Radiation therapy (RT) in patients with metastatic melanoma in regional lymph nodes may be used as adjuvant treatment, or occasionally as definitive treatment, when surgery is not feasible or contraindicated. The rationale for adjuvant RT in patients with stage III melanoma is to reduce the risk of regional node field recurrence, which can cause significant morbidity and seriously reduce quality of life. The notion that melanoma rarely responds to RT has been dispelled by a recent randomized study in patients with AJCC stage III melanoma that demonstrated a significant reduction in node field recurrence with the addition of adjuvant RT.¹ Whether improved regional control improves survival remains speculative. However, metastasis to a regional node field undoubtedly indicates an increased risk of distant metastasis, with a progressive reduction in survival associated with increasing tumor burden in the node field.²

Node Field Recurrence Following Therapeutic Node Dissection

Multiple surgical series have reported a range of node field recurrence rates, which vary considerably according to the extent of lymph node involvement. Node field recurrences range from 15% to 60%, with a median of approximately 30% (Table 17-1). As expected, locoregional relapse rates tend to increase with worsening histopathologic features. The most important prognostic factor appears to be the presence of extranodal tumor extension, including matted nodes. In a randomized study, extranodal extension was associated with a hazard ratio of 1.69 for node field recurrence after adjusting for other known prognostic factors.³ The number of positive nodes and size of involved nodes are also important; recurrence rates of 60% to 80% have been reported for multiple nodes or nodes >6-cm diameter.⁴ The site of the node field is also relevant, with higher relapse rates in the neck (35% to 45%) compared with the axilla (25% to 35%) and the groin (10% to 20%).⁴

Results of Adjuvant Radiation Therapy After Nodal Dissection

To reduce these high rates of node field relapse, adjuvant RT has been recommended when adverse pathological features have been identified. An earlier phase III trial comparing lymph node dissection alone versus lymph node dissection plus adjuvant RT reported a trend toward improved survival in the RT arm, but there was no comment on the effect on locoregional control.⁵ The trial used an unusual split course RT schedule.

The Australia and New Zealand Melanoma Trials Group (ANZMTG) and the Trans Tasman Radiation Oncology Group (TROG) completed a randomized phase III trial to address the role of adjuvant RT following regional node surgery.¹ The trial recruited 250 patients over a 5-year period and the primary endpoint of the trial was node field control. Eligible patients were required to have had palpable nodal disease at presentation and to have undergone therapeutic node field dissection. Eligibility was based on the tumor burden in the node field, including the number of involved nodes (≥1 parotid, ≥2 cervical or axillary, ≥3 inguinal nodes); presence of extranodal spread; and size of involved nodes (≥3-cm diameter in neck, ≥4 cm in axilla and groin). Following their node field surgery, patients were randomized to observation or adjuvant RT (48 Gy in 20 fractions over 4 weeks). With a median follow-up of 73 months (range 21 to 116), there was a substantial, statistically significant reduction in risk of nodal relapse with immediate adjuvant RT (HR 0.52; 95% CI 0.32 to 0.98, p = 0.023), but no significant difference in relapse-free or overall survival was observed. On multivariate analysis, the presence of extranodal spread (HR 1.69) and the use of RT (HR 0.49) were significant negative and positive prognostic factors for node field relapse. For overall survival, extranodal spread (HR 1.70), number of positive nodes (HR 1.42), and male gender (HR 1.68) were negative prognostic factors. The quality of life was assessed by the FACT-G and regional symptomatology questionnaire at regular intervals until the first recurrence or for 5 years after randomization. There was no significant difference in quality of life as measured by FACT-G between the two groups. Those who were randomized to radiation had worse regional symptoms, mainly subcutaneous fibrosis. However, very few patients experienced grade 3 or grade 4 RT toxicity. There was an increased risk of lymphoedema (for groin disease only) for patients receiving radiotherapy.

In addition to this randomized study, a number of large melanoma centers, particularly in North America and Australia, have reported their experiences and outcomes. The results of some of these series are summarized in Table 17-2. The indications for RT and the fractionation schedules varied widely, although most groups used hypofractionated schedules. In the largest series, involving 615 patients, a 5-year regional control rate of 81% was achieved after nodal dissection and adjuvant RT.⁶ On multivariate analysis, the use of adjuvant RT was associated with an improvement in disease-specific survival.

Conventional Fractions Versus Hypofractionation

The optimal fractionation of RT for melanoma is not well defined, with some centers favoring hypofractionation (30 to 33 Gy in 5 to 6 fractions, 2 fractions per week), whereas the ANZMTG/TROG randomized trial used 48 Gy in 20 fractions (5 fractions per week). Large fraction size has the potential of achieving better response rates based on previous radiobiological findings that suggested melanoma cells are radioresistant, with a small alpha/beta ratio.⁷ The RTOG 83-05 trial randomized 137 patients with palpable nodal disease or soft tissue disease to definitive RT with either 32 Gy in 4 fractions or 50 Gy in 25 fractions.⁸ There was no significant difference in the response rates for the two RT schedules, with an overall complete response rate of 23.8% and a partial response rate of 34.9%. However, this study did not report the acute and late toxicity data. Another study, involving 35 patients, showed a complete response rate of 9% if ≤ 5 Gy per treatment was used. The response rate increased to 50% if radiation doses ≥ 5 Gy per treatment were used.⁷ A study of 83 patients with melanomas of the head and neck region from the 1980s demonstrated a 2-year locoregional control rate of 95% with large doses of adjuvant RT (24 to 30 Gy in 4 to 5 fractions at 5 to 6 Gy per fraction) to the tumor bed and regional lymph nodes. Another obvious advantage of hypofractionation is the reduction in the number of radiotherapy department attendances that are required (improving patient convenience, and with health economics benefits also). However, the potential for worse late radiation toxicity associated with hypofractionated treatment is of concern. Whether 48 Gy in 20 fractions is less damaging to normal tissues than 30 to 33 Gy in 5 to 6 fractions is an interesting and unresolved issue. There is a need for further studies using modern RT techniques to determine the optimal fractionation for melanoma, with endpoints including oncologic outcomes, toxicity, and quality of life assessments.

Radiation Therapy Following Excision of Macroscopic Nodal Disease Only

Some patients who present with macroscopic nodal disease are not suitable for a therapeutic node dissection because of age and medical comorbidites. There are retrospective data to support the use of local excision of the macroscopic nodal disease only in these patients, but with the addition of adjuvant RT. The MD Anderson Cancer Center reported a group of 36 patients who received adjuvant RT to the neck following limited excision of all palpable nodes. With a median follow-up of 5.3 years, the actuarial 5-year regional control and distant metastasis-free survival rates were 93% and 59%, respectively.⁹ Similar results were obtained in a series of 28 patients treated at Melanoma Institute Australia, in whom the 5-year regional control rate was 78% and the overall survival rate was 50.4%.¹⁰

The results of adjuvant RT following incomplete excision of macroscopic disease in regional node fields have also been reported. By contrast with the impressive regional control rates of approximately 90% obtained with adjuvant RT for presumed microscopic disease, infield control rates fall to approximately 50% when macroscopic disease remains.¹¹ On this basis, every effort should be made to remove all macroscopic disease.

Radiation Therapy for Unresectable Nodal Disease

Occasionally, patients present with initially unresectable nodal disease without distant metastasis. Preoperative RT has been used to downstage the disease. Standard fractionation (50 Gy in 25 fractions) is generally recommended to reduce the potentially adverse effect of large fraction size on postoperative wound healing. Operability of the disease can then be assessed at 4 to 6 weeks after completion of RT. Increasingly, this group of patients is being treated with neoadjuvant systemic therapy as they are at high risk of developing systemic disease. Palliative RT for unresectable nodal melanoma is beneficial in most patients. Reported complete response rates are 23% to 74% and the partial response rates are 25% to 45%.^11–13

Radiation Therapy in Patients with AJCC Stage IV Melanoma

When melanoma has spread from its original site on the skin to distant sites beyond the regional lymph nodes, a patient has stage IV disease, according to the internationally accepted AJCC/UICC staging system.¹⁴ M1a metastases are in skin, subcutaneous tissue, or non-regional lymph nodes; M1b metastases are in the lungs; M1c metastases are at any distant site but also with an elevated serum lactate dehydrogenase (LDH) level.¹⁴ A diagnosis of stage IV melanoma indicates that the disease is not curable, and that the patient’s prognosis is limited.

The prognosis of patients with stage IV disease is affected by many factors other than just the location of distant disease. These factors include patient, tumor, and treatment-related factors. Patient factors include age, sex (with men traditionally doing worse), and performance status. Tumor factors include systemic disease burden (a surrogate for which is LDH), rate of disease progression (a measure of which is disease-free interval), and BRAF mutation status. Treatment factors affecting prognosis include previous treatments, side effects, and treatment interactions. The anticipated impact of treatment is of particular concern as survival is limited, and it is important that the patient’s remaining time is spent with an acceptable quality of life. Other treatment factors include access to new, effective systemic therapies.