Reconsidering Adjuvant Radiotherapy for High-Risk Cutaneous Melanoma

While adjuvant radiotherapy has long been considered ineffective for the treatment of cutaneous melanoma, recent research and our careful analysis of the literature indicate that it may be useful for individuals at high risk for local recurrence at the primary tumor site or regional recurrence at the site of lymph node metastasis(1),(2).

Adjuvant Radiotherapy after Resection of High-Risk Lymph Node Metastases

For patients with macroscopic (palpable) lymph node metastasis from cutaneous melanoma, the risk of regional recurrence after lymphadenectomy varies. In some patients with high-risk features the risk of regional recurrence exceeds 30 percent (3):

Criteria for Inclusion in Trial (Eligible if Any of These were Met)

Lymph Node Region Extracapsular Extension Involved Lymph Nodes (n) Size of Lymph Nodes (cm)
Parotid Yes >1 >3
Neck Yes >2 >3
Axilla Yes >2 >3
Groin Yes >3 >4

 Until recently, only one small randomized trial had demonstrated marginal improvement in disease-free and overall survival after adjuvant radiotherapy for macroscopic (palpable) and biopsy-confirmed nodal metastases from cutaneous melanoma (4).

The Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group subsequently initiated large randomized trials, but neither was completed due to poor enrollment.

Fortunately, the Trans Tasman Radiation Oncology Group (TROG) and Australia and New Zealand Melanoma Trials Group (ANZMTG) were successful in completing a randomized trial of adjuvant radiotherapy versus observation alone after lymphadenectomy.

In the trial of 250 subjects, those receiving adjuvant radiotherapy were significantly less likely to have a melanoma recurrence at the site of lymphadenectomy (Figure 1).  However, there was no difference in the rate of melanoma recurrence at sites outside the lymph node region (outside the radiotherapy field) (3).

Figure 1. Cumulative incidence of lymph node field relapse (as first site of relapse) in patients undergoing adjuvant radiotherapy (red) or observation (blue) after lymphadenectomy for high-risk lymph node metastasis from cutaneous melanoma in the Trans Tasman Radiation Oncology Group 02.01 / Australia and New Zealand Melanoma Trials Group 01.02 trial(3). (Figure from Lancet Oncology) (3).
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Adjuvant Radiotherapy after High-Risk Primary Tumor Resection

Several prospective trials indicate that the probability of local recurrence of a primary tumor following adequate surgical resection is less than 5 percent. However, a subgroup of primary melanomas may be at increased risk of local recurrence, such as those located in the head and neck (where adequate surgical margins may be difficult to achieve), or those associated with neurotropism (perineural or intraneural melanoma invasion, a common feature in desmoplastic melanoma).

Several retrospective analyses have reported that selective use of adjuvant radiotherapy is associated with a significantly lower rate of local recurrence in these patients (following surgical resection of neurotropic and/or desmoplastic melanoma (4)).

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Prospective Clinical Trial at Memorial Sloan Kettering Cancer Center

We are the only site in North America participating in the first prospective, randomized clinical trial designed to determine if adjuvant radiotherapy after excision of neurotropic melanoma of the head and neck is associated with improved local control of the primary tumor.

Figure 2. Trans Tasman Radiation Oncology Group 08.09 / Australia and New Zealand Melanoma Trials Group 01.09 trial, “A Randomised Trial of Post-Operative Radiation Therapy Following Wide Excision of Neurotropic Melanoma of the Head and Neck.”
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Potential Side Effects

Some people experience lymphedema and subcutaneous tissue fibrosis following adjuvant radiotherapy.  However, the use of advanced radiotherapy technology (see Figure 3) may help reduce some of the side effects.

At MSK, we are also attempting to identify biomarkers that may help identify patients most likely to benefit from radiotherapy for melanoma.

Ongoing research efforts strive to minimize the side effects of radiotherapy while maximizing the benefit in appropriately selected patients.

Figure 3.  Comparison of adjuvant radiotherapy for resected high-risk axillary lymph node metastases from cutaneous melanoma using conventional 2-D and intensity-modulated techniques. In this case, intensity-modulated radiotherapy provides a more homogeneous dose of radiation to a limited target volume and prevents unnecessary irradiation of the lung and subcutaneous tissues, possibly reducing the side effects of treatment.
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  1. Barker CA, Lee NY. Radiation therapy for cutaneous melanoma. Dermatologic clinics 2012;30:525-33.

  2. Stevens G, McKay MJ. Dispelling the myths surrounding radiotherapy for treatment of cutaneous melanoma. The lancet oncology 2006;7:575-83.

  3. Burmeister B, Henderson M, Thompson J, et al. Adjuvant Radiotherapy Improves Regional (Lymph Node Field) Control in Melanoma Patients after Lymphadenectomy: Results of an Intergroup Randomized Trial (TROG 02.01/ANZMTG 01.02). Int J Radiat Oncol 2009;75:S2-S.

  4. Creagan ET, Cupps RE, Ivins JC, et al. Adjuvant radiation therapy for regional nodal metastases from malignant melanoma: a randomized, prospective study. Cancer 1978;42:2206-10.

  5. Vongtama R, Safa A, Gallardo D, Calcaterra T, Juillard G. Efficacy of radiation therapy in the local control of desmoplastic malignant melanoma. Head & Neck 2003;25:423-8.

  6. Strom T, Caudell JJ, Han D, et al. Radiotherapy influences local control in patients with desmoplastic melanoma. Cancer 2013.

  7. Guadagnolo BA, Prieto V, Weber R, Ross MI, Zagars GK. The role of adjuvant radiotherapy in the local management of desmoplastic melanoma. Cancer 2013.