Elsevier

The Lancet

Volume 358, Issue 9285, 15 September 2001, Pages 866-869
The Lancet

Articles
Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial

https://doi.org/10.1016/S0140-6736(01)06068-8Get rights and content

Summary

Background

Less than half of patients with melanoma that has spread to local draining regional lymph nodes (stage III melanoma) live with no disease for 5 years or longer after surgery. We aimed to see whether interferon alpha-2a increased survival prospects in these patients.

Methods

444 patients from 23 centres in the WHO Melanoma Programme had complete lymphadenectomy for pathologically proven regional nodal spread of melanoma and were randomly assigned to receive either 3 MU subcutaneously of recombinant interferon alpha-2a three times a week for 3 years, or to observation alone after surgery. Patients were stratified by centre, nodes with macroscopic or microscopic melanoma, number of affected nodes, and nodal metastatic spread. Treatment was continued for 3 years or until first sign of relapse.

Findings

424 patients entered the study. 5-year disease-free survival of those who had surgery plus interferon alpha-2a was 27·5% (95% Cl 21·7–33·6); for those who received surgery alone, survival was 28·4% (22·5–34·6) (p=0·50). Neither Kaplan-Meier cumulative survival rates, nor multivariate anaysis of survival, showed a difference between those who had surgery and interferon alpha-2a (35%, 95% Cl 29–42) and those who had surgery alone (37%, 31–44).

Interpretation

Patients with melanoma that has spread to the local draining regional lymph nodes tolerate well 3 MU of interferon alpha-2a given subcutaneously three times a week for 3 years, but this treatment does not improve either disease-free or overall survival.

Introduction

Over the past 20 years, tumour prognosis and 5-year disease-free survival for patients with melanoma confined to the primary site has improved. This improvement is probably because melanomas are being detected at an earlier stage than previously, and tumours are therefore thinner at time of surgery. However, once melanoma spreads to local draining lymph nodes, 5-year disease-free survival falls substantially (ranging from 20 to 40%).1 Over 80% of these patients will have microscopic spread of melanoma cells beyond the draining lymph nodes. Thus, adjuvant non-surgical therapy is needed after removal of nodes for melanoma patients with Union international contre le cancer (UICC) stage III disease.

Large, well-conducted, randomised, controlled trials looking at chemotherapy, immunotherapy, or combined therapy have not provided reliable evidence of a survival advantage with any adjuvant regimen.2, 3, 4 Use of interferon alpha-2a in patients with thick primary tumours and no evidence of spread beyond the primary site suggested a beneficial effect in disease-free survival, but not in overall survival.5, 6 Kirkwood and colleagues7 showed a significant improvement in disease-free survival and a small but significant effect in overall survival for patients with lymph-node involvement and melanoma who were given high-dose interferon alpha-2a over 1 year. However, a subsequent trial by the same group failed to confirm these findings.8

We have undertaken a randomised controlled trial on a large population of patients with melanomas that involve regional draining lymph nodes. Our aim was to measure disease-free and overall survival of such patients, and to assess toxic effects and acceptability of long-term adjuvant therapy with recombinant interferon alpha-2a. The trial is WHO Melanoma Programme Trial 16.

Section snippets

Patients

Between June, 1990, and December, 1993, we investigated 444 patients from 23 centres belonging to the WHO Melanoma Programme who had primary malignant melanoma that had spread to the regional draining lymph nodes. The trial protocol was approved by the ethical committee of the National Cancer Institute of Milan, and by ethics committees of all other participating centres.

Patients with primary cutaneous malignant melanoma and regional node metastases either patholologically proven, or presented

Results

225 of 444 (51%) patients were randomly assigned to receive interferon alpha-2a and 219 (49%) to receive surgery only. Table 1 shows the characteristics of these patients. 18 patients did not meet protocol requirements (figure 1). Median follow-up time was 88 months (range 67–108). The 5-year disease-free survival rate of patients who had surgery and interferon alpha-2a was 28% (95% CI 22–34) and for those who had surgery alone was 28% (23–35) (Figure 2). The two survival figures did not differ

Discussion

Our results show that interferon alpha-2a given 3 MU a week for 3 years does not affect either disease-free survival or overall survival of patients with melanoma and regional node metastases that were clinically detectable after surgery. Our preliminary report of the same group of patients10 showed a significant increase in disease-free survival for patients given interferon alpha-2a and an increase in overall survival in subsets. Neither of these findings has been maintained with longer

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