; on the other hand they are more active in physical exercise than controls
[44]. In addition, testosterone deficiency will additionally impair sexuality, espe-
cially libido, and erectile function will be reduced.

12.6 Summary

Long-term survivors of TGCC experience disorders of gonadal and sexual function.

Metabolic syndrome and hypogonadism have been documented to affect 35–40 %
of men and coincide with increased morbidity. Treatment of hypogonadism can be
performed effectively with no relevant side effects and may prevent further health
restrictions. Paternity rates are reduced in testicular cancer patients compared to
healthy men. Both the disease itself and its treatment may impair spermatogenesis.
In respect to fertility, cryopreservation of spermatozoa is an effective preventive
strategy and may be mandatory for those men that still wish to father a child. The
prediction of individual risk factors for permanent or intermittent impairment of
spermatogenesis after end of treatment is not possible yet. However, reduced semen
quality at time of diagnoses is associated with worse recovery rates. FSH may be
helpful if normalised after end of treatment. Sexual disorders are frequent and may
concern libido, sexual satisfaction, ejaculation, orgasm and erectile function.
Complaints should be taken serious and should be treated adequately.

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