Pathological features of primary melanoma, particularly thickness and ulceration, make it possible to identify patients with stage II disease who are at high risk of local or systemic recurrence (see section 3.7). Once patients have had melanoma recurrence in the local regional lymph nodes (stage III disease), over 50% will subsequently develop further metastatic spread. These observations support attempts to identify adjuvant treatment such as chemotherapy, immunotherapy and radiotherapy, given after complete clinical surgical clearance of melanoma.

An RCT of adjuvant chemotherapy and immunotherapy including the use of BCG and DTIC (see section 8.2) reported negative results.¹⁵⁸ A number of well designed trials of adjuvant therapy open to new patients are ongoing. Evidence level 1+

6.1 Radiotherapy following lymph node dissection

Three retrospective cohort studies,^{159, 160, 161} two studies using historical controls^{162, 163} and an observational study were identified.¹⁶⁴ Studies in small numbers of patients have shown that outcomes following lymph node dissection plus radiotherapy were not significantly different from those following dissection alone.¹⁶⁵ Evidence level 3,1-

The routine use of adjuvant radiotherapy is not recommended for patients who have had therapeutic lymph node dissections.

6.2 Immunotherapy

6.2.1 INTERFERON

The observation that a large number of primary melanomas undergo partial regression and a small number of melanoma patients experience total regression of the whole melanoma has led to the concept of using either specific or non-specific immune stimulation as therapy for melanoma.

Adjuvant interferon a has been used in at least 10 large RCTs involving over 5,000 patients.^{166, 167, 168, 169, 170, 171, 172, 173, 174, 175} Interferon dosage, frequency and route of administration and total duration of therapy all varied, but no trial reported significant overall survival benefit for interferon-treated patients. Several of the larger studies do report longer disease-free intervals after surgery^{169, 170, 171} but there is no evidence of a dose or duration of treatment effect. Toxic effects of interferon include extreme lassitude, muscle aches, headache, rigors, nausea, vomiting, and marrow toxicity, the latter being the cause of death in two patients in the first reported high dose study. Evidence level 1++

Final results are not yet available for some of these trials, and until these are published it would be premature to offer interferon to patients with AJCC stage II or stage III melanoma.

Adjuvant interferon should not be used for AJCC stage II and III melanoma patients other than in a trial setting.

Patients with AJCC stage II and III disease should be offered entry into RCTs to confirm whether or not interferon therapy extends the disease-free interval after surgery.

6.2.2 VACCINES

Melanoma vaccines are still in the research phase. There are some Phase I and II studies that do not have controls. The vaccinia melanoma oncolysate (VMO) RCT involved 217 patients but did not show an advantage for the vaccine.¹⁷⁶ An RCT including 700 patients compared vaccinia melanoma cell lysates (VMCL) to no immunotherapy and found that VMCL did not significantly improve overall survival or relapse-free survival.¹⁷⁷ An RCT comparing interferon alfa-2b with a GM2 ganglioside vaccine was closed early when the interferon showed evidence of increased relapse-free survival and overall survival.¹⁷⁸ Melanoma vaccines are not currently available commercially. Evidence level 1-,1++

Patients should be entered into vaccine clinical trials as appropriate.