NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Testicular Cancer
Version 2.2020 — November 20, 2019

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Table of Contents
Testicular Cancer Discussion

*Timothy Gilligan, MD/Chair † Ellis G. Levine, MD † Kanishka Sircar, MD ≠

Case Comprehensive Cancer Center/ Roswell Park Cancer Institute The University of Texas
University Hospitals Seidman Cancer MD Anderson Cancer Center
Center and Cleveland Clinic Taussig Thomas Longo, MD ω
Cancer Institute Duke Cancer Institute David C. Smith, MD †
University of Michigan Rogel Cancer Center
*Daniel W. Lin, MD/Vice-Chair ω Will Lowrance, MD, MPH ω
Fred Hutchinson Cancer Research Center/ Huntsman Cancer Institute Katherine Tzou, MD §
Seattle Cancer Care Alliance at the University of Utah Mayo Clinic Cancer Center

*Rahul Aggarwal, MD † ‡ Þ Bradley McGregor, MD † *Daniel Vaena, MD ‡

UCSF Helen Diller Family Dana-Farber/Brigham and Women's St. Jude Children’s Research Hospital/
Comprehensive Cancer Center Cancer Center The University of Tennessee
Health Science Center
David Chism, MD, MS † Paul Monk, MD † David Vaughn, MD †
Vanderbilt-Ingram Cancer Center The Ohio State University Comprehensive Abramson Cancer Center
Cancer Center - James Cancer Hospital at the University of Pennsylvania
*Nicholas Cost, MD ω and Solove Research Institute
University of Colorado Cancer Center Kosj Yamoah, MD, PhD §
Ithaar H. Derweesh, MD ω *Joel Picus, MD ‡ Moffitt Cancer Center
UC San Diego Moores Cancer Center Siteman Cancer Center at Barnes-
Jewish Hospital and Washington Jonathan Yamzon, MD ω
Hamid Emamekhoo, MD University School of Medicine City of Hope National Medical Center
University of Wisconsin
Carbone Cancer Center *Phillip Pierorazio, MD ω NCCN
The Sidney Kimmel Comprehensive Alyse Johnson-Chilla, MS
Darren R. Feldman, MD † Cancer Center at Johns Hopkins Jennifer Keller, MSS
Memorial Sloan Kettering Cancer Center Lenora A. Pluchino, PhD
Soroush Rais-Bahrami, MD ω
*Daniel M. Geynisman, MD ‡ O'Neal Comprehensive
Fox Chase Cancer Center Cancer Center at UAB
Steven L. Hancock, MD § Þ
Philip Saylor, MD †
Stanford Cancer Institute Massachusetts General Hospital
Chad LaGrange, MD ω Cancer Center
Fred & Pamela Buffett Cancer Center ‡ Hematology/Hematology oncology
Þ Internal medicine
† Medical oncology
≠ Pathology
Continue § Radiotherapy/Radiation oncology
ω Urology
NCCN Guidelines Panel Disclosures
* Discussion writing committee member

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Table of Contents
Testicular Cancer Discussion

NCCN Testicular Cancer Panel Members

Summary of the Guidelines Updates Clinical Trials: NCCN believes that
the best management for any patient
Workup, Primary Treatment, and Pathologic Diagnosis (TEST-1) with cancer is in a clinical trial.
Pure Seminoma: Postdiagnostic Workup and Clinical Stage (TEST-2) Participation in clinical trials is
• Stage IA, IB (TEST-3) especially encouraged.
• Stage IS (TEST-3)
• Stage IIA, IIB (TEST-4) To find clinical trials online at NCCN
• Stage IIC, III (TEST-4) Member Institutions, click here:
• Postchemotherapy Management (TEST-5) nccn.org/clinical_trials/member_
Nonseminoma: Postdiagnostic Workup and Clinical Stage (TEST-6) institutions.aspx.
• Stage I with and without Risk Factors, Stage IS (TEST-7) NCCN Categories of Evidence and
• Stage IIA, IIB (TEST-8) Consensus: All recommendations
• Postchemotherapy Management (TEST-9) are category 2A unless otherwise
• Postsurgical Management (TEST-10) indicated.
• Stage IS, IIA S1, IIB S1, IIC, IIIA, IIIB, IIIC, and Brain Metastases (TEST-11)
See NCCN Categories of Evidence
• Postchemotherapy Management of Partial and Incomplete Response to Primary Treatment (TEST-12)
and Consensus.
Recurrence and Second-Line Therapy (TEST-13)
Prior Second-Line Therapy; Postchemotherapy Management (TEST-14) NCCN Categories of Preference:
Third-Line Therapy (TEST-15) All recommendations are considered
appropriate.
Follow-up for Seminoma (TEST-A)
Follow-up for Nonseminoma (TEST-B) See NCCN Categories of Preference.
Principles of Radiotherapy for Pure Testicular Seminoma (TEST-C)
Risk Classification for Advanced Disease (TEST-D)
Primary Chemotherapy Regimens for Germ Cell Tumors (TEST-E)
Second-Line Chemotherapy Regimens for Metastatic Germ Cell Tumors (TEST-F)
Third-Line Chemotherapy Regimens for Metastatic Germ Cell Tumors (TEST-G)
Principles of Surgery for Germ Cell Tumors (TEST-H)
Principles of Imaging (TEST-I)
Staging (ST-1)

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to
treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual
clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations
or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may
not be reproduced in any form without the express written permission of NCCN. ©2019.
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NCCN Guidelines Version 2.2020 NCCN Guidelines Index

Table of Contents
Testicular Cancer Discussion

Updates in Version 2.2020 of the NCCN Guidelines for Testicular Cancer from Version 1.2020 include:
MS-1
The Discussion section has been updated to reflect the changes in the algorithm.

Updates in Version 1.2020 of the NCCN Guidelines for Testicular Cancer from Version 1.2019 include:
TEST-1 TEST-5
• Footnotes • Footnote cc added: In rare cases, nonseminomatous elements will
Footnote b modified: Mildly elevated, non-rising AFP levels may be identified, and if they are non-teratomatous then proceed in the
not indicate presence of germ cell tumor. Decisions to treat should same fashion as for viable seminoma above.
not be based on AFP values <20 ng/mL. Further workup should be
considered before initiating treatment for mildly elevated beta-hCG TEST-6
(generally <20 IU/L) since other factors, including hypogonadism • Clinical Stage
and marijuana use, can cause false-positive results. See IS moved from top pathway to bottom pathway
Discussion. • Footnotes
Footnote d added: Consider measuring baseline levels of gonadal Footnote removed: For select cases of clinical stage IIA disease
function. with borderline retroperitoneal lymph nodes, waiting 4–6 weeks
Footnote e added: Inguinal exploration with exposure of testis with and repeating imaging (chest/abdomen/pelvic CT with contrast) to
direct observation and directed biopsy. confirm staging before initiating treatment can be considered.
Footnote hh modified: Risk factors include lymphovascular
TEST-2 invasion or invasion of spermatic cord or scrotum. Some centers
• Footnote m added: The panel recommends staging tumors with consider predominance of embryonal carcinoma as an additional
discontinuous invasion of the spermatic cord as pT3 (high-risk stage risk factor for relapse.
I) and not as M1 (stage III) as is recommended in the 8th edition of
the AJCC Cancer Staging Manual. If surveillance is elected, the pelvis TEST-7
should be included in the imaging due to a higher risk of pelvic • Footnotes
relapses in these patients. See Discussion. Footnote jj added: Retroperitoneal lymph node dissection (RPLND)
is preferred as primary treatment for tumors with transformed
TEST-3 teratoma. Patients with stage I pure teratoma and normal markers
• Primary Treatment should receive either surveillance or RPLND. See Discussion.
Treatment modified: Surveillance for pT1-pT3 tumors (strongly Footnote kk modified: RPLND is recommended within 4 weeks of
preferred) CT scan and 7–10 days of marker measurement.
• RT (20 Gy, preferred or 25.5 Gy)
• Footnotes TEST-8
Footnote u modified: Elevated tumor markers increase the risk of • Footnote mm added: RPLND is preferred as primary treatment
disease outside of the retroperitoneum. Therefore, systemic therapy for stage II tumors with transformed teratoma, and should be
should be encouraged. See Primary Chemotherapy Regimens for considered for stage II tumors with teratoma predominance in
Germ Cell Tumors (TEST-E). patients with normal markers. See Discussion.
Continued

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Table of Contents
Testicular Cancer Discussion

Updates in Version 1.2020 of the NCCN Guidelines for Testicular Cancer from Version 1.2019 include:
TEST-11 TEST-15
• Primary Treatment • Third-Line Therapy, top pathway modified: Clinical trial (preferred) or
Response categories modified here and on TEST-12: Incomplete High-dose chemotherapy or Consider surgical salvage if solitary site
Partial response, residual masses with abnormal AFP and/or beta-
hCG levels
• Footnotes TEST-A 1 of 2
Footnote removed: Patients should receive adequate treatment for • Table 1, Clinical Stage I Seminoma: Surveillance After Orchiectomy
brain metastases, in addition to cisplatin-based chemotherapy. Year 2 column for H&P modified: Every 6-12 mo
Footnote removed: Salvage chemotherapy should be reserved Year 2 column for Abdominal ± Pelvic CT modified: Every 6-12 mo
for patients with rising AFP, beta-hCG, or other evidence of
progressive disease. TEST-B 1 of 3
• Table 5, Clinical Stage I without Risk Factors, NSGCT: Active
TEST-12 Surveillance
• Partial response categories added here and on TEST-14: Year 2 column for Abdominal ± Pelvic CT modified: Every 6-12 mo
Elevated and rising AFP and/or beta-hCG levels
Elevated but stable AFP and/or beta-hCG levels TEST-B 2 of 3
Mildly elevated and normalizing AFP and/or beta-hCG levels • Table 8, Clinical Stage II-III NSGCT: Surveillance After Complete
Response to Chemotherapy ± Post-Chemotherapy RPLND
TEST-13 Years 4 and 5 columns for Abdominal ± Pelvic CT added: As
• Recurrence and Second-Line Therapy with prior chemotherapy clinically indicated
This section has significant changes • Footnotes
• Footnotes Footnote f added: Patients who have an incomplete response to
Footnote removed: Examples of systems used to estimate chemotherapy require more frequent imaging than is listed on this
prognosis are: 1) Fossa SD, Cvancarova, Chen L, et al. J Clin Oncol table.
2011;29:963-970; 2) Fedyanin M, Tryakin A, Kanagavel D, et al. Urol Footnote j added: For patients with unresectable residual masses
Oncol 2013;31:499-504; and 3) Masterson TA, Carver BS, Shayegan or resected residual masses containing viable cancer.
B, et al. Urology 2012;79:1079-1084.
Footnote vv modified: Includes best supportive care and palliative TEST B 3 of 3
care. See NCCN Guidelines for Palliative Care. Footnote k modified: Patients who undergo RPLND and are found
to have pN0 disease or pN1 pure teratoma need only 1 CT scan
at postoperative month 3–4 and then as clinically indicated. See
Discussion.

Continued
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Testicular Cancer Discussion

Updates in Version 1.2020 of the NCCN Guidelines for Testicular Cancer from Version 1.2019 include:
TEST-C TEST-G 1 of 3
• General Treatment Information • Third-Line Chemotherapy Regimens for Metastatic Germ Cell
Sub-Bullet 2 modified: All patients, with the exception of those Tumors
who have undergone bilateral orchiectomy, should be treated with Other Recommended Regimens dosing added:
a scrotal shield. The legs should be separated by a rolled towel ◊◊Gemcitabine/paclitaxel/oxaliplatin
of approximately the same diameter as the scrotal shield and its ––Gemcitabine 800 mg/m2 IV over 30 minutes on Days 1 and 8
stand. ––Paclitaxel 80 mg/m2 IV over 60 minutes on Days 1 and 8
––Oxaliplatin 130 mg/m2 IV over 2 hours on Day 1
TEST-D ▪▪Administered on a 21-day cycle for 8 cycles
• Footnote b added: Referral to a high-volume center is recommended ◊◊Gemcitabine/oxaliplatin
for patients with extragonadal germ cell tumors. See Discussion. ––Gemcitabine 1000–1250 mg/m2 IV over 30 minutes on Days 1
and 8 followed by
TEST-E ––Oxaliplatin 130 mg/m2 IV over 2 hours on Day 1
• Primary Chemotherapy Regimens for Germ Cell Tumors ▪▪Administered on a 21-day cycle until disease progression or
Other Recommended Regimens unacceptable toxicity
◊◊Regimen instructions modified: Ifosfamide 1200 mg/m2 on Days ◊◊Gemcitabine/paclitaxel
1–5 with mesna protection ––Gemcitabine 1000 mg/m2 IV over 30 minutes on Days 1, 8, and
15
TEST-F ––Paclitaxel 100 mg/m2 IV over 60 minutes on Days 1, 8, and 15
• Second-Line Chemotherapy Regimens for Metastatic Germ Cell ▪▪Administered on a 28-day cycle for 6 cycles
Tumors ◊◊Etoposide (oral)
TIP Regimen instructions modified: Ifosfamide 1500 mg/m2 IV ––Etoposide 50–100 mg PO daily on Days 1–21
on Days 2–5 with mesna protection Mesna 300 mg/m2 IV over 15 ▪▪Administered on a 28-day cycle until disease progression or
minutes before ifosfamide, then at 4 and 8 hours from the start of unacceptable toxicity
each ifosfamide dose daily on Days 2–5 Regimens that are Useful in Certain Circumstances dosing added:
VeIP Regimen instructions modified: Mesna 240 mg/m2 IV over 15 ◊◊Pembrolizumab (for MSI-H/dMMR tumors)
minutes before ifosfamide, then at 4 and 8 hours from the start of ––Pembrolizumab 200 mg IV over 30 minutes on Day 1
each ifosfamide dose daily on Days 1–5 Ifosfamide 1200 mg/m2 IV ▪▪Administered on a 21-day cycle until disease progression or
on Days 1–5 with mesna protection unacceptable toxicity

Continued
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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NCCN Guidelines Version 2.2020 NCCN Guidelines Index

Table of Contents
Testicular Cancer Discussion

Updates in Version 1.2020 of the NCCN Guidelines for Testicular Cancer from Version 1.2019 include:
TEST-G 2 of 3 TEST-H
• Third-Line Chemotherapy Regimens for Metastatic Germ Cell Tumor • Principles of Surgery for Germ Cell Tumors
Preferred Regimens dosing added: Post-Chemotherapy Setting
◊◊Gemcitabine/paclitaxel/oxaliplatin ◊◊Bullet 5 added: Limited data suggest increased frequency
––Gemcitabine 800 mg/m2 IV over 30 minutes on Days 1 and 8 of aberrant recurrences with the use of minimally invasive
––Paclitaxel 80 mg/m2 IV over 60 minutes on Days 1 and 8 laparoscopic or robotic approaches to RPLND. Therefore,
––Oxaliplatin 130 mg/m2 IV over 2 hours on Day 1 minimally invasive RPLND is not recommended as standard
▪▪Administered on a 21-day cycle for 8 cycles management at this time.
◊◊Gemcitabine/oxaliplatin • Reference added: Calaway AC, Einhorn LH, Masterson TA, et al.
––Gemcitabine 1000–1250 mg/m2 IV over 30 minutes on Days 1 Adverse surgical outcomes associated with robotic retroperitoneal
and 8 followed by lymph node dissection among patients with testicular cancer. Eur
––Oxaliplatin 130 mg/m2 IV over 2 hours on Day 1 Urol 2019 June 4 [Epub ahead of print].
▪▪Administered on a 21-day cycle until disease progression or
unacceptable toxicity
◊◊Gemcitabine/paclitaxel ST-2 and ST-3
––Gemcitabine 1000 mg/m2 IV over 30 minutes on Days 1, 8, and • Changes made on these pages to align with the American Joint
15 Committee on Cancer (AJCC) TNM Staging Classification for Testis
––Paclitaxel 100 mg/m2 IV over 60 minutes on Days 1, 8, and 15 Cancer 8th ed, 2017
▪▪Administered on a 28-day cycle for 6 cycles
◊◊Etoposide (oral)
––Etoposide 50–100 mg PO daily on Days 1–21
▪▪Administered on a 28-day cycle until disease progression or
unacceptable toxicity
Regimens that are Useful in Certain Circumstances dosing added:
◊◊Pembrolizumab (for MSI-H/dMMR tumors)
◊◊Pembrolizumab 200 mg IV over 30 minutes on Day 1
▪▪Administered on a 21-day cycle until disease progression or
unacceptable toxicity
• Footnotes
Footnote a added: If VIP or TIP received as second-line therapy,
high-dose chemotherapy is the preferred third-line option.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Testicular Cancer Discussion

WORKUP PRIMARY TREATMENTa PATHOLOGIC DIAGNOSIS

See
• Discuss sperm banking, if Pure seminoma (pure
Postdiagnostic
clinically indicated seminoma histology and AFP
Workup and
• Radical inguinal orchiectomy normal; may have elevated
Clinical Stage
• H&P • Consider inguinal biopsye of beta-hCG)b
(TEST-2)
• Alpha-fetoprotein (AFP)b contralateral testis if:
Suspicious
• beta-hCGb,c Ultrasound showing
testicular
• LDH intratesticular mass concerning Nonseminomatous germ
mass
• Chemistry profiled for testicular cancerf cell tumor (NSGCT) See
• Testicular ultrasound Cryptorchid testis (includes mixed seminoma/ Postdiagnostic
Marked atrophy nonseminoma tumors and Workup and
Suspicious mass seminoma histology with Clinical Stage
• Consider testicular prosthesis elevated AFP)b (TEST-6)

a Though rare, when a patient presents with rapidly increasing beta-hCG or AFP and symptoms related to disseminated disease with a testicular mass, chemotherapy
can be initiated immediately without waiting for a biopsy diagnosis or performing orchiectomy.
b Mildly elevated, non-rising AFP levels may not indicate presence of germ cell tumor. Decisions to treat should not be based on AFP values <20 ng/mL. Further workup
should be considered before initiating treatment for mildly elevated beta-hCG (generally <20 IU/L) since other factors, including hypogonadism and marijuana use, can
cause false-positive results. See Discussion.
c Quantitative analysis of beta subunit.
d Consider measuring baseline levels of gonadal function.
e Inguinal exploration with exposure of testis, with direct observation and directed biopsy.
f Biopsies are not recommended for microcalcifications.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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TEST-1
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Testicular Cancer - Pure Seminoma Discussion

PATHOLOGIC DIAGNOSIS POSTDIAGNOSTIC WORKUP CLINICAL STAGE

Stage
IA, IBm
See Primary Treatment
• Abdominal/pelvic CTi and Follow-up (TEST-3)
• Chest x-ray Stage
• Chest CTi if: IS
Pure seminomag Positive abdominal CT or
(pure seminoma histology abnormal chest x-ray
and AFP normal;h may • Repeat beta-hCG, LDH, and AFP
have elevated beta-hCGb) since TNM staging is based on post-
orchiectomy valuesb,j Stage
• Brain MRI,k if clinically indicatedl IIA,n IIB
• Recommend sperm banking, if clinically See Primary Treatment
indicated and Follow-up (TEST-4)
Stage
IIC, IIIm

b Mildly elevated, non-rising AFP levels may not indicate presence of germ cell tumor. Decisions to treat should not be based on AFP values <20 ng/mL. Further workup
should be considered before initiating treatment for mildly elevated beta-hCG (generally <20 IU/L) since other factors, including hypogonadism and marijuana use, can
cause false-positive results. See Discussion.
g Mediastinal primary seminoma should be treated by risk status used for gonadal seminomas with etoposide/cisplatin for 4 cycles or bleomycin/etoposide/cisplatin for
3 cycles.
h If AFP is elevated, treat as nonseminoma.
i With contrast.
j Elevated values should be followed after orchiectomy with repeated determination to allow precise staging. Follow declining markers until normalization or plateau.
Staging is based on marker levels at the time that the patient starts postorchiectomy therapy (for example, for patients starting chemotherapy for disseminated disease,
prognostic category and staging should be assigned based on the serum tumor marker levels on day 1 of cycle 1 of chemotherapy).
k With and without contrast.
l Eg, beta-hCG >5000 IU/L, or extensive lung metastasis.
m The panel recommends staging tumors with discontinuous invasion of the spermatic cord as pT3 (high-risk stage I) and not as M1 (stage III) as is recommended in the
8th edition of the AJCC Cancer Staging Manual. If surveillance is elected, the pelvis should be included in the imaging due to a higher risk of pelvic relapses in these
patients. See Discussion.
n For select cases of clinical stage IIA disease with borderline retroperitoneal lymph nodes, waiting 4–6 weeks and repeating imaging (chest/abdomen/pelvic CT with
contrast) to confirm staging before initiating treatment can be considered.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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TEST-2
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Table of Contents
Testicular Cancer - Pure Seminoma Discussion

CLINICAL PRIMARY TREATMENTo FOLLOW-UP

STAGE

Recurrence, treat
Surveillance for pT1-pT3 tumors according to extent
See Follow-up for Seminoma, Table 1 (TEST-A 1 of 2)
(strongly preferred) of disease at
relapsev
or

Stage Recurrence, treat

Single-agent carboplatinp,q See Follow-up for Seminoma, Table 2 (TEST-A 1 of 2) according to extent
IA, IB (AUC=7 x 1 cycle or AUC=7 x 2 cycles) of disease at
relapsev
or
Recurrence, treat
RTr (20 Gy or 25.5 Gy)s See Follow-up for Seminoma, Table 2 (TEST-A 1 of 2) according to extent
of disease at
relapsev
Repeat elevated serum tumor marker Recurrence, treat
Stage
measurementb and assess with chest/abdominal/ according to extent
IS
pelvic CT (with contrast) to scan for evaluable of disease at
diseaset,u relapsev

q There
 are limited long-term follow-up data on the toxicity and efficacy of
carboplatin. A recent population-based study suggested patients with larger
tumors, rete testis involvement, or both derive a smaller reduction in relapse rate
b Mildly elevated, non-rising AFP levels may not indicate presence of germ cell with 1 cycle of carboplatin than previously reported. See Discussion.
tumor. Decisions to treat should not be based on AFP values <20 ng/mL. Further r See Principles of Radiotherapy for Pure Testicular Seminoma (TEST-C).
workup should be considered before initiating treatment for mildly elevated s For stage I seminoma, long-term follow-up studies indicate an increase in late
beta-hCG (generally <20 IU/L) since other factors, including hypogonadism and toxicities with radiation treatment. See Discussion.
marijuana use, can cause false-positive results. See Discussion. t For further information on stage IS, see Discussion.
o Discuss sperm banking prior to chemotherapy or radiation treatment. u Elevated tumor markers increase the risk of disease outside of the
p Recommend abdomen/pelvic CT scan and chest x-ray or CT scan within the 4 retroperitoneum. Therefore, systemic therapy should be encouraged. See Primary
weeks prior to the initiation of chemotherapy to confirm staging, even if scan was Chemotherapy Regimens for Germ Cell Tumors (TEST-E).
done previously. See Principles of Imaging (TEST-I). v Patients should not be treated based upon an elevated LDH alone.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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TEST-3
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Testicular Cancer - Pure Seminoma Discussion

CLINICAL PRIMARY TREATMENTo FOLLOW-UP

STAGEw Recurrence, treat
RT to include para-aortic and ipsilateral See Follow-up for Seminoma,
iliac lymph nodes to a dose of 30 Gyr according to extent of
Table 3 (TEST-A 2 of 2)
Stage disease at relapsev
or
IIA
Primary chemotherapy:z
BEPaa for 3 cycles or EP for 4 cycles

See Post-Chemotherapy
Primary chemotherapy (preferred):z Management and Follow-up (TEST-5)
BEPaa for 3 cycles or EP for 4 cycles
Stage or
IIB RT in select non-bulky (≤3 cm) cases Recurrence, treat
See Follow-up for Seminoma,
to include para-aortic and ipsilateral according to extent of
Table 3 (TEST-A 2 of 2)
iliac lymph nodes to a dose of 36 Gyr disease at relapsev

Primary chemotherapy:z
BEPaa for 3 cycles (category 1)
Good risky
or
EP for 4 cycles (category 1) See Post-Chemotherapy
Stage Management and Follow-up (TEST-5)
IIC, IIIx
Primary chemotherapy:z
Intermediate BEPaa for 4 cycles (category 1) Preferred Regimens
riskw,y or BEP = Bleomycin/etoposide/cisplatin
VIP for 4 cycles EP = Etoposide/cisplatin
Other Recommended Regimens
VIP = Etoposide/ifosfamide/cisplatin
o Discuss sperm banking prior to chemotherapy or radiation treatment.
r See Principles of Radiotherapy for Pure Testicular Seminoma (TEST-C).
v Patients should not be treated based upon an elevated LDH alone. x All stage IIC and stage III seminomas are considered good-risk disease except for
w Intermediate risk in seminoma is based on metastases to organs other than the stage III disease with non-pulmonary visceral metastases (eg, bone, liver, brain),
lungs (stage IIIC). Stage IIIB does not apply to pure seminomas. Patients with which is considered intermediate risk.
elevated AFP have nonseminomas. In patients with a serum beta-hCG >1000 y See Risk Classification for Advanced Disease (TEST-D).
IU/L, consider the possibility of an NSGCT, re-review surgical specimen with z See Primary Chemotherapy Regimens for Germ Cell Tumors (TEST-E).
pathology, and consider discussion with a high-volume center. LDH and beta-hCG aa Consider a bleomycin-free regimen in patients with reduced or borderline GFR
alone should not be used to stage or risk stratify patients with pure seminoma. and in patients older than 50 years of age.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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STAGE IIA, IIB, IIC, III AFTER PRIMARY POST-CHEMOTHERAPY FOLLOW-UP

TREATMENT WITH CHEMOTHERAPY MANAGEMENT

No residual mass or
Recurrence,
residual mass See Follow-
See Second-Line
≤3 cm and normal Surveillance up for
Therapy (TEST-13)
serum AFP and Seminoma,
beta-hCG Table 3
(TEST-A 2 of
2)
Surveillance See Follow-up for
Seminoma, Table 4
Residual Negative Surveillance (TEST-A 2 of 2)
mass or
• Chest,
abdominal, (>3 cm) Complete 2 cycles adjuvant
pelvic CT and resection chemotherapydd
Consider
scani normal Positive
PET/CT scan
• Serum serum for viable
from skull
tumor AFP and seminomacc
base to mid- Resection of Incomplete
markers beta-hCG
thigh (6 wks residual mass resection Second-line
or more post- Positivebb or chemotherapyee
or
chemotherapy) Biopsy Progression

Negative See Follow-up for

for viable Seminoma, Table 4
seminomacc (TEST-A 2 of 2)

Progressive disease
(growing mass or See Second-Line Therapy (TEST-13) Recurrence,
rising markers) See Second-Line
i With contrast.
Therapy (TEST-13)
bb If PET/CT is borderline, consider surveillance and repeat PET/CT or CT. See Principles of Imaging (TEST-I).
cc In rare cases, nonseminomatous elements will be identified, and if they are non-teratomatous then proceed in the same fashion as for viable seminoma above.
dd If complete resection of all residual disease, consider chemotherapy for 2 cycles (EP or TIP or VIP or VeIP). If resection
incomplete, full course of second-line therapy
is recommended (see TEST-13). If a biopsy is performed and is positive, consider surgery if complete resection is possible or full course of second-line chemotherapy.
ee See Second-Line Chemotherapy Regimens for Metastatic Germ Cell Tumors (TEST-F).

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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PATHOLOGIC DIAGNOSIS POSTDIAGNOSTIC WORKUPff CLINICAL STAGE

Stage I with and

See Primary Treatment
without risk
(TEST-7)
factorsm,hh

• Chest/abdominal/pelvic CTi
• Repeat beta-hCG, LDH, AFP
NSGCT (includes mixed
because TNM staging is based on
seminoma/nonseminoma See Primary
post-orchiectomy valuesb,j Stage IIA,IIB
tumors and seminoma Treatment (TEST-8)
• Brain MRI,k if clinically indicatedgg
histology with elevated AFP)b
• Recommend sperm banking, if
clinically indicated

Stage IS, IIC, IIIA,m See Primary

IIIB,m IIIC,m and brain Treatment (TEST-11)
metastasis

b Mildly elevated, non-rising AFP levels may not indicate presence of germ cell k With and without contrast.
tumor. Decisions to treat should not be based on AFP values <20 ng/mL. Further m The panel recommends staging tumors with discontinuous invasion of
workup should be considered before initiating treatment for mildly elevated the spermatic cord as pT3 (high-risk stage I) and not as M1 (stage III) as
beta-hCG (generally <20 IU/L) since other factors, including hypogonadism and is recommended in the 8th edition of the AJCC Cancer Staging Manual. If
marijuana use, can cause false-positive results. See Discussion. surveillance is elected, the pelvis should be included in the imaging due to a
i With contrast. higher risk of pelvic relapses in these patients. See Discussion.
j Elevated values should be followed after orchiectomy with repeated determination ff PET/CT scan is not clinically indicated for nonseminoma.
to allow precise staging. Follow declining markers until normalization or gg Eg, beta-hCG >5000 IU/L, extensive lung metastasis, choriocarcinoma,
plateau. Staging is based on marker levels at the time that the patient starts neurologic symptoms, non-pulmonary visceral metastasis, or AFP >10,000 ng/mL.
postorchiectomy therapy (for example, for patients starting chemotherapy for hh Risk factors include lymphovascular invasion or invasion of spermatic cord or
disseminated disease, prognostic category and staging should be assigned based scrotum. Some centers consider predominance of embryonal carcinoma as an
on the serum tumor marker levels on day 1 of cycle 1 of chemotherapy). additional risk factor for relapse.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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CLINICAL PRIMARY TREATMENTii,jj

STAGE
Surveillance (preferred) See Follow-up for Nonseminoma,
Table 5 (TEST-B 1 of 3)
or
Stage I without Nerve-sparing RPLNDkk,ll See Postsurgical Management
risk factorshh (TEST-10)
or
Primary chemotherapy:p,z See Follow-up for Nonseminoma,
BEP for 1 cycle Table 7 (TEST-B 2 of 3)

Surveillance See Follow-up for Nonseminoma,

Table 6 (TEST-B 1 of 3)
or

Stage I with Primary chemotherapy:p,z See Follow-up for Nonseminoma,

risk factorshh BEP for 1 cycle Table 7 (TEST-B 2 of 3)

or
See Postsurgical Management
Nerve-sparing RPLNDkk,ll
(TEST-10)
Persistent
Stage
marker See Primary Treatment (TEST-11)
IS
elevationb
hh Risk factors include lymphovascular invasion or invasion of spermatic cord or
b Mildly elevated, non-rising AFP levels may not indicate presence of germ cell scrotum. Some centers consider predominance of embryonal carcinoma as an
tumor. Decisions to treat should not be based on AFP values <20 ng/mL. Further additional risk factor for relapse.
workup should be considered before initiating treatment for mildly elevated ii Treatment options listed based on preference. See Discussion.
beta-hCG (generally <20 IU/L) since other factors, including hypogonadism and jj Retroperitoneal lymph node dissection (RPLND) is preferred as primary treatment
marijuana use, can cause false-positive results. See Discussion. for tumors with transformed teratoma. Patients with stage I pure teratoma and
p Recommend abdomen/pelvic CT scan and chest x-ray or CT scan within the 4 normal markers should receive either surveillance or RPLND. See Discussion.
weeks prior to the initiation of chemotherapy to confirm staging, even if scan was kk RPLND is recommended within 4 weeks of CT scan and 7–10 days of marker
done previously. See Principles of Imaging (TEST-I). measurement.
z See Primary Chemotherapy Regimens for Germ Cell Tumors (TEST-E). ll See Principles of Surgery for Germ Cell Tumors (TEST-H).

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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CLINICAL STAGE PRIMARY TREATMENT

See Postsurgical
Nerve-sparing RPLNDkk,ll
Management (TEST-10)
or
Markers negative
Primary chemotherapyz: See Postchemotherapy
Stage
BEP for 3 cycles or EP for 4 cycles Management (TEST-9)
IIAmm
Persistent marker
See Primary Treatment (TEST-11)
elevationb

Primary chemotherapy:z See Postchemotherapy

BEP for 3 cycles or EP for 4 cycles Management (TEST-9)
Lymph node metastases,
within lymphatic drainage or
sites
Markers Nerve-sparing RPLNDkk,ll in highly See Postsurgical
negative selected cases Management (TEST-10)

Multifocal, symptomatic, or
Stage Primary chemotherapy:z See Postchemotherapy
lymph node metastases with
IIBmm BEP for 3 cycles or EP for 4 cycles Management (TEST-9)
aberrant lymphatic drainage

Persistent marker elevationb See Primary Treatment (TEST-11)

Preferred Regimens
BEP = Bleomycin/etoposide/cisplatin
EP = Etoposide/cisplatin

b Mildly elevated, non-rising AFP levels may not indicate presence of germ cell tumor. Decisions to treat should not be based on AFP values <20 ng/mL. Further workup
should be considered before initiating treatment for mildly elevated beta-hCG (generally <20 IU/L) since other factors, including hypogonadism and marijuana use, can
cause false-positive results. See Discussion.
z See Primary Chemotherapy Regimens for Germ Cell Tumors (TEST-E).
kk RPLND is recommended within 4 weeks of CT scan and 7–10 days of marker measurement.
ll See Principles of Surgery for Germ Cell Tumors (TEST-H).
mm RPLND is preferred as primary treatment for stage II tumors with transformed teratoma, and should be considered for stage II tumors with teratoma predominance in
patients with normal markers. See Discussion.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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POSTCHEMOTHERAPY MANAGEMENT

Negative markers, See Follow-up for

residual mass (≥1 cm) Nerve-sparing bilateral RPLNDkk,ll,nn Nonseminoma, Table 8
on CT scan (TEST-B 2 of 3)

Stage IIA, • Abdominal/pelvic

IIB treated CTi
with primary • Consider chest CTi
chemotherapy or chest x-ray
See Follow-up for
Surveillance Nonseminoma, Table 8
(TEST-B 2 of 3)
Negative markers, no
or
mass, or residual mass
<1 cm on CT scan See Follow-up for
Nerve-sparing bilateral RPLNDkk,ll,nn
Nonseminoma, Table 8
in selected cases (category 2B)
(TEST-B 2 of 3)

i With contrast.
kk RPLND is recommended within 4 weeks of CT scan and 7–10 days of marker measurement.
ll See Principles of Surgery for Germ Cell Tumors (TEST-H).
nn Referral to high-volume centers should be considered for surgical resection of masses post-chemotherapy.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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POSTSURGICAL MANAGEMENT

See Follow-up for Nonseminoma,

pN0 Surveillance
Table 9 (TEST-B 3 of 3)

See Follow-up for Nonseminoma,

Surveillance (preferred)
Table 10 (TEST-B 3 of 3)
or
Chemotherapy:z
pN1
• BEP for 2 cycles See Follow-up for Nonseminoma,
or Table 9 (TEST-B 3 of 3)
Stage I with and
• EP for 2 cycles
without risk factors,hh
IIA, IIB treated with
primary nerve-sparing
RPLND Chemotherapy (preferred):z
• BEP for 2 cycles See Follow-up for Nonseminoma,
pN2
or Table 9 (TEST-B 3 of 3)
• EP for 2 cycles
or
See Follow-up for Nonseminoma,
Surveillance
Table 10 (TEST-B 3 of 3)
Chemotherapy:z
• BEP for 3 cycles See Follow-up for Nonseminoma,
pN3
or Table 9 (TEST-B 3 of 3)
• EP for 4 cycles
pN1, pN2
Preferred Regimens
EP = Etoposide/cisplatin
Other Recommended Regimens
BEP = Bleomycin/etoposide/cisplatin
pN3
z See Primary Chemotherapy Regimens for Germ Cell Tumors (TEST-E). Preferred Regimens
hh Risk factors include lymphovascular invasion or invasion of spermatic cordor scrotum. Some centers BEP = Bleomycin/etoposide/cisplatin
consider predominance of embryonal carcinoma as an additional risk factor for relapse. EP = Etoposide/cisplatin

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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CLINICAL PRIMARY TREATMENTpp POST-CHEMOTHERAPY MANAGEMENT

STAGE
Primary If original
Good risky chemotherapy:z stage, Surveillance
Stage IS BEP for 3 cycles stage IS
Complete
Stage IIA, S1 (category 1) response, Surveillance
Stage IIB, S1 or negative If original See
Stage IIC EP for 4 cycles For recurrence,
markers stage, or Follow-up for
Stage IIIA (category 1) See Second-
T any N1-3, Nonseminoma,
Line Therapy
Primary M0-1 Nerve-sparing Table 8
(TEST-13)
chemotherapy:z bilateral (TEST-B 2 of 3)
Intermediate BEP for 4 cyclesqq RPLNDkk,ll,nn
Partial response, in selected cases
risky (category 1)
residual masses (category 2B)
Stage IIIB or
with normal AFP
VIP for 4 cyclesrr
and beta-hCG levels
(category 1)
OR
Primary
chemotherapy:z Partial response, See Post-Chemotherapy Management (TEST-12)
BEP for 4 cycles residual masses
Poor risky,oo (category 1) with abnormal AFP
Stage IIIC or and/or beta-hCG
VIP for 4 cycles in levelsss
selected patientsrr
(category 1)
Preferred Regimens
Brain Primary chemotherapyz ± RT ± surgery, BEP = Bleomycin/etoposide/cisplatin
metastases if clinically indicated EP = Etoposide/cisplatin
Other Recommended Regimens
VIP = Etoposide/ifosfamide/cisplatin
y See Risk Classification for Advanced Disease (TEST-D). oo Consider consultation with a high-volume center.
z See Primary Chemotherapy Regimens for Germ Cell Tumors (TEST-E). pp To assess response after treatment, CT with contrast of chest/abdomen/pelvis
kk RPLND is recommended within 4 weeks of CT scan and 7–10 days of marker and any other sites of disease is recommended.
measurement. qq If intermediate risk is based on LDH 1.5–3 times the upper limit of normal, then
ll See Principles of Surgery for Germ Cell Tumors (TEST-H). BEP for 3 cycles can be considered.
nn Referral to high-volume centers should be considered for surgical resection of rr Patients who may not tolerate bleomycin.
masses post-chemotherapy. ss Recommend referral to a high-volume center.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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RESPONSE AFTER POST-CHEMOTHERAPY

PRIMARY TREATMENT MANAGEMENT
Teratoma
Partial response, Surgical Surveillance
or necrosis
residual masses resection of
with normal AFP all residual Residual embryonal,
and beta-hCG levels massesnn yolk sac, Chemotherapy for 2
choriocarcinoma, or cycles (EPtt or TIP or VIP
seminoma element or VeIP)z,ee

Elevated and See Second-Line Therapy

rising AFP and/ (TEST-F)
or beta-hCG
Partial See For
levelsb
response, Follow-up for recurrence,
residual Nonseminoma, See Second-
masses with Elevated but Table 8 Line Therapy
abnormal stable AFP Close surveillance (TEST-B 2 of 3) (TEST-13)
AFP and/or and/or beta-
beta-hCG hCG levelsb
levelsss Teratoma or Surveillance
necrosis
Mildly
elevated and Consider
surgical Residual
normalizing embryonal, yolk
AFP and/ resection of Chemotherapy for 2
all residual sac, chorio-
or beta-hCG carcinoma, cycles (EPtt or TIP or VIP Preferred Regimens
levelsb massesnn or VeIP)z,ee EPtt = Etoposide/cisplatin
or seminoma
TIP = Paclitaxel/ifosfamide/cisplatin
element
VIP = Etoposide/ifosfamide/cisplatin
VeIP = Vinblastine/ifosfamide/cisplatin
b Mildlyelevated, non-rising AFP levels may not indicate presence of germ cell tumor. ee See Second-Line Chemotherapy Regimens for Metastatic Germ Cell Tumors
Decisions to treat should not be based on AFP values <20 ng/mL. Further workup (TEST-F).
should be considered before initiating treatment for mildly elevated beta-hCG nn Referral to high-volume centers should be considered for surgical resection of
(generally <20 IU/L) since other factors, including hypogonadism and marijuana use, masses post-chemotherapy.
can cause false-positive results. See Discussion. ss Recommend referral to a high-volume center.
z See Primary Chemotherapy Regimens for Germ Cell Tumors (TEST-E). tt Consider EP for low-volume residual disease.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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RECURRENCEuu SECOND-LINE THERAPYpp,vv

• Clinical trial (preferred)

Early relapse
• Chemotherapyee
(recurrrence ≤2 years
Conventional-dose therapy (VeIP or TIP)
after completion of
High-dose chemotherapy
primary treatment)
• Consider surgical salvage if solitary site
• Recommend sperm banking if clinically indicated

Prior chemotherapy Post Second-Line

Therapy (TEST-14)

• Surgical salvage, if resectable (preferred)

Late relapse • Clinical trial, if unresectable
(recurrence >2 years • Chemotherapyee
after completion of Conventional-dose therapy (VeIP or TIP)
primary treatment) High-dose chemotherapy
• Recommend sperm banking if clinically indicated

Treat per risk status on TEST-11

No prior
and
chemotherapy
Recommend sperm banking

Preferred Regimens
• High-dose chemotherapyee
• TIP = Paclitaxel/ifosfamide/cisplatin
• VeIP = Vinblastine/ifosfamide/cisplatin

ee See Second-Line Chemotherapy Regimens for Metastatic Germ Cell Tumors (TEST-F).
pp To assess response after treatment, CT with contrast of chest/abdomen/pelvis and any other sites of disease is recommended.
uu It is preferred that patients with recurrent nonseminoma be treated at centers with expertise in the management of this disease.
vv Includes best supportive care and palliative care. See NCCN Guidelines for Palliative Care.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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RECURRENCEuu POST SECOND-LINE THERAPYpp,vv

Complete Surveillance
response, or
negative markers Nerve-sparing bilateral RPLNDkk,ll,nn
in selected cases (category 2B) Surveillance

Teratoma Surveillance
or necrosis
Partial response, Surgical
residual masses resection of
with normal AFP all residual Residual
Prior embryonal,
second-
and beta-hCG massesnn
levels yolk sac,
line choriocarcinoma, Surveillance
See Follow- For
therapy or seminoma up for
element recurrence,
Nonseminoma, See Third-
Elevated and rising AFP See Third- Table 8 line therapy
and/or beta-hCG levelb Line Therapy (TEST-B 2 of 3) (TEST-15)
(TEST-G)
Partial Elevated but
response stable AFP Close
residual and/or beta- surveillance
masses with hCG levelsb
abnormal Teratoma
AFP and/or or necrosis Surveillance
beta-hCG Mildly Consider
levelsss elevated and surgical
normalizing resection of Residual embryonal,
AFP and/ all residual yolk sac,
or beta-hCG massesnn choriocarcinoma, or Surveillance
levelsb seminoma element

nn Referral to high-volume centers should be considered for surgical resection of masses

b Mildly elevated, non-rising AFP levels may not indicate presence of germ cell tumor. post-chemotherapy.
Decisions to treat should not be based on AFP values <20 ng/mL. Further workup should pp To assess response after treatment, CT with contrast of chest/abdomen/pelvis and any
be considered before initiating treatment for mildly elevated beta-hCG (generally <20 IU/L) other sites of disease is recommended.
since other factors, including hypogonadism and marijuana use, can cause false-positive ss Recommend referral to a high-volume center.
results. See Discussion. uu It is preferred that patients with recurrent nonseminoma be treated at centers with
kk RPLND is recommended within 4 weeks of CT scan and 7–10 days of marker expertise in the management of this disease.
measurement. vv Includes best supportive care and palliative care. See NCCN Guidelines for Palliative
ll See Principles of Surgery for Germ Cell Tumors (TEST-H). Care.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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RECURRENCEuu THIRD-LINE THERAPYpp,vv

Clinical trial (preferred)

Prior first- and second-line
or
conventional dose chemotherapy
High-dose chemotherapyww
or
Consider surgical salvage if solitary site

Clinical trial (preferred)

or
Conventional dose salvage chemotherapyww
Prior Prior high-dose or
chemotherapy chemotherapy Consider surgical salvage if solitary site
or
MSI/MMR testing if progression after high-dose chemotherapy
or third-line therapyww

Surgical salvage, if resectable (preferred)

Late relapse
or
(recurrence >2 years after
Chemotherapyww
completion of second-
• Conventional-dose therapy
line chemotherapy)
• High-dose chemotherapy (if not previously received)

pp To assess response after treatment, CT with contrast of chest/abdomen/pelvis and any other sites of disease is recommended.
uu It is preferred that patients with recurrent nonseminoma be treated at centers with expertise in the management of this disease.
vv Includes best supportive care and palliative care. See NCCN Guidelines for Palliative Care.
ww See Third-Line Chemotherapy Regimens for Metastatic Germ Cell Tumors (TEST-G).

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Testicular Cancer - Pure Seminoma Discussion

FOLLOW-UP FOR SEMINOMA

No single follow-up plan is appropriate for all patients. The follow-up for seminoma tables are to provide guidance, and should be modified for the individual
patient based on sites of disease, biology of disease, and length of time on treatment and may be extended beyond 5 years at the discretion of the
physician. Reassessment of disease activity should be performed in patients with new or worsening signs or symptoms of disease, regardless of the time
interval from previous studies. Further study is required to define optimal follow-up duration. See NCCN Guidelines for Survivorship.

Table 1 Clinical Stage I Seminoma: Surveillance After Orchiectomy

Year (at month intervals)
1 2 3 4 5d

H&Pa,b Every 3–6 mo Every 6 mo Every 6–12 mo Annually Annually

Abdominal ± At 3, 6, If Recurrence, treat according to

Every 6 mo Every 6–12 mo Every 12–24 mo extent of disease at relapse
Pelvic CTc,e and 12 mo

Chest x-ray As clinically indicated, consider chest CT with contrast in symptomatic patients.

Table 2 Clinical Stage I Seminoma: Surveillance After Adjuvant Treatment (Chemotherapy or Radiation)
Year (at month intervals)
1 2 3 4 5d

H&Pa,b Every 6–12 mo Every 6–12 mo Annually Annually Annually

If Recurrence, treat according to

Abdominal ±
Annually Annually Annually —— extent of disease at relapse
Pelvic CTc,e

Chest x-ray As clinically indicated, consider chest CT with contrast in symptomatic patients.

a Serum tumor markers are optional. e Inselect circumstances, an MRI can be considered to replace an abdominal/pelvic CT. The
b Testicular ultrasound for any equivocal exam. MRI protocol should include all the nodes that need to be assessed. The same imaging
c With or without contrast. modality (CT or MRI) should be used throughout surveillance. See Principles of Imaging
d CT is not recommended beyond 5 years unless clinically indicated. (TEST-I).

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
TEST-A
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Testicular Cancer - Pure Seminoma Discussion

FOLLOW-UP FOR SEMINOMA

Table 3 Clinical Stage IIA and Non-Bulky IIB Seminoma: Surveillance After Radiotherapy or Post-Chemotherapyf
Year (at month intervals)
1 2 3 4 5d

H&Pa,b Every 3 mo Every 6 mo Every 6 mo Every 6 mo Every 6 mo

Abdominal ± At 3 mo, then If Recurrence, treat according to

Annually Annually As clinically indicated extent of disease at relapse
Pelvic CTe,g at 6–12 mo

Chest x-rayh Every 6 mo Every 6 mo ——

Table 4 Bulky Clinical Stage IIB, IIC, and Stage III Seminoma: Surveillance Post-Chemotherapy
Year (at month intervals)
1 2 3 4 5d
H&P and
Every 2 mo Every 3 mo Every 6 mo Every 6 mo Annually
markersb

Abdominal/ As clinically If Recurrence, see TEST-13.

Every 4 mo Every 6 mo Annually Annually
Pelvic CTe,g,h,i,j,k indicated

Chest x-rayh Every 2 mol Every 3 mol Annually Annually Annually

a Serum tumor markers are optional. h Chest

x-ray may be used for routine follow-up, but chest CT with contrast is preferred
b Testicular ultrasound for any equivocal exam. in the presence of thoracic symptoms.
d CT is not recommended beyond 5 years unless clinically indicated. i Patients with PET-negative residual mass measuring >3 cm following chemotherapy
e In select circumstances, an MRI can be considered to replace an abdominal/pelvic CT. should undergo an abdominal/pelvic CT scan with contrast every 6 months for the first
The MRI protocol should include all the nodes that need to be assessed. The same year then annually for 5 years.
imaging modality (CT or MRI) should be used throughout surveillance. See Principles j Patients with residual masses may require more frequent imaging based on clinical
of Imaging (TEST-I). judgment.
f Assuming no residual mass or residual mass <3 cm and normal tumor markers. k PET/CT scan of skull base to mid-thigh as clinically indicated.
g With contrast. l Add chest CT with contrast if supradiaphragmatic disease present at diagnosis.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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Testicular Cancer - Nonseminoma Discussion

FOLLOW-UP FOR NONSEMINOMA

No single follow-up plan is appropriate for all patients. The follow-up for nonseminoma tables are to provide guidance, and should be modified for the
individual patient based on sites of disease, biology of disease, and length of time on treatment and may be extended beyond 5 years at the discretion of the
physician. Reassessment of disease activity should be performed in patients with new or worsening signs or symptoms of disease, regardless of the time
interval from previous studies. Further study is required to define optimal follow-up duration.

Table 5 Clinical Stage I without Risk Factors, NSGCT: Active Surveillance

Year (at month intervals)
1 2 3 4 5
H&P and
Every 2 mo Every 3 mo Every 4–6 mo Every 6 mo Annually
markersa
Abdominal If Recurrence, see TEST-13.
Every 4–6 mo Every 6 mo Annually As clinically indicated
± Pelvic CTb,c
At mo 4 and
Chest x-rayd Annually Annually Annually Annually
12

Table 6 Clinical Stage I with Risk Factors, NSGCT: Active Surveillance

Year (at month intervals)
1 2 3 4 5
H&P and
Every 2 mo Every 3 mo Every 4–6 mo Every 6 mo Annually
markersa

Abdominal As clinically If Recurrence, see TEST-13.

Every 4 mo Every 4–6 mo Every 6 mo Annually
± Pelvic CTb,c indicated

As clinically
Chest x-rayd Every 4 mo Every 4–6 mo Every 6 mo Annually
indicated

a Testicular ultrasound for any equivocal exam.

b With contrast.
c In select circumstances, an MRI can be considered to replace an abdominal/pelvic CT. The MRI protocol should include all the nodes that need to be assessed. The
same imaging modality (CT or MRI) should be used throughout surveillance. See Principles of Imaging (TEST-I).
d Chest x-ray may be used for routine follow-up, but chest CT with contrast is preferred in the presence of thoracic symptoms.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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Testicular Cancer - Nonseminoma Discussion

FOLLOW-UP FOR NONSEMINOMA

Table 7 Clinical Stage IA/B NSGCT: Treated with 1 Cycle of Adjuvant BEP Chemotherapy or Primary RPLND
Year (at month intervals)
1 2 3 4 5
H&P and
Every 3 mo Every 3 mo Every 6 mo Every 6 mo Annually
markersa

Abdominal ± If Recurrence, see TEST-13.

Annually Annuallye — — —
Pelvic CTb,c

Chest x-rayd Every 6–12 mo Annually — — —

Table 8 Clinical Stage II–III NSGCT: Surveillance After Complete Response to Chemotherapy ± Post-chemotherapy RPLNDf
Year (at month intervals)
1 2 3 4 5
H&P and
Every 2 mo Every 3 mo Every 6 mo Every 6 mo Every 6 mo
markera

Abdominal ±
Every 6 mo Every 6–12 mo Annually As clinically indicatedj
Pelvic CTb,c,g If Recurrence, see TEST-13.

Chest x-rayd,h Every 6 mo Every 6 mo Annuallyi Annuallyi —

a Testicular ultrasound for any equivocal exam.

b With contrast. e Optional for patients treated with primary RPLND.
c In select circumstances, an MRI can be considered to replace an abdominal/ g Patients with clinicalstage II disease treated with chemotherapy who undergo
pelvic CT. The MRI protocol should include all the nodes that need to be post-chemotherapy RPLND and are found to have pN0 disease or pN1 pure
assessed. The same imaging modality (CT or MRI) should be used throughout teratoma need only 1 CT scan at postoperative month 3–4 and then as clinically
surveillance. See Principles of Imaging (TEST-I). indicated. See Discussion.
d Chest x-ray may be used for routine follow-up, but chest CT with contrast is h Chest CT with contrast if supradiaphragmatic disease at baseline.
preferred in the presence of thoracic symptoms. i Chest x-ray is optional at months 36 and 48.
f Patients who have an incomplete response to chemotherapy require more j For patients with unresectable residual masses or resected residual masses
frequent imaging than is listed on this table. containing viable cancer.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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FOLLOW-UP FOR NONSEMINOMA

Table 9 Pathologic Stage IIA/B NSGCT: Post-Primary RPLND and Treated with Adjuvant Chemotherapy
Year (at month intervals)
1 2 3 4 5
H&P and
Every 6 mo Every 6 mo Annually Annually Annually
markersa

Abdominal/ 4 mo after
As clinically indicated If Recurrence, see TEST-13.
Pelvic CTb,c,k RPLND

Chest x-rayd Every 6 mo Annually Annually Annually Annually

Table 10 Pathologic Stage IIA/B NSGCT: Post-Primary RPLND and NOT Treated with Adjuvant Chemotherapyl
Year (at month intervals)
1 2 3 4 5
H&P and
Every 2 mo Every 3 mo Every 4 mo Every 6 mo Annually
markersa

Abdominal/ If Recurrence, see TEST-13.

At 3–4 mom Annually As clinically indicated
Pelvic CTb,c

Every 3–6
Chest x-rayd Every 2–4 mo Annually Annually Annually
mo

a Testicular ultrasound for any equivocal exam. k Patients who undergo RPLND and are found to have pN0 disease or pN1 pure
b With contrast. teratoma need only 1 CT scan at postoperative month 3–4 and then as clinically
c In select circumstances, an MRI can be considered to replace an abdominal/ indicated. See Discussion.
pelvic CT. The MRI protocol should include all the nodes that need to be l Patients with clinical stage IIA/IIB nonseminoma who undergo primary RPLND
assessed. The same imaging modality (CT or MRI) should be used throughout and are found to have pN0 disease (no tumor or teratoma, pathologic stage I)
surveillance. See Principles of Imaging (TEST-I). should revert to the surveillance schedule for low-risk NSGCT with the exception
d Chest x-ray may be used for routine follow-up, but chest CT with contrast is that only 1 CT scan is needed postoperatively around month 4 (Table 5).
preferred in the presence of thoracic symptoms. m This schedule assumes a complete resection has taken place.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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Testicular Cancer - Pure Seminoma Discussion

PRINCIPLES OF RADIOTHERAPY FOR PURE TESTICULAR SEMINOMA

General Principles
• Modern radiotherapy involves smaller fields and lower doses than were used in the past. References are provided to support current
recommended management.
• The mean dose (Dmean) and dose delivered to 50% of the volume (D50%) of the kidneys, liver, and bowel are lower with CT-based
anteroposterior-posteroanterior (AP-PA) three-dimensional conformal radiation therapy (3D-CRT) than intensity-modulated radiation therapy
(IMRT).1 As a result, the risk of second cancers arising in the kidneys, liver, or bowel may be lower with 3D-CRT than IMRT, and IMRT is not
recommended.2
• Timing of Radiotherapy:
Radiotherapy should start once the orchiectomy wound has fully healed.
Patients should be treated 5 days per week.
Patients who miss a fraction should be treated with the same total dose and with the same fraction size, extending the overall treatment
time slightly.
• Antiemetic medication significantly improves nausea. See the NCCN Guidelines for Antiemesis. Antiemetic prophylaxis is encouraged at
least 2 hours prior to each treatment, and some cases may require more frequent dosing.

Preparation for Radiotherapy

• A discussion of semen analysis and sperm banking prior to orchiectomy is recommended in patients who wish to preserve fertility.3,4
• If sperm banking is desired, it should be performed prior to imaging and the delivery of adjuvant therapy.

General Treatment Information

• Treatment Planning Principles
A non-contrast CT simulation should be performed with the patient supine, arms at his sides, in the treatment position.
◊◊Immobilization with a cast may be used to improve the reproducibility of patient setup.
◊◊All patients, with the exception of those who have undergone bilateral orchiectomy, should be treated with a scrotal shield.

Stage I (TEST-C 2 of 5)
Stage IIA, IIB (TEST-C 3 of 5)
References
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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Testicular Cancer - Pure Seminoma Discussion

PRINCIPLES OF RADIOTHERAPY FOR PURE TESTICULAR SEMINOMA

Stage I
• Dose: For stages IA, IB: Recommended radiation dose regimens are listed in the table below for the minority of patients who prefer adjuvant
treatment, realizing that there is a high likelihood of salvage should a relapse occur during surveillance.5
Table 1
Total Dose (Gy) Dose per Fraction (Gy) Number of Fractions
20 (preferred) 2.0 10
25.5 1.5 17
19.8 1.8 11
21.6 1.8 12
• Para-aortic (PA)-Strip Fields6 - Field Arrangement:
In patients with no history of pelvic or scrotal surgery, para-aortic strip irradiation may be delivered with opposed AP-PA fields. The weights
of the fields may be equal.
◊◊Recent nodal mapping studies suggest that fields should target the retroperitoneal lymph nodes but not necessarily the ipsilateral renal
hilar nodes (see Lateral borders).7,8
◊◊Superior and inferior borders: Borders may be determined by bony anatomy.
◊◊The superior border should be placed at the bottom of vertebral body T10/T11.9
◊◊The inferior border should be placed at the inferior border of vertebral body L5.6,10
◊◊Lateral borders:
◊◊Conventionally, PA-strip fields are approximately 10 cm wide, encompassing the tips of the transverse processes of the PA vertebrae.
◊◊The location of the kidneys within the PA-strip fields varies from patient to patient.
▪▪For patients whose kidneys are relatively medial, small renal blocks may be added at the level of T12. The right and left kidney D50%
should be ≤8 Gy (ie, no more than 50% of each kidney can receive 8 Gy or higher).1 If only one kidney is present, the kidney D15%
should be ≤20 Gy (ie, no more than 15% of the volume of the kidney can receive 20 Gy or higher).1
▪▪An alternative 3D-CRT planning technique is to base the lateral borders on vascular structures on a treatment planning CT scan
without contrast. The aorta and inferior vena cava (IVC) may be contoured on the CT scan; one should allow a 1.2- to 1.9-cm margin
on the aorta and IVC to include the para-aortic, paracaval, interaortocaval, and preaortic nodes in the clinical target volume.7,11
The planning target volume is then established by uniformly expanding the clinical target volume by 0.5 cm in all directions to
account for treatment setup errors.12 A uniform 0.7-cm margin should be provided on the planning target volume to the block edge to
take beam penumbra into account (Figure 1, see TEST-C 4 of 5).1
Special Considerations
• Ipsilateral pelvic surgery (eg, inguinal herniorrhaphy or orchiopexy) may alter the lymphatic drainage of the testis. As a result, irradiation of
the ipsilateral iliac and inguinal lymph nodes, including the surgical scar from prior surgery, has been advocated even in stage I patients.8,13
Stage IIA-IIB (TEST-C 3 of 5)
References
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
TEST-C
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Stage II PRINCIPLES OF RADIOTHERAPY FOR PURE TESTICULAR SEMINOMA

• Patients should not receive primary RT if they have a horseshoe (pelvic) kidney, inflammatory bowel disease, or a history of RT.
• For clinical stage IIA–B patients, treatment is delivered in two consecutive AP-PA phases (modified dog-leg fields and cone down). There is
no break between the 2 phases.
• Modified Dog-Leg Fields:
Dose:
◊◊The initial phase consists of treatment of modified dog-leg fields to 20–25.5 Gy (see Table 1 on TEST-C 2 of 5 for dose fractionation
options).
◊◊Boost gross disease to achieve a total dose of approximately:
Table 2: Boost to Gross Disease
Stage Total Dose (Gy) Dose per Fraction (Gy)
IIA 30 1.8–2.0 Gy per fraction
IIB 36 1.8–2.0 Gy per fraction
Target: The fields should include the retroperitoneal and proximal ipsilateral iliac lymph nodes.
◊◊Modified dog-leg fields as described by Classen et al are preferred.14
◊◊Care should be taken to ensure coverage of the ipsilateral common, external, and proximal internal iliac lymph nodes down to the top of
the acetabulum.
◊◊The fields can be set up using bony landmarks or by contouring the vascular structures, as for stage I.
▪▪The superior border should be placed at the bottom of vertebral body T10/T11.15
▪▪The inferior border should be placed at the top of the acetabulum.14
▪▪The medial border for the lower aspect of the modified dog-leg fields extends from the tip of the contralateral transverse process of
the fifth lumbar vertebra toward the medial border of the ipsilateral obturator foramen.
▪▪The lateral border for the lower aspect of the modified dog-leg fields is defined by a line from the tip of the ipsilateral transverse
process of the fifth lumbar vertebra to the superolateral border of the ipsilateral acetabulum.
▪▪Preferably, one should contour the aorta and IVC from the bottom of the T10/T11 vertebra inferiorly and ipsilateral iliac arteries and
veins down to the top of the acetabulum. One should provide a 1.2- to 1.9-cm margin on these vascular structures for the clinical
target volume.7,11 The planning target volume is then established by uniformly expanding the clinical target volume by 0.5 cm in all
directions to account for treatment setup errors.12 A uniform 0.7-cm margin should be provided on the planning target volume to the
block edge to take beam penumbra into account (Figure 2, see TEST-C 4 of 5).1
▪▪It is not necessary to include the ipsilateral inguinal nodes or the inguinal scar in the AP-PA fields unless the patient has a history of
ipsilateral pelvic surgery (eg, inguinal herniorrhaphy or orchiopexy).
• Cone Down:
Dose: The second phase (cone down) of the radiotherapy consists of daily 1.8–2 Gy fractions to a cumulative total dose of approximately
30 Gy for stage IIA and 36 Gy for stage IIB.14
Target: The nodal mass (gross tumor volume) must be contoured. A uniform, 2-cm margin from the gross tumor volume to block edge
should be provided for the AP-PA cone down fields. (Figure 3, see TEST-C 4 of 5).
Stage I (TEST-C 2 of 5)
Note: All recommendations are category 2A unless otherwise indicated. References
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
TEST-C
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Testicular Cancer - Pure Seminoma Discussion

PRINCIPLES OF RADIOTHERAPY FOR PURE TESTICULAR SEMINOMA

Treatment Modalities
• Linear accelerators with >6 MV photons should be used when possible.

Target Volumes by Stage (or location)

Figure 1: Figure 2: Figure 3:
Stage I RT Field Stage II RT Large Field Stage II Cone-down Field

Stage I (TEST-C 2 of 5)
Stage IIA, IIB (TEST-C 3 of 5)
References
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
TEST-C
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PRINCIPLES OF RADIOTHERAPY FOR PURE TESTICULAR SEMINOMA

REFERENCES
1 Zilli T, Boudreau C, Doucet R, et al. Bone marrow-sparing intensity-modulated radiation therapy for Stage I seminoma. Acta Oncol 2011;50:555-562.
2 Hall EJ, Wuu CS. Radiation-induced second cancers: the impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys 2003;56:83-88.
3 Ragni G, Somigliana E, Restelli L, et al. Sperm banking and rate of assisted reproduction treatment: insights from a 15-year cryopreservation program for male cancer
patients. Cancer 2003;97:1624-1629.
4 Saito K, Suzuki K, Iwasaki A, et al. Sperm cryopreservation before cancer chemotherapy helps in the emotional battle against cancer. Cancer 2005;104:521-524.
5 Garmezy B, Pagliaro LC. Choosing treatment for stage I seminoma: who should get what? Oncology (Williston Park) 2009;23:753-759.
6 Fossa SD, Horwich A, Russell JM, et al. Optimal planning target volume for stage I testicular seminoma: A Medical Research Council randomized trial. Medical
Research Council Testicular Tumor Working Group. J Clin Oncol 1999;17:1146.
7 Dinniwell R, Chan P, Czarnota G, et al. Pelvic lymph node topography for radiotherapy treatment planning from ferumoxtran-10 contrast-enhanced magnetic resonance
imaging. Int J Radiat Oncol Biol Phys 2009;74:844-851.
8 McMahon CJ, Rofsky NM, Pedrosa I. Lymphatic metastases from pelvic tumors: anatomic classification, characterization, and staging. Radiology 2010;254:31-46.
9 Bruns F, Bremer M, Meyer A, et al. Adjuvant radiotherapy in stage I seminoma: is there a role for further reduction of treatment volume? Acta Oncol 2005;44:142-148.
10 Classen J, Schmidberger H, Meisner C, et al. Para-aortic irradiation for stage I testicular seminoma: results of a prospective study in 675 patients. A trial of the
German testicular cancer study group (GTCSG). Br J Cancer 2004;90:2305-2311.
11 Shih
 HA, Harisinghani M, Zietman AL, et al. Mapping of nodal disease in locally advanced prostate cancer: rethinking the clinical target volume for pelvic nodal
irradiation based on vascular rather than bony anatomy. Int J Radiat Oncol Biol Phys 2005;63:1262-1269.
12 Boujelbene N, Cosinschi A, Khanfir K, et al. Pure seminoma: a review and update. Radiat Oncol 2011;6:90.
13 Jones WG, Fossa SD, Mead GM, et al. Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I Testicular Seminoma: a report on Medical Research
Council Trial TE18, European Organisation for the Research and Treatment of Cancer Trial 30942 (ISRCTN18525328). J Clin Oncol 2005;23:1200-1208.
14 Classen J, Schmidberger H, Meisner C, et al. Radiotherapy for stages IIA/B testicular seminoma: final report of a prospective multicenter clinical trial. J Clin Oncol
2003;21:1101-1106.
15 Paly JJ, Efstathiou JA, Hedgire SS, et al. Mapping patterns of nodal metastases in seminoma: rethinking radiotherapy fields. Radiother Oncol 2013;106:64-68.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
TEST-C
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Testicular Cancer Discussion

RISK CLASSIFICATION FOR ADVANCED DISEASE

(post-orchiectomy)a

Risk Status Nonseminoma Seminoma

Good Risk Testicular or retroperitoneal primary Any primary site
tumorb and
and No nonpulmonary visceral metastases
No nonpulmonary visceral metastases and
and Normal AFP
Post-orchiectomy markers- all of: Any hCG
AFP < 1,000 ng/mL Any LDH
hCG < 5,000 iu/L
LDH < 1.5 x upper limit of normal
Intermediate Testicular or retroperitoneal primary Any primary site
Risk tumorb and
and Nonpulmonary visceral metastases
No nonpulmonary visceral metastases and
and Normal AFP
Post-orchiectomy markers- any of: Any hCG
AFP 1,000–10,000 ng/mL Any LDH
hCG 5,000–50,000 iu/L
LDH 1.5–10 x upper limit of normal
Poor Risk Mediastinal primary tumorb No patients classified as poor
or prognosis
Nonpulmonary visceral metastases
or
Post-orchiectomy markers- any of:
AFP > 10,000 ng/mL
hCG > 50,000 iu/L
LDH > 10 x upper limit of normal
Source: Figure 4 from the International Germ Cell Cancer Collaborative Group: International Germ Cell Consensus
Classification: A Prognostic Factor-Based Staging System for Metastatic Germ Cell Cancers. J Clin Oncol
1997;15(2):594-603. Reprinted with permission of the American Society of Clinical Oncology.

a Markers used for risk classification are post-orchiectomy.

b Referral to a high-volume center is recommended for patients with extragonadal germ cell tumors. See Discussion.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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PRIMARY CHEMOTHERAPY REGIMENS FOR GERM CELL TUMORS

Preferred Regimens
• BEP
Etoposide 100 mg/m2 IV on Days 1–5
Cisplatin 20 mg/m2 IV on Days 1–5
Bleomycin 30 units IV weekly on Days 1, 8, and 15 or Days 2, 9, and 16
Repeat every 21 days1

• EP
(Option only for good-risk patients [see TEST-D], patients with pathologic stage II disease, and patients with viable germ cell tumor at
surgery following first-line chemotherapy)
Etoposide 100 mg/m2 IV on Days 1–5
Cisplatin 20 mg/m2 IV on Days 1–5
Repeat every 21 days2

Other Recommended Regimens

• VIP3
(Option only for intermediate or poor-risk patients or patients with viable germ cell tumor at surgery following first-line chemotherapy
[See TEST-5 and TEST-11])
Etoposide 75 mg/m2 IV on Days 1–5
Ifosfamide 1200 mg/m2 on Days 1–5 with mesna protection
Cisplatin 20 mg/m2 IV on Days 1–5
Repeat every 21 days4

1 Saxman SB, Finch D, Gonin R, Einhorn LH. Long-term follow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-
prognosis germ-cell tumors: The Indiana University Experience. J Clin Oncol 1998;16:702-706.
2 Xiao H, Mazumdar M, Bajorin DF, et al. Long-term follow-up of patients with good-risk germ cell tumors treated with etoposide and cisplatin. J Clin Oncol 1997;15:2553-
2558.
3 VIP: This regimen is high risk for febrile neutropenia and granulocyte colony-stimulating factors (G-CSFs) should be used (See NCCN Guidelines for Hematopoietic
Growth Factors).
4 Nichols CR, Catalano PJ, Crawford ED, et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced
disseminated germ cell tumors: An Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study. J Clin Oncol
1998;16:1287-1293.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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SECOND-LINE CHEMOTHERAPY REGIMENS FOR METASTATIC GERM CELL TUMORS

Conventional-Dose Chemotherapy Regimens High-Dose Chemotherapy Regimens

Preferred Regimens Preferred Regimens

• TIP1 • Carboplatin/etoposide
Paclitaxel 250 mg/m2 IV on Day 1 Carboplatin 700 mg/m2 (body surface area) IV
Ifosfamide 1500 mg/m2 IV on Days 2–5 with mesna protection Etoposide 750 mg/m2 IV
Cisplatin 25 mg/m2 IV on Days 2–5 Administer 5, 4, and 3 days before peripheral blood stem cell infusion for
Repeat every 21 days2 2 cycles4

• VeIP1 • Paclitaxel/ifosfamide/carboplatin/etoposide
Vinblastine 0.11 mg/kg IV Push on Days 1–2 Paclitaxel 200 mg/m2 IV over 24 hours on Day 1
Ifosfamide 1200 mg/m2 IV on Days 1–5 with mesna protection Ifosfamide 2000 mg/m2 over 4 hours with mesna protection on Days 2–4
Cisplatin 20 mg/m2 IV on Days 1–5 Repeat every 14 days for 2 cycles followed by
Repeat every 21 days3 Carboplatin AUC 7–8 IV over 60 minutes on Days 1–3
Etoposide 400 mg/m2 IV on Days 1–3
Administer with peripheral blood stem cell support at 14- to 21-day
intervals for 3 cycles5

1 TIP, VeIP: These regimens are high risk for febrile neutropenia and G-CSFs should be used (See NCCN Guidelines for Hematopoietic Growth Factors).
2 Kondagunta GV, Bacik J, Donadio A, et al. Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular
germ cell tumors. J Clin Oncol 2005;23:6549-6555.
3 Loehrer PJ Sr, Lauer R, Roth BJ, et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med
1988;109:540-546
4 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;357:340-348.
5 Feldman DR, Sheinfeld J, Bajorin DF et al. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis.
J Clin Oncol 2010;28:1706-1713.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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THIRD-LINE CHEMOTHERAPY REGIMENS FOR METASTATIC GERM CELL TUMORSa

High-Dose Chemotherapy NOT Previously Received
Preferred Regimens (High-Dose Chemotherapy)
• Carboplatin/etoposide
Carboplatin 700 mg/m2 (body surface area) IV
Etoposide 750 mg/m2 IV
Administered 5, 4, and 3 days before peripheral blood stem cell infusion for 2 cycles1
• Paclitaxel/ifosfamide/carboplatin/etoposide
Paclitaxel 200 mg/m2 IV over 24 hours on Day 1
Ifosfamide 2000 mg/m2 over 4 hours with mesna protection on Days 2–4
Repeat every 14 days for 2 cycles followed by
Carboplatin AUC 7–8 IV over 60 minutes on Days 1–3
Etoposide 400 mg/m2 IV on Days 1–3
Administered with peripheral blood stem cell support at 14- to 21-day intervals for 3 cycles2
Other Recommended Regimens
• Gemcitabine/paclitaxel/oxaliplatin3
Gemcitabine 800 mg/m2 IV over 30 minutes on Days 1 and 8
Paclitaxel 80 mg/m2 IV over 60 minutes on Days 1 and 8
Oxaliplatin 130 mg/m2 IV over 2 hours on Day 1
Administered on a 21-day cycle for 8 cycles
• Gemcitabine/oxaliplatin4-6
Gemcitabine 1000–1250 mg/m2 IV over 30 minutes on Days 1 and 8
followed by
Oxaliplatin 130 mg/m2 IV over 2 hours on Day 1
Administered on a 21-day cycle until disease progression or unacceptable toxicity
• Gemcitabine/paclitaxel7,8
Gemcitabine 1000 mg/m2 IV over 30 minutes on Days 1, 8, and 15
Paclitaxel 100 mg/m2 IV over 60 minutes on Days 1, 8, and 15
Administered on a 28-day cycle for 6 cycles
• Etoposide (oral)9
Etoposide 50–100 mg PO daily on Days 1–21
Administered on a 28-day cycle until disease progression or unacceptable toxicity
Useful in Certain Circumstances
• Pembrolizumab (for MSI-H/dMMR tumors)10,11
Pembrolizumab 200 mg IV over 30 minutes on Day 1
Administered on a 21-day cycle until disease progression or unacceptable toxicity
a If VeIP or TIP received as second-line therapy, high-dose chemotherapy is the preferred third-line option.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
TEST-G
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THIRD-LINE CHEMOTHERAPY REGIMENS FOR METASTATIC GERM CELL TUMORSa

High-Dose Chemotherapy Previously Received

Preferred Regimens
• Gemcitabine/paclitaxel/oxaliplatin3
Gemcitabine 800 mg/m2 IV over 30 minutes on Days 1 and 8
Paclitaxel 80 mg/m2 IV over 60 minutes on Days 1 and 8
Oxaliplatin 130 mg/m2 IV over 2 hours on Day 1
Administered on a 21-day cycle for 8 cycles
• Gemcitabine/oxaliplatin4-6
Gemcitabine 1000–1250 mg/m2 IV over 30 minutes on Days 1 and 8
followed by
Oxaliplatin 130 mg/m2 IV over 2 hours on Day 1
Administered on a 21-day cycle until disease progression or unacceptable toxicity
• Gemcitabine/paclitaxel7,8
Gemcitabine 1000 mg/m2 IV over 30 minutes on Days 1, 8, and 15
Paclitaxel 100 mg/m2 IV over 60 minutes on Days 1, 8, and 15
Administered on a 28-day cycle for 6 cycles
• Etoposide (oral)9
Etoposide 50–100 mg PO daily on Days 1–21
Administered on a 28-day cycle until disease progression or unacceptable toxicity

Useful in Certain Circumstances

• Pembrolizumab (for MSI-H/dMMR tumors)10,11
Pembrolizumab 200 mg IV over 30 minutes on Day 1
Administered on a 21-day cycle until disease progression or unacceptable toxicity

a If VeIP or TIP received as second-line therapy, high-dose chemotherapy is the preferred third-line option.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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THIRD-LINE CHEMOTHERAPY REGIMENS FOR METASTATIC GERM CELL TUMORS

REFERENCES
1 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;357:340-348.
2 Feldman DR, Sheinfeld J, Bajorin DF et al. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis.
J Clin Oncol 2010;28:1706-1713.
3 Bokemeyer C, Oechsle K, Honecker F, et al; German Testicular Cancer Study Group. 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;19:448-453.
4 Pectasides D, Pectasides M, Farmakis D, et al. Gemcitabine and oxaliplatin (GEMOX) in patients with cisplatin-refractory germ cell tumors: a phase II study. Ann Oncol
2004;15:493-497.
5 Kollmannsberger C, Beyer J, Liersch R, et al. Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory germ cell
cancer: a study of the German Testicular Cancer Study Group. J Clin Oncol 2004;22:108-114.
6 De Giorgi U, Rosti G, Aieta M, et al. Phase II study of oxaliplatin and gemcitabine salvage chemotherapy in patients with cisplatin-refractory nonseminomatous germ
cell tumor. Eur Urol 2006;50:1032-1038.
7 Einhorn LH, Brames MJ, Juliar B, Williams SD. Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following
high-dose chemotherapy with tandem transplant. J Clin Oncol 2007;25:513-516.
8 Mulherin BP, Brames MJ, Einhorn LH. Long-term survival with paclitaxel and gemcitabine for germ cell tumors after progression following high-dose chemotherapy with
tandem transplant. Am J Clin Oncol 2015;38:373-376.
9 Miller JC, Einhorn LH. Phase II study of daily oral etoposide in refractory germ cell tumors. Semin Oncol 1990;17:36-39.
10 Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409-413.
11 Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509-2520.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF SURGERY FOR GERM CELL TUMORS

• RPLND is the standard approach to the surgical management of NSGCTs in both the primary and post-chemotherapy setting. Referral to
high-volume centers with experience in performing RPLNDs should be considered.

• A template dissection or a nerve-sparing approach to minimize the risk of ejaculatory disorders should be considered in patients undergoing
primary RPLND for stage I nonseminoma.

• The “split and roll” technique in which lumbar vessels are identified and sequentially ligated allows resection of all lymphatic tissue around
and behind the great vessels (ie, aorta, IVC) and minimizes the risk of an in-field recurrence.

Post-Chemotherapy Setting
• Referral to high-volume centers should be considered for surgical resection of masses post-chemotherapy.

• Completeness of resection is a consistent independent predictor of clinical outcome. In post-chemotherapy RPLND, surgical margins should
not be compromised in an attempt to preserve ejaculation. Additional procedures and resection of adjacent structures may be required.

• Post-chemotherapy RPLND is indicated in patients with metastatic NSGCT with a residual retroperitoneal mass following systemic
chemotherapy and normalized post-chemotherapy serum tumor markers.

• A full bilateral template RPLND should be performed in all patients undergoing RPLND in the post-chemotherapy setting, with the boundaries
of dissection being the renal hilar vessels (superiorly), ureters (laterally), and the common iliac arteries (inferiorly).

• Limited data suggest increased frequency of aberrant recurrences with the use of minimally invasive laparoscopic or robotic approaches to
RPLND. Therefore, minimally invasive RPLND is not recommended as standard management at this time.1

1 Calaway AC, Einhorn LH, Masterson TA, et al. Adverse surgical outcomes associated with robotic retroperitoneal lymph node dissection among patients with testicular
cancer. Eur Urol 2019 June 4 [Epub ahead of print].

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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PRINCIPLES OF IMAGING
Staging
Pure Seminoma and Nonseminoma
• Abdominal/pelvic CT scan with contrast and chest x-ray or CT scan is recommended within 4 weeks prior to the initiation of chemotherapy to
confirm staging, even if scan was performed previously. (TEST-3, TEST-7)
Chest CT should be performed if abdominal/pelvic CT or chest x-ray is abnormal.

Treatment Response Assessment

Pure Seminoma
• Consider PET/CT scan (skull base to mid-thigh) for a residual mass >3 cm post primary chemotherapy. (TEST-5)
• PET/CT scan should be performed at least 6 weeks following completion of chemotherapy.
A negative PET/CT following chemotherapy is very reassuring. If PET/CT scan is positive, resection or interventional radiology-guided
biopsy should be considered. An alternative is to wait an additional 8–12 weeks and repeat PET/CT scan to assess for changes. If the mass
is persistently FDG-avid on PET, then resection or biopsy is recommended.

Surveillance
Pure Seminoma and Nonseminoma (TEST-A and TEST-B)
• MRI with contrast can be considered in select circumstances in place of an abdominal/pelvic CT.
MRI protocol should include visualization of retroperitoneal and pelvic nodes.
• Use the same imaging modality (CT or MRI) throughout surveillance.
• In stage I seminoma and nonseminoma, chest x-rays should be obtained when abdominal/pelvic CT scans are performed. Additional chest
imaging is not indicated under normal circumstances. In a retrospective review of nearly 560 patients, 76 patients relapsed with only four
patients having disease in the chest, one of whom had an abnormal chest x-ray (but also in the setting of an elevated AFP).1 Similar data
from Daugaard et al showed no role for chest x-ray in detecting relapse.2 Other series have also called into question the value of chest
x-rays in this and other surveillance settings for germ cell tumors.3,4

1 De La Pena H, Sharma A, Glicksman C, et al. No longer any role for routine follow-up chest x-rays in men with stage I germ cell cancer. Eur J Cancer 2017;84:354-
359.
2 Daugaard G, Gundgaard MG, Mortensen MS, et al. Surveillance for stage I nonseminoma testicular cancer: outcomes and long-term follow-up in a population-based
cohort. J Clin Oncol 2014;32:3817-3823.
3 Tolan S, Vesprini D, Jewett MA, et al. No role for routine chest radiography in stage I seminoma surveillance. Eur Urol 2010;57:474-479.
4 Gietema JA, Meinardi MT, Sleijfer DT, et al. Routine chest X-rays have no additional value in the detection of relapse during routine follow-up of patients treated with
chemotherapy for disseminated non-seminomatous testicular cancer. Ann Oncol 2002;13:1616-1620.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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American Joint Committee on Cancer (AJCC)

TNM Staging Classification for Testis Cancer 8th ed., 2017

Table 1. Definitions for T, N, M

Clinical T Primary Tumor
cTX Primary tumor cannot be assessed
cT0 No evidence of primary tumor
cTis Germ cell neoplasia in situ
cT4 Tumor invades scrotum with or without vascular/lymphatic invasion
Note: Except for Tis confirmed by biopsy and T4, the extent of the primary tumor is classified
by radical orchiectomy. TX may be used for other categories for clinical staging.

Pathological T Primary Tumor

pTX Primary tumor cannot be assessed
pT0 No evidence of primary tumor
pTis Germ cell neoplasia in situ
pT1 Tumor limited to testis (including rete testis invasion) without lymphovascular invasion
pT1a* Tumor smaller than 3 cm in size
pT1b* Tumor 3 cm or larger in size
pT2 Tumor limited to testis (including rete testis invasion) with lymphovascular invasion
OR
Tumor invading hilar soft tissue or epididymis or penetrating visceral mesothelial layer
covering the external surface of tunica albuginea with or without lymphovascular invasion
pT3 Tumor directly invades spermatic cord soft tissue with or without lymphovascular invasion
pT4 Tumor invades scrotum with or without lymphovascular invasion
*Subclassification of pT1 applies to only pure seminoma.

Continued

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing.

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American Joint Committee on Cancer (AJCC)

TNM Staging Classification for Testis Cancer 8th ed., 2017

Table 1 (continued)
Clinical N Regional Lymph Nodes M Distant Metastasis
cNX Regional lymph nodes cannot be assessed M0 No distant metastases
cN0 No regional lymph node metastasis M1 Distant metastases
cN1 Metastasis with a lymph node mass 2 cm or smaller in greatest M1a Non-retroperitoneal nodal or pulmonary metastases
dimension
OR M1b Non-pulmonary visceral metastases
Multiple lymph nodes, none larger than 2 cm in greatest
dimension
cN2 Metastasis with a lymph node mass larger than 2 cm but not S Serum Markers
larger than 5 cm in greatest dimension SX Marker studies not available or not performed
OR
Multiple lymph nodes, any one mass larger than 2 cm but not S0 Marker study levels within normal limits
larger than 5 cm in greatest dimension S1 LDH <1.5 x N* and hCG (mIU/mL) <5,000
cN3 Metastasis with a lymph node mass larger than 5 cm in and AFP (ng/mL) <1,000
greatest dimension S2 LDH 1.5–10 x N* or hCG (mIU/mL) 5,000–50,000
or AFP (ng/mL) 1,000–10,000
S3 LDH >10 x N* or hCG (mIU/mL) >50,000
Pathological N Regional Lymph Nodes or AFP (ng/mL) >10,000
pNX Regional lymph nodes cannot be assessed
pN0 No regional lymph node metastasis
pN1 Metastasis with a lymph node mass 2 cm or smaller in
greatest dimension and less than or equal to five nodes
positive, none larger than 2 cm in greatest dimension
pN2 Metastasis with a lymph node mass larger than 2 cm but
not larger than 5 cm in greatest dimension; or more than
five nodes positive, none larger than 5 cm; or evidence of
extranodal extension of tumor
pN3 Metastasis with a lymph node mass larger than 5 cm in
greatest dimension
Continued
Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing.

*N indicates the upper limit of normal for the LDH assay.

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American Joint Committee on Cancer (AJCC)

TNM Staging Classification for Testis Cancer 8th ed., 2017

Table 2. AJCC Prognostic Stage Groups Histologic Grade (G)

T N M S • Germ cell tumors are not graded
Stage 0 pTis N0 M0 S0
Stage I pT1-T4 N0 M0 SX
Stage IA pT1 N0 M0 S0
Stage IB pT2 N0 M0 S0
pT3 N0 M0 S0
pT4 N0 M0 S0
Stage IS Any pT/TX N0 M0 S1-3
Stage II Any pT/TX N1-3 M0 SX
Stage IIA Any pT/TX N1 M0 S0
Any pT/TX N1 M0 S1
Stage IIB Any pT/TX N2 M0 S0
Any pT/TX N2 M0 S1
Stage IIC Any pT/TX N3 M0 S0
Any pT/TX N3 M0 S1
Stage III Any pT/TX Any N M1 SX
Stage IIIA Any pT/TX Any N M1a S0
Any pT/TX Any N M1a S1
Stage IIIB Any pT/TX N1-3 M0 S2
Any pT/TX Any N M1a S2
Stage IIIC Any pT/TX N1-3 M0 S3
Any pT/TX Any N M1a S3
Any pT/TX Any N M1b Any S

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing.

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NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred intervention affordability.
Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
intervention or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion Nonseminoma Stage IIB ............................................................ MS-17

Advanced Metastatic Nonseminoma .......................................... MS-18

Table of Contents
Second-Line and Subsequent Therapy for Metastatic Germ Cell Tumors
Overview ............................................................................................ MS-2 ......................................................................................................... MS-20

Literature Search Criteria and Guidelines Update Methodology.......... MS-3 Second-Line Therapy ................................................................ MS-20

Clinical Presentation, Workup and Primary Treatment ........................ MS-3 Third-Line Therapy .................................................................... MS-21

Clinical Presentation .................................................................... MS-3 Treatment of Brain Metastases......................................................... MS-22

Workup ........................................................................................ MS-4 Summary.......................................................................................... MS-22

Primary Treatment ....................................................................... MS-4 References ....................................................................................... MS-23

Staging ............................................................................................... MS-5

Risk Classification for Advanced Disease .................................... ,MS-6

Pure Seminoma.................................................................................. MS-6

Pure Seminoma Stages IA and IB ................................................ MS-6

Pure Seminoma Stage IS ........................................................... MS-10

Pure Seminoma Stages IIA and IIB ............................................ MS-10

Pure Seminoma Stages IIC and III ............................................. MS-12

Nonseminoma .................................................................................. MS-13

Nonseminoma Stage I Without Risk Factors ............................... MS-14

Nonseminoma Stage I With Risk Factors.................................... MS-15

Nonseminoma Stage IS ............................................................. MS-16

Nonseminoma Stage IIA ............................................................ MS-16

MS-1
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extragonadal GCTs be referred to high-volume centers with experience in

Overview
managing these tumors.
Testicular cancer is relatively uncommon and accounts for <1% of all male
The serum tumor markers alpha-fetoprotein (AFP) and beta-human
tumors.1 However, it is the most common solid tumor in men between the
chorionic gonadotropin (beta-hCG) are critical in determining prognosis,
ages of 20 and 34 years, and the global incidence has been steadily rising
and assessing treatment outcomes in patients with testicular GCTs. Levels
over the past several decades.1-7 An estimated 9560 new cases of
of these serum tumor markers should be determined before and after
testicular cancer will be diagnosed in the United States in 2019 resulting in
treatment and throughout the follow-up period. Marker levels are very
about 410 deaths, which reflects the excellent 5-year survival rate for this
useful for monitoring all stages of nonseminomas and are also useful in
disease (~95%).1,8 Several risk factors for testicular cancer have been
monitoring stage II and III seminomas, because elevated marker levels
identified, including personal or family history of testicular cancer and
may be an early sign of relapse. In addition, lactate dehydrogenase (LDH)
cryptorchidism.2,9,10
is important for determining prognosis and is used to help risk-stratify
Testicular germ cell tumors (GCTs) comprise 95% of malignant tumors patients starting first-line chemotherapy for disseminated
arising in the testes and are categorized into two main histologic subtypes: nonseminomatous tumors.14 LDH should not be used to risk stratify
seminoma and nonseminoma.2,11,12 Nonseminomas are less common, but patients with pure seminoma. Although serum LDH concentrations are
are more aggressive and often include multiple cell types. When both elevated in about half of men with advanced testicular cancer, LDH is a
seminoma and elements of nonseminoma are present, management less specific marker for testicular cancer compared to AFP and beta-hCG.
follows that of a nonseminoma. The four types of nonseminomas are Therefore, decisions regarding treatment should not be made based on
embryonal carcinoma, choriocarcinoma, yolk sac tumor, and teratoma.11 mildly elevated (<3 x upper limit of normal [ULN]) LDH alone.
Most nonseminomas are mixed tumors of these four subtypes. Teratomas
Beta-hCG is the most commonly elevated serum tumor marker in
are sometimes classified as either mature or immature, but this distinction
testicular cancer. Elevated serum concentrations of beta-hCG may be
is of no known significance in adult men and does not affect management
present with both seminomatous and nonseminomatous tumors. However,
in these patients. Rarely, a teratoma may contain elements of a somatic
in seminoma patients with beta-hCG levels >1000 IU/L, consider the
cancer, such as a sarcoma or adenocarcinoma, and is then referred to as
possibility of nonseminoma and re-review the surgical specimen with
a teratoma with somatic type malignancy. Teratomas with somatic
pathology. Discussion with a high-volume center experienced in the
transformation are managed somewhat differently from other GCTs.
management of these patients should also be considered. Additionally,
Rarely, GCTs may originate in extragonadal sites (usually the patients with post-orchiectomy beta-hCG levels >5000 IU/L should receive
retroperitoneum or mediastinum). Patients with an extragonadal primary a brain MRI since they are at an increased risk of having brain
site are managed similarly to patients with testicular GCTs regarding metastases. Further workup should be considered before initiating
systemic therapies and management of residual masses.13 However, due treatment for mildly elevated beta-hCG (generally <20 IU/L), since other
to their rarity, the NCCN Panel recommends that patients with factors such as hypogonadism, hyperthyroidism, and marijuana use can
cause elevations of beta-hCG.15-17 Intramuscular injection of 300 mg of

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testosterone cypionate may be administered in cases of mild beta-hCG from the stroma are also not covered in these guidelines, since they
elevations of unclear etiology in order to exclude hypogonadism as a account for <5% of cases.
cause. Elevated beta-hCG has also been reported in other tumors, such
as lymphoma, bladder cancer, and adenocarcinomas, and is thus not Literature Search Criteria and Guidelines Update
specific for GCTs. Additionally, heterophile antibodies have been reported Methodology
to result in substantially elevated false-positive beta-hCG results (>400
Prior to the update of this version of the NCCN Guidelines for Testicular
IU/L); therefore, clinicians should consider repeating the test using a
Cancer, an electronic search of the PubMed database was performed
different assay if a false positive is suspected due to the absence of
using the following search terms: ‘testicular cancer’ and ‘germ cell tumor,’
radiographic evidence of disease.18,19
The PubMed database was chosen as it remains the most widely used
Elevated serum AFP is not associated with pure seminoma. Among resource for medical literature and indexes peer-reviewed biomedical
nonseminoma GCTs, it is particularly associated with yolk sac tumors but literature.23
can also be produced by embryonal carcinomas and teratoma. When
The search results were narrowed by selecting studies in humans
patients with a histologically “pure” seminoma have an elevated level of
published in English. Results were confined to the following article types:
AFP, it is generally interpreted as meaning the tumor is a mixed GCT and
Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV;
that undetected nonseminomatous GCT elements are present in addition
Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic
to the seminoma.14,20-22 Therefore, the diagnosis of a seminoma is
Reviews; and Validation Studies.
restricted to pure seminoma histology and normal serum AFP levels.
However, a small number of people have a chronically elevated serum The data from key PubMed articles as well as articles from additional
AFP level and clinicians should be cautious about initiating treatment for a sources deemed as relevant to these Guidelines and/or discussed by the
mildly elevated but stable AFP. In addition, other tumors such as panel have been included in this version of the Discussion section (eg, e-
hepatocellular carcinomas and gastric carcinomas can cause AFP publications ahead of print, meeting abstracts). Any recommendations for
elevation. If an elevation of serum AFP is due to a metastatic which high-level evidence is lacking are based on the panel’s review of
nonseminomatous GCT, then the AFP typically will be steadily rising. lower-level evidence and expert opinion.
Generally, decisions to treat should not be based solely on AFP values The complete details of the development and update of the NCCN
<20 ng/mL. Guidelines are available at www.NCCN.org.
These guidelines pertain to all stages of testicular GCTs and should be
closely followed to maximize the potential for cure and to avoid Clinical Presentation, Workup and Primary Treatment
unnecessary side effects, complications, and late toxicities. It is important Clinical Presentation
to note that pediatric GCTs are managed differently from adult GCTs and
are not covered in these guidelines. Additionally, testicular tumors arising Testicular cancer most often presents as a painless or painful testicular
nodule, mass, enlargement, or induration (hardening). Often, patients will

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present with testicular discomfort or swelling suggestive of epididymitis or considered during radical inguinal orchiectomy if desired by the patient.26-
28
orchitis. A trial of antibiotics is never warranted in a man with a mass In cases where the ultrasound shows an ambiguous abnormality that
suspicious for GCT, but can be considered in men with pain without a might be malignant, an open inguinal biopsy (testis-sparing surgery or
mass on further work-up. Other patients may present with enlarged lymph partial orchiectomy) with intraoperative frozen section analysis can be
nodes of the lower neck or upper chest (supraclavicular), a retroperitoneal performed, but such cases are extremely rare. Reflex orchiectomy is
mass, gynecomastia, venous thrombosis, or pulmonary embolism. recommended in most circumstances should malignancy be detected.
Similarly, an open inguinal biopsy of the contralateral testis can be
Workup considered if an ambiguous suspicious mass is identified on ultrasound or
If testicular cancer is being considered as a possibility, then a transscrotal if the testis is cryptorchid or shows marked atrophy.29 However, biopsies
ultrasound with Doppler should be performed. Testicular ultrasound serves are not recommended for microcalcifications.
to confirm the presence of a testicular mass, determine whether a mass is Sperm banking should be discussed with patients of reproductive age, if
intra- or extratesticular, and explore the contralateral testis.24 Testicular clinically indicated, before undergoing any therapeutic intervention that
GCTs are typically heterogeneous, hypoechoic and vascular on may compromise fertility, including surgery, radiation therapy (RT), or
ultrasound. If the ultrasound findings show a mass concerning for chemotherapy.30-33 If sperm banking is desired, it may be performed before
malignancy, then an inguinal orchiectomy is generally performed to make orchiectomy in patients with risk factors for infertility (atrophic contralateral
a diagnosis. Transscrotal biopsies of the testes should not be performed testicle, history of infertility), but certainly should be considered prior to
because violating the scrotum increases the risk of local or atypical subsequent therapy in patients who desire future fertility..
regional recurrence and can complicate management. In addition, a
Further management is dictated by histology, stage, and whether the
thorough history and physical examination should be performed. Serum
cancer is a pure seminoma or a nonseminoma (includes mixed GCTs that
tumor markers (LDH, AFP, and beta-hCG) need to be assessed as they
are partially comprised of seminoma and tumors that are
are used for prognosis and staging.12 Marker levels should be assessed
histopathologically described as pure seminomas in patients with elevated
both before and after orchiectomy. Elevated levels of beta-hCG, LDH, or
serum AFP). Though rare, when a patient presents with: 1) markedly
AFP should be followed up with repeated tests to allow for precise staging.
elevated beta-hCG or AFP levels; 2) a testicular mass and/or disease
Given the higher rates of hypogonadism in the testicular cancer
distribution typical for a testicular, retroperitoneal, or mediastinal GCT; and
population, measuring baseline levels of gonadal function can also be
3) a clinical scenario where, due to the bulk, signs, or symptoms of
considered.
disease, the risk of delaying systemic therapy outweighs the benefit of a
Primary Treatment tissue diagnosis, chemotherapy may be initiated immediately without
waiting for a biopsy diagnosis or performing orchiectomy. Consolidative
Radical inguinal orchiectomy is the primary treatment for most patients
orchiectomy may be performed after completion of systemic therapy.
who present with a testicular mass that is concerning for malignancy on
ultrasound.25 Concurrent insertion of testicular prosthesis may be

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volume of embryonal carcinoma without also having LVI, and the value of
Staging
embryonal carcinoma predominance in predicting relapse in the absence
Staging of testicular GCTs is based upon determination of the extent of of LVI is unclear.39,46,49,53 Therefore, predominance of embryonal
disease and assessment of post-orchiectomy levels of serum tumor carcinoma is not used by the NCCN Guidelines to risk stratify stage I
markers.12 The tumor (T), node (N), and metastasis (M) staging system nonseminoma patients. Stage I nonseminoma patients with a high volume
used by the AJCC is the internationally accepted standard for cancer of embryonal carcinoma and no evidence of LVI are neither high risk nor
staging and is a major factor influencing prognosis and treatment low risk and could be considered for adjuvant therapy. The NCCN
decisions. The AJCC TNM staging system incorporates serum tumor Guidelines do not recommend risk-adapted treatment for stage I pure
marker elevation as a distinct category (S), which is unique to this organ seminoma.
site. The extent of the primary tumor is classified after orchiectomy;
The 8th edition of the AJCC Cancer Staging Manual also introduced
therefore, pathologic (p) staging is assigned to the primary tumor (T).
changes to pathologic staging based on the type of spermatic cord
The 8th edition of the AJCC Cancer Staging Manual introduced invasion of involvement. Currently, continuous involvement of the spermatic cord soft
the epididymis and hilar soft tissue as new pathologic criteria used for T tissue by the primary tumor is staged as pT3, whereas discontinuous
classification of stage I testicular GCTs.12,34 Due to the excellent clinical spermatic cord involvement by invasion of lymphovascular spaces is now
outcomes seen in testicular cancer, large-scale follow-up studies have considered as a metastatic deposit (pM1).12 This significant change results
historically used tumor relapse rather than tumor-specific survival to in patients with discontinuous spermatic cord involvement being upstaged
validate the relevance of pathologic parameters used for staging.12 from high risk stage I to stage III disease independent of radiologic or
However, the association of hilar soft tissue and epididymal invasion with serologic assessment, which the panel is concerned may lead to
relapse of stage I disease has not been validated. Current data only overtreatment. The evidence used to support this change is unclear;
support their association with having advanced-stage disease at the time presently, there are no persuasive data showing differences in clinical
of diagnosis.35,36 Therefore, it is the opinion of the panel that these factors outcomes between men with discontinuous spematic cord involvment
should not be used for clinical decision-making in the management of compared to men with continuous involvement. A recent retrospective
these patients. Instead, the NCCN Guidelines recommend managing analysis assessing the impact of different patterns of spermatic cord
patients with stage I nonseminoma based on the presence or absence of involvement on clinical stage and patient outcomes found no significant
lymphovascular invasion (LVI), invasion of the spermatic cord, or invasion differences in either clinical stage at presentation or risk of recurrence
of the scrotum, which are risk factors known to be associated with an based on the type of spermatic cord involvement (continuous versus
increased risk of relapse.37-45 Predominance of embryonal carcinoma has discontinuous).54 Therefore, for management decisions, the panel
also been proposed as a prognostic indicator of relapse in stage I recommends staging GCTs with discontinuous invasion of the spermatic
nonseminoma, with several studies showing that a high proportion of cord as pT3 (high-risk stage I) and not as pM1 (stage III) as is
embryonal carcinoma in the primary tumor (>50%) is associated with an recommended by the AJCC. If surveillance is elected as primary
increased risk of relapse.39,46-53 However, very few patients have a high

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management, the pelvis should be included in the imaging due to a higher patient starts post-orchiectomy therapy. Elevated levels should be
risk of pelvic relapses in these patients. followed with repeated measurement to allow for precise staging.
Declining markers should be followed until normalization or plateau.
To assess for metastatic disease, imaging studies of the chest, abdomen,
Beta-hCG and LDH may be elevated in patients with seminoma; however,
and pelvis should be performed. Such studies typically include CT scans
elevated LDH and beta-hCG alone should not be used to stage or risk
of the abdomen and pelvis and CT scan or x-ray of the chest. PET scans
stratify patients with pure seminoma. An elevated AFP indicates
should not be used to stage testicular GCTs. In select patients, brain MRI
nonseminoma unless another cause of the elevated AFP (such as liver
should also be performed; these patients include those with neurologic
disease) is identified. Patients with seminoma arising from an
symptoms, post-orchiectomy serum beta-hCG >5000 IU/L, or extensive
extragonadal site, such as the mediastinum, are usually diagnosed via
lung metastases. In patients who had elevated serum tumor markers prior
biopsy and treated with standard chemotherapy regimens according to risk
to orchiectomy, it is important to obtain the half-life kinetics of the tumor
classification. The NCCN Panel recommends performing a brain MRI if
markers after orchiectomy if the markers are declining because a slower-
beta-hCG levels exceed 5000 IU/L or there is extensive metastatic
than-expected decline often indicates the presence of metastatic disease.
disease in the lungs (as noted above, a beta-hCG >1000 IU/L is rare in
Risk Classification for Advanced Disease seminoma and a value >5000 IU/L is generally indicative of a
nonseminomatous GCT). Sperm banking should be recommended, if
In 1997, the International Germ Cell Cancer Consensus Group (IGCCCG)
clinically indicated, to patients who will be undergoing adjuvant therapy.
defined a classification system based on identification of clinically
independent prognostic features such as extent of disease and post- Pure Seminoma Stages IA and IB
orchiectomy levels of serum tumor markers. This classification system
Primary Treatment for Pure Seminoma Stages IA and IB
categorizes patients with testicular GCTs into good-, intermediate-, or
poor-risk groups.55 When determining a patient’s risk classification, the Since most patients with stage I pure seminoma are cured by orchiectomy
relevant serum tumor marker value is the value on day 1 of cycle 1 of first- alone, the NCCN Panel strongly prefers surveillance as the standard post-
line chemotherapy. Definitions of stage and risk classification in these orchiectomy management option for these patients. However, since 15%
guidelines are done according to the IGCCCG classifications. to 20% of patients on surveillance will experience relapse, the panel
recommends chemotherapy with one or two cycles of single-agent
Pure Seminoma carboplatin, or RT (20 Gy or 25.5 Gy) to decrease the risk of relapse in
certain patients. Disease-specific survival for stage I disease approaches
If a pure seminoma is detected, an abdominal/pelvic CT scan with contrast
100% irrespective of the management strategy used.56
should be performed to assess the retroperitoneal lymph nodes. A chest x-
ray is also recommended. A chest CT with contrast is indicated if the
Surveillance: Several studies evaluating surveillance for the management
abdominal/pelvic CT or the chest x-ray shows evidence of metastatic
of stage I seminoma have been conducted.57-62 The relapse rates seen in
disease. Measurement of beta-hCG, LDH, and AFP levels should be
these studies have ranged from 15% to 20%, with most disease relapse
repeated since TNM staging is based on marker levels at the time the
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detected in the infradiaphragmatic lymph nodes. The best established risk dose carboplatin versus RT in terms of relapse-free survival.70 In an intent-
factor for relapse of pure seminoma is increased size of the primary to-treat analysis, the relapse-free survival rates at 5 years were 96% in the
tumor.63 As the tumor size increases the risk of relapse also increases, but RT arm and 94.7% in the carboplatin arm (hazard ratio [HR], 1.25; P =
any cutoff point is arbitrary.57,59,64,65-67 Although the 8th edition of the AJCC .37). One seminoma-related death occurred after RT and none occurred
Cancer Staging Manual uses a cutoff point of 3 cm to subclassify stage I after carboplatin. Additionally, patients given carboplatin were less
pure seminoma, this small cutoff size was chosen in an effort to be lethargic and less likely to take time off work than patients receiving RT.
conservative due to the large variability in size cutoffs reported in the Therefore, the authors concluded that a single dose of carboplatin is less
literature.12 Additionally, some studies have reported that rete testis toxic and as effective in preventing disease relapse as adjuvant RT in men
invasion is an independent risk factor for relapse in stage I pure seminoma with stage I pure seminoma after orchiectomy.70 However, it should be
while others have reported that it is not.57,59,63-65,68 A recent systematic noted that there are limited long-term follow-up data regarding the toxicity
review determined that rete testis invasion is significantly associated with and efficacy of carboplatin.57,71 A recent non-randomized population-based
risk of relapse in stage I seminoma patients managed by surveillance.68 In study of 897 patients with stage I seminoma suggested that patients with
contrast, another recent systematic review found rete testis invasion to be tumor size >4 cm, rete testis invasion, or both derive a smaller reduction in
significantly associated with relapse in only 4 out of the 13 studies relapse rate with one cycle of carboplatin than previously reported.57,59,71
analyzed.63 Due to these concerns, the NCCN Panel discourages risk- After a median follow-up of 5.6 years, the relapse rate in patients with one
adapted management in stage I pure seminoma and instead strongly or both risk factors was 15.5% for patients managed by surveillance
recommends surveillance for all patients who are able to adhere to the versus 9.3% for patients who received one cycle of carboplatin.57 An
surveillance schedule. If surveillance is not applicable, alternative options absolute reduction in the risk of relapse by only 6.2% may not be sufficient
are either adjuvant chemotherapy with single-agent carboplatin or to justify the use of single-cycle adjuvant carboplatin.71 Platinum-based
adjuvant RT as described below. Each approach has distinct advantages chemotherapy has been associated with cardiac toxicity and an increased
and disadvantages that should be discussed with patients and their risk for secondary cancers.72-74 However, whether such long-term risks
families in order to pick the best treatment approach on an individual ensue from single-agent carboplatin as dosed for seminoma remains
basis. unknown. Therefore, more data are needed to assess the value of one
cycle of carboplatin in treating patients with stage I seminoma.
Adjuvant Chemotherapy: Oliver et al reported the initial results of a trial
Use of two cycles of adjuvant carboplatin in this setting has also been
that randomized 1477 patients with stage I seminoma to receive either RT
studied. The second and third Spanish Germ Cell Cancer Cooperative
(n = 885) or 1 cycle of intravenous carboplatin (n = 560) at the dose AUC x
Group studies reported that two cycles of adjuvant carboplatin is effective
7 (ie, based on the formula 7 x [glomerular filtration rate (GFR, mL/min) +
in reducing the risk of relapse in high-risk stage I seminoma patients, with
25 mg]).69 At a follow-up of 3 years, the relapse-free survival rates for both
a 5-year relapse-free survival rate of 96.2% and a 5-year overall survival
groups were similar (95.9% for the RT group and 94.8% for the carboplatin
(OS) rate of 100%.75,76 The efficacy of two cycles of adjuvant carboplatin
group), which established the noninferiority of carboplatin compared to
was confirmed in a study by the Hellenic Cooperative Oncology Group,
RT.69 The mature results of this trial confirmed the noninferiority of single-

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which reported a 5-year relapse-free survival rate of 96.8% among 138 nodes.83,84 Special circumstances, such as ipsilateral pelvic surgery, may
stage I seminoma patients treated with this regimen.77 A recent alter the lymphatic drainage of the testis. Therefore, irradiation of the
prospective study reported the treatment outcomes of 725 stage I ipsilateral iliac and inguinal lymph nodes has been advocated in such
seminoma patients managed by surveillance, one cycle of carboplatin, or patients.83,85,86 It should be noted that patients treated with para-aortic RT
two cycles of carboplatin.78 Although disease-specific survival was 100% have a slightly higher rate of pelvic relapse compared with those treated
for all three strategies, crude relapse rates were significantly higher with with “dog-leg’’ RT.86-89 Prophylaxis to the mediastinum is not provided,
the one-cycle regimen (5%) compared to the two-cycle regimen (1.5%) because relapse rarely occurs at this site and mediastinal radiotherapy
after a median follow-up of 30 months. The crude relapse rate for introduces additional toxicities and late effects.
surveillance was 8.2%. Furthermore, one cycle of carboplatin
The NCCN Panel prefers active surveillance to the routine use of adjuvant
demonstrated low efficacy to control large tumors. Regardless of the
therapy for stage I seminoma patients, because the risk of relapse is low
regimen used, performing abdominal/pelvic CT scan with contrast and
when considered in relation to the potential harms of adjuvant therapy.
chest x-ray or CT scan is recommended within 4 weeks prior to the
However, if adjuvant chemotherapy is given, the NCCN Panel
initiation of chemotherapy to confirm staging, even if scans were
recommends carboplatin (AUC x 7) for either 1 or 2 cycles for patients with
previously performed.
stage IA or IB pure seminoma. If RT is delivered, the panel recommends a
total dose of 20 Gy administered in 10 fractions of 2.0 Gy each.90
Adjuvant Radiation Therapy: Numerous studies have found an increased
Alternatively, a total dose of 25.5 Gy can be given in 17 fractions of 1.5 Gy
risk for late toxicities, including development of secondary malignancies, in
each.91 Other RT dose schedules are listed in the Principles of
seminoma patients treated with RT; however, many of these patients were
Radiotherapy for Pure Testicular Seminoma in the algorithm (see Table 1
treated at a time when treatment fields were larger and radiation doses
on TEST-C 2 of 5). Patients at higher risk for morbidity from RT, such as
were higher than those currently used.79,80 One population-based study
those with a history of inflammatory bowel disease or prior RT, are
reported that RT for stage I seminoma was associated with an 80%
generally not given primary RT.
increase in the risk of death from secondary cancers.81 Another study
found that moderate-dose infradiaphragmatic RT for stage I seminoma
Follow-up for Pure Seminoma Stages IA and IB After Primary Treatment
was associated with an increased risk for secondary cancers in organs
within the radiation field.82 A recent multicenter cohort study reached Although no single follow-up plan is applicable to all patients, the NCCN
similar conclusions, reporting that the risk of developing an Panel has provided guidance for the follow-up of patients with testicular
infradiaphragmatic solid malignant neoplasm increased by 8% per Gy of GCTs for the first 5 years after the completion of therapy. These
radiation dose administered (95% CI, 6%–9%; P < .001).74 Additionally, recommendations may be individualized and extended beyond 5 years at
one study reported that RT might increase the risk of a subsequent the discretion of the physician. Follow-up strategies for patients with stage
cardiac event,72 but other analyses have not confirmed this risk.81 I seminoma vary according to the treatment modality received by the
patient (surveillance vs. adjuvant therapy). An analysis of >5000 stage I
Nodal mapping studies suggest that treatment fields should target the
seminoma patients from various trials reported that the 5-year relapse rate
retroperitoneal lymph nodes but not necessarily the ipsilateral renal hilar
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was higher with surveillance (18.6%) compared to RT (4.8% with marker-only relapse, since most patients with elevated markers will also
extended-field RT and 3.6% with para-aortic RT) or chemotherapy (6.1% have evidence of relapse on imaging. Additionally, in one of the largest
with 1 cycle of carboplatin and 2.3% with 2 cycles of carboplatin).88 An prospectively maintained databases of stage I seminoma patients
analysis of data from the Danish Testicular Cancer database reached managed with surveillance, it was reported that routine measurement of
similar conclusions, reporting that the 10-year cumulative incidence of serum tumor markers did not aid in the early diagnosis of relapse.96
disease recurrence was 32% for high-risk (tumor size ≥6 cm) stage I Therefore, routine measurement of serum tumor markers can be safely
seminoma patients given surveillance versus 2.8% for those given omitted from stage I seminoma surveillance schedules.
adjuvant RT.92 An analysis of data from the National Cancer Database
There is controversy regarding how many imaging studies should be
examined the survival outcomes of 33,094 stage I seminoma patients who
performed in patients on active surveillance. The NCCN Panel
received surveillance, chemotherapy, or RT as primary treatment after
recommends an abdominal/pelvic CT scan with or without contrast at 3, 6,
orchiectomy.93 Although OS was high for all strategies, results showed a
and 12 months during the first year, every 6 months for year 2, every 6–12
small absolute survival advantage for adjuvant therapy (RT or
months for year 3, and then every 12 to 24 months for years 4 and 5. CT
chemotherapy) over active surveillance at 10 years (95% vs. 93.4%; HR,
is not recommended beyond 5 years, unless clinically indicated. A clinical
0.58; P < .0005). However, in this study, surveillance was defined as not
trial in the United Kingdom entitled TRISST (MRC TE24/TRial of Imaging
having undergone radiation or chemotherapy, meaning that no distinction
and Schedule in Seminoma Testis) is currently investigating whether MRI
was made between patients who underwent surveillance and patients who
or a reduced CT schedule could be used as a safe and effective
never followed up. Thus, patients for whom active treatment was
alternative to standard CT-based surveillance in the management of stage
recommended but who never came in for treatment would have been
I seminoma (Clinical Trial ID: NCT00589537).97 The panel regards MRI as
considered to have undergone surveillance even if they never had any
an appropriate option that can be considered to replace abdominal/pelvic
surveillance visits or tests. Independent of the treatment modality received
CT in select circumstances. The MRI protocol should include visualization
by the patient, the risk of relapse is highest in the first 2 years following
of all the nodes that need to be assessed, including the retroperitoneal
treatment.88 In the event of relapse, clinicians should keep in mind the
and pelvic nodes, and should be performed in centers with experience in
potential for development of a second primary tumor in the contralateral
interpreting MRI results for testicular cancer. The same imaging modality
testis.
(CT or MRI) should be used throughout surveillance.
Follow-up During Active Surveillance: Follow-up for patients with stage I Several studies have suggested that relapses in the lung are rarely
seminoma managed with active surveillance after orchiectomy is outlined detected by chest x-ray alone in patients with stage I seminoma managed
in Table 1 on TEST-A 1 of 2 in the algorithm and includes a history and by active surveillance.98-100 In a recent retrospective analysis of 886 stage I
physical examination, with optional measurement of serum tumor markers, seminoma patients, 83 patients experienced relapse.99 All relapses were
performed every 3 to 6 months for the first year, every 6 months for year 2, detected by either rising tumor markers and/or follow-up CT scan; not a
every 6 to 12 months for year 3, and annually for years 4 and 5.76,94,95 The single relapse was detected by routine chest x-ray alone. Other studies
measurement of serum tumor markers is optional due to the rarity of have reported similar results, calling into question the value of chest x-rays

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in surveillance settings for stage I seminomatous GCTs.98,100 Therefore, therefore, systemic therapy should be encouraged. However, physicians
routine chest imaging, including chest x-ray and chest CT with contrast, are cautioned against treating a patient based on mildly elevated LDH or
should be reserved for patients with thoracic symptoms. beta-hCG alone, as other causes may be responsible for elevation of
these markers. Persistent elevation of serum markers is usually evidence
Follow-up After Adjuvant Treatment: Follow-up of patients treated with of metastatic disease, which will show up radiographically if doubt exists in
adjuvant therapy (chemotherapy or RT) is outlined in Table 2 on TEST-A 1 the diagnosis.
of 2 in the algorithm and includes a history and physical examination, with
optional measurement of post-orchiectomy serum tumor markers Follow-up for Pure Seminoma Stage IS
performed every 6 to 12 months for the first 2 years and annually for years
The NCCN Panel recommends repeating measurements of serum tumor
3, 4, and 5. A meta-analysis of 2466 patients reported that relapse rarely
markers and performing imaging studies (chest/abdominal/pelvic CT with
occurred >3 years after treatment with RT or carboplatin (0.2% of
contrast) to scan for evaluable disease.
patients).56 Since the rate of relapse beyond 3 years is very low for
patients treated with chemotherapy or RT, the NCCN Panel recommends Pure Seminoma Stages IIA and IIB
performing an abdominal/pelvic CT scan with or without contrast annually
Primary Treatment for Pure Seminoma Stages IIA and IIB
for the first 3 years only. In select circumstances, an MRI can be
considered to replace an abdominal/pelvic CT. The MRI protocol should Stage IIA pure seminoma is defined as metastatic disease to lymph
include visualization of the retroperitoneal and pelvic nodes and should be nodes, with a lymph node mass measuring ≤2 cm in greatest diameter.12 A
performed in centers with experience in interpreting MRI results for lymph node mass measuring 2 to 5 cm in greatest diameter is classified as
testicular cancer. The same imaging modality (CT or MRI) should be used stage IIB disease.12 To confirm staging before initiating treatment in select
throughout surveillance. Chest x-rays should be obtained only when cases of stage IIA disease with borderline retroperitoneal lymph nodes,
clinically indicated and chest CT scans with contrast should be considered waiting 4 to 6 weeks after initial imaging assessment and repeating
for symptomatic patients. CT is not recommended beyond 5 years, unless chest/abdominal/pelvic CT scans with contrast may be considered.
clinically indicated. Relapses are treated according to the stage at
Options for the primary treatment of stage IIA and IIB seminomas include
relapse.56 However, patients should not be treated based upon an
RT or chemotherapy with 3 cycles of bleomycin, etoposide, and cisplatin
elevated LDH level alone.
(BEP) or 4 cycles of etoposide and cisplatin (EP).101-103 If chemotherapy is
given, both EP and BEP are preferred regimens in this setting. However, a
Pure Seminoma Stage IS
bleomycin-free regimen should be considered in patients with reduced or
Primary Treatment for Pure Seminoma Stage IS borderline GFR, in patients older than 50 years of age, and in patients with
Stage IS pure seminoma is very uncommon and requires persistent COPD or other lung disease resulting in reduced pulmonary function.
elevation of serum tumor markers following orchiectomy. Elevated tumor Different studies have reported different outcomes with regard to whether
markers increase the risk of disease outside the retroperitoneum; chemotherapy or RT is more effective in this setting. Two recent studies
utilized data from the National Cancer Database to assess survival
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outcomes according to treatment strategy in stage IIA/B seminoma stage IIB seminoma,103,106 with RT being reserved for select patients with
patients. A retrospective study by Glaser et al compared RT with multi- non-bulky (≤3 cm) disease.101
agent chemotherapy in 1772 stage IIA–C seminoma patients treated with
The target fields for RT for stage IIA/B disease should include the para-
orchiectomy.104 After a median follow-up of 65 months, 5-year OS was
aortic and proximal ipsilateral iliac lymph nodes. Treatment is delivered in
significantly higher with RT compared to chemotherapy in stage IIA
two consecutive anteroposterior-posteroanterior (AP/PA) phases with no
patients (99% vs. 93%; HR, 0.28; 95% CI, 0.09–0.86; P = .027). However,
break in between. The initial phase consists of treatment of modified dog-
no significant difference in 5-year OS was seen in stage IIB patients
leg fields at a dose of 20 Gy delivered in 10 fractions of 2.0 Gy each or
treated with post-orchiectomy RT or chemotherapy (95.2% vs. 92.4%). A
25.5 Gy delivered in 17 fractions of 1.5 Gy each. The panel prefers
similar study by Paly et al evaluated data from the same database during
modified dog-leg fields as described by Classen et al.101 The second
the same time period and reached similar conclusions. This retrospective,
phase (cone down) consists of daily 1.8- to 2-Gy fractions to a cumulative
non-randomized study evaluated 1885 stage IIA/B seminoma patients
total dose of 30 Gy for stage IIA patients and 36 Gy for stage IIB
selected to receive either adjuvant chemotherapy or adjuvant RT.105
patients.101 Prophylactic mediastinal RT is not indicated for the
Receipt of adjuvant chemotherapy was associated with decreased 5-year
management of stage II disease.107 For details on field arrangement, see
OS in stage IIA patients (HR, 13.33; P < .01), but not in stage IIB patients
Principles of Radiotherapy for Pure Testicular Seminoma in the algorithm.
(HR, 1.39; P = .45). These studies were not randomized trials and
treatment decisions were based on the treating physician’s clinical Follow-up for Pure Seminoma Stages IIA and Non-bulky IIB After
judgment, which presumably was influenced by the specific characteristics Primary Treatment
of each patient. Therefore, it is possible that patients with more extensive
The recommended follow-up schedule for patients with stage IIA and non-
disease were selected for chemotherapy. Nevertheless, these studies
bulky stage IIB seminoma after RT or chemotherapy is outlined in Table 3
provide some support for the use of RT over chemotherapy to treat stage
on TEST-A 2 of 2 in the algorithm and includes a history and physical
IIA seminoma. In contrast, a study by Mortensen et al evaluating 363
examination with optional measurement of post-orchiectomy serum tumor
patients with stage II–III seminoma reported that the relapse rate was 6%
markers, performed every 3 months for year 1 and then every 6 months
among patients treated with chemotherapy compared to 12.6% among
for years 2 through 5.
those treated with RT. It should be noted that chemotherapy was used for
more advanced stage disease than RT in this study.67 This has led some An abdominal/pelvic CT scan with contrast is recommended at 3 months
physicians to prefer chemotherapy for stage II patients; however, these and 6 to 12 months for year 1; annually for years 2 and 3; and then as
results must be interpreted with caution since this study was not a clinically indicated for years 4 and 5. In select circumstances, an MRI can
randomized trial and did not specifically compare the two treatment be considered to replace an abdominal/pelvic CT. The MRI protocol
modalities for stage IIA disease. Therefore, the NCCN Guidelines should include visualization of the retroperitoneal and pelvic nodes and
recommend either RT or chemotherapy as primary treatment for both should be performed in centers with experience in interpreting MRI results
stage IIA and IIB seminoma. However, chemotherapy is preferred for for testicular cancer. The same imaging modality (CT or MRI) should be
used throughout surveillance. CT is not recommended beyond 5 years,
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unless clinically indicated. Chest x-ray is recommended every 6 months as described in Table 3 on TEST-A 2 of 2 in the algorithm and discussed
for the first 2 years only. Chest x-ray may be used for routine follow-up, in the section above on Follow-up for Pure Seminoma Stages IIA and
but chest CT with contrast is preferred in the presence of thoracic Non-bulky IIB After Primary Treatment.
symptoms.
Surveillance is also recommended for patients with a residual mass >3 cm
and normal serum AFP and beta-hCG levels. Additionally, a PET/CT scan
Pure Seminoma Stages IIC and III
from skull base to mid-thigh can be considered to better delineate the
Primary Treatment for Pure Seminoma Stages IIC and III presence of viable residual tumor since CT alone cannot discriminate
Patients with stage IIC or stage III seminomas are classified as either between residual neoplastic lesions and necrotic or fibrotic tissue.117-121
good or intermediate risk. Intermediate risk in seminoma is based on PET can provide useful metabolic information on these lesions, which may
metastases to organs other than the lungs. All stage IIC and stage III aid in the early detection of recurrent disease in patients with normal CT
seminomas are considered good risk except for stage IIIC disease, which findings, since functional abnormalities usually precede morphologic
involves non-pulmonary visceral metastases (eg, bone, liver, brain) and is ones.121 However, testicular GCTs are typically slow-growing and have low
considered intermediate risk. Standard primary chemotherapy is used for uptake of 18-fluorodeoxyglucose (FDG) on PET scans, often resulting in
both groups of patients. However, 3 cycles of BEP or 4 cycles of EP are unclear images of testicular lesions.122 Additionally, the abdomen and
recommended for patients with good-risk disease (both preferred),108-110 retroperitoneal space are sites of non-specific FDG uptake, which can lead
while more intensive chemotherapy with 4 cycles of BEP (preferred) or 4 to false-positive results.122 Possible sources of false-negative results
cycles of etoposide, mesna, ifosfamide, and cisplatin (VIP) is include small malignant lesions (<3 cm) and lesions with low proliferative
recommended for patients with intermediate-risk disease.111-116 VIP should indices.121 Therefore, accurate interpretation of PET scans is paramount
be reserved for patients with a contraindication to bleomycin (ie, a reduced and possible positive findings should be corroborated with the
or borderline GFR, older than 50 years of age, COPD or other lung corresponding CT results. PET/CT is not indicated for residual masses ≤3
disease resulting in reduced pulmonary function). All of these cm due to its low diagnostic accuracy in small tumors.121
chemotherapy options are category 1 recommendations except for VIP, To reduce the incidence of false-positive results due to inflammation, the
which is a category 2A recommendation. PET/CT scan should be performed at least 6 weeks after the completion of
the last cycle of chemotherapy in patients with a residual mass >3 cm and
Management of Pure Seminoma Stages IIA, IIB, IIC, and III After
normal serum tumor marker levels.121,123 A negative PET/CT following
Chemotherapy
chemotherapy is very reassuring. If the PET/CT is negative, surveillance is
After primary treatment with chemotherapy, patients with stage IIA, IIB, recommended as described in the next section on Follow-up for Pure
IIC, or III seminoma should be evaluated by CT scan with contrast of the Seminoma Bulky Stage II and Stage III After Chemotherapy. If the PET/CT
chest, abdomen, and pelvis as well as measurement of serum tumor is positive, resection or interventional radiology (IR)-guided biopsy of the
markers. Patients with normal serum AFP and beta-hCG levels and either residual mass should be considered. If the residual disease is completely
no residual mass or a residual mass ≤3 cm should undergo surveillance resected and histopathology shows viable seminoma, 2 cycles of adjuvant

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chemotherapy with the following regimens: EP, TIP (paclitaxel, ifosfamide, Chest x-ray is recommended every 2 months for year 1, every 3 months
cisplatin),124 VIP, or VeIP (vinblastine, mesna, ifosfamide, cisplatin) is for year 2, and annually for years 3 through 5. While chest x-ray may be
recommended.125,126 If the resection is incomplete and the pathology used for routine follow-up, chest CT with contrast is preferred for patients
shows viable seminoma, or if there is progressive disease (growing mass with thoracic symptoms or residual masses or nodules in the chest.
or rising markers), a full course of second-line chemotherapy (4 cycles of Patients with residual masses may require more frequent imaging based
TIP or 4 cycles of VeIP; both preferred) is recommended.124-127 In rare on clinical judgment. However, CT is not recommended beyond 5 years
cases, nonseminomatous elements may be identified in the biopsy unless clinically indicated. Since viable tumor cells have been found in
specimen. If these elements are nonteratomatous, then management tumors >3 cm with a negative post-chemotherapy PET scan,129 the NCCN
should proceed in the same fashion as for viable seminoma. Borderline Panel recommends that patients with a residual mass measuring >3 cm
PET/CT results require careful interpretation by experienced clinicians. If and negative PET results after chemotherapy should undergo an
the PET/CT is borderline, consider surveillance and repeat PET/CT or CT abdominal/pelvic CT scan with contrast every 6 months for the first year
in 8 to 12 weeks to assess for changes. If the mass is persistently FDG- and then annually for 5 years.
avid on PET/CT, then resection or biopsy is recommended. Following
adjuvant or second-line chemotherapy, patients should undergo follow-up Nonseminoma
as discussed in the next section. Patients should also adhere to this
Nonseminomatous GCTs include nonseminoma tumors, mixed
follow-up schedule if their biopsy results are negative for viable seminoma.
seminoma/nonseminoma tumors, and seminoma tumors in patients with
elevated serum AFP levels. To assess for metastatic disease, CT scans of
Follow-up for Pure Seminoma Bulky Stage II and Stage III After
the chest, abdomen, and pelvis should be performed. Use of PET/CT scan
Chemotherapy
is not clinically indicated for nonseminoma.130,131 In select patients, brain
The recommended follow-up schedule for patients with bulky stage II or MRI should also be performed; these patients include those with
stage III seminoma after treatment with chemotherapy is outlined in Table neurologic symptoms, post-orchiectomy serum beta-hCG >5000 IU/L or
4 on TEST-A 2 of 2 in the algorithm and includes a history and physical AFP >10000 ng/mL, non-pulmonary visceral metastasis, or extensive lung
examination as well as measurement of serum tumor marker levels every metastases. Elevated levels of serum beta-hCG, LDH, or AFP should be
2 months for year 1, every 3 months for year 2, every 6 months for years 3 followed up with repeated tests. Repeated measurement of serum tumor
and 4, and once during year 5. Abdominal/pelvic CT scans with contrast markers is important because TNM staging is based on post-orchiectomy
are recommended every 4 months for year 1, every 6 months for year 2, values. In patients who had elevated serum tumor markers prior to
annually for years 3 and 4, and then as clinically indicated for year 5.128 In orchiectomy, it is important to obtain the half-life kinetics of the tumor
select circumstances, an MRI can be considered to replace an markers after orchiectomy if the markers are declining, because a slower-
abdominal/pelvic CT. The MRI protocol should include visualization of the than-expected decline often indicates the presence of metastatic disease.
retroperitoneal and pelvic nodes and should be performed in centers with The NCCN Panel emphasizes that mildly elevated, non-rising AFP levels
experience in interpreting MRI results for testicular cancer. The same may not indicate the presence of a GCT. Therefore, decisions to treat
imaging modality (CT or MRI) should be used throughout surveillance.
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should not be based on AFP levels <20 ng/mL. Similarly, further workup Nonseminoma Stage I Without Risk Factors
should be considered before initiating treatment for mildly elevated beta-
Primary Treatment for Nonseminoma Stage I Without Risk Factors
hCG (generally <20 IU/L). Sperm banking should be recommended to
patients of reproductive age, if clinically indicated, before undergoing any The NCCN Panel recommends treating stage I nonseminoma patients
therapeutic intervention that may compromise fertility.30-33 based on the presence or absence of risk factors known to be associated
with an increased risk of relapse (LVI, invasion of the spermatic cord, or
Treatment options for clinical stage I disease after inguinal orchiectomy
invasion of the scrotum).37-45 However, regardless of risk factors, stage I
include surveillance, systemic therapy, and retroperitoneal lymph node
nonseminoma patients with normal post-orchiectomy serum AFP and
dissection (RPLND). Patients with clinical stage I pure teratoma and
beta-hCG levels have three management options after orchiectomy:
normal markers should receive either surveillance or RPLND. Stage II
surveillance,42,49,134,135 nerve-sparing RPLND,136 or chemotherapy (1 cycle
disease may be treated with systemic therapy or RPLND. Systemic
of BEP)137,138 as primary treatment. The major difference in the
therapy is preferred if serum tumor markers are elevated and/or if the
management of low-risk and high-risk patients is that surveillance is
enlarged lymph nodes are >3 cm in greatest dimension. RPLND is
preferred for patients with stage I nonseminoma without risk factors,
preferred as primary treatment for stage I or II tumors with transformed
whereas all three management options should be carefully considered
teratoma, and should be considered for stage II tumors with teratoma
when risk factors are present. The survival rates for stage I nonseminoma
predominance if serum tumor markers are normal. The major morbidity
managed with surveillance, nerve-sparing RPLND, or one cycle of BEP
associated with bilateral RPLND is retrograde ejaculation, resulting in
chemotherapy exceed 98%. However, the high survival rate associated
infertility. Nerve-sparing dissection techniques preserve antegrade
with surveillance depends on adherence to periodic follow-up
ejaculation in 90% of cases.132 Therefore, nerve-sparing RPLND is
examinations and subsequent chemotherapy for the 20% to 30% of
recommended. Limited data suggest increased frequency of aberrant
patients who relapse. Therefore, patients who choose surveillance should
recurrences with the use of minimally invasive laparoscopic or robotic
adhere to the follow-up schedule. When nerve-sparing RPLND is
approaches to RPLND. A recent study of recurrence patterns in patients
performed, it should be done within 4 weeks of a CT scan and within 7 to
following robotic RPLND found that recurrences were highly variable, were
10 days of repeat serum marker testing to ensure accurate presurgical
in unusual locations, and were associated with a high treatment burden.133
staging.139 Similarly, for patients electing one cycle of BEP, an
Therefore, minimally invasive RPLND is not recommended as standard
abdominal/pelvic CT scan and chest x-ray or CT scan is recommended
management at this time. Stage II and stage III disease treated with
within 4 weeks prior to the initiation of chemotherapy to confirm staging,
systemic chemotherapy should be followed by surgical resection of any
even if scans were done previously.
residual masses.
Management of Nonseminoma Stage I Without Risk Factors After
RPLND
If the resected lymph nodes are negative for malignancy (pN0) after nerve-
sparing RPLND, the patient should undergo surveillance. For positive
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lymph nodes (pN1 to pN3), the decision whether to use adjuvant patients managed by surveillance. Chest x-ray is not indicated in years 3,
chemotherapy is based on the degree of nodal involvement. Surveillance 4, and 5 for stage I nonseminoma patients without risk factors treated with
is the preferred option for patients with pN1 disease, while chemotherapy adjuvant BEP or primary RPLND.
is the preferred option for patients with pN2 disease. However,
chemotherapy is the only option for patients with pN3 disease. Nonseminoma Stage I With Risk Factors
Recommended chemotherapy regimens include two cycles of either EP Primary Treatment for Nonseminoma Stage I With Risk Factors
(preferred) or BEP for patients with pN1 or pN2 disease140,141 and 3 cycles
Surveillance, adjuvant chemotherapy (1 cycle of BEP), or nerve-sparing
of BEP or 4 cycles of EP (both preferred) for patients with pN3 disease.
RPLND are the recommended primary treatment options for stage I
Follow-up for Nonseminoma Stage I Without Risk Factors nonseminoma patients with LVI, invasion of the spermatic cord, or
invasion of the scrotum. In a prospective trial by SWENOTECA, stage I
The long-term follow-up for stage I nonseminoma patients without risk
nonseminoma patients with or without LVI received 1 course of adjuvant
factors includes a history and physical examination, serum tumor marker
BEP.138 The relapse rate at 5 years was 3.2% for patients with LVI and
assessment, abdominal/pelvic CT scan, and chest x-ray. In select
1.6% for patients without LVI. Five-year OS was 100% in both groups.37
circumstances, an MRI can be considered to replace an abdominal/pelvic
The results after a median follow-up of 7.9 years confirmed the low
CT scan. The MRI protocol should include visualization of the
relapse rate with 1 course of adjuvant BEP, especially in patients with
retroperitoneal and pelvic nodes and should be performed in centers with
LVI.37 Several other studies using two cycles of BEP as primary treatment
experience in interpreting MRI results for testicular cancer. The same
for stage I nonseminoma patients have similarly reported relapse-free
imaging modality (CT or MRI) should be used throughout surveillance. All
survival rates >95%.135,141,143-146 However, late consequences of cisplatin-
imaging in this setting is performed with contrast. The frequency of these
based chemotherapy, such as hearing damage and loss, cardiovascular
tests varies with the primary treatment modality received by the patient
conditions, hypertension, and neuropathy, have been reported during
(see Tables 5 and 7 on TEST-B in the algorithm). It should be noted that
long-term follow-up.147-155 Therefore, one cycle of BEP is recommended
routine chest x-ray may have limited value for detecting relapse in stage I
due to its lower toxicity. Surveillance is also a recommended primary
nonseminoma patients. In a recent retrospective study, a total of 76
treatment option for stage I nonseminoma patients with risk factors.
relapses were detected among 561 stage I nonseminoma patients
However, it should be noted that LVI is a significant predictor of relapse
managed by active surveillance following orchiectomy.99 All relapses were
when orchiectomy is followed by surveillance alone.25
detected by either rising serum tumor markers and/or abnormal routine
follow-up CT scans; not a single relapse was detected by chest x-ray Management of Nonseminoma Stage I With Risk Factors After RPLND
alone. Similar results have been reported in other studies, calling into
The management of stage I nonseminoma patients with risk factors after
question the value of chest x-rays in surveillance settings for stage I
primary RPLND is similar to that of stage I nonseminoma patients without
nonseminomatous GCTs.49,100,142 The current schedule for routine chest x-
risk factors, as described above.
ray in the follow-up of stage I nonseminoma patients without risk factors is
two chest x-rays in year 1 and one chest x-ray in years 2 through 5 in
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Follow-up for Nonseminoma Stage I With Risk Factors Primary Treatment for Nonseminoma Stage IS
The long-term follow-up for stage I nonseminoma patients with risk factors The NCCN Panel recommends that stage IS nonseminoma patients be
includes history and physical examination, serum tumor marker treated with primary chemotherapy if the elevated marker is AFP or beta-
assessment, chest x-ray, and abdominal/pelvic CT scan. In select hCG. For the purposes of this guideline, the NCCN Panel assumes that
circumstances, an MRI can be considered to replace an abdominal/pelvic patients with stage IS disease have markers in the S1 range. It would be
CT scan. The MRI protocol should include visualization of the extraordinarily rare for a patient to have an AFP >1000 ng/mL or a beta-
retroperitoneal and pelvic nodes and should be performed in centers with hCG >5000 IU/L and yet have no evidence of metastatic disease on
experience in interpreting MRI results for testicular cancer. The same imaging studies. These guidelines cannot address every possible
imaging modality (CT or MRI) should be used throughout surveillance. All situation, and the management of those rare patients with T any, N0, M0,
imaging in this setting is performed with contrast. The frequency of these S2-3 disease should be individualized; consultation with a high volume
tests varies with the primary treatment modality received by the patient center is recommended. The vast majority of stage IS patients have serum
(see Tables 6 and 7 on TEST-B in the algorithm). Chest x-ray may be tumor markers in the S1 range, and they should receive primary
used for routine follow-up, but chest CT with contrast is preferred in chemotherapy for good-risk disease: either 3 cycles of BEP or 4 cycles of
patients with thoracic symptoms. EP (both preferred). Both regimens are category 1 recommendations, and
either is preferable to initial RPLND as these patients nearly always have
Nonseminoma Stage IS disseminated disease.156,157
Patients with stage IS nonseminoma exhibit persistent elevation of serum
Management of Nonseminoma Stage IS After Primary Treatment
tumor markers post-orchiectomy, but no radiographic evidence of disease.
However, mildly elevated levels of AFP or beta-hCG after orchiectomy The management of patients with stage IS nonseminoma after primary
must be interpreted with caution. Mildly elevated, non-rising AFP levels treatment with chemotherapy is described below in Advanced Metastatic
(<20 ng/mL) may not indicate the presence of a GCT and should not be Nonseminoma (see Management of Good-, Intermediate-, and Poor-Risk
used to guide treatment decisions. In addition, hyperthyroidism, marijuana Nonseminoma After Chemotherapy).
use, hypogonadism, and heterophile antibodies can result in significant
elevations of beta-hCG.15-19 Elevated beta-hCG due to metastatic disease Nonseminoma Stage IIA
typically rises steadily on serial measurements. In patients with mildly Primary Treatment for Nonseminoma Stage IIA
elevated but stable beta-hCG and no other evidence of metastatic
Primary treatment for patients with stage IIA nonseminoma depends on
disease, repeating the test using a different assay should be considered.
post-orchiectomy serum tumor marker levels. For patients with normal
Furthermore, many different conditions can result in an elevation of LDH,
post-orchiectomy levels of AFP and beta-hCG, the NCCN Panel
including many benign conditions. Therefore, patients should not be
recommends either nerve-sparing RPLND or chemotherapy with 3 cycles
treated with chemotherapy for systemic disease if the only evidence of
of BEP or 4 cycles of EP as primary treatment options (both BEP and EP
systemic disease is an elevation of LDH.
are preferred regimens).158,159 Chemotherapy is considered particularly
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appropriate if the patient has multifocal disease. For stage IIA patients with rationale for this extended region of dissection is the greater likelihood of
persistently elevated AFP and/or beta-hCG levels, the NCCN Panel bilateral disease with greater tumor burden.165 Referral to high-volume
recommends primary chemotherapy with 3 cycles of BEP or 4 cycles of centers should be considered for surgical resection of masses post-
EP (both category 1; both preferred).136,160 A bleomycin-free regimen chemotherapy. For patients with no residual mass or a residual mass <1
should be considered in patients with reduced or borderline GFR, in cm, surveillance is recommended. Nerve-sparing bilateral RPLND is a
patients over the age of 50, and in patients with COPD or other lung category 2B recommendation in this setting and may be performed in
disease resulting in reduced pulmonary function. selected cases.
Management of Nonseminoma Stage IIA After Primary Treatment
Follow-up for Nonseminoma Stage IIA
Treatment options following primary nerve-sparing RPLND include either The long-term follow-up for stage IIA nonseminoma patients includes a
surveillance or chemotherapy, depending on the number of positive lymph history and physical examination, serum tumor marker assessment, chest
nodes identified. Since RPLND is likely a curative procedure in patients x-ray, and abdominal/pelvic CT scan. In select circumstances, an MRI can
with pN0 disease, surveillance is recommended for this group. be considered to replace an abdominal/pelvic CT. The MRI protocol
Surveillance is also the preferred option for patients with pN1 disease, should include visualization of the retroperitoneal and pelvic nodes and
although chemotherapy with 2 cycles of either EP or BEP can also be should be performed in centers with experience in interpreting MRI results
considered.136,161 If chemotherapy is given, EP is the preferred regimen in for testicular cancer. The same imaging modality (CT or MRI) should be
this setting. The risk of relapse in clinical stage IIA nonseminoma patients used throughout surveillance. All imaging in this setting is performed with
with pN2 or pN3 disease after RPLND is >50%.136,162 This risk is reduced contrast. The frequency of these tests varies with the primary treatment
to <1% with 2 cycles of adjuvant cisplatin-based chemotherapy.136,163,164 modality and post-surgical management received by the patient (see
Therefore, the NCCN Panel prefers 2 cycles of adjuvant chemotherapy Tables 8, 9, and 10 on TEST-B in the algorithm). Chest x-ray may be used
with EP (preferred regimen) or BEP to surveillance for pN2 disease and for routine follow-up, but chest CT with contrast is preferred in patients
recommends full-course chemotherapy (and not surveillance) for pN3 with thoracic symptoms.
disease (either 3 cycles of BEP or 4 cycles of EP; both preferred).
Nonseminoma Stage IIB
Subsequent management after primary chemotherapy depends on the
size of the residual mass on CT scan. Patients should thus undergo Primary Treatment for Nonseminoma Stage IIB
abdominal/pelvic CT scan with contrast within a month of completing Primary treatment for patients with stage IIB nonseminoma depends on
chemotherapy; chest CT with contrast or chest x-ray may also be post-orchiectomy tumor marker levels and radiographic findings. When
considered. If the residual mass is ≥1 cm after chemotherapy, nerve- tumor marker levels are normal, the CT findings determine the proper
sparing bilateral RPLND is recommended. A bilateral RPLND involves course of treatment. If abnormal radiographic findings are limited to lymph
removal of lymphatic tissue between both ureters, spanning from the node metastases within lymphatic drainage sites in the retroperitoneum
diaphragmatic crus to the bifurcation of the common iliac arteries. The (ie, the landing zone), patients may receive primary chemotherapy with

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either 3 cycles of BEP or 4 cycles of EP (both preferred) or primary nerve- Advanced Metastatic Nonseminoma
sparing RPLND (reserved for highly selected cases). Both options of
The primary chemotherapy options for patients with advanced metastatic
primary chemotherapy or primary nerve-sparing RPLND are comparable
nonseminoma are based on the IGCCCG risk classification, which
in terms of outcome, but side effects and toxicity are different.159 The
categorizes patients as good, intermediate, or poor risk based on
reported relapse-free survival with either approach is close to 98%.162-
164,166,167
identification of clinically independent prognostic features such as extent
If metastatic disease (based on radiographic findings) is not
of disease and post-orchiectomy levels of serum tumor markers.55 When
confined to within the lymphatic drainage sites (ie, multifocal or
determining a patient’s risk classification, the relevant serum tumor marker
symptomatic lymph node metastases with aberrant lymphatic drainage
value is the value on day 1 of cycle 1 of first-line chemotherapy.
sites), primary chemotherapy (3 cycles of BEP or 4 cycles of EP; both
preferred) is recommended. For stage IIB nonseminoma patients with Primary Treatment for Good-Risk Nonseminoma
persistent marker elevation, the recommended treatment option is also
The IGCCCG good-risk group includes patients with stages IS, IIA (S1),
primary chemotherapy with either 3 cycles of BEP or 4 cycles of EP (both
IIB (S1), IIC, and IIIA disease. Treatment for good-risk disease is designed
category 1; both preferred). A bleomycin-free regimen should be
to limit toxicity while maintaining maximal efficacy. Presently, two
considered in patients with reduced or borderline GFR, in patients older
regimens are recommended by the NCCN Panel: 3 cycles of BEP108,110,168
than 50 years of age, and in patients with COPD or other lung disease
or 4 cycles of EP109,110,168 (both category 1; both preferred). While both
resulting in reduced pulmonary function.
regimens are well tolerated and cure approximately 90% of patients with
Management of Nonseminoma Stage IIB After Primary Treatment good-risk disease,168,169 four cycles of EP should be considered in patients
with reduced or borderline GFR, in patients older than 50 years of age,
The management of patients with stage IIB nonseminoma after primary
and in patients with COPD or other lung disease resulting in reduced
treatment with either nerve-sparing RPLND or chemotherapy is similar to
pulmonary function.
the post-primary management scheme outlined above for patients with
stage IIA nonseminoma (see Management of Nonseminoma Stage IIA Primary Treatment for Intermediate-Risk (Stage IIIB) Nonseminoma
After Primary Treatment).
For patients with intermediate-risk disease, the cure rate is approximately
Follow-up for Nonseminoma Stage IIB 70% with the standard chemotherapy regimen of 4 cycles of BEP.170,171
Therefore, the NCCN Panel recommends 4 cycles of BEP (preferred), or 4
The long-term follow-up schedule for stage IIB nonseminoma patients is
cycles of VIP170,172 for patients who may not tolerate bleomycin, for the
similar to the follow-up schedule outlined above for patients with stage IIA
treatment of intermediate-risk (stage IIIB) nonseminoma. Both regimens
nonseminoma and is dependent upon the primary treatment modality and
are category 1 recommendations. However, if intermediate-risk status is
post-surgical management received by the patient (see Follow-up for
based solely on LDH levels 1.5 to 3 x ULN, then 3 cycles of BEP can be
Nonseminoma Stage IIA and Tables 8, 9, and 10 on TEST-B in the
considered.
algorithm).

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Primary Treatment for Poor-Risk (Stage IIIC) Nonseminoma with either EP, TIP, VIP, or VelP should be administered. All regimens are
preferred in this setting, though EP should be reserved for patients with
The standard chemotherapy regimen for poor-risk disease is 4 cycles of
low-volume residual disease.
BEP (preferred). Alternatively, 4 cycles of VIP can be used to treat
patients who may not tolerate bleomycin.172 Both regimens are category 1 Further management for patients who experience a partial radiographic
recommendations. However, fewer than 50% of patients with poor-risk response to chemotherapy (residual masses) with abnormal tumor marker
nonseminoma experience a durable complete response to 4 cycles of levels is guided by the kinetics of the tumor markers. If tumor marker
BEP, and at least 30% die of their disease.55,173 Therefore, consultation levels are elevated and persistently rising, the NCCN Panel recommends
with a high-volume center should be considered for the management of a full course of second-line chemotherapy (see Second-Line Therapy
these patients.169 below). Patients with elevated but stable marker levels should be closely
surveilled. Patients with mildly elevated and normalizing markers should
Management of Good-, Intermediate-, and Poor-Risk Nonseminoma be considered for surgical resection of residual masses with subsequent
After Chemotherapy post-surgical management as discussed above. The NCCN Panel
At the conclusion of primary chemotherapy, chest/abdominal/pelvic CT recommends referral to a high-volume center for the management of
scan with contrast and measurement of serum tumor marker levels are patients with a partial response to primary chemotherapy and abnormal
indicated to assess treatment response. If a complete response to marker levels.
chemotherapy is found by radiographic imaging and the tumor marker
Follow-up for Good-, Intermediate-, and Poor-Risk Nonseminoma
levels are normal, the NCCN Panel recommends surveillance. Nerve-
sparing bilateral RPLND can be considered in select cases for patients The long-term follow-up for patients with good-, intermediate-, and poor-
who had retroperitoneal lymphadenopathy prior to chemotherapy risk nonseminoma after chemotherapy (with or without post-chemotherapy
(category 2B).174 RPLND is recommended within 4 weeks of the CT scan RPLND) includes history and physical examination, serum tumor marker
and 7 to 10 days of marker measurement. Referral to high-volume centers assessment, chest x-ray, and abdominal/pelvic CT scan. The frequency of
should be considered for surgical resection of residual masses following these tests is outlined in Table 8 on TEST-B. Patients who have an
chemotherapy. incomplete response to chemotherapy require more frequent imaging than
is outlined in the table. Patients who undergo RPLND and are found to
If there is a partial radiographic response to chemotherapy (as indicated
have pN0 disease or pN1 pure teratoma need only 1 CT scan at
by the presence of residual masses) and tumor marker levels are normal,
postoperative month 3 to 4 and then as clinically indicated. In select
then surgical resection of all residual masses is recommended.175-178 As
circumstances, an MRI can be considered to replace an abdominal/pelvic
previously stated, referral to high-volume centers should be considered for
CT. All imaging in this setting is performed with contrast. Chest x-ray may
surgical resection of masses post-chemotherapy. If only necrotic debris or
be used for routine follow-up, but chest CT with contrast is preferred in
teratoma is present in the resected tissue, the patient should be put under
patients with thoracic symptoms.
surveillance. If embryonal, yolk sac, choriocarcinoma, or seminoma
elements are found in the residual mass, then 2 cycles of chemotherapy
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with high-dose chemotherapy in patients with relapsed GCTs.187 The

Second-Line and Subsequent Therapy for Metastatic
foundation of the TIGER trial was formed based on the results of a large
Germ Cell Tumors retrospective analysis by Lorch et al, which demonstrated the superiority
Second-Line Therapy of carboplatin-based high-dose chemotherapy compared to cisplatin-
based conventional-dose chemotherapy with respect to 2-year
Patients with disease relapse following first-line therapy, or those who do
progression-free survival (50% vs. 28%; P < .001) and 5-year OS (53% vs.
not experience a durable complete response to first-line therapy, should
41%, P < .001).188,189 The TIGER trial will randomize patients with
receive second-line therapy. Patients with recurrent disease who have not
unequivocal disease progression following cisplatin-based primary
been treated with prior chemotherapy should be managed per their risk
chemotherapy to receive conventional-dose TIP or high-dose paclitaxel
status, as described in the preceding sections. It is preferred by the panel
plus ifosfamide followed by high-dose carboplatin plus etoposide with stem
that patients with recurrent nonseminoma be treated at centers with
cell support. OS is the primary endpoint. Secondary endpoints include
expertise in the management of this disease. Second-line therapy options
progression-free survival, response rate, toxicity, quality of life, and
for patients with early relapses (within 2 years of the completion of primary
biological correlates.187,188 This trial is currently recruiting patients and
therapy) include enrollment in a clinical trial (preferred), conventional-dose
participation is highly encouraged (Clinical Trial ID: NCT02375204).
chemotherapy, or high-dose chemotherapy. If chemotherapy is given, both
conventional-dose and high-dose regimens are preferred in this setting. Management of Metastatic Germ Cell Tumors After Second-Line
The conventional-dose regimens are TIP or VeIP.124,179-181 The high-dose Therapy
regimens include high-dose carboplatin plus etoposide followed by
autologous stem cell transplant,182 or paclitaxel plus ifosfamide followed by To assess response after second-line therapy, a CT scan with contrast of
high-dose carboplatin plus etoposide with stem cell support.183 the chest, abdomen, pelvis, and any other sites of disease is
Alternatively, surgical salvage may be considered if the recurrent mass is recommended. Levels of serum tumor markers should also be measured.
in a solitary resectable site.184 Late relapses (>2 years after completion of Patients with a complete response to second-line therapy with normal
primary therapy) occur in 2% to 3% of testicular cancer survivors.185,186 marker levels should be put under surveillance. Alternatively, select
patients may receive nerve-sparing bilateral RPLND (category 2B),
The NCCN Panel prefers surgical salvage for these patients, if the
followed by surveillance. For patients with a partial response to second-
recurrent mass is resectable.184 If it is unresectable, chemotherapy
(conventional-dose or high-dose) is the preferred option. Clinical trial line therapy (as indicated by residual masses on CT scan) and normal
enrollment is also an option for patients with unresectable late relapses. marker levels, surgical resection of all residual masses is recommended
followed by surveillance. Patients with a partial response to second-line
Since it is not currently known whether high-dose chemotherapy is better therapy (residual masses) and abnormal marker levels should be
than conventional-dose chemotherapy in the second-line setting for managed according to the kinetics of the tumor markers. If tumor marker
patients with relapsed disease, the NCCN Panel recommends clinical trial levels are elevated and persistently rising, the NCCN Panel recommends
enrollment for these patients. An ongoing, randomized, international phase third-line therapy (see Third-Line Therapy below). Patients with elevated
III trial (TIGER) will compare second-line conventional-dose chemotherapy but stable tumor marker levels should be closely surveilled. Patients with
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mildly elevated and normalizing markers should be considered for surgical (GEMOX) is based on data from phase II studies investigating the efficacy
resection of residual masses followed by surveillance. and toxicity of GEMOX in patients with relapsed or cisplatin-resistant
GCTs.191,193,195 These studies showed that GEMOX is safe for patients
Third-Line Therapy with cisplatin-resistant testicular GCTs and may offer a chance of
Participation in a clinical trial is the preferred treatment option for patients long-term survival.191,193,195 Gemcitabine and paclitaxel is another option
who experience relapse following first- and second-line therapy. that has shown promising results in a phase II study.192 Follow-up results
Alternatively, patients previously treated with conventional-dose showed long-term disease-free survival in patients who progressed after
chemotherapy can receive high-dose regimens or be considered for high-dose chemotherapy and had not received prior paclitaxel or
surgical salvage if the recurrent mass is in a solitary resectable site. gemcitabine.194 A phase II study of patients with treatment-resistant GCTs
Alternative options for patients previously treated with high-dose regimens also found the combination of gemcitabine, oxaliplatin, and paclitaxel to be
include conventional-dose salvage chemotherapy, surgical salvage (if effective with acceptable toxicity.190 The overall response rate was 51%
solitary resectable site), and microsatellite instability/mismatch repair with 5% of patients achieving a complete response. A second study
(MSI/MMR) testing (if disease progresses after high-dose chemotherapy reported similar results.196 Additionally, high-dose single-agent oral
or third-line therapy). The preferred treatment option for patients who etoposide was shown to be effective in a phase II study involving patients
experience a late relapse (>2 years after completion of second-line who had previous treatment with cisplatin/etoposide combination
therapy) is surgical salvage, if the recurrent mass is resectable. regimens.197
Conventional-dose or high-dose chemotherapy (if not previously received), Pembrolizumab, an anti-PD-1 antibody, was approved by the FDA for the
are also options for patients with late relapse. treatment of patients with unresectable or metastatic MSI-H/dMMR solid
In order to maintain optimal efficacy and limit treatment-related toxicities, tumors that have progressed following prior treatment and who have no
the chemotherapy regimens previously received by the patient should be satisfactory alternative treatment options.198 This first-ever tissue- and site-
taken into account when deciding on third-line therapy options. High-dose agnostic indication was based on data from phase II clinical trials that
chemotherapy is the preferred third-line option if it has not been previously demonstrated the efficacy of pembrolizumab in MSI-H/dMMR solid
received. If high-dose chemotherapy was previously received by the tumors.199,200 In the only trial (phase II) investigating the efficacy of
patient, then palliative chemotherapy is the preferred third-line treatment immunotherapy in testicular cancer, 12 patients with nonseminoma GCTs
option. Additionally, the panel considers pembrolizumab immunotherapy to who progressed after first-line cisplatin-based therapy and ≥1 salvage
be useful in certain circumstances (ie, in patients with MSI-high/deficient regimen (high-dose or conventional-dose chemotherapy) were treated with
MMR [MSI-H/dMMR] tumors). pembrolizumab.201 Two patients achieved stable disease for 28 and 19
weeks, respectively, but no partial or complete responses were observed.
The recommended third-line palliative chemotherapy options for patients
There were six grade 3 adverse events, but no immune-related adverse
with intensively pretreated, cisplatin-resistant, or refractory GCTs are
events were reported. Therefore, pembrolizumab was well tolerated but
combinations of gemcitabine with paclitaxel and/or oxaliplatin,190-196 or oral
appears to have limited single-agent activity in refractory GCTs. However,
etoposide.197 The recommendation for gemcitabine and oxaliplatin
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larger phase II and phase III trials of pembrolizumab in patients with treatment decisions.202,204 Therefore, management decisions are usually
metastatic or refractory testicular cancers are needed to fully assess the based on institutional preferences, which may in part explain the large
value of this therapy, especially in treating MSI-H/dMMR testicular GCTs. variation in treatment modalities received by these patients. The NCCN
Guidelines recommend primary cisplatin-based chemotherapy for patients
Treatment of Brain Metastases with brain metastases. The addition of RT to chemotherapy regimens can
Brain metastases from testicular GCTs are relatively rare and occur also be considered.207 Surgical resection of metastatic brain lesions
should be performed if clinically indicated and feasible.
almost exclusively in patients with nonseminoma histology.202 The
development of brain metastases may be more common in patients with a
Summary
higher burden of systemic disease; lung, liver, and/or bone metastases;
high levels of serum beta-hCG (>5000 IU/L); and in those who experience The NCCN Guidelines for Testicular Cancer provide an evidence- and
relapse after cisplatin-based chemotherapy. The prognosis of patients with consensus-based treatment approach for the management of adult
brain metastases from testicular GCTs is poor, with >50% of patients patients with seminomatous and nonseminomatous testicular GCTs.
dying within one year of diagnosis.202,203 Patients with additional adverse Testicular GCTs are sensitive to platinum-based chemotherapy and
prognostic factors, especially those with metachronous brain metastases, patients have high cure rates even with metastatic disease. Although the
have even worse outcomes.202,204,205 majority of metastatic testicular GCTs are cured with chemotherapy, 20%
to 30% of patients will relapse after first-line chemotherapy and require
In a recent retrospective analysis, Loriot et al reported on the pattern of
additional treatment strategies. The ongoing international phase III TIGER
relapse among patients with poor-risk nonseminomatous GCTs previously
trial aims to determine whether high-dose or conventional-dose
treated with chemotherapy.206 After a median follow-up of 4.1 years, 32%
chemotherapy is more effective in the second-line setting for patients with
were found to have radiographic evidence of brain metastases. The brain
relapsed disease. Patients with platinum-refractory or relapsing tumors
was the only site of progression in 54% of these patients and 19%
after second-line therapy have very poor outcomes despite salvage
experienced progression in the brain as the first progression event.
treatments with no effective alternative therapies. Targeted therapies
Furthermore, involvement of the brain was more common among patients
appear to have limited activity in this setting, although more robust clinical
who were previously treated with high-dose chemotherapy (29%)
trials are needed to assess their value in treating testicular GCTs.
compared to BEP (12%). These data suggest that brain metastases from
Prognosis for patients with brain metastases remains poor, with a lack of
testicular GCTs may occur more frequently than previously thought, often
evidence from prospective trials to guide treatment decisions. Therefore,
as the only site of progression, and may be more likely to occur in poor-
the NCCN panel encourages patients with metastatic, recurrent, or
risk patients previously treated with high-dose chemotherapy. However, it
platinum-refractory testicular GCTs to participate in well-designed clinical
is unknown whether this effect was due to the lower cerebral drug
trials investigating novel therapeutic strategies to enable further advances
penetrance of the high-dose regimen.
for the management of this disease.
The optimal management of brain metastases from testicular GCTs is
controversial, with a lack of evidence from prospective trials to guide
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10. Greene MH, Kratz CP, Mai PL, et al. Familial testicular germ cell
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Testicular Cancer Discussion

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NCCN Guidelines Version 2.2020 Table of Contents
Testicular Cancer Discussion

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NCCN Guidelines Version 2.2020 Table of Contents
Testicular Cancer Discussion

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NCCN Guidelines Version 2.2020 Table of Contents
Testicular Cancer Discussion

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NCCN Guidelines Index

NCCN Guidelines Version 2.2020 Table of Contents
Testicular Cancer Discussion

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Testicular Cancer Discussion

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Testicular Cancer Discussion

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NCCN Guidelines Index

NCCN Guidelines Version 2.2020 Table of Contents
Testicular Cancer Discussion

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