REVIEW ARTICLE
Dan L. Longo, M.D., Editor
Recent Developments in Radiotherapy
Deborah E. Citrin, M.D.
N Engl J Med 2017; 377:1065-1075September 14, 2017DOI:
10.1056/NEJMra1608986
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REVIEW
It is estimated that 470,000 patients receive radiotherapy
each year in the United States.1 As
many as half of patients with cancer will receive radiotherapy.2 Improvements
in diagnosis, therapy, and supportive care have led to increasing numbers of
cancer survivors.3 In response, the emphasis of radiation oncology has
expanded beyond cure to include reducing side effects, particularly late
effects, which may substantially affect a patient’s quality of life.
Radiotherapy is used to treat benign
and malignant diseases and can be used
alone or in combination with chemotherapy, surgery, or both. For primary tumors
or metastatic deposits, palliative radiotherapy is often used to reduce pain or
mass effect (due to spinal cord compression, brain metastases, or airway
obstruction). Therapeutic radiation can be delivered from outside the patient,
known as external-beam radiation therapy, or EBRT (see the Glossary in
the Supplementary Appendix, available with the full text of
this article at NEJM.org), by implanting radioactive sources in cavities or
tissues (brachytherapy), or through systemic administration of
radiopharmaceutical agents. Multiple technological and biologic advances have
fundamentally altered the field of radiation oncology since it was last
reviewed in the Journal.4
RECENT TECHNOLOGICAL ADVANCES
Target Delineation
Defining the extent of a tumor, known as target delineation,
is a critical first step in planning radiation treatments, since accurate
localization reduces the chance of unintentional exclusion of tumor from
radiation exposure and allows maximal sparing of normal tissues. Typically,
radiation treatment planning begins with a simulation, in which a set of
computed tomographic (CT) images is obtained while the patient is immobilized
in a position deemed adequate for the radiation treatment. Complementary
imaging studies, such as magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose
positron-emission tomography (FDG-PET), can be electronically fused to the
planning CT scan or can be used as the primary imaging study for planning. In
this way, complementary imaging techniques can be incorporated into the
treatment-planning process. A margin of uninvolved, normal tissue adjacent to
the tumor is often included in target delineation to account for variations in
daily patient setup and alignment, motion of organs during treatment, and any
uncertainty about the extent of the disease.
CT-based delineation of the radiation target is a great
improvement over target delineation in the pre-CT era; however, CT still
provides challenges for radiation oncologists. For example, lung cancers may
cause airway obstruction and distal atelectasis, making it difficult to
differentiate tumor from collapsed lung on CT images (Figure 1FIGURE 1Effect
of 18F-Fluorodeoxyglucose Positron-Emission Tomography (FDG-PET) on Target
Delineation in a Patient with Lung Cancer.). With the use of FDG-PET in
patients with lung cancer, target volumes can be defined on the basis of
metabolic activity,5 which correlates closely with pathological findings.6,7 As
data have emerged that indicate that targeting only visible mediastinal tumor
results in few isolated recurrences in lymph nodes that were not intentionally
targeted,8-10 FDG-PET has had an increasingly important role in
defining the extent of mediastinal disease and reducing the radiation volume in
patients with lung cancer. Similarly, FDG-PET has contributed to delineation of
the radiation target volume for a range of other tumor types, such as cervical
cancer, lymphoma, and head and neck cancers.
For several cancers, such as central nervous system tumors,
head and neck cancers, sarcomas, and cervical cancers, MRI, as compared with
CT, provides enhanced visualization of the tumor and surrounding organs that
are at risk for injury. MRI is susceptible to geometric distortion and
artifacts, so consideration of these limitations and careful quality assurance
procedures are key to its use for treatment planning.11 As
these advanced imaging techniques have improved the visualization of tumors,
there is growing interest in highly conformal and focal radiotherapy, in which
the radiation dose drops off rapidly outside the target.
Treatment Planning and Delivery
The ability to more accurately define tumor targets has
provided a strong rationale for devising radiation treatments that closely
conform to the tumor, spurring refinements in radiation treatment planning,
daily localization, and treatment delivery. Traditional radiation treatments
deliver a consistent intensity of radiation across the treatment field. The
development of dynamic multileaf collimators — small movable metal leaves that
shape the radiation field and alter the intensity of radiation delivered to
portions of the field and that are used in combination with conformal
radiotherapy — has exponentially increased the potential complexity of
treatment plans. Defining how to alter the intensity of the beam to make the
treatment most conformal requires advanced computation. This includes inverse
treatment planning, in which dose goals and the relative importance of each
goal are defined by the prescribing physician, and the treatment-planning
system iteratively becomes better until an acceptable plan is generated. The
delivery of modulated radiation beams, a technique known as intensity-modulated
radiation therapy (IMRT), has resulted in the capacity to shape the high-dose
region to match complex target volumes while maximally sparing surrounding
normal tissues in a way that would not be possible with conventional radiation
treatment methods. Additional refinements, such as volumetric-modulated
arc therapy (VMAT), in which modulated treatments are delivered as the
radiation treatment machine rotates in an arc around the patient, have both
improved conformality (the ability to sculpt, or conform, the dose closely to
the target) and reduced treatment times (Figure 2FIGURE 2Comparison of
Three-Dimensional Conformal Treatment Planning and Volumetric-Modulated Arc
Therapy (VMAT).).
Traditionally, patients were aligned for daily radiation
treatment with the use of external skin marks and tattoos, and positioning was
verified on the basis of weekly radiographs that correlated bony anatomy to
treatment-planning images. The adoption of more conformal approaches has
necessitated enhanced confidence in tumor location. Today, many linear
accelerators are capable of performing CT imaging or high-quality digital
radiography to ensure that the tumor is in the expected location. The use of
frequent pretreatment imaging that references the original radiation plan,
known as image-guided radiation therapy (IGRT), has increased certainty
regarding tumor location for daily treatments. In some cases, small markers
visible on radiographs, known as fiducial markers, can be implanted within or
near the tumor for imaging before or during the treatment to ensure accurate
localization.
Although patients can be immobilized reproducibly for daily
treatment, tumors are often situated in organs that move with normal bodily
functions: breathing, peristalsis, swallowing, filling, and emptying. A variety
of approaches have been used to account for tumor motion. For example, patients
can be asked to hold their breath during inhalation or exhalation for the
planning scan and treatment. A recent advance is four-dimensional CT, which can
be used to acquire treatment-planning images at multiple phases of the
ventilatory cycle. This method provides an understanding of tumor motion
during the ventilatory cycle, allowing the margin of normal tissue to be
expanded in each direction only as much as needed to encompass the tumor during
ventilation. Alternatively, treatment delivery can be restricted to phases of
the ventilatory cycle in which the tumor falls within a prespecified location,
a technique known as respiratory gating. Collectively, these methods serve to
increase certainty about tumor location while minimizing unnecessary radiation
to surrounding normal tissues.
Traditionally, radiation treatments have been fractionated,
or broken into multiple doses, to leverage differences in radiation response
between tumor and normal tissue, such as reoxygenation of tumor, repair,
redistribution of tumor cells into sensitive phases of the cell cycle, and repopulation
between doses.12 Fractionation of the total radiation dose can yield
cures while reducing toxicity, as compared with single doses that are
associated with similar tumor-control rates. In recent years, there has
been substantial interest in regimens involving a relatively large dose per
fraction and highly conformal techniques. With these regimens, ablative doses
are delivered over a period of 1 to 2 weeks, in contrast to the previous
standard of using protracted fractionation, with daily treatments lasting for
many weeks. These highly conformal techniques, known as stereotactic body
radiation therapy (SBRT) (also called stereotactic ablative radiotherapy
[SABR]), have been used for both curative and palliative treatment and have
demonstrated efficacy in randomized trials for some tumors.13,14
The biologic rationale for SBRT is complex but presumes that
the observed antitumor effect is a consequence not only of direct tumor-cell
killing but also of indirect killing through mechanisms such as vascular
collapse and immune effects.15 Since
the doses delivered with SBRT are ablative, the therapeutic advantage of this
technique can be realized only when the treatments are highly conformal to
allow maximum exclusion of normal tissues. Thus, SBRT requires careful and
reproducible immobilization of the patient, with organ motion accounted for and
minimized and with a clear understanding of the extent of the tumor. SBRT is
not appropriate if there is uncertainty about the extent of the tumor or if
large volumes of normal tissue would require treatment to address the
possibility of microscopic disease.
Stereotactic radiation treatment with the use of single
doses or only a few fractions has been used for some central nervous system
tumors for many years; however, expanding the treatment to extracranial tumors
has been a more recent development. Emerging evidence suggests that SBRT can
provide exceptional local control for a variety of tumor types and locations.
Because patients are carefully immobilized and targeting is so precise, the
treatment can be delivered with inclusion of only the smallest margin of
surrounding normal tissue. Since the approach uses multiple-beam techniques or
arc therapy (IMRT or VMAT), the dose drops off rapidly outside the target,
minimizing the exposure of normal surrounding tissues to radiation doses
exceeding their tolerance. Although SBRT approaches have been incorporated into
clinical practice, they are not appropriate for all clinical scenarios, and the
long-term toxicity and efficacy of these approaches are still being determined
for many tumors and locations. The size of the lesion requiring treatment and
its proximity to critical normal tissues with high sensitivity to radiation
must be carefully considered.
Another method of delivering highly conformal therapy is the
use of protons and heavy ions, which differ from the more commonly used
electrons and photons in terms of how they interact with tissue and deposit the
radiation dose, generally resulting in a reduced dose beyond the target (Fig.
S1 in the Supplementary Appendix). Heavy ions, such as carbon ions,
have shown promise in early clinical trials. Because of its tremendous cost,
however, this technology is currently available at only a few centers around
the world. In contrast, proton therapy is currently available at several
centers in the United States. The benefit of proton therapy for many tumor
sites, such as the prostate, remains unproved, given the paucity of evidence of
greater tumor control or less toxicity with proton therapy than with other
approaches.16 Many in the oncologic community are eagerly
awaiting data from randomized trials comparing current radiotherapeutic
techniques with proton therapy. The use of protons is an accepted
alternative with potential advantages over photon therapy for selected tumors
of the central nervous system and for selected tumors in children.17,18
Brachytherapy, the implantation of radioactive sources in a
body cavity or tumor, is perhaps the most conformal type of radiation
treatment. This approach often allows delivery of higher doses than those
delivered with the use of EBRT, since the radiation generally does not reach
uninvolved normal tissue. For some tumors, the benefit of the dose escalation afforded
by brachytherapy may be superior to that of EBRT alone.19 The
integration of CT and MRI into treatment planning and post-brachytherapy
implant assessment, which is now standard practice for some tumor sites, allows
more precise delineation of tumor and a better understanding of the exposure of
tumor and normal tissue to radiation.20,21 Real-time
planning, in which the dose is calculated during the implantation procedure,
provides increased flexibility to deliver the radiation dose where desired,
with minimal exposure of normal tissues. Today, brachytherapy plays a
major role in the treatment of several cancers, including prostate and
gynecologic cancers.
USING COMBINATION THERAPY TO REDUCE THE INTENSITY OF
RADIOTHERAPY
For some cancers, such as early-stage Hodgkin’s disease,
radiotherapy has long been successful in contributing to disease control,
although concerns about late side effects, including second cancers, have
prompted efforts to reduce the intensity of radiotherapy. With the introduction
of effective, less toxic systemic therapy, radiotherapy treatment volumes have
consistently been reduced from classic “extended fields,” which included
uninvolved nodal regions, to much smaller regions of nodal involvement22,23 and
to even smaller involved sites24 (Figure 3FIGURE 3Evolution of
Radiation Treatment Volumes for Hodgkin’s Lymphoma.). Similarly, the doses
delivered have been decreased over time, potentially further reducing the risk
of late radiation toxicity. Reduced-intensity or reduced-volume radiotherapy
has also been used in other clinical scenarios, such as partial breast
irradiation in selected patients. Because the long-term effects of treatment
may take years to become manifest, the magnitude of any benefit with respect to
late toxicity from these modified treatment regimens has yet to be fully
defined. Similarly, the side effects of surgery and chemotherapy must be taken
into account to ensure that the composite therapy yields an overall benefit in
terms of both disease control and reduced toxicity.25,26
ENHANCING THE RESPONSE TO RADIOTHERAPY
Radiation from external or implanted sources interacts with
tissues in a way that drugs simply cannot because it is not bound by
bioavailability, permeability of blood vessels, excretion, or metabolism. The
ability to deliver a consistent dose of radiation from an external or implanted
source is constrained primarily by the laws of physics. Nevertheless, some
tumor types or even regions within tumors may have reduced sensitivity to the
tumoricidal effects of radiation, through mechanisms such as hypoxia and
accelerated repopulation of tumor cells during treatment, potentially resulting
in a reservoir of resistant tumor capable of surviving radiotherapy.
Targeting tumor resistance to radiotherapy has long been a
goal in the field of radiation oncology. Methods of enhancing antitumor effects
have included accelerated fractionation and hyperfractionation of the radiation
dose, so that the killing effects on tumor exceed those on normal tissues. Both
approaches generally involve a shorter period of treatment in order to prevent
accelerated tumor-cell regrowth, which can occur with more prolonged treatment.
These methods have been found in some cases to improve local control and
survival.
An alternative method of increasing the efficacy of
radiotherapy involves delivery of agents that may enhance the treatment
response. In the 1990s and early 2000s, a wealth of data from randomized trials
suggested that concurrent use of systemic chemotherapy and radiotherapy can
increase local control and, in some situations, survival. Combined chemotherapy
and radiotherapy have also provided an opportunity to preserve organs that otherwise
would have been surgically removed, such as the larynx and bladder. The
benefits of combining these treatments have not been without cost. In some
cases, the addition of chemotherapy has increased the risk or severity of
treatment side effects, such as dermatitis, diarrhea, and hematologic toxicity.
Nevertheless, the consistently enhanced efficacy of treatment with this
combined approach in randomized trials has led to the use of concurrent
chemoradiation as a cornerstone of care for diverse cancers, such as locally
advanced gynecologic cancers and head and neck, gastrointestinal, brain, and
thoracic cancers.
Despite the improvements in disease control afforded by
technical advances in radiotherapy and the addition of chemotherapy, the search
continues for agents that can provide similar or greater radiation-induced
tumor-cell killing with reduced toxicity. Radiation not only damages the DNA of
cancer cells but also initiates an array of prosurvival, inflammatory, and
mitogenic signal-transduction pathways. As a growing number of inhibitors of
signal transduction and DNA repair have been developed, a tremendous
opportunity has emerged for selectively sensitizing tumors to irradiation
through targeting of these pathways. The goal of these endeavors is to develop
agents that can be used to enhance the efficacy of radiation delivered to the
tumor while minimizing additional toxicity. Several ongoing clinical trials,
ranging from phase 1 to phase 3, are investigating radiation sensitizers
serving as an alternative or addition to radiosensitizing chemotherapy for the
treatment of various tumors and tumor sites.
More recently, the impressive successes of immunotherapy in
the treatment of metastatic cancer have led to tremendous excitement at the
prospect of combining immunotherapy and radiotherapy. Preclinical studies
have suggested that localized irradiation has immunomodulatory effects that may
enhance tumor recognition. Compelling evidence of the efficacy of radiotherapy
as a complement to immunotherapy has been observed with vaccines.27,28 More
recently, it was observed that delivery of radiation in combination with
antibodies against cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)
resulted in regression of unirradiated tumors (known as an abscopal response),
providing proof of concept that this approach can be successfully translated
into use in patients.29,30
The underlying mechanisms by which radiotherapy enhances
immune recognition and may complement immunotherapy are complex and the subject
of intensive study (Figure 4FIGURE 4Radiation as
an Immune Modulator.). Radiation-induced injury and killing of tumor cells
result in immunogenic modulation and immunogenic cell death. In immunogenic
modulation, cell-surface molecules are altered and soluble factors are
elaborated in a fashion that enhances tumor antigen presentation to T cells.31-33 Immunogenic
cell death is characterized by localization of calreticulin and other
endoplasmic reticulum proteins at the cell surface.34,35 Simultaneously,
the release of tumor-cell DNA, ATP, and high-mobility group box 1 (HMGB1), a
chromatin-associated protein, from irradiated tumor cells can trigger an immune
response through activation of dendritic cells and enhanced antigen
presentation.36,37 Although radiation has the capacity to enhance
the immunogenicity of tumors, the observed effects are not capable of
stimulating a coordinated and effective immune response by themselves, since
abscopal tumor responses to localized palliative radiotherapy as a single
treatment approach are rarely observed.
A number of immunosuppressive effects of localized
irradiation have been described that may counteract the immunogenic effects,
especially when conventionally fractionated radiation or larger treatment
volumes that can result in lymphopenia are used.38,39 Radiation
can alter the balance of regulatory T cells and local immunomodulatory
cytokines, such as transforming growth factor β (TGF-β).40 These
changes may suppress antitumor immunity. In addition, radiation may alter the
number and phenotype of infiltrating macrophages, which may also serve as an
immunosuppressive factor.41,42 Thus,
radiation alone may not be capable of stimulating a coordinated and effective
immune response.
A number of variables must be considered for effective
clinical use of combined radiotherapy and immunotherapy,43 including
the total radiation dose,31,44 dose
fractionation,44-46 sequencing of immunotherapy, types and
combinations of immunotherapeutic agents, and underlying tumor and host
factors. These variables are being studied in preclinical models, but their
applicability to human tumors is unclear. The optimal dose fractionation may
require a balance between initiating immunogenic cell death and minimizing the
immunosuppressive effects of hypoxia and vascular collapse seen with higher
doses.42 Alternative forms of radiation delivery, such as
the administration of radiopharmaceutical agents, which have shown tremendous
promise in the treatment of metastatic prostate cancer,47 are
also being explored in this context. More than 100 registered clinical
trials are attempting to realize synergy between radiation and immunotherapy
(as indicated by a search for the two terms on the ClinicalTrials.gov website).
UNDERSTANDING AND TREATING RADIATION TOXICITY
As with any cancer therapy, radiation treatments can have
short-term and long-term side effects that limit treatment tolerability and
affect the quality of life. A growing appreciation of the importance of
patient-reported outcomes in assessing the toxicity of cancer therapy48 has
led to the development of the Patient-Reported Outcomes Version of the Common
Terminology Criteria for Adverse Events.49,50 The
rates of moderate and severe toxicity from radiotherapy have consistently
decreased over the past several decades as a direct consequence of refinements
in imaging, treatment planning, and treatment delivery. For many common
cancers, such as breast and prostate cancers, severe late toxicity attributable
to radiotherapy occurs infrequently.51-55 The
site of treatment and type of tumor often drive this risk of injury, with
higher rates of toxicity observed when curative doses may approach the
tolerance of surrounding normal tissues.
The radiobiologic understanding of normal tissue injury,
especially the molecular events leading to injury, has evolved in a fashion
analogous to the technological advancements in treatment delivery. Pathways
implicated in radiation injury present fresh opportunities for prevention,
mitigation, and treatment. An example of such an identified pathway is
senescence in normal-tissue stem cells, with accelerated aging as a consequence
of cancer treatment. Cellular senescence, which is a normal consequence of
aging, can result from DNA damage, oxidative stress, and chronic inflammation.
Senescent stem cells are unable to replenish themselves and injured cells; they
may also contribute to disease through the secretion of proinflammatory
factors, a phenomenon known as the senescence-associated secretory phenotype (Figure 5FIGURE 5Senescence in
Cancer Therapy.).56,57 Laboratory studies have confirmed the importance
of senescence as a cause of radiation toxicity in bone marrow and lung58,59 and
of toxicity from DNA-damaging chemotherapy.59 Additional
work has suggested that the factors elaborated by senescent cells may
contribute to tumor progression.60,61These
findings are of __accelerated aging in bone marrow transplant recipients and
patients who have received cancer therapy.62,63Preventing
or clearing senescent cells has recently been shown to reduce the toxicity of
radiation and to mitigate aging-related illnesses in animal models.59,64-66 These
studies provide great hope that the short- and long-term toxic effects of
radiotherapy and cancer therapy can be effectively mitigated.
A variety of immunomodulatory, profibrotic, and
proinflammatory cytokines are also known to be involved in the initiation and
perpetuation of radiation injury — most notably, TGF-β.67,68 Targeting
these molecules and pathways to mitigate radiation toxicity is an area of
active study. There is renewed interest in developing agents that can
simultaneously sensitize tumors to radiation and reduce the likelihood of
long-term radiation injury. Given that several of the pathways involved in
these processes overlap, it is highly likely that therapeutic agents will continue
to be evaluated in this context.
CONCLUSIONS
A rapid evolution of technology has progressively increased
the safely deliverable radiation dose, minimized exposure of uninvolved normal
tissue, increased the accuracy of tumor delineation, and substantially reduced
the expected toxicity of treatment. As a consequence, the toxicity of
radiotherapy has consistently decreased, and escalated radiation doses have, in
many cases, led to improvements in disease control. Efforts to increase the
efficacy of therapy and minimize the risk of injury from radiation treatment
continue to evolve.
______________________________________________________________________________
Recent Developments in Radiotherapy
N Engl J Med 2017; 377:2200-2201November 30, 2017DOI:
10.1056/NEJMc1713349
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To the Editor:
Citrin (Sept. 14 issue)1 provides a comprehensive review of developments in
radiotherapy. However, I think that advances in personalized radiotherapy
should also have been discussed. Emerging evidence suggests that cancer is a
very heterogeneous disease necessitating individualized treatment protocols.2 Radiosensitivity-predictive assays based on
genotypic signatures of tumors have been shown to distinguish between certain
radiosensitive tumors and radioresistant tumors.3 This model has implications for the selection of
patients for various doses of radiotherapy and radiosensitizing combination
treatment.
Furthermore, cancers can be classified according to
“radiomics,” a temporal set of radiologic data characterized by the underlying
pathophysiological features and heterogeneity of the tumor.4Various degrees of radiosensitivity among subclones can
therefore be exploited by adaptive doses of radiation on the basis of
genotypically driven radiomic signatures. This approach complements biopsies
and allows for the noninvasive tracking of radiomic changes without intratumor
sampling errors.
Finally, mathematical models have been developed that take
into account tumor heterogeneity, dynamically acquired radioresistance, and
normal tissue damage. These models have been used to inform dose fractionation,
leading to prolonged survival among mice.5 Therefore, personalized radiotherapy offers great
hope in the era of precision medicine.
Kelvin Yan, M.D.
University of Oxford, Oxford, United Kingdom
University of Oxford, Oxford, United Kingdom
No potential conflict of interest relevant to this letter
was reported.
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