ECOG E1684: What the Melanoma Trial Found

The question this trial asked

Melanoma removed by surgery sometimes comes back. In the 1980s there was nothing to give afterward that was known to help.

ECOG E1684 tested whether interferon alfa-2b, a drug that had shown activity against melanoma that had already spread, could lower that risk when given after surgery. Treatment given after surgery to reduce the chance of return is called adjuvant therapy.

Who was in it, and what they got

The trial enrolled 287 patients whose melanoma had been removed by surgery and who were at high risk of it returning. That meant either a deep primary tumor, classed as T4, or cancer that had reached the regional lymph nodes.

They were randomly assigned to one of two arms. One got interferon alfa-2b at the maximum tolerated dose: 20 million units per square meter of body surface daily into a vein for a month, then 10 million units per square meter under the skin three times a week for 48 weeks. The other got observation only, meaning no drug.

A year of injections against nothing. That comparison is the whole trial.

What it found

The results appeared in the Journal of Clinical Oncology in 1996, with a mature median follow-up of 6.9 years:

• Median time before the melanoma came back rose from 1.0 year to 1.7 years
• Median overall survival rose from 2.8 years to 3.8 years
• The share of patients who stayed continuously free of disease rose from 26% to 37%
• Relapse-free survival p = 0.0023, overall survival p = 0.0237, both one-sided

The authors noted the effect on relapse was most pronounced early in the treatment period, and that the benefit was greatest among patients whose lymph nodes were involved.

They were equally clear about the cost. Toxicity required dose modification in the majority of patients. This is a drug given continuously for a year.

Why it mattered, and why the story got complicated

E1684 was the first randomized trial to show that any treatment after melanoma surgery could delay relapse and extend survival. Interferon was approved in 1995 and became the standard adjuvant option for roughly two decades.

Then came E1690, the larger follow-on intergroup trial, reported in 2000. It enrolled 642 patients, of whom 608 were eligible. It compared high-dose interferon for a year, low-dose interferon for two years, and observation.

It confirmed a relapse-free survival benefit. Five-year relapse-free survival was 44% with high-dose interferon, 40% with low-dose, and 35% with observation. But the authors wrote that neither dose had demonstrated an overall survival benefit compared with observation.

So the first trial's headline finding, that people lived longer, was not reproduced. Our page on reading clinical trial results explains why one positive trial is a starting point rather than an ending.

What replaced it

Adjuvant interferon is no longer standard. Immune checkpoint inhibitors and targeted therapies took its place. NCI's current melanoma summary lists surgery, chemotherapy, radiation therapy, immunotherapy and targeted therapy as the treatment types in use.

The staging that decides who is offered adjuvant treatment has also become more precise. NCI describes melanoma staging as depending on the thickness of the tumor, whether cancer has spread to lymph nodes or other parts of the body, and other factors. Our page on melanoma stages covers the categories, and melanoma treatment by stage covers what follows each one.

The numbers today

The American Cancer Society projects 112,000 new US melanoma cases in 2026 and 8,510 deaths, and SEER republishes those projections. Five-year relative survival across all stages, for people diagnosed between 2016 and 2022, is 94.7%.

By how far it had spread when found, it is 100.0% while still confined to the skin, 76.0% once it has reached nearby lymph nodes, and 34.0% once it has spread further. Seventy-seven percent are found while still confined. These are group averages from past years and describe no individual.

The 76.0% figure describes the population E1684 was studying. The gap between that and 100.0% is what adjuvant treatment tries to close.

When to get checked

Melanoma is one of the few cancers you can see. Take these to a doctor:

• A mole where one half does not match the other
• Ragged, notched or blurred edges on a mole
• Uneven color: black, brown and tan, sometimes with white, gray, red, pink or blue
• A mole wider than about 6 millimeters, roughly a quarter inch, though melanomas can be smaller
• Any mole that has changed over the past few weeks or months
• A dark streak under a fingernail or toenail with no injury to explain it
• A sore that has not healed in four weeks

Change over time is the strongest single signal. A mole that has looked the same for twenty years is not the one to worry about.

What this does not mean

• E1684 enrolled 287 patients, small by modern standards, and its p-values were one-sided, a less conservative test than the two-sided standard.
• The survival benefit was not reproduced in E1690, which was more than twice the size.
• Toxicity was severe enough to force dose reductions in most patients, and that shaped how many people were willing to take it.
• Adjuvant interferon is not current standard care for melanoma. This page describes history.
• Trial participants meet specific entry criteria, so results do not automatically apply to everyone with the same diagnosis.

Sources

• Kirkwood JM et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: ECOG Trial EST 1684. J Clin Oncol 1996;14:7-17. PMID 8558223, NCBI eutils record — https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=8558223&retmode=xml
• Kirkwood JM et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 2000;18:2444-58. PMID 10856105, NCBI eutils record — https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=10856105&retmode=xml
• NCI PDQ, Melanoma Treatment (Patient Version) — https://www.cancer.gov/types/skin/patient/melanoma-treatment-pdq
• NCI, Common Moles, Dysplastic Nevi, and Risk of Melanoma — https://www.cancer.gov/types/skin/moles-fact-sheet
• SEER Cancer Stat Facts, Melanoma of the Skin — https://seer.cancer.gov/statfacts/html/melan.html

How this article was prepared

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

The National Cancer Information Foundation publishes Cancer Explained. This page is for learning. It is not medical advice and does not suggest a test or treatment.

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