Journal of Surgical Oncology 2014;109:370–375
Radiation Therapy for Advanced and Metastatic Melanoma GERALD B. FOGARTY, BSc, MBBS, PhD, FRANZCR1,2* AND ANGELA HONG, MBBS, PhD, FRANZCR(FRO)1,3 1
2
Melanoma Institute Australia, Poche Centre, North Sydney, Australia Genesis Cancer Care, Mater Sydney Radiation Oncology Centre, Mater Hospital, North Sydney, Australia 3 Department of Radiation Oncology, Royal Prince Alfred Hospital, Camperdown, Australia
Radiation therapy (RT) is an important modality in cancer treatment. However, the general perception is that melanoma is radio‐resistant. High quality clinical trials are helping to establish the place of RT in select scenarios of advanced disease at primary, regional, and distant sites. New RT techniques need to be integrated with effective new systemic therapies within a multidisciplinary environment to ensure optimum patient outcomes. It is important that radiation oncologists embrace this opportunity.
J. Surg. Oncol. 2014;109:370–375. ß 2013 Wiley Periodicals, Inc.
KEY WORDS: melanoma; radiation therapy; metastasis; review; clinical trial
A HISTORY OF RADIATION THERAPY FOR MELANOMA Radiation therapy (RT) is an important modality in cancer treatment. However, many clinicians involved in the management of patients with melanoma do not have radiotherapy on their list of treatment options because of a general perception that melanoma is radio‐resistant. This perception is based on historical data, which used techniques and doses that have long been superseded [1]. Later, laboratory [2,3] and clinical radiobiological results [4] suggested that large radiation doses per fraction were the preferred technique. Hypo‐fractionated regimens became popular. One regimen for high‐risk postoperative patients in whom most gross disease had been resected was 21 Gray (Gy) in three fractions of 7 Gy each, delivered on days 1, 7, and 21 [5]. This gave greater than 90% local control at 4 years. Ang et al. gave 30 Gy in five fractions of 6 Gy each in the postoperative to patients with primary node‐ negative cutaneous melanomas of the head and neck setting who were considered to be at high risk for local‐regional relapse [6]. In 174 patients, the actuarial 5‐year local‐regional control rate for the whole group was 88%, better than the 50% observed in historical controls treated without RT. Despite these impressive results, RT was still not regarded as a mainstream treatment in melanoma. The problem with hypofractionation is that when large fraction sizes are given, the total dose delivered needs to be reduced to avoid excessive toxicity. This may compromise disease control. Unfortunately, large fractions sizes are also associated with increased late in‐field effects, which are dominated by fibrosis, especially in skin [7]. Patients who did survive had late radiation complications, giving RT a bad name. Randomized trials showed that hypofractionation gave no clinical advantage over standard fractionation [8,9]. At the same time, surgical techniques improved and as a result surgery won the ascendancy, with radiation oncologists, in the main, retreating from the field. Where patients were referred for RT, it was usually as a last resort. Large symptomatic lesions requiring palliation that had already failed other therapies were treated by ROs with some degree of nihilism. Often the lesions did not respond, reinforcing the pessimism. Better techniques and improved radiobiological knowledge are putting RT back in the treatment arsenal for patients with melanoma. High quality trials involving RT are being conducted around the world, several under the auspices of the Australian and New Zealand Melanoma Trials Group (ANZMTG), and will help define the place of modern RT in current melanoma therapeutics. The Trans Tasman Radiation
ß 2013 Wiley Periodicals, Inc.
Oncology Group (TROG) is also involved in some of these trials. These trials will be mentioned in following sections. It is important to emphasize that RT is a form of local therapy. Therefore trial endpoints are mostly local control. With the propensity of patients with Stage 3 melanoma to develop distant metastasis, it is unlikely that any local control benefit provided by RT will translate to a distant relapse free or overall survival benefit.
FUNDAMENTALS OF RADIATION THERAPY RT works by causing double‐stranded breaks in the DNA of cells, rendering them unable to divide, and so stopping cancers from growing. Normal cells have effective radiation repair mechanisms, tumor cells do not. This difference, among others, is exploited in RT. In a course of fractionated RT, normal cells can repair between the fractions and survive, whereas tumor cells cannot. Thus RT can sterilize a mixed population of tumor and normal cells, allowing only the normal cells to survive. RT is therefore excellent in situations where normal tissue conservation is important. Case studies show that occasionally RT may also have an abscopal effect, causing regression of metastatic disease at distant sites [10–12]. Traditionally, the logical role for RT is in regional control, where further normal tissue sacrifice by surgery would be mutilating. The paradigm of surgery for local control, with removal of macroscopic disease for cure and histologic prognostication, RT for regional control of microscopic disease, especially in draining lymph nodes; and systemic therapy for distant control from blood‐borne tumor cells is well established in solid tumors such as breast and rectal cancer. This combination of therapies has increased progression‐free survival, with better quality of life. This pattern exists in many tumor types on the basis
Disclosure Statement: The authors declare that there are no conflicts of interest. *Correspondence to: Dr. Gerald Fogarty, BSc, MBBS, PhD, FRANZCR, Melanoma Institute Australia, Poche Centre, 40 Rocklands Road, North Sydney, NSW 2060, Australia. Fax: þ61‐2‐9458‐8088. E‐mail: gerald. [email protected] Received 30 June 2013; Accepted 24 October 2013 DOI 10.1002/jso.23509 Published online 27 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
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of well‐designed international trials. Multidisciplinary trials in melanoma that include RT are needed and still evolving.
MODALITIES OF RADIATION THERAPY There are different ways in which RT can be delivered. The modality chosen is that which enables maximum dose to the tumor volume, thereby increasing the chance of control or cure, while minimizing dose to the surrounding normal tissues, thereby decreasing side effects. This concept is called maximizing dose conformality; it is a part of maximizing the therapeutic ratio, a fundamental concept governing all cancer therapies. Better conformality spares dose to normal tissues so that the dose per fraction to tumor can be escalated. This allows fewer treatments, or even a single treatment. This type of RT is often called radiosurgery. Special equipment is needed that allows stereotaxic localization, hence the term stereotactic radiosurgery (SRS). The amount of radiation delivered causes tumor ablation, with the net effect similar to surgical removal, but without the morbidity of an operation and physical disruption of surrounding normal tissue. SRS depends on patient immobilization and was first used in the brain, where skull fixation is relatively easy [13]. Stereotactic body radiotherapy (SBRT) can now treat disease in the rest of the body even in moving organs, for example, lung and liver metastases [14]. Traditionally, radiation modalities are divided into External Beam RT (EBRT) or teletherapy; and brachytherapy (BT). EBRT involves radiation being beamed into a patient from a relatively distant source. For BT the radiation source is put into or onto the tumor. These modalities are governed by the Inverse Square Law, which states that the measured radiation intensity at any point outside the radiation source is inversely proportional to the square of the distance from the source. That is, as the distance from the source increases, the measured radiation decreases dramatically. With BT, a high dose is delivered to the tumor, but by the time the radiation dose cloud reaches more distant normal tissue, the intensity is much less. BT is used extensively in treating uveal melanoma for eye preservation. A randomized trial showed that there was eye preservation but no worse survival with BT versus enucleation [15]. BT can also be used to treat cutaneous [9,16–18] and mucosal [19] melanomas. In a phase one trial of hyperthermia with low dose rate BT [20] the control rate in a small number of patients with cutaneous melanoma metastases was excellent. Internal organ BT is also possible but the organ needs to be accessible and suitable for implantation. It also depends on local expertise, the availability of technology (e.g., transrectal ultrasound for prostate, MRI co‐registration for cervix) and dedicated BT hardware and planning systems. With EBRT, by the time the radiation reaches the tissue from a relatively distant source (often a meter when a linear accelerator is used) the rate of dose fall‐off is much less per unit distance from the source. It is therefore excellent for irradiating large volumes in a homogeneous fashion, for example, whole brain radiotherapy (WBRT). The problem with EBRT is that to irradiate an internal organ, significant normal tissues in the entry and exit beams may also be irradiated (e.g., causing alopecia with WBRT). This effect can be decreased by newer radiation techniques including intensity‐modulated radiotherapy (IMRT) and its logical progression, volumetric modulated arc therapy (VMAT) [21]. This enables WBRT with hippocampal sparing [22] a technique that is important because it results in reduced long‐term cognitive deficits [23,24]. The use of non‐coplanar beams, for example, gamma knife and cyber knife systems—essentially dilute the impact of radiation on normal tissue by administering treatment from a plethora of different directions, in many different planes, so that only the tumor gets the full dose (Fig. 1). Particle, or more precisely Hadron therapy, the most common of which is proton therapy, has no exit beam, that is, the beam that passes through Journal of Surgical Oncology
Fig. 1. This simplified diagram of the Gamma knife shows how the beams treat from many different directions, in many different planes, so that the dose is diluted through surrounding normal tissue. Only the tumor, which is at the intersection of all the beams, gets full dose (Figure courtesy of Elekta). the rest of the body after hitting the target (Fig. 2). Hadron therapy is the most conformal EBRT, and challenges BT for conformality of dose in uveal melanoma according to a recent meta‐analysis [25].
RADIATION THERAPY FOR ADVANCED MELANOMA RT for advanced melanoma includes RT given to the primary site. The historical background and indications for RT in this scenario are well described in Hong et al. [26] Surgery is the mainstay of treatment to the primary site. Not only can this be curative but it also provides histopathologic data that aid in prognostication and indicate whether further therapies are indicated. Possible further therapies include RT when the disease is more advanced. Indications for adjuvant RT to the primary site include close or positive margins where further surgery is not possible, lymphatic invasion, multiple recurrences, and a desmoplastic neurotropic pattern [26]. A recent retrospective study of 82 patients showed in‐field loco‐regional control at 5 years was 87% after hypofractionated RT and 78% after conventionally fractionated RT, with a low risk of RT complications [27]. RT following wide excision of neurotropic melanoma of the head and neck is currently being investigated in a randomized trial. The ANZMTG 01/09/TROG 08‐09/RTN2 trial is a one‐to‐one randomized trial of postoperative RT versus observation (Clinicaltrials.gov Identifier: NCT00975520). The trial is open at 12 Australian sites with 20 patients accrued of a total of 100 patients needed, and will help answer this controversial question. All patients will be followed up for 5 years and if the lesion recurs locally, it will be re‐excised, re‐staged and the patient will continue on follow up. The primary end point is time to in‐
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Fogarty et al. adjunct nodal RT trial ANZMTG 01/02 TROG 02.01 of lymphadenectomy followed by adjuvant RT (ART) or observation in patients with palpable metastatic disease in regional lymph nodes who were considered at high risk for further recurrence was recently reported [37]. Participating patients at high risk of regional relapse (1 parotid, 2 cervical or axillary, or 3 groin positive nodes; or extra‐ nodal spread of tumor; or minimum metastatic node diameter of 3 cm (neck or axilla) or 4 cm (groin) received ART (48 Gy in 20 fractions) or observation (OBS). The outcomes in 217 fully eligible (109 ART, 108 OBS) patients with a mean follow‐up 73 months (range 21–116) were analyzed. Regional recurrence was halved in the ART arm (HR ¼ 0.52 [0.31–0.88] P ¼ 0.023) but, as expected, there was no statistically significant effect on survival (HR ¼ 1.13 [0.82–1.55] P ¼ 0.21). Patient quality of life (QOL) showed no difference between the ART and OBS arms but regional symptoms were higher as expected in the ART arm (P ¼ 0.035). It will be interesting to see the impact of this positive trial on clinical practice.
RADIATION THERAPY FOR STAGE IV DISEASE
Fig. 2. This figure compares the depth dose characteristics of a 10 MV photon beam (solid line) with a proton beam (dashed line). The gray area shows the large entrance and exit beam needed by the photon beam to cover the tumor volume. This extra radiation is deposited in surrounding normal tissue which may suffer adversely from this. The proton beam has a smaller entrance beam and no exit beam, giving better dose conformality. field relapse and secondary end points include progression‐ free survival, overall survival, patterns of relapse, late toxicity, and quality of life. Lentigo maligna (LM) is a form of primary in situ melanoma. When dermal invasive melanoma develops in a LM, it is termed LM melanoma (LMM). LMM is the third most common of the four main invasive melanoma subtypes and has metastatic potential. The lifetime risk of developing LMM within a LM has been reported to be as low as 5% [28] and as high as 50% [29], with the time to transformation varying between a few months to more than 30 years. Physician bias is to treat LM to avoid the risk of missing a LMM [30,31]. LM frequently involves the face near critical anatomical structures and non‐surgical therapies, including RT, are increasingly used. A literature review [32] described 537 patients with LM treated with definitive primary RT with median reported follow‐up times of 3 years. There were only 18 recurrences documented in a total of 349 assessable patients (5%), and salvage was successful in the majority of cases of recurrent LM. Progression to LMM occurred in five patients (5/349 ¼ 1.4%) all of whom had poor outcomes. There were five marginal recurrences of 123 assessable patients. Another randomized trial, ANZMTG 02.12, called the RADICAL trial, is almost to commence patient accrual. This trial is investigating imiquimod versus RT in LM mapped with reflectance confocal microscopy (RCM) when staged surgical excision with 5 mm margins is not possible, is refused, or fails. RT has also been used to treat primary mucosal melanoma in both definitive and adjuvant settings. Retrospective reviews suggest that surgery and RT, or stereotactic RT techniques, are superior to conventional RT alone [33–36].
RADIATION THERAPY FOR METASTATIC MELANOMA RT for metastatic melanoma includes RT given to regional lymph nodes, also well described in Hong et al. [26] The final results of and Journal of Surgical Oncology
RT has an important role in the management of melanoma patients with Stage IV disease when lesions are symptomatic or about to become symptomatic. The latter use of RT is named pre‐emptive RT and is controversial. There are special cases to consider in melanoma. In particular is the concept of pace of disease. Melanoma metastases can grow rapidly or slowly. For example, a patient referred for treatment of a melanoma brain metastasis at the age of 38 had a history of having a cutaneous melanocytic lesion excised at the age of two. In this patient the disease free interval was 36 years. The possibility of prolonged survival is important for RT as the impact of late effects when using hypofractionated palliative regimes must be considered. Brain metastases (BMs) are common in patients with stage IV melanoma and often the cause of death. Traditionally patients with BMs presented when symptoms developed and were treated by surgical removal for mass effect followed by WBRT. This type of WBRT is effectively adjuvant treatment intended to prevent further macroscopic brain disease. With the advent of widespread magnetic resonance imaging (MRI) and screening MRI for clinical trials purposes, BMs are now often found when small volume and asymptomatic, and can be treated with SRS techniques. The efficacy of recently discovered drugs that cross the blood–brain barrier such as ipilimumab [38] and dabrafenib for patients with BRAF mutant BMs [39] have impacted on the need for WBRT. The role of WBRT after local treatment of brain metastases is particularly controversial. Proponents say that radiotherapy to prevent or delay neurological decline from further macroscopic disease is worthwhile palliation. Opponents argue against radiotherapy as there has never been a survival benefit demonstrated, there are now melanoma drugs effective in the brain, there is a risk of neurotoxicity from WBRT and melanoma is radio‐resistant anyway. To clarify the role of WBRT in this setting a randomized trial called the WBRTMel trial is currently accruing patients (Clinicaltrials.gov Identifier: NCT01503827). This ANZMTG 01/07; TROG 08.05 trial is comparing immediate WBRT to observation following local treatment of one to three intracranial metastases of melanoma [40]. The trial is open in over 20 centers in four countries and by October 2013 had accrued 129 patients out of a target 200. An interim analysis 12 months following randomization of the 100th patient is due in late 2013. The primary end point is the proportion of patients with distant intracranial failure after 12 months, as assessed by MRI scanning. Secondary end points include detailed QOL and neurocognitive function measures. Melanoma can metastasize to unexpected places. Small bowel metastases are not amenable to radiation treatment as the small bowel moves in an unpredictable fashion and so the target lesions can move out
Therapies for Melanoma of the beam. The small bowel is also radiosensitive and can suffer side effects at low RT doses which are not consistent with worthwhile palliation. Fixed lesions in the abdomen can be treated, for example, in the duodenum, para‐aortic lymph nodes and adrenal glands [41]. Mobile organs such as lung and liver metastases can be treated with new techniques and modalities [14]. Rare sites, such as the atrium [42] have been successfully treated, avoiding the use of major surgery in the essentially palliative setting.
PALLIATIVE RADIATION THERAPY Palliative treatments are for the relief of symptoms. RT is effective in this scenario in melanoma patients. Pain and mass effect can be treated with RT. Hemorrhage can be controlled by low dose RT [43]. Skin lesions can be treated with many modalities, but RT is an option that should not be overlooked [44].
TREATMENT DECISIONS BY RADIATION ONCOLOGISTS IN THE CURRENT ERA OF EFFECTIVE TARGETED THERAPIES With the advent of impressive new drugs that are active in the brain, and new techniques of RT that can deliver ablative doses accurately, current melanoma therapy represents a fascinating challenge for the present‐day radiation oncologist. The radiation oncologist needs to make treatment decisions, but the scientific foundations upon which these decisions are based are in a state of flux, changing as the results of new trials are reported. A summary of decisions that radiation oncologists dealing with melanoma need to make, and the changing landscapes currently affecting them, is detailed below.
Decision One: To Treat With RT or Not? Symptomatic masses of metastatic melanoma can now be effectively treated with targeted systemic therapies [39]. Patients with BRAF mutant metastatic disease can have their fulminant disease course suddenly stopped and stabilized [45], typically for periods of 8–9 months. RT is increasingly reserved for the time when systemic therapies have failed. Interactions between RT and new drugs have now been reported and need to be considered, especially in the consent process [46,47].
Decision Two: Intention of Treatment? The intention can be radical, aiming for complete tumor ablation, or palliative (treating for actual or impending symptom relief). Patient performance status is a factor influencing treatment intent. New effective systemic drugs are having significant impact on performance status [48]. New systemic therapies have elevated metastatic melanoma from an imminently fatal to a chronic disease in some patients. As survival times increase, debilitating RT late effects from hypofractionation can become apparent. Avoiding these is becoming increasingly important, for example, sparing the hippocampus in WBRT to avoid dementia [22].
Decision Three: What Volume to Treat? Radiation oncologists treat volumes at risk. Radiosensitive organ volumes should be avoided. This requires an oncological knowledge of the pathways of tumor spread, especially for microscopic regional disease that is not apparent on imaging. This requires precision in volume definition and the ability to conform the radiation dose cloud to only that volume. The latter is now possible as the technology of radiation treatment delivery exponentially expands. What might previously have been fortuitously covered by entrance and exit beams with old technologies may now not be. Knowledge of and harnessing technologies developed by other specialities, for example, Journal of Surgical Oncology
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lymphoscintigraphy to aid in radiotherapy field design in the head and neck, is important for radiation oncologists with a melanoma interest.
Decision Four: What Modality to Use? What modality (or modalities)—External beam, brachytherapy, particles, etc., should be used? This decision is treatment volume dependent. Discerning which modalities are clinically relevant is challenging and depends on what the local department has available in terms of hardware and technical expertise. Patients may have to travel to other centers to be treated with special techniques, for example, gamma knife therapy.
Decision Five: What Total Dose to Use? This is controversial and trials are needed. Radiation oncologists treating melanoma consider it to be a genus rather than a species of diseases and would like to discover a clinically relevant and easily measurable marker that would divide melanomas into those that are radio‐responsive (like small cell lung cancer) and those that are relatively unresponsive (like sarcoma). The discovery of this marker may have an effect in RT in the same way as BRAF status has divided melanoma for the medical oncology community into mutation positive and wild type. Resistant melanoma could receive a higher dose or other treatments. This would help to personalize RT dose parameters.
Decision Six: What Fractionation Pattern to Use? This is also controversial and more trials are needed to provide guidance. The recent positive trial reported by Burmeister et al. [49] used 48 Gy in 20 fractions at five per week in the adjuvant post‐operative setting. Ang et al. [6] used 30 Gy in five fractions at two per week in the adjuvant setting in the unoperated neck with good effect. New trials could be stratified for molecular targets.
CONCLUSION: THE FUTURE OF RADIATION THERAPY FOR MELANOMA RT is a major treatment modality in many tumor types, its value having been established by high quality trials. Other trials have tested new conformal techniques and hypofractionation, leading to a better understanding of radiobiology. Trials in melanoma testing new combinations of RT with drugs and surgery are needed. However RT, due to the current lack of engagement of many radiation oncologists in the management of melanoma, may find itself outside the standard treatment paradigms for melanoma. It is therefore urgent for radiation oncologists to become involved in melanoma treatment programs. The BRAF experience has supported the concept that melanoma is a genus of cancers, and not a single species. Each melanoma is different, with some metastasizing early, some late, most never. The clinical experience of radiation oncologists reflects this. Some metastatic melanoma deposits are exquisitely radiosensitive, others grow through RT. Radiation oncologists need to find the BRAF equivalent in metastatic melanoma, to find which ones should be treated with RT, and which should not. The future will probably bring a better ability to predict disease evolution and therefore to select treatments. The era of personalized medicine has arrived for patients with metastatic melanoma [50]. A logical and personalized approach to eradication of metastatic melanoma cannot be undertaken by one clinician alone. Many specialities are needed and hence the treatment of melanoma metastases can only go forward on a multidisciplinary platform. The involvement of radiation oncologists in the multidisciplinary melanoma team is essential.
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ACKNOWLEDGMENT The authors gratefully acknowledge the assistance of Dr Helena Jang in formatting this article.
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Radiation Therapy for Advanced and Metastatic Melanoma GERALD B. FOGARTY, BSc, MBBS, PhD, FRANZCR1,2* AND ANGELA HONG, MBBS, PhD, FRANZCR(FRO)1,3 1
2
Melanoma Institute Australia, Poche Centre, North Sydney, Australia Genesis Cancer Care, Mater Sydney Radiation Oncology Centre, Mater Hospital, North Sydney, Australia 3 Department of Radiation Oncology, Royal Prince Alfred Hospital, Camperdown, Australia
Radiation therapy (RT) is an important modality in cancer treatment. However, the general perception is that melanoma is radio‐resistant. High quality clinical trials are helping to establish the place of RT in select scenarios of advanced disease at primary, regional, and distant sites. New RT techniques need to be integrated with effective new systemic therapies within a multidisciplinary environment to ensure optimum patient outcomes. It is important that radiation oncologists embrace this opportunity.
J. Surg. Oncol. 2014;109:370–375. ß 2013 Wiley Periodicals, Inc.
KEY WORDS: melanoma; radiation therapy; metastasis; review; clinical trial
A HISTORY OF RADIATION THERAPY FOR MELANOMA Radiation therapy (RT) is an important modality in cancer treatment. However, many clinicians involved in the management of patients with melanoma do not have radiotherapy on their list of treatment options because of a general perception that melanoma is radio‐resistant. This perception is based on historical data, which used techniques and doses that have long been superseded [1]. Later, laboratory [2,3] and clinical radiobiological results [4] suggested that large radiation doses per fraction were the preferred technique. Hypo‐fractionated regimens became popular. One regimen for high‐risk postoperative patients in whom most gross disease had been resected was 21 Gray (Gy) in three fractions of 7 Gy each, delivered on days 1, 7, and 21 [5]. This gave greater than 90% local control at 4 years. Ang et al. gave 30 Gy in five fractions of 6 Gy each in the postoperative to patients with primary node‐ negative cutaneous melanomas of the head and neck setting who were considered to be at high risk for local‐regional relapse [6]. In 174 patients, the actuarial 5‐year local‐regional control rate for the whole group was 88%, better than the 50% observed in historical controls treated without RT. Despite these impressive results, RT was still not regarded as a mainstream treatment in melanoma. The problem with hypofractionation is that when large fraction sizes are given, the total dose delivered needs to be reduced to avoid excessive toxicity. This may compromise disease control. Unfortunately, large fractions sizes are also associated with increased late in‐field effects, which are dominated by fibrosis, especially in skin [7]. Patients who did survive had late radiation complications, giving RT a bad name. Randomized trials showed that hypofractionation gave no clinical advantage over standard fractionation [8,9]. At the same time, surgical techniques improved and as a result surgery won the ascendancy, with radiation oncologists, in the main, retreating from the field. Where patients were referred for RT, it was usually as a last resort. Large symptomatic lesions requiring palliation that had already failed other therapies were treated by ROs with some degree of nihilism. Often the lesions did not respond, reinforcing the pessimism. Better techniques and improved radiobiological knowledge are putting RT back in the treatment arsenal for patients with melanoma. High quality trials involving RT are being conducted around the world, several under the auspices of the Australian and New Zealand Melanoma Trials Group (ANZMTG), and will help define the place of modern RT in current melanoma therapeutics. The Trans Tasman Radiation
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Oncology Group (TROG) is also involved in some of these trials. These trials will be mentioned in following sections. It is important to emphasize that RT is a form of local therapy. Therefore trial endpoints are mostly local control. With the propensity of patients with Stage 3 melanoma to develop distant metastasis, it is unlikely that any local control benefit provided by RT will translate to a distant relapse free or overall survival benefit.
FUNDAMENTALS OF RADIATION THERAPY RT works by causing double‐stranded breaks in the DNA of cells, rendering them unable to divide, and so stopping cancers from growing. Normal cells have effective radiation repair mechanisms, tumor cells do not. This difference, among others, is exploited in RT. In a course of fractionated RT, normal cells can repair between the fractions and survive, whereas tumor cells cannot. Thus RT can sterilize a mixed population of tumor and normal cells, allowing only the normal cells to survive. RT is therefore excellent in situations where normal tissue conservation is important. Case studies show that occasionally RT may also have an abscopal effect, causing regression of metastatic disease at distant sites [10–12]. Traditionally, the logical role for RT is in regional control, where further normal tissue sacrifice by surgery would be mutilating. The paradigm of surgery for local control, with removal of macroscopic disease for cure and histologic prognostication, RT for regional control of microscopic disease, especially in draining lymph nodes; and systemic therapy for distant control from blood‐borne tumor cells is well established in solid tumors such as breast and rectal cancer. This combination of therapies has increased progression‐free survival, with better quality of life. This pattern exists in many tumor types on the basis
Disclosure Statement: The authors declare that there are no conflicts of interest. *Correspondence to: Dr. Gerald Fogarty, BSc, MBBS, PhD, FRANZCR, Melanoma Institute Australia, Poche Centre, 40 Rocklands Road, North Sydney, NSW 2060, Australia. Fax: þ61‐2‐9458‐8088. E‐mail: gerald. [email protected] Received 30 June 2013; Accepted 24 October 2013 DOI 10.1002/jso.23509 Published online 27 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
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of well‐designed international trials. Multidisciplinary trials in melanoma that include RT are needed and still evolving.
MODALITIES OF RADIATION THERAPY There are different ways in which RT can be delivered. The modality chosen is that which enables maximum dose to the tumor volume, thereby increasing the chance of control or cure, while minimizing dose to the surrounding normal tissues, thereby decreasing side effects. This concept is called maximizing dose conformality; it is a part of maximizing the therapeutic ratio, a fundamental concept governing all cancer therapies. Better conformality spares dose to normal tissues so that the dose per fraction to tumor can be escalated. This allows fewer treatments, or even a single treatment. This type of RT is often called radiosurgery. Special equipment is needed that allows stereotaxic localization, hence the term stereotactic radiosurgery (SRS). The amount of radiation delivered causes tumor ablation, with the net effect similar to surgical removal, but without the morbidity of an operation and physical disruption of surrounding normal tissue. SRS depends on patient immobilization and was first used in the brain, where skull fixation is relatively easy [13]. Stereotactic body radiotherapy (SBRT) can now treat disease in the rest of the body even in moving organs, for example, lung and liver metastases [14]. Traditionally, radiation modalities are divided into External Beam RT (EBRT) or teletherapy; and brachytherapy (BT). EBRT involves radiation being beamed into a patient from a relatively distant source. For BT the radiation source is put into or onto the tumor. These modalities are governed by the Inverse Square Law, which states that the measured radiation intensity at any point outside the radiation source is inversely proportional to the square of the distance from the source. That is, as the distance from the source increases, the measured radiation decreases dramatically. With BT, a high dose is delivered to the tumor, but by the time the radiation dose cloud reaches more distant normal tissue, the intensity is much less. BT is used extensively in treating uveal melanoma for eye preservation. A randomized trial showed that there was eye preservation but no worse survival with BT versus enucleation [15]. BT can also be used to treat cutaneous [9,16–18] and mucosal [19] melanomas. In a phase one trial of hyperthermia with low dose rate BT [20] the control rate in a small number of patients with cutaneous melanoma metastases was excellent. Internal organ BT is also possible but the organ needs to be accessible and suitable for implantation. It also depends on local expertise, the availability of technology (e.g., transrectal ultrasound for prostate, MRI co‐registration for cervix) and dedicated BT hardware and planning systems. With EBRT, by the time the radiation reaches the tissue from a relatively distant source (often a meter when a linear accelerator is used) the rate of dose fall‐off is much less per unit distance from the source. It is therefore excellent for irradiating large volumes in a homogeneous fashion, for example, whole brain radiotherapy (WBRT). The problem with EBRT is that to irradiate an internal organ, significant normal tissues in the entry and exit beams may also be irradiated (e.g., causing alopecia with WBRT). This effect can be decreased by newer radiation techniques including intensity‐modulated radiotherapy (IMRT) and its logical progression, volumetric modulated arc therapy (VMAT) [21]. This enables WBRT with hippocampal sparing [22] a technique that is important because it results in reduced long‐term cognitive deficits [23,24]. The use of non‐coplanar beams, for example, gamma knife and cyber knife systems—essentially dilute the impact of radiation on normal tissue by administering treatment from a plethora of different directions, in many different planes, so that only the tumor gets the full dose (Fig. 1). Particle, or more precisely Hadron therapy, the most common of which is proton therapy, has no exit beam, that is, the beam that passes through Journal of Surgical Oncology
Fig. 1. This simplified diagram of the Gamma knife shows how the beams treat from many different directions, in many different planes, so that the dose is diluted through surrounding normal tissue. Only the tumor, which is at the intersection of all the beams, gets full dose (Figure courtesy of Elekta). the rest of the body after hitting the target (Fig. 2). Hadron therapy is the most conformal EBRT, and challenges BT for conformality of dose in uveal melanoma according to a recent meta‐analysis [25].
RADIATION THERAPY FOR ADVANCED MELANOMA RT for advanced melanoma includes RT given to the primary site. The historical background and indications for RT in this scenario are well described in Hong et al. [26] Surgery is the mainstay of treatment to the primary site. Not only can this be curative but it also provides histopathologic data that aid in prognostication and indicate whether further therapies are indicated. Possible further therapies include RT when the disease is more advanced. Indications for adjuvant RT to the primary site include close or positive margins where further surgery is not possible, lymphatic invasion, multiple recurrences, and a desmoplastic neurotropic pattern [26]. A recent retrospective study of 82 patients showed in‐field loco‐regional control at 5 years was 87% after hypofractionated RT and 78% after conventionally fractionated RT, with a low risk of RT complications [27]. RT following wide excision of neurotropic melanoma of the head and neck is currently being investigated in a randomized trial. The ANZMTG 01/09/TROG 08‐09/RTN2 trial is a one‐to‐one randomized trial of postoperative RT versus observation (Clinicaltrials.gov Identifier: NCT00975520). The trial is open at 12 Australian sites with 20 patients accrued of a total of 100 patients needed, and will help answer this controversial question. All patients will be followed up for 5 years and if the lesion recurs locally, it will be re‐excised, re‐staged and the patient will continue on follow up. The primary end point is time to in‐
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Fogarty et al. adjunct nodal RT trial ANZMTG 01/02 TROG 02.01 of lymphadenectomy followed by adjuvant RT (ART) or observation in patients with palpable metastatic disease in regional lymph nodes who were considered at high risk for further recurrence was recently reported [37]. Participating patients at high risk of regional relapse (1 parotid, 2 cervical or axillary, or 3 groin positive nodes; or extra‐ nodal spread of tumor; or minimum metastatic node diameter of 3 cm (neck or axilla) or 4 cm (groin) received ART (48 Gy in 20 fractions) or observation (OBS). The outcomes in 217 fully eligible (109 ART, 108 OBS) patients with a mean follow‐up 73 months (range 21–116) were analyzed. Regional recurrence was halved in the ART arm (HR ¼ 0.52 [0.31–0.88] P ¼ 0.023) but, as expected, there was no statistically significant effect on survival (HR ¼ 1.13 [0.82–1.55] P ¼ 0.21). Patient quality of life (QOL) showed no difference between the ART and OBS arms but regional symptoms were higher as expected in the ART arm (P ¼ 0.035). It will be interesting to see the impact of this positive trial on clinical practice.
RADIATION THERAPY FOR STAGE IV DISEASE
Fig. 2. This figure compares the depth dose characteristics of a 10 MV photon beam (solid line) with a proton beam (dashed line). The gray area shows the large entrance and exit beam needed by the photon beam to cover the tumor volume. This extra radiation is deposited in surrounding normal tissue which may suffer adversely from this. The proton beam has a smaller entrance beam and no exit beam, giving better dose conformality. field relapse and secondary end points include progression‐ free survival, overall survival, patterns of relapse, late toxicity, and quality of life. Lentigo maligna (LM) is a form of primary in situ melanoma. When dermal invasive melanoma develops in a LM, it is termed LM melanoma (LMM). LMM is the third most common of the four main invasive melanoma subtypes and has metastatic potential. The lifetime risk of developing LMM within a LM has been reported to be as low as 5% [28] and as high as 50% [29], with the time to transformation varying between a few months to more than 30 years. Physician bias is to treat LM to avoid the risk of missing a LMM [30,31]. LM frequently involves the face near critical anatomical structures and non‐surgical therapies, including RT, are increasingly used. A literature review [32] described 537 patients with LM treated with definitive primary RT with median reported follow‐up times of 3 years. There were only 18 recurrences documented in a total of 349 assessable patients (5%), and salvage was successful in the majority of cases of recurrent LM. Progression to LMM occurred in five patients (5/349 ¼ 1.4%) all of whom had poor outcomes. There were five marginal recurrences of 123 assessable patients. Another randomized trial, ANZMTG 02.12, called the RADICAL trial, is almost to commence patient accrual. This trial is investigating imiquimod versus RT in LM mapped with reflectance confocal microscopy (RCM) when staged surgical excision with 5 mm margins is not possible, is refused, or fails. RT has also been used to treat primary mucosal melanoma in both definitive and adjuvant settings. Retrospective reviews suggest that surgery and RT, or stereotactic RT techniques, are superior to conventional RT alone [33–36].
RADIATION THERAPY FOR METASTATIC MELANOMA RT for metastatic melanoma includes RT given to regional lymph nodes, also well described in Hong et al. [26] The final results of and Journal of Surgical Oncology
RT has an important role in the management of melanoma patients with Stage IV disease when lesions are symptomatic or about to become symptomatic. The latter use of RT is named pre‐emptive RT and is controversial. There are special cases to consider in melanoma. In particular is the concept of pace of disease. Melanoma metastases can grow rapidly or slowly. For example, a patient referred for treatment of a melanoma brain metastasis at the age of 38 had a history of having a cutaneous melanocytic lesion excised at the age of two. In this patient the disease free interval was 36 years. The possibility of prolonged survival is important for RT as the impact of late effects when using hypofractionated palliative regimes must be considered. Brain metastases (BMs) are common in patients with stage IV melanoma and often the cause of death. Traditionally patients with BMs presented when symptoms developed and were treated by surgical removal for mass effect followed by WBRT. This type of WBRT is effectively adjuvant treatment intended to prevent further macroscopic brain disease. With the advent of widespread magnetic resonance imaging (MRI) and screening MRI for clinical trials purposes, BMs are now often found when small volume and asymptomatic, and can be treated with SRS techniques. The efficacy of recently discovered drugs that cross the blood–brain barrier such as ipilimumab [38] and dabrafenib for patients with BRAF mutant BMs [39] have impacted on the need for WBRT. The role of WBRT after local treatment of brain metastases is particularly controversial. Proponents say that radiotherapy to prevent or delay neurological decline from further macroscopic disease is worthwhile palliation. Opponents argue against radiotherapy as there has never been a survival benefit demonstrated, there are now melanoma drugs effective in the brain, there is a risk of neurotoxicity from WBRT and melanoma is radio‐resistant anyway. To clarify the role of WBRT in this setting a randomized trial called the WBRTMel trial is currently accruing patients (Clinicaltrials.gov Identifier: NCT01503827). This ANZMTG 01/07; TROG 08.05 trial is comparing immediate WBRT to observation following local treatment of one to three intracranial metastases of melanoma [40]. The trial is open in over 20 centers in four countries and by October 2013 had accrued 129 patients out of a target 200. An interim analysis 12 months following randomization of the 100th patient is due in late 2013. The primary end point is the proportion of patients with distant intracranial failure after 12 months, as assessed by MRI scanning. Secondary end points include detailed QOL and neurocognitive function measures. Melanoma can metastasize to unexpected places. Small bowel metastases are not amenable to radiation treatment as the small bowel moves in an unpredictable fashion and so the target lesions can move out
Therapies for Melanoma of the beam. The small bowel is also radiosensitive and can suffer side effects at low RT doses which are not consistent with worthwhile palliation. Fixed lesions in the abdomen can be treated, for example, in the duodenum, para‐aortic lymph nodes and adrenal glands [41]. Mobile organs such as lung and liver metastases can be treated with new techniques and modalities [14]. Rare sites, such as the atrium [42] have been successfully treated, avoiding the use of major surgery in the essentially palliative setting.
PALLIATIVE RADIATION THERAPY Palliative treatments are for the relief of symptoms. RT is effective in this scenario in melanoma patients. Pain and mass effect can be treated with RT. Hemorrhage can be controlled by low dose RT [43]. Skin lesions can be treated with many modalities, but RT is an option that should not be overlooked [44].
TREATMENT DECISIONS BY RADIATION ONCOLOGISTS IN THE CURRENT ERA OF EFFECTIVE TARGETED THERAPIES With the advent of impressive new drugs that are active in the brain, and new techniques of RT that can deliver ablative doses accurately, current melanoma therapy represents a fascinating challenge for the present‐day radiation oncologist. The radiation oncologist needs to make treatment decisions, but the scientific foundations upon which these decisions are based are in a state of flux, changing as the results of new trials are reported. A summary of decisions that radiation oncologists dealing with melanoma need to make, and the changing landscapes currently affecting them, is detailed below.
Decision One: To Treat With RT or Not? Symptomatic masses of metastatic melanoma can now be effectively treated with targeted systemic therapies [39]. Patients with BRAF mutant metastatic disease can have their fulminant disease course suddenly stopped and stabilized [45], typically for periods of 8–9 months. RT is increasingly reserved for the time when systemic therapies have failed. Interactions between RT and new drugs have now been reported and need to be considered, especially in the consent process [46,47].
Decision Two: Intention of Treatment? The intention can be radical, aiming for complete tumor ablation, or palliative (treating for actual or impending symptom relief). Patient performance status is a factor influencing treatment intent. New effective systemic drugs are having significant impact on performance status [48]. New systemic therapies have elevated metastatic melanoma from an imminently fatal to a chronic disease in some patients. As survival times increase, debilitating RT late effects from hypofractionation can become apparent. Avoiding these is becoming increasingly important, for example, sparing the hippocampus in WBRT to avoid dementia [22].
Decision Three: What Volume to Treat? Radiation oncologists treat volumes at risk. Radiosensitive organ volumes should be avoided. This requires an oncological knowledge of the pathways of tumor spread, especially for microscopic regional disease that is not apparent on imaging. This requires precision in volume definition and the ability to conform the radiation dose cloud to only that volume. The latter is now possible as the technology of radiation treatment delivery exponentially expands. What might previously have been fortuitously covered by entrance and exit beams with old technologies may now not be. Knowledge of and harnessing technologies developed by other specialities, for example, Journal of Surgical Oncology
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lymphoscintigraphy to aid in radiotherapy field design in the head and neck, is important for radiation oncologists with a melanoma interest.
Decision Four: What Modality to Use? What modality (or modalities)—External beam, brachytherapy, particles, etc., should be used? This decision is treatment volume dependent. Discerning which modalities are clinically relevant is challenging and depends on what the local department has available in terms of hardware and technical expertise. Patients may have to travel to other centers to be treated with special techniques, for example, gamma knife therapy.
Decision Five: What Total Dose to Use? This is controversial and trials are needed. Radiation oncologists treating melanoma consider it to be a genus rather than a species of diseases and would like to discover a clinically relevant and easily measurable marker that would divide melanomas into those that are radio‐responsive (like small cell lung cancer) and those that are relatively unresponsive (like sarcoma). The discovery of this marker may have an effect in RT in the same way as BRAF status has divided melanoma for the medical oncology community into mutation positive and wild type. Resistant melanoma could receive a higher dose or other treatments. This would help to personalize RT dose parameters.
Decision Six: What Fractionation Pattern to Use? This is also controversial and more trials are needed to provide guidance. The recent positive trial reported by Burmeister et al. [49] used 48 Gy in 20 fractions at five per week in the adjuvant post‐operative setting. Ang et al. [6] used 30 Gy in five fractions at two per week in the adjuvant setting in the unoperated neck with good effect. New trials could be stratified for molecular targets.
CONCLUSION: THE FUTURE OF RADIATION THERAPY FOR MELANOMA RT is a major treatment modality in many tumor types, its value having been established by high quality trials. Other trials have tested new conformal techniques and hypofractionation, leading to a better understanding of radiobiology. Trials in melanoma testing new combinations of RT with drugs and surgery are needed. However RT, due to the current lack of engagement of many radiation oncologists in the management of melanoma, may find itself outside the standard treatment paradigms for melanoma. It is therefore urgent for radiation oncologists to become involved in melanoma treatment programs. The BRAF experience has supported the concept that melanoma is a genus of cancers, and not a single species. Each melanoma is different, with some metastasizing early, some late, most never. The clinical experience of radiation oncologists reflects this. Some metastatic melanoma deposits are exquisitely radiosensitive, others grow through RT. Radiation oncologists need to find the BRAF equivalent in metastatic melanoma, to find which ones should be treated with RT, and which should not. The future will probably bring a better ability to predict disease evolution and therefore to select treatments. The era of personalized medicine has arrived for patients with metastatic melanoma [50]. A logical and personalized approach to eradication of metastatic melanoma cannot be undertaken by one clinician alone. Many specialities are needed and hence the treatment of melanoma metastases can only go forward on a multidisciplinary platform. The involvement of radiation oncologists in the multidisciplinary melanoma team is essential.
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ACKNOWLEDGMENT The authors gratefully acknowledge the assistance of Dr Helena Jang in formatting this article.
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