Originally published as JCO Early Release 10.1200/JCO.2004.10.907 on December 9 2003

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Adjuvant Interferon Therapy for Melanoma: High-Dose, Low-Dose, No Dose, Which Dose?

Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA

Melanoma presents formidable problems across the clinical spectrum—from prevention and early detection to treatment of high-risk and metastatic disease. In white populations, the worldwide incidence of invasive primary cutaneous melanoma has been rising for decades, making it a public health issue of growing importance. In the United States, almost 50,000 new cases are expected in 2003 [1].

Recently, clinical management of melanoma has advanced through more precise staging. The use of sentinel lymph node biopsy for accurate staging of regional lymph nodes and, more recently, the recognition of the prognostic significance of ulceration have greatly refined the precision with which clinicians can determine prognosis [2]. Two of the most important predictors of relapse (and, therefore, survival) are Breslow’s thickness of the primary melanoma, and regional lymph node status. Patients with melanomas larger than 4 mm thick have an approximately 50% risk of relapse, while those with lymph node involvement have a 50% to 85% risk of metastasis depending on the number of lymph nodes involved and other factors [3]. Thus, a group of patients can be defined who are appropriate candidates for postsurgical adjuvant therapy.

During the past 20 years, numerous agents have been evaluated in a series of both nonrandomized and randomized adjuvant therapy trials in melanoma patients. Many of these clinical trials suffered from serious methodological problems such as inadequate statistical power, use of inappropriate controls, and lack of stratification for known prognostic factors. However, the major obstacle to the success of adjuvant therapy of melanoma has been the lack of active agents. Agents that have demonstrated little or no benefit include BCG, levamisole, interferon gamma, interleukin-2, retinoids, dacarbazine, and megestrol acetate [4].

While controversies are common in medicine, few aspects of the treatment of malignant melanoma have stimulated as much controversy as the interpretation of the adjuvant interferon alfa (IFN) trials for patients with resected high-risk melanoma. This has resulted largely from conflicting results of successive randomized controlled trials, the first of which demonstrated a statistically significant overall survival benefit for high-dose IFN compared with surgery alone [5-7]. Interpretations of these data and the resultant treatment recommendations vary widely, with proponents proclaiming high-dose IFN as standard therapy, while opponents, analyzing the same data, believe that the routine use of IFN cannot be recommended outside of the context of a clinical trial. Interestingly, the interpretation of the same clinical trial data varies widely geographically. In the United States, a high-dose IFN regimen, with a 1-month induction course, is most commonly used. In Europe and the UK, a low-dose, prolonged duration schedule has been more widely used. However, even in the United States, there has not been widespread acceptance of high-dose IFN, with clinicians and patients often believing that this treatment is either ineffective or too toxic.

As with most controversies, the truth lies somewhere in between, and this story is no less complex than many other medical controversies. What is generally agreed on by both the skeptics and the true believers? First, the data from the completed randomized clinical trials consistently demonstrate that high-dose IFN is associated with an approximate 10% improvement in relapse-free survival (RFS). This favorable effect of high-dose IFN on RFS should no longer be debated. Multiple randomized trials have shown that HDI for one year improves RFS compared with surgery alone [5,6]. Second, given general agreement on the benefit of surviving without relapse, there would probably be little controversy about the use of high-dose IFN were it not for the high incidence of serious toxicity. The most common acute side effects are flu-like syndrome with constitutional symptoms of fever, chills, headache, and myalgias. More chronic toxicities include anorexia, malaise, depression, abnormal liver enzymes, and weight loss. In most studies of high-dose IFN, grade 3 and 4 toxicities occur in approximately one-third of patients, although most toxicity is rapidly reversible on discontinuation or dose reduction of the IFN [8]. The third point of consensus is that a series of randomized trials of low-dose and intermediate-dose IFN indicate that there may be improvement in RFS. However, this is where agreement ends and controversy begins.

The major question with all of the adjuvant IFN trials is whether therapy improves overall survival (OS), in particular high-dose IFN, offsetting the toxicity of therapy and the burdensome duration of the therapy. That the interpretation of OS data would become the focus of the controversy is problematic, as improvement in OS is generally accepted as an indicator of efficacy for an adjuvant therapy. Only the first randomized clinical trial of high-dose IFN (E1684) in the adjuvant setting demonstrated a survival benefit, with subsequent randomized trials failing to provide confirmatory results in terms of overall survival [5,6]. Even among those who are strong advocates of IFN therapy in high-risk melanoma, debate persists regarding the optimal dose and schedule of IFN. In addition, after 20 years of study, the mechanisms responsible for IFN’s antitumor activity remain unknown. Is it an immunomodulator, an antiangiogenesis agent, or does it have direct antiproliferative effects against melanoma? Given this lack of understanding, surrogate markers of various biologic consequences cannot be used to guide dose selection and duration of therapy. With respect to duration, in some trials, transient improvement in RFS seems to fade when IFN is discontinued, leading some to suggest that more prolonged administration of IFN is needed to achieve a durable, potentially curative effect. Thus, the optimal duration of adjuvant IFN therapy remains unclear, with 1 month, 1 year, 18 months, 2 years, and 5 years all currently undergoing investigation.

With respect to dose, there is also considerable debate. Randomized clinical trials have evaluated very low-dose (0.5 to 1 million units [MU]), low-dose (3 MU), intermediate dose (5 to 10 MU), and high-dose (> 10 MU), all with different schedules and various routes of administration (intravenous, subcutaneous, and intramuscular). The use of low-dose IFN was pioneered by Cascinelli et al who conducted a randomized trial of 3 megaunits of IFN three times a week for 3 years, compared with surgery alone in patients with high-risk melanoma [9]. Although the preliminary results suggested a positive outcome, the final analysis demonstrated no improvement in RFS and OS. Additional investigation of low-dose IFN gave similar results [10-12].

It was against this backdrop, in 1995, that an additional trial of low-dose IFN was felt to be warranted. In this issue of the Journal of Clinical Oncology, Hancock et al [13] report the results of AIM HIGH, a United Kingdom study of low-dose, extended duration IFN in high-risk resected cutaneous melanoma. In this study, the goal was to recruit 1,000 patients with high-risk node-negative melanoma ( 4 mm) with positive nodes, local recurrence, or in-transit disease. Patients were randomly assigned to either 3 MU of IFN-2a given by subcutaneous injection three times per week for 2 years or until disease recurrence (whichever occurred first), or to no further treatment. The study was terminated after 674 patients had been recruited throughout 5 years on the advice of the Data Safety Monitoring Committee, as it was felt that extending the period of enrollment to complete accrual was statistically unlikely to alter the preliminary analysis. The median duration of follow-up was 3.1 years. Disease recurred in 426 patients (63%; 211 IFN v 215 control), and 46 patients died (151 IFN v 156 control). The OS and RFS rates at 5 years were 44% and 32%, respectively. There was no significant difference in OS or RFS between the IFN-treated and control arms (odds ratio, 0.94; 95% CI, 0.75 to 1.18; P = .6 for OS; odds ratio, 0.91; 95% CI, 0.75 to 1.10; P = .3 for RFS). Subgroup analysis by disease stage, age, and sex did not show any clear differences between the treated and control groups in either OS or RFS. As expected, low-dose interferon was fairly well tolerated. The primary side effects were fatigue, rigors, and mood disturbance. Grade 3 toxicities were seen in 15% of patients, much lower than reported on high-dose IFN studies. The authors conclude that extended duration low-dose IFN is not significantly better than surgery alone for resected high-risk melanoma.

From a clinical perspective, the study by Hancock et al was well conducted. However, many lessons can be learned from this study, including some of the recurring design problems that have characterized most of the randomized IFN trials conducted to date. First is the sample size. From the perspective of adjuvant trials in melanoma, the Hancock trial was one of the largest, with approximately 300 patients per treatment arm. However, as summarized by Sondak [4], detection of a clinically meaningful 5% increase in 5-year survival in a two-armed trial would require enrollment of more than 2,500 patients (80% power). Such patient numbers are extremely difficult to obtain for an adjuvant melanoma study. This sample size problem is compounded by the inclusion of patients with varying risks of recurrence with potential imbalances between treatment arms due to insufficient surgical staging of enrolled patients. Peculiar to melanoma trials, compared with most other malignancies, is that pathological assessment of regional lymph nodes has not been required to enter adjuvant studies. This was also true in the Hancock study. While the baseline characteristics and prognostic factors between the treatment and control arms are said to be well matched, it was not mandatory for patients with histologically thick primary melanomas and clinically node-negative disease to undergo surgical evaluation of regional lymph nodes with either sentinel lymph node surgery or prophylactic lymph node dissection. Certainly, for the majority of breast cancer, colon cancer, and lung cancer adjuvant studies, surgical staging includes an assessment of nodal status for protocol entry. This should be true for melanoma as well. In the recently updated 2002 American Joint Committee on Cancer (AJCC) staging system for melanoma, the 5-year overall survival for patients with melanoma more than 4 mm thick ranges from 45.1% to 67.4% [3]. Better stratification would have resulted from knowing whether these patients (representing 20% of the patients enrolled on the AIM HIGH study) had regional lymph node involvement. This same issue confounds the interpretation of E1690, one of the randomized high-dose IFN trials that failed to show an OS advantage for IFN [6]. In addition, when the AIM HIGH trial was initiated, the important prognostic significance of the number of regional lymph nodes involved with melanoma and primary melanoma ulceration was not fully recognized, and was not accounted for in the stratification process. Again, using the 2002 AJCC staging system for patients with node-positive disease, the 5-year OS ranges from 26% to 69%, depending on the number of lymph nodes involved, whether they were identified microscopically or clinically, or whether the primary melanoma was ulcerated [3]. Despite the fact that the same methodological problems in this trial were encountered in prior adjuvant melanoma trials, the results of the study by Hancock et al are important and add to the growing body of evidence that low-dose IFN for patients with high-risk melanoma is not beneficial.

An area not addressed by the AIM HIGH study is the role of intermediate doses of IFN for high-risk melanoma. The rationale for a study of intermediate doses of IFN has been driven by the lack of survival benefit for low-dose regimens tested to date, together with the toxicity of the high-dose regimen. This is currently being addressed in European Organization for Research and Treatment of Cancer 18-952, a study that has enrolled more than 1,400 node-positive patients in a three-armed study using an intermediate-dosing strategy for IFN-2b in the adjuvant setting. In this study, the efficacy of two intermediate-dosing regimens of IFN-2b, 10 MU subcutaneously three times for 4 weeks, followed by either 10 MU subcutaneously three times each week for 1 year, or 5 MU subcutaneously three times each week for 2 years are compared with surgery alone. Similarly, the Scandinavian Melanoma Cooperative Group is also exploring intermediate-dose regimens. From today’s perspective, the role of intermediate-dose IFN in the adjuvant therapy of melanoma remains to be established.

My top ten conclusions regarding adjuvant IFN therapy for high-risk resected melanoma are: (1) High-dose IFN is the only treatment showing activity against melanoma in the adjuvant setting. It prolongs 5-year RFS by approximately 10%. (2) The impact of high-dose IFN on OS is less clear, with conflicting results from a series of randomized clinical trials. This is problematic, as improvement in overall survival is the best measure of efficacy for an adjuvant therapy. (3) The toxicity of high-dose IFN is substantial and limits both patient and physician acceptance. Toxicity can be lessened by using aggressive supportive measures, including antidepressants and appropriate dose-reduction strategies. (4) Available data show no benefit of low-dose IFN in the adjuvant setting in terms of OS. This is further supported by the article by Hancock et al. (5) The potential role of intermediate-dose IFN will be clarified as large randomized clinical trials mature. (6) Sentinel lymph node biopsy should play a central role in staging the regional lymph nodes in patients with melanomas larger than 1 mm or thinner, if the lesion has important unfavorable attributes, such as ulceration. Furthermore, sentinel lymph node staging should be mandatory for all future adjuvant melanoma trials. (7) Adjuvant trials in patients with high-risk resected melanoma should continue to include a surgery-alone control arm. (8) High-dose IFN is approved by the US Food and Drug Administration for the treatment of patients with thick primary melanomas and those with node-positive disease; however, the US Food and Drug Administration approval of a therapy does not necessarily constitute the standard of care for all patients. (9) There is a single, curative therapy of choice for primary melanoma: simple excision of melanoma, detected early before disease progression. (10) "When a thing ceases to be a subject of controversy, it ceases to be a subject of interest" (Willam Hazlitt [1778 to 1830], English writer, essayist).

The optimal care for a patient with high-risk melanoma in 2003 is not clear. Decisions require the integration of the existing evidence, the judgment of experienced clinicians, and the informed input from patients. IFN is an appropriate option for some patients with melanoma. The challenge now is to go beyond these initial results. This will require more innovative and efficient clinical trials, and further refinement of risk groups based on the use of molecular genetic factors, particularly gene expression profiles. This will become more vital as less toxic and more effective therapies are identified. Continued participation by physicians and our patients in well-designed randomized clinical trials will facilitate continued progress in the treatment of melanoma.

Author’s Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

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