Questions and Answers: New Findings About Interferon Therapy for MelanomaNational Cancer Institute A clinical trial of the drug interferon alpha-2b (Intron-A) to treat high-risk melanoma has yielded new information that physicians and patients can take into consideration when deciding on therapy. The following questions and answers give details about the study and its preliminary findings.
This clinical trial compared interferon alpha-2b -- both high-dose and low-dose interferon alpha-2b -- to no additional treatment after surgery for patients with melanoma at high risk for recurrence. Patients at high risk included in this study had either deep primary lesions or primary melanoma with disease in nearby lymph nodes. Designated E1690, the trial was sponsored by the National Cancer Institute (NCI) and carried out by the Eastern Cooperative Oncology Group (ECOG), the Southwest Oncology Group (SWOG), and the Cancer and Leukemia Group B (CALGB), all large groups of cancer researchers who joined together to conduct this study. (Because it involved three different cooperative cancer trials groups, E1690 is also called an "Intergroup" trial in the accompanying abstract.) 
E1690 found that patients who received high-dose interferon after surgery had an appreciably longer time before their disease recurred (relapse-free survival). However, they did not live significantly longer overall than patients who had no post-surgical treatment on the trial. Low-dose interferon appeared to have less effect on relapse-free survival and also had no effect on overall survival.
Interferons are produced naturally by cells in the body to help fight infections and tumors. Interferon alpha-2b is one of several kinds of interferon produced by recombinant DNA technology that are being tested as cancer treatments (see questions 12 and 13). Common side effects of high-dose interferon include fatigue, fever and chills, muscle aches, lack of appetite, and headache. Most people compare the symptoms to having a flu-like illness. These symptoms can usually be controlled with acetaminophen products (such as Tylenol). Less commonly, patients can develop nausea and vomiting against which anti-emetics (anti-nausea medications) are usually successful. Depression can occur and occasionally anti-depressant therapy is required. Physicians must carefully monitor liver function tests and white blood cell counts (granulocytes) of patients on interferon alpha-2b. Abnormal levels on these laboratory tests require careful dose adjustments to avoid dangerous side-effects.
Patients with melanoma at high risk for recurrence were divided randomly into three groups, or trial "arms," after surgery. One group received high doses of interferon and one received lower doses (details of the regimen are provided in the accompanying abstract). The third group received no additional therapy on the trial (the "observation arm"). Each arm of the trial included more than 200 patients; in total, 642 patients took part in the study.
In the group of patients who received high-dose interferon, the average time to recurrence of disease was 28 percent longer compared to the untreated observation group. For those on low-dose interferon, the average time to recurrence was 10 percent longer than in the untreated group. However, patients receiving interferon (in both the high- and low-dose arms) did not live appreciably longer than patients who did not receive interferon in this study. The reason that interferon did not prolong overall survival (as it had appeared to do in an earlier study, E1684) is unclear at this time. It is known that there was not an excess of deaths due to the side effects of treatment or due to causes other than melanoma on the interferon arms.
Side effects in this study were typical of those described above and similar to those observed on the earlier study (E1684). Two deaths due to interferon side effects occurred in the present trial; both of these were in the low-dose interferon arm.
The finding that interferon did not prolong survival overall differs from that of the earlier melanoma trial (E1684). In this earlier study, about 287 patients were divided into two groups, one of which received high-dose interferon and one of which received no further treatment after surgery. Patients on the high-dose interferon arm of E1684 had a longer overall survival, as well as a longer time to recurrence, compared to patients on the observation arm. (The findings were published in the Journal of Clinical Oncology, Vol. 14, No. 1, January 1996, pages 7-17).
It is not clear why they differ. Researchers are conducting further analyses in an effort to shed some light on the different findings. When results of the two trials are "pooled" - that is, the patients on both the E1684 and E1690 high-dose interferon arms are compared to patients on both observation arms - the combined analysis demonstrates longer relapse-free survival for patients who received high-dose interferon but not a longer overall survival. Also, it was found that for patients who did not receive treatment with interferon, there was an appreciable improvement in overall survival in E1690 compared to E1684. There are various possible explanations for this, but the genuine reason(s) are not known with certainty. However, this improvement could explain, in part, the difficulty of demonstrating an impact of interferon on survival.
The investigators are searching for factors that might explain this finding. One possibility is that the patients on the observation arm, who relapsed earlier, received treatment at the time of relapse and so survived the same length of time as those who had received interferon treatment immediately after surgery. These treatments after relapse may have included interferon, interleukin-2, vaccines, chemotherapy, or surgery. The exact type of additional treatments in the patients on the E1690 study is currently being sought by the researchers and may yield an explanation of the study results.
No. The current data represent the initial study findings after a median follow-up of 52 months. A complete report is currently being prepared by the researchers and will be submitted to a scientific journal for publication. At this point, 86 percent to 91 percent of the anticipated events (recurrences of melanoma) have occurred. (That is, the study was designed to show statistically significant results after a certain number of relapses, and 86 percent to 91 percent of those relapses have occurred.) ECOG does plan further follow-up on patients in this study and updated analyses may be presented in the future. In addition, other studies currently under way may help in better understanding the role of interferon.
Data from this trial, E1690, and the earlier trial, E1684, do not make possible any blanket recommendations concerning interferon therapy for high-risk melanoma. However, they do provide more information than was available previously, suggesting that high-dose interferon is active and can appreciably prolong the time to relapse. As for survival, the two studies do not permit a final answer, and further follow-up, results from other studies as they become available, and additional new studies are required. Physicians and patients should carefully consider this new information when weighing the risks and benefits of interferon therapy.
Through its cooperative trial groups, the NCI is sponsoring three large, randomized, controlled trials (phase III) that will provide more information about interferon in the treatment of melanoma. - A study comparing post-surgical therapy with a vaccine, called GM2-KLH/QS-21, to high-dose interferon alpha-2b in node-positive patients (protocol E1694). Projected completion date: 1999 - A study of chemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alpha-2b versus the first three drugs alone in patients with metastatic melanoma (protocol E3695). Projected completion date: 2000 - A study of post-surgical radiotherapy with or without high-dose interferon alpha-2b in patients with metastatic melanoma (protocol E3697). Projected completion date: 2000 13. Is interferon under study for other cancers? Currently, NCI's cancer database, PDQ, contains more than 70 clinical trials now under way in the United States using interferon alpha. Alone and in combination with other drugs, it is being used to treat a wide variety of cancers, including leukemias and lymphomas; squamous cell carcinomas of the cervix, skin, head and neck, and esophagus; and kidney, breast, colorectal, and ovarian cancers. 14. How can patients and physicians get more information about melanoma or interferon? Call the NCI's Cancer Information Service (CIS) at 1-800-4-CANCER (1-800-422-6237) or go to the NCI's Web site for clinical trials, http://cancertrials.nci.nih.gov. Both the CIS and the Web site have information on melanoma. Both also provide access to the PDQ database to find clinical trials using interferon as well as many other cancer-fighting drugs. Also available online and through the CIS are booklets in lay language includin What You Need to Know About Melanoma and Taking Part in Clinical Trials: What Cancer Patients Need to Know.
For more information, or to contact National Cancer Institute, see their website at: www.cancer.gov |
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