Review

Contemporary radiotherapy: present and future

Ravi A Chandra*, Florence K Keane*, Francine E M Voncken, Charles R Thomas Jr

Oncology care is increasingly a multidisciplinary endeavour, and radiation therapy continues to have a key role across Published Online
the disease spectrum in nearly every cancer. However, the field of radiation oncology is still one of the most poorly June 21, 2021
https://doi.org/10.1016/
understood of the cancer disciplines. In this Review, we attempt to summarise and contextualise developments within S0140-6736(21)00233-6
the field of radiation oncology for the non-radiation oncologist. We discuss advancements in treatment technologies
*Contributed equally
and imaging, followed by an overview of the interplay with advancements in systemic therapy and surgical techniques.
Department of Radiation
Finally, we review new frontiers in radiation oncology, including advances within the metastatic disease continuum, Medicine, Oregon Health &
reirradiation, and emerging types of radiation therapy. Science University, Portland,
OR, USA (R A Chandra MD,
Introduction tumours can be effectively treated and side-effects can be C R Thomas Jr MD); Department
of Radiation Oncology,
Although the beginnings of modern radiotherapy can be minimised. Massachusetts General
traced back to the discovery of the x-ray in the late 1800s, The evolution of modern radiotherapy is shown in Hospital, Boston, MA, USA
the field of radiation oncology has had multiple figure 1. Historically, radiotherapy was planned and (F K Keane MD); Department of
Radiation Oncology,
renaissances since its formal inception six decades ago.1,2 delivered in two dimensions, with treatment fields
Netherlands Cancer Institute,
As imaging and treatment delivery techniques have based on bony anatomy. Treatment fields were large and Amsterdam, Netherlands
improved, the applications of radiation oncology have the radiotherapy dose delivered was heterogeneous due (F E M Voncken MD)
expanded. Approximately half3,4 of patients are estimated to differences in tissue densities and limits of planning Correspondence to:
to receive radiotherapy at some point after a diagnosis of capabilities. The use of CT imaging enabled an increase Dr Ravi A Chandra, Department
of Radiation Medicine, Oregon
cancer, with indications spanning curative treatment to in precise delineation of both tumour and healthy
Health & Science University,
symptom palliation. tissues. Additionally, the development of conformal Portland, OR 97239, USA
Close collaboration across oncological fields is crucial radiotherapy with three-dimensional planning tech­ [email protected]
to improve treatment and ensure the optimal application niques facilitated not only measurement of the dose
of radiotherapy. There have been multiple advances and volume of radiotherapy delivered to tumours and
in radiotherapy. For this Review, we aimed to provide organs at risk of injury, but also an understanding of
a useful and pragmatic overview for non-radiation the interaction between radiotherapy dose and toxicity.5
oncologists, with an emphasis on how technological The use of intensity-modulated radiotherapy and
enhancements have led to smaller treatment volumes, image-guided radiotherapy has also revolutionised the
shorter treatment times, better outcomes, and decreased treatment of many malignancies, with substantial
toxicity. We have focused on data from randomised trials, reduction in treatment-related toxicities and improve­
consensus guidelines, and promising emerging research ments in long-term outcomes.6–8 With the advancements
that have transformed the field. We also look at the in techniques, complex targets can be treated at high
potential effect of current technologies and how they doses with millimetre accuracy and steep dose fall-off
might shape the field during the coming decades. to spare healthy tissues. Other developments include
use of linear accelerators with onboard MRI or PET
New technology: evolving radiotherapy scanners, permitting greater tissue definition during
Improvements in diagnostic imaging, treatment treatment than without their use and allowing for
planning, and treatment delivery have enabled more adaptive therapy as tumour size or location changes
accurate and precise treatment of diseased tissue and during treatment (figure 2). Expanded parenteral appli­
avoidance of healthy tissues. This has expanded the cations for radio­therapy, such as radium-223 in prostate
so-called therapeutic window, the dose range in which cancer,9 theranostics, gamma knife radiosurgery, and

Search strategy and selection criteria A B C

References for this Review were identified through searches
of PubMed and MEDLINE for articles, including high quality
reviews, reports of practice changing, and randomised trial
data, from Jan 1, 1980, to Dec 31, 2020, with search terms
such as “radiotherapy”, “charged particle therapy”,
“3D conformal radiotherapy”, “intensity-modulated
radiotherapy”, and “randomized trial”. Emphasis was placed
Figure 1: The evolution of radiation therapy from two dimensional to stereotactic body radiotherapy
on articles less than 10 years old. We organised new (A) Two-dimensional planning image quality is poor and treatment fields (the area inside the black line) are large;
developments into topical areas, which then formed the basis as planning and imaging techniques improved, treatment by intensity-modulated radiotherapy (B) and
for additional searches. stereotactic body radiotherapy (C) techniques were enabled. The dark blue lines in (B) and (C) represent the
planning target volume; the other coloured lines represent the different isodose lines.

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 Review

A B C Currently, access to charged particle therapy varies

widely, and criteria for its use in adult patients is an area
Collimator with 192 radioactive of active research (table 1), with trials focusing on
1·5 T wide bore
source in eight sectors
PET arc PET arc
not only overall and progression-free survival, but also
quality of life and cost-effectiveness. Although there are
many potential benefits to charged particle therapy, it has
Treatment several potential unique uncertainties15 that might affect
beam Each sector can move outcomes. To take advantage of the dosimetric benefits of
independently from each other
proton therapy, accurate prediction of the range of the
D
proton beam in tissue is needed, but this range can be
1 Cyclotron 4 3 Gantry affected by multiple factors, including, but not limited
Using magnetic fields, the cyclotron 1 The gantry can rotate 360° around
Patient to, patient set-up, imaging, motion of both the target
can accelerate hydrogen protons to the patient to position the nozzle
two-thirds the speed of light and surrounding organs, biological effects, and dose
2 Electromagnets 2 4 Nozzle
Magnets focus the proton beams A 9500 kg magnet guides the beam
calculation uncer­tainties. Monte Carlo simulations can be
3
towards the gantry to the patient through a nozzle used to assess some of these uncertainties.15 Randomised
data to support the efficacy of proton therapy is essential.
E F For example, a randomised trial in locally advanced
non-small-cell lung cancer did not show an improvement
in toxicity with proton therapy compared with intensity-
modulated radio­therapy.16 In some countries, eligibility is
restricted to individual photon-to-proton plan comparison,
weighing the probability of healthy tissue complica­
tion between proton therapy and intensity-modulated
radiotherapy techniques and estimating the short-term
Figure 2: New types of radiotherapy treatment machines
and long-term benefit of each. In other situations, access
Different tumour locations and types are expected to benefit from these new treatment facilities. to proton therapy is driven mostly by financial means
(A) An MRI-containing linear accelerator; MRI-guided treatment is mostly applied in tumour areas with poor and patient insurance coverage. Randomised trials are
visibility on CT or an organ with motion. Reproduced with permission of Elekta (Stockholm, Sweden). ongoing (eg, NCT02603341, NCT01617161, NCT03801876,
(B) A PET-containing linear accelerator, a treatment of special interest when boost strategies to metabolic
activity are prescribed. Reproduced with permission of Reflexion (Hayward, CA, USA). (C) Gamma knife
NCT01993810, NCT01893307, NCT02179086, and
treatment unit; an advance of the gamma knife technique with the steep dose gradient, and it is mainly used in NCT03180502).
brain metastasis. Reproduced with permission of Elekta. (D) The basic design of a cyclotron-based proton Although improvements in radiotherapy treatment
facility, often requiring multiple buildings. Reproduced with permission of IBA International planning and delivery have affected all patients treated
(Louvain-la-Neuve, Belgium). (E) A depiction of a single room proton unit. Reproduced with permission of
Mevion (Littleton, MA, USA). (F) A carbon ion facility. Charged particle therapy is of most interest when a steep
with radiotherapy, one of the greatest impacts has been in
dose gradient is needed to reduce the healthy tissue toxicity of an adjacent organ. Reproduced with permission the increasing use of hypofractionated radiotherapy,
of MedAstron (Wiener Neustadt, Austria). which uses fewer fractions of radiotherapy with a higher
dose per fraction than conventionally fractionated radio­
imaged-guided brachytherapy techniques, have also therapy (typically in doses of 1·8–2·0 Gy per fraction
expanded the radiation oncology arsenal. Examples of for conventionally fractionated radiotherapy). Hypofrac­
novel radiotherapy techniques are shown in figure 3; tionated radiotherapy was traditionally limited to palliative
several of these techniques will be discussed in this treat­ment, wherein the intent of treatment was to improve
Review. symptoms but not to cure. Single-fraction courses have
Although most patients worldwide are treated with been shown to be equally effective as multiple-fraction
photon therapy, the use of charged particle therapy, courses of radiotherapy in palliative treatment.17 By
including proton and carbon ion therapy, has substan­ contrast, definitive-intent radiotherapy is delivered in
tially increased (figure 2). Charged particle therapy is small daily doses over multiple weeks to deliver an
characterised by steep dose falloff with a minimal exit effective tumouricidal dose, while minimising toxicity.
dose beyond a specified target.10,11 Treatment plans with The improvement of delivery techniques has facilitated
charged particle therapy can often greatly decrease the the use of shorter courses of radiotherapy, with the aim of
exposure of healthy tissues to radio­therapy, potentially reducing treat­ment times and maintaining or improving
reducing short-term and long-term side-effects.12,13 outcomes from conventionally fractionated radiotherapy.
Decreased exposure to healthy tissues is especially For example, in patients with early-stage breast cancer
important in the treatment of paediatric patients, in receiving whole breast irradiation, multiple randomised
whom exposure of radiation dose to healthy organs can trials have established the efficacy and safety of
have detrimental long-term effects,12 and when treating hypofractionated radiotherapy compared with conven­
tumours in close proximity to crucial healthy structures tionally fractionated radiotherapy,18–21 and these regimens
(eg, head and neck tumours near the base of the are recommended over conventionally fractionated
skull).14 radiotherapy.22

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 Review

The most prominent example of hypofrac­ tionation,

stereotactic radiosurgery or stereotactic body radiotherapy
(SBRT), involves delivery of a full treatment dose over one
to five treatments. Initially developed for the treatment of
intracranial tumours, stereotactic treatment has been
adapted for use in multiple other body sites, including
thoracic, gastrointestinal, genitourinary, and osseous
sites. Unlike conventionally fractionated or hypofrac­
tionated radio­ therapy, SBRT, which is also known as Intensity-modulated Volumetric arc therapy is a Breath-hold technique; after deep inspiration
radiotherapy is a planning planning technique in breath hold, the radiotherapy dose to the heart
stereotactic ablative body radiotherapy, is characterised by technique in which the which the dose of multiple can be reduced, which reduces late cardiac
delivery of an ablative dose of radiotherapy to tumours. As dose is modulated with beams in an arc are toxicity
multiple beams modulated
will be discussed, stereotactic radiosurgery and SBRT have
helped create entirely new indications for radiotherapy,
and their role continues to expand with advances in
systemic therapy. Novel radiation techniques

New imaging: improved target definition,

quantification of response, and novel therapies
Improvements in diagnostic imaging have enabled more Cone beam CT MRI of a liver
registration of a lung lesion before
precise identification of both target volumes and healthy tumour before treatment with
tissue in radiotherapy treatment planning. For example, treatment with stereotactic body
stereotactic body radiotherapy
improvements in MRI have allowed a more complete radiotherapy with MRI-guided
assessment of intracranial disease burden than before. radiotherapy
Coupled with advances in radiotherapy planning, this
enhanced assessment of intracranial disease has led to a
shift in the management of brain metastases, from whole
brain radiotherapy to targeted treatments with stereo­
tactic radiosurgery or hippocampal-sparing whole brain
radiotherapy.23
Additional advances in radiotherapy treatment imaging
include the development of four-dimensional (4D) CT, Figure 3: Examples of novel radiotherapy techniques
IGRT is a technique that enables precise delivery of radiotherapy by checking the set-up with imaging before
wherein CTs are acquired throughout the respiratory cycle,
treatment. Examples of cone beam CT IGRT (lung) and MRI IGRT (liver). The red lines represent the gross tumour
facilitating more precise measurement of tumour move­ volume and the pink lines the planning target volume. IGRT=image-guided radiotherapy.
ment than conventional, or free-breathing, CT (video).
4D CT is particularly important in treatment of sites in the with target definition by national societies.25 International See Online for video
lung and liver, where respiratory motion can be quite collaboration and guidelines are essential to overcome
substantial. intercontinental differences in radiotherapy.
Imaging at the time of treatment delivery is also crucial Advanced imaging techniques can also have an
(figure 4). Linear accelerators can be equipped with essential role in the assessment of treatment response
advanced on-board imaging, such as cone beam CT, and the need for additional therapies. For example, in
which enable real-time identification of tumour position. gastro-oesophageal junction cancer, PET-CT to evaluate
MRI-linear accelerators, which combine an MRI unit response to treatment after induction chemotherapy has
with a linear accelerator, provide an additional layer been used for the selection of concurrent systemic
of imaging assessment before treatment, which is therapy with radiotherapy.26 The role of functional
particularly important in areas with organ motion and imaging for radiotherapy intensification or de-
where tumour and healthy structures have similar tissue intensification is an area of ongoing research. Tumour
density, such as the pancreas or liver.24 The development heterogeneity can be visualised by functional MRI,27
of these techniques enabled use of smaller planning giving room to target specific areas of the tumour.28
treatment volumes than before their development, Other advancements include the development of rational
sparing larger volumes of healthy tissue. dosing of radiotherapy based on imaging and prediction
With improvements in imaging and refinements in of treatment response.
treatment planning and delivery, there is also an increased
potential for heterogeneity between treatment centres. To New biology: a changing role with systemic
mitigate for this potential, the European Organisation for therapy
Research and Treatment of Cancer has instituted Radia­ Developments in systemic therapy have also trans­
tion Therapy Quality Assurance procedures. Consensus formed the role of radiotherapy, enabling treatment
guidelines have also been developed for assistance with smaller radiotherapy fields, which has decreased

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Malignancy Trial design Number of Study groups Primary outcome Secondary outcomes Inclusion of
planned cost-
participants effectiveness
analysis
NCT02603341 Breast cancer Randomised 1278 Photon therapy vs Effectiveness of photon 5-year disease control, quality of life, Yes
phase 3 proton therapy therapy vs proton therapy in association of radiation dose and quality
reducing major of life, and cardiac toxicity; and 15-year
cardiovascular events disease-free survival, overall survival,
and risk of secondary malignancies
NCT01617161 Prostate cancer Randomised 400 Proton therapy vs IMRT Compare bowel function at Disease-specific quality of life at 2 years; Yes
phase 3 24 months after radiation cost-effectiveness at 2 years; radiation
dose and bowel, urinary, and erectile
function; biomarkers, or prostate cancer
behaviour; and disease-specific and overall
survival at 10 years
NCT03801876 Oesophageal Randomised 300 Proton therapy vs Overall survival and grade 3 Pathological response rate; grade 4 Yes
cancer phase 3 photon therapy or worse cardiopulmonary lymphopenia during chemoradiation,
adverse events related to lymphocyte counts; locoregional failure;
protocol treatment distant metastasis-free survival;
progression-free survival; quality-adjusted
life-years; and cost–benefit analysis
NCT01993810 Non-small-cell Randomised 330 Proton therapy vs Overall survival Progression-free survival; adverse events; Yes
lung cancer phase 3 photon therapy and cost-effectiveness analysis
NCT01893307 Oropharyngeal Randomised 360 IMPT vs IMRT Phase 2: rates and severity of 2-year disease-related outcomes; Yes
cancer phase 2 and late grade 3–5 toxicity during patient-reported outcomes; physician-
phase 3 2 years after completion of reported toxicity; quality-adjusted
treatment; and phase 3: life-years; cost–benefit analysis;
progression-free survival and biomarker analysis
NCT02179086 Glioblastoma Randomised 606 Photon radiotherapy Overall survival Compare dose-escalated photon therapy No
phase 2 randomised patients to and dose-escalated proton therapy;
standard dose photon toxicities; cognitive symptom severity;
radiotherapy or dose- neurocognitive function;
escalated proton and lymphopenia
therapy vs dose-
escalated radiotherapy
NCT03180502 IDH mutation, Randomised 120 IMRT vs proton beam Change in cognition Quality of life; symptoms; cognition No
low to phase 2 therapy measurement; incidence of adverse
intermediate events; local control; overall survival;
grade gliomas progression-free survival; dose-response
relationship; and tumour molecular
status
IMPT=intensity-modulated proton therapy. IMRT=intensity-modulated radiation therapy.

Table 1: Ongoing trials for the comparative effectiveness of IMRT and proton beam therapy

the potential short-term and long-term side-effects of previous treatments, and thus the radiotherapy-related
radiotherapy. One example of this decrease in side- morbidity is decreased.
effects has been in Hodgkin lymphoma. This highly Immunotherapy29–31 and targeted therapies32–34 have also
radio-responsive disease was historically treated greatly improved patient outcomes, particularly for
successfully with radiotherapy alone, with treatment of patients with locally advanced or metastatic disease.
the primary tumour and draining nodal basins. Studies have shown the potential for radiotherapy
Although patients, often diagnosed in their first few to stimulate or potentiate the immune response to
decades of life, were in complete remission, they also checkpoint inhibitors,35–38 and thus there is interest in
had a risk of long-term morbidity due to the large combining radiotherapy with immunotherapy for
radiotherapy fields. With integration of chemotherapy therapeutic gain.39 Reports of radiotherapy increasing
into treatment and the use of PET or CT to assess response to checkpoint inhibition, even in so-called
response, the care of patients has evolved. For example, immunologically cold tumours, such as PD-L1-negative
patients with Hodgkin lymphoma who require non-small-cell lung cancer,40 microsatellite stable colorectal
treatment with radiotherapy are now typically treated cancer,41 and pancreatic cancer,42 have additionally piqued
with chemotherapy followed by radiotherapy to involved the interest of clinicians and researchers in this area.
lymph nodes (termed involved site or involved nodal Radiotherapy has both immunostimulatory and immuno­
radiotherapy depending on planning techniques). suppressive effects that are independent of systemic
Smaller volumes and lower doses are used than for therapy, including changes in tumour microenvironment,43

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altered cytokine expression,44 upregulation of transcrip­

A
tion factors,45 induction of cell death,46 and promotion of
antigen cross-presentation.47 The optimal integration of
radiotherapy with immunotherapy is an area of research,
with preclinical trials highlighting optimal dose and
fractionation and the underlying mechanisms of action,
including stimulation of the production of type I
interferon via the cGAS–STING pathway.48
Improvements in targeted therapy, particularly
developments in tyrosine kinase inhibitors that have
improved CNS activity, have also affected treatments.49,50
B
For example, select patients with oncogene-drive lung
cancers and brain metastases now receive CNS-penetrant
T2-weighted MRI
tyrosine kinase inhibitors alone, with radiotherapy
reserved for patients who do not respond to or progress
through treatment. Additional study is crucial to identify
potential side-effects of these approaches.
The potential interactions of radiotherapy with
ADC map

immunotherapy and targeted therapies is an area of

ongoing research, particularly given the potential for
increased side-effects when immunotherapy is delivered
in proximity to radiotherapy. Clinicians should be aware Fraction 1 Fraction 6 Fraction 12 Fraction 16 Fraction 21 Fraction 25 Fraction 31

of the potential risk of interaction of radiotherapy with Figure 4: Advanced imaging technique examples in treatment planning and treatment response analysis
these agents.51 Knowledge of the mechanism of cancer (A) Multiple complementary imaging methods used to define treatment volumes, including MRI, CT, and
inhibition of these drugs, medication half-life, and, functional methods. Reproduced with permission from Clifton David Fuller, MD, PhD (MD Anderson Cancer
consequently, the potential interaction mechanism with Center, University of Texas, Houston, TX, USA). (B) MRI-based acquisition during a course of treatment to
understand treatment response and adapt treatment volumes. Reproduced with permission from
healthy tissue adjacent to the location of radiotherapy Clifton David Fuller. ADC=apparent diffusion coefficient.
field should be used to establish how to sequence both
treatments. The potential for overlapping toxicities, such significant reduction in tumour control with the use of
as pneumonitis, between radiotherapy and systemic concurrent cetuximab as compared with cisplatin. Add­
therapies needs to be con­­ sidered. The decision on itional randomised trials are ongoing (eg, NCT02254278),
whether to directly overlap systemic therapies with but these results highlight the challenges associated
radiotherapy or hold systemic therapies during treatment with treatment deintensification, even in groups with
should be a joint decision between the treating radiation favourable out­comes. Additional studies to refine treat­
oncologist and the medical oncologist, considering the ment subgroups will be crucial to these efforts.57,58
overall burden of disease, potential length of radiotherapy Genetic classification systems are also defining distinct
treatment course, and the overlapping risks of both subsets of disease that might warrant adjustments in
treatments. Whenever possible, we encourage patients to treatment intensity or fields.59 Molecular profiling of
enrol in clinical trials so that these decisions and their tumours has provided insights on sensitivity of tumours
effects can be prospectively assessed. to radiotherapy.59–66 For example, KEAP1 and NFE2L2
Improved understanding of tumour biology has also mutations have been identified as markers of radiation
led to interest in treatment de-escalation, with the aim resistance in lung squamous cell carcinomas.67 In
of maintaining or improving upon previous outcomes hepatocellular carcinoma, mutations in KRAS and TP53
and minimising toxicity. Appropriate selection of have been significantly associated with risk of local
patients for de-escalation is crucial, as shown by the failure (ie, tumour regrowth) after proton SBRT.68
results of trials on de-escalation in human papillomavirus- Similarly, in rectal adenocarcinoma, concurrent KRAS
related oropharyngeal squamous cell carcinoma. Human and TP53 mutations have been associated with an
papillomavirus-related oropharyngeal squamous cell insufficient response to neoadjuvant chemoradiotherapy.69
carcinoma is associated with more favourable outcomes Iden­tification of these mutations, and others, might help
than human papillomavirus-negative tumours,52,53 to the to better predict those patients who are most at risk of
extent that the most recent American Joint Commission local tumour progression and therefore facilitate the
on Cancer staging system downgraded the staging of development of personalised radiotherapy prescriptions.
human papillomavirus-related oropharyngeal squamous
cell carcinoma.54 However, in randomised trials by New surgical cooperation: evolving framework
Gillison and colleagues55 and Mehanna and colleagues56 of care
of cetuximab with concurrent radiotherapy versus With the increase of multimodality treatment use,
cisplatin with concurrent radiotherapy there was a outcomes for many cancer patients have improved;

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however, treatment intensification often comes with an increasing interest in the potential for use in patients
effect on patients’ quality of life. The need for treatment with oesophageal86,87 and rectal cancer.88,89 Studies on the
intensification to improve outcomes or de-intensification use of organ preserva­tion are highlighted in table 2.81–86,88–91
to improve quality of life differs between cancers. Multidisciplinary response assessment is crucial to
Substantial improvements in outcomes for breast, identify patients who are candidates for organ preserva­
Hodgkin lymphoma, and head and neck cancer have tion, particularly when making the decision to omit
resulted in exploring de-escalation of treatments. The resection in patients who are candidates for resection.
balance and need of both surgery and radiotherapy is The development of improved tools for response
shifting with the changing effectiveness of the treatment assessment will ideally allow the tailoring of treatment
options. For other tumour types, treatment intensification options for escalation or de-escalation of multimodality
is being explored with the aim to increase the success treatment, as appropriate.
of radical surgery and improve long-term outcomes
(eg, pancreatic, gastric, or oesophageal cancer).70–73 Special example: stereotactic radiosurgery or
The changing balance between surgery and radio­ SBRT
therapy is best highlighted by the development of The development and increasing use of stereotactic
modern breast cancer treatment. Systematic ran­ radiosurgery and SBRT in multiple disease sites has
domised trials,74–76 done in the 1970s and 1980s, guided ushered in a new era of radiotherapy. There is established
the development of breast cancer surgical techniques data for SBRT in nearly every cancer subsite that
from the Halsted radical mastectomy to the simple radiation oncologists treat, with indications ranging
mastectomy, and then to breast conservation therapy. from early-stage disease (eg, in lung cancer) to locally
The refinement of axillary nodal evaluation, from axillary advanced disease (eg, unresectable pancreatic cancer)
lymph node dissection (ALND) to sentinel lymph node and metastatic disease. These techniques are particularly
biopsy (SLNB),77–79 has also reduced patient morbidity. In appealing given the short course of treatment and
early-stage breast cancer, SLNB has largely replaced small volumes treated, which correlate with a typically
ALND, and in cases of lymph node metastases at SLNB, favourable side-effect profile. For example, in patients
axillary radiotherapy has replaced ALND.79 Oncoplastic with early-stage non-small-cell lung cancer who are not
techniques and modern radiotherapy principles are candidates for lobectomy, SBRT is the standard of care,92
now improving cosmetic and functional outcomes for and is associated with improved outcomes and reduced
patients. toxicity compared with conventionally fractionated
For head and neck cancer, the use of robotic surgical radio­­­therapy.93 Although there are no completed ran­
techniques has increased the use of surgery for treatment domised trials comparing SBRT to resection, SBRT also
of oropharyngeal tumours, enabling resection of tumours compared favourably to lobectomy in a pooled analysis
that were previously deemed inaccessible due to potential of partici­pants in two randomised trials; however, as
morbidity. Assessment of the risks and benefits of each both trials did not have complete accrual, this analysis
different approach will be crucial to ensure patients was limited by a small number of participants and a low
receive optimal combinations of treatment methods. For number of events.94 Additional randomised trials,
example, although some patients will be able to avoid including on the role of SBRT versus sublobar resection,
chemotherapy after resection, others might still require are ongoing (eg, NCT02468024, NCT02984761, and
both chemotherapy and radiotherapy, thereby increasing NCT01753414).
their overall burden of side-effects. The randomised One particularly exciting area is the potential role of
phase 2 ORATOR trial80 included patients with oropha­ stereotactic radiosurgery and SBRT in the treatment of
ryngeal squamous cell carcinoma who were randomly metastatic disease. Prognostically, and perhaps obviously,
assigned to chemoradiotherapy or transoral robotic a patient with two sites of metastatic disease might have a
surgery with concurrent neck dissection. Oncological better outcome than a patient with 20, yet both are
outcomes of both treatments were similar, but the toxicity considered stage IV. It has long been known that particular
profile of both treatments differed. Swallowing-related patients with few sites of metastasis, such as adrenal
quality of life was improved with radiotherapy compared metastases in T1-2N0 lung cancer,95 liver metastases in
with surgery, although this was not a clinically meaningful colorectal cancer,96 or pulmonary metastases in sarcoma,97
difference. This study pro­vides valuable information on can undergo aggressive local treatment of all sites of
the potential side-effects associated with both approaches.80 disease with long-term disease control. However, there
Multidisciplinary assessment before the start of treatment has been controversy as to whether patients with more
will be essential for ensuring that patients’ functional and than one site of metastatic disease can also benefit from
oncological outcomes are maximised. aggressive local therapy.
Finally, organ preservation represents an essential Molecular profiling studies have begun to define
tool for patient wellbeing. Organ preservation is well phenotypes of oligometastatic (low-volume metastatic
established in anal cancer,81,82 head and neck cancer,83 disease at diagnosis) and oligoprogressive (low-volume
cervical cancer,84 and bladder cancer,85 and there is progressive sites after systemic therapy) disease.98–100

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Correlative studies on tumour genetic diversity and Advances in biomarkers, such as circulating tumour
tumour evolution have lent support to the hypothesis DNA,101,102 have also led to improvements in assessment
that multiple distinct biological pathways influence of disease burden. These advances are particularly
oligometastatic and oligoprogressive disease in patients. important for patients who have received radiotherapy,

Publication Study design Population Study groups Organ preservation Progression-free Overall survival Conclusions
year rate survival
Laryngeal cancer
VA Larynx 1991 Randomised Stage 3 or Induction 64% overall; of those Higher rate of local 68% vs 68% Larynx preservation is
Trial83 phase 3 trial stage 4 glottic or chemotherapy for two requiring recurrence but lower (p=0·9846) feasible without a
supraglottic cycles with radiotherapy laryngectomy, rate of distant detriment to overall
squamous cell starting with cycle three 56% had thyroxine recurrence in survival in appropriately
cancer vs laryngectomy and disease chemoradiotherapy selected patients
postoperation group than in the
radiotherapy control
Anal cancer
Nigro and 1974, and Case reports At least 2 cm Fluorouracil and 38 (84%) of 45 had 7 (16%) of 45 had 89% overall survival Standard of care for anal
colleagues81 follow-up squamous cell mitomycin with complete response to positive biopsy and at 50 months for squamous cell carcinoma
in 1983 carcinoma of the concurrent radiotherapy chemoradiotherapy ultimately recurred patients with became chemoradiation,
and 1985 anal canal (30 Gy in 15 fractions) negative biopsy with abdominoperineal
without distant after resection reserved for
metastases chemoradiotherapy patients with positive
biopsy after treatment
James and 2013 2×2 Squamous cell Radiotherapy with 3-year colostomy-free 5-year disease-free 5-year overall Mitomycin and
colleagues82 randomised carcinoma of the concurrent cisplatin and survival was 68% with survival was 69% with survival was 79% fluorouracil with
factorial trial anus without fluorouracil vs mitomycin and mitomycin and with mitomycin or concurrent radiotherapy
distant radiotherapy with fluorouracil with fluorouracil with fluorouracil are standard of care for
metastasis mitomycin and concurrent concurrent radiotherapy anal squamous cell
fluorouracil, with or radiotherapy carcinoma
without two courses of
maintenance cisplatin
and fluorouracil
Cervical cancer
Landoni and 1997 Randomised Stage 1B and 2A Radical hysterectomy For tumours >4 cm, 5-year disease-free 5-year overall Combination of surgery
colleagues84 phase 3 trial cervical with or without rate of pelvic relapse survival was 74% for survival was and radiotherapy has
carcinoma postoperation was 70% vs 53% both groups 83% for both highest morbidity; tailor
radiotherapy vs (p=0·46) groups recommendations on the
definitive radiotherapy basis of patient and
tumour characteristics
Bladder cancer
Shipley and 1987; most Phase 2 single- T2 to T4 muscle Maximal TURBT 5-year risk decreased 5-year progression-free 5-year overall Trimodality therapy is a
colleagues90 recent group trials or invasive bladder followed by concurrent from 42% in 1986–95 survival was 66%, survival was 57%, potential alternative
and follow-up treated as per carcinoma chemoradiotherapy; to 16% in 2005–13 10-year progression- 10-year overall treatment for patients
Efstathiou in 2017 protocol salvage cystectomy free survival was 59% survival was 39% with muscle-invasive
and recommended if less bladder cancer
colleagues85 than clinical complete
response or recurrence
Oesophageal cancer
Bedenne and 2007 Randomised T3N0 to T3N1 Neoadjuvant cisplatin NA 2-year local control was 2-year overall Study was limited in that
colleagues91 phase 3 trial thoracic and fluorouracil for 57·0% with survival was 40% several patients were
(259 of oesophageal two cycles with chemoradiotherapy vs with enrolled but not
444 participants squamous cell radiotherapy if 66·4% with trimodality chemoradiotherapy randomly assigned, and
were randomly carcinoma (90%) response, randomised therapy (p=0·0014) vs 34% with there was little clinical
assigned) or to surgery vs definitive trimodality therapy staging; recommend
adenocarcinoma chemoradiotherapy (not significant) selective consideration
for surgery
Stahl and 2005 Randomised T3 to T4, N0 to Induction NA 2-year freedom from 2-year overall Surgery was associated
colleagues86 phase 3 trial N1, squamous chemotherapy followed local progression was survival was with increased local
cell carcinoma by chemoradiotherapy 64% with trimodality 40% vs 35% control but did not
to 40 Gy and surgery vs vs 41% with equivalent improve overall survival
induction chemoradiotherapy
chemotherapy followed (p=0·003)
by definitive
chemoradiotherapy to
65 Gy
(Table 2 continues on next page)

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 Review

Publication Study design Population Study groups Organ preservation Progression-free Overall survival Conclusions
year rate survival
(Continued from previous page)
Rectal cancer
van der Valk 2018 Retrospective T2 to T4, Watchful waiting 2-year incidence of 5-year disease-specific 5-year overall Close surveillance crucial
and N0 to N2 rectal offered to patients with local regrowth was survival was 94% survival was 85% with watchful waiting
colleagues88 adenocarcinoma clinical complete 25·2% (n=213); approach
response after 115 (78%) of
neodjuvant 148 patients with local
chemoradiotherapy tumour regrowth
required total
mesorectal excision
Smith and 2019 Retrospective T2 to T4, Watchful waiting 82% 5-year disease-free 5-year overall Although rectal
colleagues89 N0 to N2 rectal offered to patients with survival of 75% (95% CI survival of 73% preservation was high,
adenocarcinoma clinical complete 62–90%) in watchful (60%–89%)in overall survival was
response after waiting vs 92% watchful waiting vs worse with watchful
neoadjuvant (87%–98%) in 94% (90%–99%) waiting; this approach
chemoradiotherapy pathological complete for patients with should not be
response group pathological considered off trial
complete response
NA=not applicable. TURBT=transurethral resection of bladder tumour.

Table 2: Selected studies of organ preservation

Number of Histologies Median Maximum Consolidative Concurrent Median Time to new Adverse Overall
participants included follow-up number of therapy systemic therapy progression-free lesions events survival
metastases survival
Gomez and 74 Non-small-cell 38·8 3 Radiotherapy, Systemic therapy 14·2 months vs 14·2 months vs Four grade 3 41·2 months
colleagues104,105 lung cancer months chemoradiotherapy, as per standard of 4·4 months 6 months adverse events vs 17 months
or resection care (p=0·001) (p=0·1) vs two grade 3 (p=0·02)
adverse events
Iyengar and 29 Non-small-cell 9·6 6 Radiotherapy (SBRT Maintenance 9·7 months vs Not reported Four grade 3 Not reported
colleagues106 lung cancer months or hypofractionated chemotherapy 3·5 months adverse events
radiotherapy) (p=0·01) vs two grade 3
and one grade
4 adverse
events
Palma and 99 Breast, 25 months 5 SBRT Systemic therapy 12 months vs Not reported 29% worse 41 months vs
colleagues107 colorectal, as per standard of 6 months than or equal 21 months
non-small- care (p=0·001) to grade 2 (p=0·09)
cell lung cancer, adverse events
prostate, and vs 9% worse
others than or equal
to grade 2
adverse events
Phillips and 54 Prostate 18·8 3 SBRT None Not reported vs Rate at None Not reported
colleagues108 months 5·8 months 6 months was
(p=0·002) 16% vs 63%
(p=0·006)
Ost and 62 Prostate 36 months 3 Surgery or SBRT None 21 months vs Not reported Six grade 1 Not reported
colleagues109 13 months adverse events
(p=0·11) vs no toxicity
SBRT=stereotactic body radiotherapy.

Table 3: Randomised phase 2 trials on the role of consolidative radiotherapy in oligometastatic disease

as assessing response in previously irradiated fields can most often with SBRT, to their primary site and sites of
be challenging.103 metastatic disease. Significant differences in progression-
Simultaneously, multiple randomised phase 2 trials on free survival were reported, prompting the initiation
the use of radiotherapy in patients with oligometastatic of larger, phase 3 studies (eg, NCT03721341 and
disease have provided increasing support for the use of NCT03137771) with primary endpoints of overall, rather
SBRT (table 3104–109). In these phase 2 trials, patients with than progression-free survival. These ongoing trials will
low-volume metastatic disease were offered local therapy, include patients receiving checkpoint inhibitors, which

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 Review

is important as the previous phase 2 trials were done in, and a particular proportion of the organ parenchyma
before routine use of immunotherapy. Although some of (or functional subunits) can be removed while main­
these studies allowed enrolment of patients with up to taining the organ function. The ability of serial organs to
six metastatic sites, most patients enrolled only had one function after part removal generally implies that for
or two sites of metastasis. Randomised trials are now serial organs a maximum tolerated dose is used, and for
exploring the role of consolidative therapy in patients parallel organs the volume of the organ to a defined dose
with more than five sites of metastasis (NCT03721341 is used as a limit. Furthermore, if the radiation dose is
and NCT03137771). Taken together, studies in con­ higher than 2 Gy per fraction, the biological effective
solidative therapy could portend a future where some dose should be calculated.
kinds of cancer can be treated as a chronic disease, with Animal experiments have shown that re-irradiation of
SBRT being used periodically, and with some patients the spinal cord can be considered with caution if an
with metastatic disease being offered a chance at a cure appropriate interval is taken between treatments,
through comprehensive target ablation at diagnosis. indicating that there is potential for recovery over time.116
Defining oligometastatic disease is difficult, requiring Analysis in patients has showed that risks of myelopathy
assessment of multiple factors in addition to the number is small and depends on the cumulative dose, dose
of sites of metastasis. A joint consensus document from per treatment course, and time interval between
the European Society for Radiotherapy and Oncology treatments.117 Single-fraction or multiple-fraction SBRT is
and American Society for Radiation Oncology discussed often used for re-treatment of vertebral body metastases
several of these criteria, including the site of metastases, after conventional fractionation.118,119
feasibility of definitive local therapy, and systemic therapy Data for re-irradiation of different tumour sites are
options, all of which should be considered when defin­ increasing. In locally recurrent rectal cancer, re-irradiation
ing oligometastatic disease and identifying appropriate might be a potential treatment option with the aim to
candidates for aggressive local therapies.110 achieve a radical resection and improve long-term
Stereotactic radiosurgery and SBRT are also utilised in survival.120 In locoregional recurrent lung cancer121 and
palliative care; for example, showing excellent analgesic head and neck cancer,122 re-irradiation is also considered.
effect in patients with bone metastases.111 SBRT has Ultimately, re-irradiation is associated with increased risks
even been successfully used in benign tumours, such as compared with an initial course of radiotherapy,123 and the
trigeminal neuralgia,112 and in non-oncological care, such potential for tumour control should be balanced with
as in patients with refractory ventricular tachycardia113 the expected treatment-related toxicity. Shared decision
and other cardiac arrhythmias, suggesting potential making is of utmost importance when considering
future use outside of oncology. re-irradiation.

Evolving indications: re-irradiation Costs and gains of new treatment advances

Improved survival of patients with cancer has resulted in In the past decades, radiotherapy technology has rapidly
increased consultations for re-irradiation. In radiotherapy- evolved, and many new radiotherapy treatment options
naive patients, dose constraints and corresponding have become available in high-income countries.
toxicity profiles are robust. For re-irradiation, there is a Although these advances often reduce toxicity and
paucity of data, which limits determination of firm improve patient outcomes,15,124 they also have an
guidelines or dose constraints. Therefore, efforts to increased financial cost.125 Cost-effectiveness studies have
guide clinical decision making in re-irradiation and attempted to objectively quantify the benefit of these
determination of cumulative tolerated doses are based on treat­ments. For example, for paediatric patients who
small series and consensus recom­mendations.114,115 When have medulloblastoma, proton beam therapy is associated
re-irradiation is considered, the decision to re-treat with decreased rates of intelligence quotient decline,
depends on multiple factors; the total dose of previous hearing loss, growth hormone deficiency, coronary artery
radiation, the anticipated dose for re-irradiation, and the disease, and secondary malignant neoplasm.126,127
time interval between radio­ therapy courses should be For other radiotherapy developments (eg, hypofrac­ -
assessed. The purpose of the re-irradiation is important tionation and stereotactic radiotherapy), total fractions
(ie, whether the treatment is curative or palliative). per treatment series are greatly reduced compared with
Alternative treatment options that yield similar outcomes conventional radiotherapy. These techniques demand
to re-irradiation or have a lower chance of toxicity than more advanced image guidance than conventional
re-irradiation should also be investigated. radiotherapy, which requires more resources; however,
Knowledge of radiobiological principles is essential to the trade-off with reduction of visits shows a positive
understand the concept of dose tolerance in an organ. In cost-effective result.128–130 The cost estimations of SBRT
general, organs are classified as serial or parallel organs. and lobectomy for early-stage lung cancer were con­
A serial organ, such as the spinal cord, will lose function sidered in a Markov model.131 SBRT costs were €9234 and
if a small length of structure is sacrificed. By contrast, lobectomy costs were €10 726, with quality-adjusted
other organs (eg, liver or kidney) have redundancy built life-years of 16·35 years and 15·80 years, respectively.

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 Review

This shows that SBRT has a higher probability of One exciting technological advance is ultra-high dose
cost-effectiveness than surgery. rate radiotherapy (FLASH). Conventional radiotherapy
A new development in image-guided radiotherapy is typically delivered with dose rates around 0·03 Gy/s,
is MRI-guided radiotherapy. This technique has the over 2–7 min. But when radiotherapy is delivered in
advantage of improving target visualisation and adapting ultra-high dose rates (>40 Gy/s) in less than 1 s,
the radiation plan to the daily shape of the anatomy. These minimal deleterious effect has been observed on
advantages increase accuracy and enable reduction of the healthy tissue. Data are sparse at this time,133 but the
planning treatment volume margins and consequently potential to deliver high doses of radiotherapy with
spare more healthy tissue than radiotherapy alone. minimisation of toxicity has prompted substantial
MRI-guided radiotherapy is more costly than CT-guided interest. Similarly, accumulating data for the use of
radiotherapy. The number of patients treated on an therapeutic nanoparticles as radiosensitisers holds
MRI-linear accelerator is small due to the longer time promise to maximise treatment response. Assessment
required per fraction than a conventional linear accelerator, of response is also poised to dramatically change, as the
and the need for costly machinery and more trained use of liquid biopsy or biomarkers with circulating
personnel. With the ongoing improvements in this tumour DNA and artificial intelligence provide new
technology, the time per treatment fraction is expected to tools to assess patient disease burden.134 These tools
be reduced. However, treatment on the MRI-linear hold great promise to refine treatment by personalising
accelerator will probably remain more expensive than on a cancer care.
conventional linear accelerator. Future studies should These advances in cancer care provide great
investigate for which indications MRI-guided radiotherapy excitement and hope to our field. Although these
is a cost-effective treatment option. technological advances are important, additional refine­
These rapid innovations in high-income countries have ments in patient care are also incredibly important for
resulted in a widening disparity between high-income patient wellbeing and outcomes during and after
countries and low-income and middle-income countries. therapy. The development of artificial intelligence
The availability of radiotherapy facilities in several low- approaches, including virtual reality, has helped to
income and middle-income countries is insufficient. prepare patients for the logistics of radiotherapy. For
Worldwide, only 40–60% of patients with cancer are example, the Virtual Environment Radiotherapy Trainer
estimated to have access to radiotherapy facilities.132 system functions as a simulator for radiotherapy
Access to radiotherapy for patients with cancer in low- treatment planning and delivery and has improved
income and middle-income countries is urgently needed both staff training and the patient experience.135
to improve patient outcomes, both in the definitive Patient-reported outcomes research is also crucial to
and palliative setting. Although substantial investments better understand the physical, emotional, and social
are required for radiotherapy treatment centres, side-effects of cancer therapies. As outcomes and
including a linear accelerator or Cobalt-60 machine, survival continue to improve, continued follow-up to
skilled personnel, and maintenance, these investments assess the long-term effect of all oncological therapies
show substantial health and economic benefits.132 Even in will be essential for maximising patient quality of life.
high-income countries, where capacity seems sufficient, Finally, we would be remiss if we did not mention the
radiotherapy facilities are often concentrated in cities. effect of the COVID-19 crisis on oncological care. As we
For people living in remote regions, access to radio­ write this Review, COVID-19 has greatly impacted the
therapy can be incredibly challenging due to the long care of current and future patients with cancer world­
travel distance and need to commute for typically daily wide. Although some changes, including new oppor­
treatment visits. Expansion of radiotherapy access is tunities for telehealth, hypofractionation, and remote
essential to ensure that patients can benefit from radio­ management will probably benefit patients over time by
therapy and the technological advances described. expanding access to care, this period will probably have
long-term effects on patient diagnosis and treat­ment, as
Future for radiation oncology well as on ongoing clinical trials. The cancer community
As discussed in this Review, advances in radiotherapy will need to work together to overcome these challenges
could lead to the use of personalised radiotherapy and ensure that patient outcomes continue to improve
prescriptions, individualised treatment based on accurate over the next 60 years.
response prediction, an increase in organ preservation, Contributors
novel indications in non-oncological diseases, increased All authors contributed to writing and editing of this manuscript and
use of particle therapy, and even more robust and have approved the final version.
adaptable responses to immunomodulatory therapies Declaration of interests
than before. Technological advances in radiotherapy We declare no competing interests.
delivery will continue in the coming years. We have References
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