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Interferon Alfa Therapy for Malignant Melanoma: A Systematic Review of Randomized Controlled Trials

From the Center for Evidence-Based Medicine, University of Oxford, Nuffield Department of Clinical Medicine, Oxford Radcliffe National Health Service Trust, Oxford, United Kingdom.

Address reprint requests to Marko B. Lens, MD, Centre for Evidence-Based Medicine, University of Oxford, Nuffield Department of Clinical Medicine, Oxford Radcliffe NHS Trust, Oxford OX3 9DU, United Kingdom; email: markolens{at}aol.com

	ABSTRACT

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PURPOSE: No standard systemic adjuvant therapy has been proven to increase overall survival in melanoma patients. The effect of interferon alfa (IFN) as a single agent or in combination has been widely explored in clinical trials. The purpose of this study was to assess the benefit of IFN therapy in malignant melanoma.

METHODS: We performed a systematic review of randomized controlled trials comparing regimens with or without IFN adjuvant therapy in melanoma patients. We assessed the effect of IFN therapy on overall survival (OS), disease-free survival (DFS), melanoma recurrences, and toxicity. The quality of each trial was systematically evaluated.

RESULTS: Nine randomized controlled trials (RCTs) of IFN therapy in melanoma patients were identified. Eight were published and one was unpublished. Eight trials comprising 3,178 patients fulfilled our inclusion criteria and were analyzed. Quality assessment scores ranged from 22 to 71, with a mean score of 55.4 (95% confidence interval, 53.8 to 57.0). For OS, only one trial reported a statistically significant benefit for IFN, but our analysis did not confirm it. Two trials reported statistically significant benefit in DFS for the patients treated with IFN, but our analysis confirmed it in only one trial. There was a wide clinical heterogeneity between included trials, making meta-analysis inappropriate.

CONCLUSION: In our review, results from included RCTs demonstrated no clear benefit of IFN therapy on OS in melanoma patients. A large RCT is required to answer whether a full regimen of IFN therapy is effective and to identify the subgroups of patients who might benefit from IFN treatment.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
THE POOR PROGNOSIS OF metastatic melanoma has prompted researchers to search for an effective therapy after primary local and regional surgical interventions.¹ The relative resistance of melanoma to a wide range of chemotherapeutic agents has also led clinical oncologists to test different postsurgical adjuvant therapies in patients with advanced melanoma.^2,3 The concept of adjuvant therapy for melanoma is derived from the hypothesis that these therapies may have an effect on micrometastatic disease.⁴ There is no standard systemic adjuvant treatment with confirmed survival benefit for clinically node-negative stage I to II patients after excision of the primary melanoma, or for clinically node-positive stage III patients after regional lymphadenectomy.^5,6

Interferons (IFNs) represent a family of glycoproteins with a broad spectrum of effects: antiviral, immunomodulatory, and antiproliferative effects, prodifferentiating and the antiangiogenic effect (this last mediated by the IFN-inducible protein IP-10).^7,8 However, IFN alfa (IFN) possesses antitumor effects by a combination of its direct activities and indirect immune-mediated effects.² IFN is associated with significant side effects that have an important impact on the patient’s quality of life and the physician’s choice of adjuvant postsurgical treatment.^9,10

Several trials have examined the role of IFN as the adjuvant treatment for melanoma patients at high risk for relapse, including patients with deep primary lesions and those with lymph node involvement. We designed a systematic review of published randomized controlled trials to assess the benefit of IFN therapy in malignant melanoma.

	METHODS

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Inclusion Criteria
We included randomized controlled clinical trials assessing the use of IFN adjuvant therapy in high-risk melanoma patients. Patients had to have a clinically diagnosed cutaneous melanoma with no evidence of metastases in regional lymph nodes or at distant sites (stages I and II according to American Joint Committee on Cancer [AJCC] staging criteria) or with regional metastases (stage III). To be included in our review, a trial had to be carried out as a study of IFN monotherapy using only IFN. Studies were excluded if they used combination therapy or compared IFN treatment with some other form of systemic therapy.

Search Strategy
Our aim was to identify all relevant randomized controlled trials that were available for review by June 2001. We conducted sensitive electronic searches of MEDLINE (from 1966 to March 2001), EMBASE (from 1974 to March 2001), and the Controlled Trials Register from the Cochrane Library (Issue 4, 2000) using the recommended Cochrane Collaboration search strategy with MeSH headings "melanoma" and "interferon alpha" including all subheadings. We reviewed the references of all relevant articles found in the searches, as well as those of review articles and textbooks. We also hand-searched selective conference proceedings. No language restrictions were applied. Where possible, we contacted the authors of the trials to verify the data and obtain additional unpublished data. We contacted experts in the field and asked them about any published or unpublished work of which they might be aware.

Data Extraction and Study Appraisal
Recorded information included study characteristics (year, location, treatment dose, and schedule), patient characteristics (sex, age, tumor stage, Breslow thickness, Clark level, tumor location, histologic subtype, presence of ulceration, and nodal involvement), and outcomes.

We extracted the following data from each study: randomization process including strategy for concealment of allocation, number of randomized patients per each treatment arm, number of patients withdrawn from the study, duration of follow-up, and number of patients lost to follow-up. The main outcome measures were number of patients who relapsed, overall survival (OS), disease-free survival (DFS), and toxicity of the IFN treatment.

Two reviewers independently extracted the data from each study. Once completed, any disagreements were resolved by consensus discussion. We designed a quality evaluation questionnaire (Table 1) and each trial was given a score with a maximum of 81 points.

View this table: [in this window] [in a new window]   Table 1.  Criteria List for Methodologic Quality Assessment of Randomized Clinical Trials of IFN- Therapy for Malignant Melanoma

	RESULTS

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Study Characteristics
We retrieved 1,127 articles reporting adjuvant therapy with IFN in melanoma patients. We identified nine randomized controlled trials comparing treatment with IFN with observation in melanoma patients.^11-21 One trial²¹ did not fulfill our inclusion criteria.

Three of the studies were performed in the United States by the Eastern Cooperative Oncology Group (ECOG) and the North Central Cancer Treatment Group (NCCTG); six studies have been completed in Europe by the Austrian Malignant Melanoma Cooperative Group, the French Cooperative Group on Melanoma, the Scottish Melanoma Group, the United Kingdom Coordinating Committee on Cancer Research (UKCCCR), and the World Health Organization (WHO) Melanoma Program. Only two trials (French trial and WHO 16) had sufficient description of study design to suggest that adequate concealment of allocation had taken place; in other trials, methods for concealment of allocation were not reported or clear. Two types of IFN were used in the studies: IFN2a (Roferon; Hoffman-La Roche, Inc, Nutley, NJ) was used in five studies, and IFN2b (Intron A; Schering-Plough, Kenilworth, NJ) was used in the remaining three studies.

The characteristics of patients in these randomized controlled trials are shown in Table 2. Examination of Table 2 reveals that the scheduled treatment with IFN varied considerably in dose and duration of treatment. The doses of IFN used in the trials have varied from 3 MU three times a week to 20 MU/m²/d, and the duration of the IFN treatment ranged from 12 weeks to 3 years.

View this table: [in this window] [in a new window]   Table 2.  Characteristics of Included Randomized Controlled Trials of IFN Treatment in Melanoma Patients

The ECOG 1690 trial was the only three-arm randomized trial with two treatment groups: patients randomized to high-dose IFN and patients randomized to low-dose IFN therapy. None of the studies was placebo-controlled.

Five trials (Austrian, ECOG 1684, ECOG 1690, Scottish, and WHO 16) reported that the outcome data were analyzed by intention to treat, whereas in other studies it was not clear. Quality assessment scores ranged from 22 to 71, with a mean score of 55.4 (95% CI, 53.8 to 57.0) (Table 3).

View this table: [in this window] [in a new window]   Table 3.  Results of Methodologic Assessment of Randomized Controls of RCTs of IFN Therapy for Melanoma

The results for age, sex, Breslow thickness, disease stage (AJCC staging system for melanoma), Clark level, location of melanoma, histologic classification, presence of ulceration, and the number of metastatic regional lymph nodes were incompletely reported among all studies. The median age, reported in three trials,^11,12,15 ranged from 49 to 55 years in the IFN groups and from 50 to 52 in the controlled groups. Although the two ECOG trials did not report median age of patients, they stratified patients according the age in two groups, younger than 50 years and older than 50 years, and achieved a good balance. The WHO 16 trial did not report median age but stratified patients into four age groups, achieving a good balance. Sex of patients was reported in six trials and was well balanced among treatment and control groups.^11-15,20

Disease Characteristics
Six trials stratified treatment arms by the Breslow thickness, and the arms were well balanced for this important prognostic feature.^11-15,20 There was a wide variation among studies regarding stage of the disease (AJCC staging system for cutaneous melanoma) (Table 2). Two trials (Scottish and UKCCCR) did not report the proportion of randomized patients for each disease stage.

Although the balance between treatment arms for the disease stage was achieved in the NCCTG, ECOG 1684, and ECOG 1690 trials, disease stage was not consistent, as in these trials there were more patients with stage III melanoma. However, when evaluating survival in these trials, subgroup analysis was performed.

The number of involved lymph nodes, once metastatic spread had occurred to the locoregional lymph nodes, was reported only in the ECOG 1690 trial. The patients in this three-arm trial were well balanced for this important prognostic feature.

The NCCTG trial examined the extent of nodal involvement by dividing patients with regional metastasis into two groups: less than 20% of lymph nodes positive and more than 20% of lymph nodes positive. The WHO 16 trial included only patients with regional metastases and reported three groups of patients regarding the number of positive nodes.

The Clark level was reported as a prognostic parameter in five trials, and the groups were well balanced for it.^11-14,20 Histologic subtype classification and stratification of included patients according to this characteristic was reported in three trials (French, ECOG 1684, and ECOG 1690). Patient groups were well balanced. Although the ulceration is known to represent a very important prognostic parameter, only two ECOG trials performed randomization after stratification according to this prognostic factor. Excellent balance was achieved between groups, although the ECOG 1684 trial had almost five times more patients with no ulceration, whereas in the ECOG 1690 trial the proportion between patients with ulcerated and nonulcerated melanoma was 2:3. The sites of the melanoma as a prognostic factor was reported in five trials and the groups were well balanced.^11-14,20

Follow-Up
Follow-up was reported in all eight trials. The median follow-up among trials ranged from 489 days to 6.9 years.

Efficacy Outcomes
The primary outcomes of interest were overall survival (actuarial and median), DFS (actuarial and median), relapse rate, and toxicity (Table 4).

The ECOG 1684 trial reported statistically significant benefit in DFS for the patients treated with IFN, and our analysis confirms this. The ECOG 1690 trial demonstrated a statistically significant benefit in DFS only in melanoma patients treated with high-dose IFN2b, but the NNT did not confirm this. Although the Austrian study reported significantly prolonged DFS in patients treated with adjuvant IFN, we were unable to validate it, as there were no data available.

The French trial did not have the data regarding DFS, but reported the data on relapse-free interval showing that IFN therapy significantly improves it. The WHO 16 trial reported a statistically significant benefit in 2-year DFS for the patients treated with IFN,^18,19 but the results after the long-term follow-up demonstrated no improvement in DFS.²⁰

Relapse
The number of patients who relapsed was reported in four trials including 1,704 participants. Relapse (developed metastases) was lower (46.9% [450 of 959]) in groups in which patients were taking IFN compared with control groups (54.9% [409 of 745]).

The relapse rates ranged from 24% to 58.8% in IFN groups compared with 36.3% to 64.9% in control groups. The relapse rates were lowest in the Austrian study and highest in the NCCTG trial. Our analysis shows that only one trial (the Austrian study) demonstrated a statistically significant decrease in progression of disease for patients undergoing low-dose IFN adjuvant treatment (NNT, 9; 95% CI, 5 to 46).

Toxicity
Toxicity data were reported in all included trials except in the UKCCCR trial. Three studies reported withdrawal attributable to adverse events. The Austrian trial had to discontinue the treatment before the scheduled protocol in 3.2% of randomized patients (five of 154), the French trial in 35.0% (89 of 254), and the Scottish trial in 27.6% (13 of 47).

The reduction in the dose of IFN was reported in four trials. In the Austrian study, the dose reduction was reported in eight patients (5.2%), whereas in the Scottish trial it was reported in three patients (6.4%). The two ECOG trials reported dose reductions and/or treatment. During the induction phase, 50% (37% because of toxicity) of the patients required delays or dose reduction in the ECOG 1684 trial compared with 58% (44% because of toxicity) of patients in the high-dose arm of the ECOG 1690 trial. During the maintenance phase, delays and/or reductions occurred in 48% (36% because of toxicity) of patients from the ECOG 1684 trial and in 59% (52% because of toxicity) of the patients from the high-dose arm of the ECOG 1690 trial. In the ECOG 1684 study, the percentage of patients who received at least 80% of the planned dosage during the induction phase was 67%, whereas during the maintenance phase it was 59%.

If dosage of the treatment was changed during the trial, the average IFN dose was not calculated and/or reported in six of the studies. Only ECOG 1684 and ECOG 1690 reported average daily dose (for both, induction and maintenance phase) and the distribution of total dose received.

Only one trial (the Scottish trial) reported the number of patients who completed the IFN therapy per protocol (61.7%). In the ECOG 1684 study, 74% of patients completed the treatment until 1 year (or relapse).

The data regarding the most frequently occurring toxic events by type and degree were reported in five studies (French, ECOG 1684, ECOG 1690, NCCTG, and WHO 16). Drug-related death was reported in the ECOG 1684 trial in two patients (1.4%). No death related to therapy occurred in other studies.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Although two randomized controlled trials (ECOG 1684 and ECOG 1690, high-dose arm v observation) reported statistically significant benefit for DFS for patients treated with IFN as adjuvant therapy, our analysis confirmed this for only one included trial (ECOG 1684). For OS, the ECOG 1684 trial reported benefit for IFN, but our analysis did not confirm it, finding that no trial demonstrated statistical significance. On the basis of the results of the ECOG 1684 trial, the United States Food and Drug Administration in 1995 approved the use of high-dose IFN2b as adjuvant treatment to surgery in patients at high risk of relapse.⁴

A common problem when reviewing clinical trials investigating the same problem is the great variation in study design, which makes it difficult to combine data and reach conclusions about overall results. The trials included in this review vary in many factors such as size, end points, patient selection, quality, type of therapy, treatment schedules and doses, and duration of treatment and follow-up. These differences within the IFN trials not only introduce the possibility of significant bias but also are a source of significant heterogeneity. As a result, we have not pooled results from trials of IFN. Any recommendation should therefore be made on the basis of an evaluation of the individual studies.

At the 2001 annual meeting of the American Society of Clinical Oncology, Wheatly et al²² presented a meta-analysis of randomized controlled trials (RCTs) of IFN therapy showing the clear benefit in DFS in the groups of patients treated with IFN (odds ratio, 0.84; 95% CI, 0.77 to 0.92; P = .0001). Although they divided trials into low and high dose, we still believe there is sufficient clinical heterogeneity between trials to invalidate this methodology.

Prognosis for patients with melanomas with metastases is different from prognosis in those without nodal metastases. Survival probabilities for patients with intermediate- and high-risk melanoma range from 30% to 70%.²³ Thus, adjuvant therapy trials involving such heterogeneous groups of patients are difficult to interpret.

The included trials were relatively small in size, and the majority of them had insufficient power to detect clinically and statistically important benefits for IFN treatment. None of the studies of IFN therapy for malignant melanoma included a placebo group. Some authors consider that the prolongation in DFS in some trials can be explained by the placebo effect and that such prolongation without a concomitant prolongation in life expectancy is of questionable value.²⁴ There is no evidence that placebos might improve survival in melanoma patients, but some authors suggest conducting placebo-controlled trials that would establish whether placebo prolongs life in melanoma patients.

Because the IFN treatments in the trials were different in dose, frequency, and duration, we were unable to compare the effect of the low-dose IFN schedule versus higher doses. There also remains the question regarding the duration and dose required and the population who should receive IFN treatment. Among trials using high-dose IFN, there is no evidence that the effect of IFN induction treatment persists throughout the maintenance phase and that IFN, when given during both the induction phase and the maintenance phase, has a cumulative effect. There is no evidence regarding the size of the benefit with respect to dose. Two types of IFN—IFN2a and IFN2b—were used in the clinical trials that differ slightly in the carbohydrate components of the compound. There is not enough evidence to suggest that these two types of IFN must be assessed separately.²⁵

Sentinel lymph node mapping was introduced as a procedure to select patients with occult metastases, which might be of importance for systemic treatment.²⁶ Although patients with positive nodes after sentinel node biopsy are considered excellent candidates for IFN therapy, an open question remains whether those patients should receive low-dose or high-dose IFN therapy. IFN therapy has many toxic side effects, which led some physicians to question its utility.^27,28

RCTs on IFN therapy in melanoma did not contain complete and detailed quality-of-life assessments. It is important to evaluate patient opinions regarding the melanoma treatment by using qualitative methodology.¹⁰ IFN therapy is a high-cost treatment, and the economic burden should also be considered when evaluating IFN as treatment for melanoma patients in many countries.

To establish the effect of IFN therapy in melanoma, a large RCT is needed. This would need to have enough power to answer the question of whether a full regimen of IFN therapy is needed and to identify and define precisely the subgroups of patients who benefit from adjuvant therapy in order to offset the acknowledged toxicity of high-dose IFN.

There are several randomized trials underway, and results are awaited.²⁹ Until all these trials are concluded, many dilemmas will remain. IFN may be used in metastatic melanoma, but we must remember that its efficacy and toxicity have largely been derived only from results from phase II trials and that there is still no proven standard adjuvant therapy for high-risk cutaneous melanoma.

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10. Cole BF, Gelber RD, Kirkwood JM, et al: Quality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: An Eastern Cooperative Oncology Group study. J Clin Oncol 14: 2666-2673, 1996[Abstract/Free Full Text]

11. Pehamberger H, Soyer HP, Steiner A, et al: Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. J Clin Oncol 16: 1425-1429, 1998[Abstract/Free Full Text]

12. Grob JJ, Dreno B, de la Salmoniere P, et al: Randomised trial of interferon -2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. Lancet 351: 1905-1910, 1998[CrossRef][Medline]

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14. Kirkwood JM, Strawderman MH, Ernstoff MS, et al: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group trial EST 1684. J Clin Oncol 14: 7-17, 1996[Abstract]

15. Creagan ET, Dalton RJ, Ahmann DL, et al: Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma. J Clin Oncol 13: 2776-2783, 1995[Abstract]

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17. Hancock BW, Wheatly K, Harrison G, et al: Aim high: Adjuvant interferon in melanoma (high risk), a United Kingdom Co-ordinating Committee on Cancer Research (UKCCCR) randomised study of observation versus adjuvant low dose extended duration interferon alpha-2a in high risk resected malignant melanoma. Proc Am Soc Clin Oncol 20: 349a, 2001 (abstr 1393)

18. Casinelli N, Bufalino R, Morabito A, et al: Results of adjuvant interferon study in WHO melanoma programme. Lancet 345: 913-914, 1994

19. Casinelli N: Evaluation of efficacy of adjuvant rIFN2a in melanoma patients with regional node metastases. Proc Am Soc Clin Oncol 14: 410, 1995 (abstr)

20. Cascinelli N, Belli F, MacKie RM, et al: Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: A randomised trial. Lancet 358: 866-869, 2001[CrossRef][Medline]

21. Rusciani L, Petraglia S, Alotto M, et al: Postsurgical adjuvant therapy on melanoma: Evaluation of a 3-year randomised trial with recombinant interferon-alpha after 3 and 5 years of follow-up. Cancer 79: 2354-2360, 1997[CrossRef][Medline]

22. Wheatly K, Hancock B, Gore M, et al: Interferon-alpha as adjuvant therapy for melanoma: A meta-analysis of the randomised trials. Proc Am Soc Clin Oncol 20: 349a, 2001 (abstr 1394)

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29. Hancock BW, Harris S, Wheatley K, et al: Adjuvant interferon-alpha in malignant melanoma: Current status. Cancer Treat Rev 26: 81-89, 2000[CrossRef][Medline]

Submitted October 15, 2001; accepted December 26, 2001.

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