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Prospective Randomized Trial of Interferon Alfa-2b and Interleukin-2 as Adjuvant Treatment for Resected Intermediate- and High-Risk Primary Melanoma Without Clinically Detectable Node Metastasis

Axel Hauschild, Michael Weichenthal, Bernd-Rüdiger Balda, Jürgen C. Becker, Helmut H. Wolff, Wolfgang Tilgen, Klaus-Werner Schulte, Johannes Ring, Dirk Schadendorf, Stephan Lischner, Günter Burg, Reinhard Dummer

From the Department of Dermatology, University of Kiel, Kiel; St. Georg Hospital, Hamburg; Klinikum Augsburg, Augsburg; University of Würzburg, Würzburg; University of Lübeck, Lübeck; University of Heidelberg and University of Homburg/Saar, Heidelberg/Homburg; University of Düsseldorf, Düsseldorf; Technical University of München, München; Rudolf-Virchow Hospital, Berlin; Skin Cancer Unit, DKFZ Heidelberg; and University Hospital of Mannheim, Germany; and University of Zürich, Switzerland.

Address reprint requests to Axel Hauschild, MD, University of Kiel, Department of Dermatology, Schittenhelmstrasse 7, 24105 Kiel, Germany; email: ahauschild{at}dermatology.uni-kiel.de.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Purpose: Low-dose interferon alfa (IFN) has been shown to have limited effects in the adjuvant treatment of patients with intermediate- and high-risk primary melanoma. We hypothesized that a combination regimen with low-dose interleukin-2 (IL-2) may improve survival prospects in these patients.

Patients and Methods: After wide excision of primary melanoma without clinically detectable lymph node metastasis (pT3 to 4, cN0, M0), 225 patients from 10 participating centers were randomly assigned to receive either subcutaneous low-dose IFN2b (3 million international units [MU]/m²/d, days 1 to 7, week 1; three times weekly, weeks 3 to 6, repeated all 6 weeks) plus IL-2 (9 MU/m²/d, days 1 to 4, week 2 of each cycle) for 48 weeks, or observation alone. The primary end point was prolongation of a relapse-free interval.

Results: Of the 225 enrolled patients, 223 were found to be eligible. Median follow-up time was 79 months. All evaluated prognostic factors were well balanced between the two arms of the study. Relapses were noticed in 36 of 113 patients treated with IFN2b plus IL-2 and in 34 of 110 patients with observation alone. Five-year disease-free survival of those who had routine surgery supplemented by IFN2b and IL-2 treatment was 70.1% (95% confidence interval [CI], 61.3% to 78.9%), compared with 69.9% in those receiving surgery and observation alone (95% CI, 60.7% to 79.1%) in the intention-to-treat analysis. Evaluation of the overall survival did not show any difference between treated and untreated melanoma patients (P = .93).

Conclusion: Adjuvant treatment of intermediate- and high-risk melanoma patients with low-dose IFN2b and IL-2 is safe and well tolerated by most patients, but it does not improve disease-free or overall survival.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
DESPITE ADVANCES in prevention, early detection, and treatment of melanoma, 20% to 25% of patients with melanoma will die from metastasis. Since the various surgical approaches to primary melanoma have not been found to clearly improve the prognosis, effective systemic treatment modalities are urgently needed.

Adjuvant chemotherapy with cytotoxic agents has not demonstrated any improvement of survival prospects in randomized trials.¹ Only treatment with interferon alfa (IFN) has been beneficial in terms of prolongation of disease-free survival (DFS) in several prospective randomized studies.^2–7 In patients with melanomas thicker than 1.5 mm, the application of low-dose IFN2a regimens demonstrated an improvement of DFS as compared with untreated controls. However, an effect on overall survival was lacking.^5,6

Kirkwood et al³ demonstrated for the first time in 1996 that high-dose IFN2b prolongs not only DFS, but also overall survival in patients with melanomas thicker than 4.0 mm or lymph node metastasis. In a subsequent trial of the Eastern Cooperative Oncology Group (ECOG) comparing patients treated with high-dose IFN2b with untreated controls, the effect of IFN2b on the improvement of DFS was confirmed, but the study failed to confirm the significant effect on overall survival.⁴ In a third trial, Kirkwood et al were able to demonstrate that in lymph node–positive (77%) and lymph node–negative (23%) high-risk melanoma patients, high-dose IFN2b led to significant survival benefits in comparison with a ganglioside vaccination.²

In contrast, Cascinelli et al⁸ recently published a World Health Organization (WHO) melanoma program study of patients with clinically detectable lymph node metastasis. The study failed to demonstrate any benefits of low-dose IFN2a administered for a period of 3 years.⁸

The aim of our study was to test whether the addition of low-dose interleukin-2 (IL-2) to low-dose IFN2b would improve relapse-free survival. Secondary objectives of our study were to assess overall survival and toxic adverse effects. In addition, we carried out immunologic monitoring in a subgroup of the study population.

IL-2 has been shown to be effective at higher doses in advanced metastatic melanoma cases.^9–11 Also, combination regimens of IFN and different doses of subcutaneous or intravenous IL-2 have been used in metastatic melanoma and metastatic renal cell carcinoma cases, with varying effects.^12–17 To the best of our knowledge, this is the first controlled clinical trial on IL-2, in an adjuvant setting, for primary melanoma.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Trial Design
This prospective randomized trial was conducted in 10 different departments of dermatology at university centers and community hospitals in Germany and Switzerland. All centers were experienced in the care of patients with melanoma.

Between October 1990 and April 1995, 225 patients were randomly assigned to receive either the study medication or close observation alone. The institutional review boards of the participating centers approved the protocol, and the study patients provided informed consent. Randomization was centrally done using computer-generated random numbers, and stratified by center.

To be eligible, patients had to meet the following criteria: age between 18 and 70 years; histologically proven melanoma with pT3 to 4, Clark level IV or V, and/or tumor thickness greater than 1.5 mm according to the 1987 International Union Against Cancer (UICC) classification¹⁸; absence of clinically detectable regional node metastasis (neither elective lymphadenectomy nor sentinel node biopsy was performed); absence of visceral metastasis verified by at least a chest radiograph and abdominal ultrasound (scans of the thorax and abdomen, magnetic resonance imaging of the brain, and bone scintigraphy were considered optional); no history of other cancer (except basal cell carcinoma or carcinoma-in-situ of the cervix); complete surgical excision of the melanoma primary tumor, with safety margins of at least 3 cm; no clinically apparent thyroid dysfunctions; and WBC count greater than 4 x 10⁹/L, platelet count greater than 100 x 10⁹/L, and hemoglobin levels greater than 11 g/dL.

Other routine laboratory parameters (ie, creatinine, bilirubine, and liver enzymes) had to be less than 1.5 times that of the upper normal value. Pregnant and lactating women were excluded from the study. In women of childbearing age, effective contraception was required. Treatment had to be initiated within 4 weeks of final removal of the primary melanoma.

A central histology review was not performed; however, all participating centers were uniformly well trained in dermatohistopathology and thus self-reviewed all external diagnoses, including measurement of tumor thickness, at their institutions.

Treatment Schedule
Patients randomly assigned to the treatment arm received the schedule displayed in Figure 1. One treatment cycle, lasting for 6 weeks, consisted of IFN2b (Intron A; Essex Pharma, Munich, Germany) at a dose of 3 million international units (MU)/m²/d subcutaneously, on days 1 to 7 in the first week, followed by subcutaneously administered IL-2 (Proleukin; Chiron Therapeutics, Ratingen, Germany) in doses of 9 MU/m²/d on days 1 through 4 in the second week. During weeks 3 to 6, IFN2b at a dose of 3 MU/m²/d was given three times per week. Altogether, eight treatment cycles, accounting for a 48-week schedule without resting periods, were administered. Patients were trained to self-administer the drugs subcutaneously at their homes. In most cases, the initiation of treatment was performed concurrently with the postsurgical follow-up at the hospitals of the participating centers.

View larger version (12K): [in this window] [in a new window]   Fig 1. Scheme of treatment. Treatment cycles consisted of interferon alfa 2b (IFN2b) subcutaneously at 3 million international units (MU)/m2/d on days 1 to 7; interleukin-2 (IL-2) subcutaneously at 9 MU/m2/d on days 8 to 11; followed by IFN2b at 3 MU three times weekly for four weeks. These cycles were performed eight times for a total of 48 weeks.

Follow-up examinations took place every 3 months for the first 3 years, every 6 months for the subsequent 2 years, and yearly thereafter. If symptoms arose, patients were instructed to come earlier for examinations. At follow-up, patients had complete clinical examinations, abdominal ultrasound 3 times monthly in the first 2 years (yearly thereafter), as well as yearly chest radiographs. If necessary, additional scans were performed. We performed routine blood evaluations weekly during the first month and once per month thereafter. Blood assessment included RBC and WBC counts, and evaluation of liver enzymes, glucose levels, thyroid hormones (TSH, T₃, T₄), creatinine levels, and creatinkinase concentrations.

We documented the dates and sites of recurrences, and the dates and causes of deaths. The WHO toxicity scale was used to report adverse events. Written information instructed patients to use acetaminophen or metamizole to treat flu-like symptoms. A patient’s diary was given to the patients to document adverse or toxic effects of the medication. Physicians at the participating centers who were responsible for the patients received training courses on the management of adverse reactions to IFN2b or IL-2, once or twice per year from 1991 to 1995.

Serologic Immunomonitoring
To assess immunomonitoring in a subgroup of treated patients, the following parameters were evaluated by blood collection and processing: soluble IL-2 receptors, ß₂-microglobulin and neopterin serum concentrations, development of autoantibodies to cardiolipin and thyroglobulin, and detection of antibodies to IFN2b and IL-2 (solid enzyme immunoassay). The results have been published elsewhere.¹⁹ The influence of a combination of IFN2b and IL-2 on the lysis of melanoma cells was evaluated in vitro.²⁰

Statistical Analysis
The primary objective of the study was the prolongation of DFS. Secondary end points included overall survival and tolerability of the treatment. The trial was designed to detect a treatment effect of 15% improvement in 5-year DFS (observation alone, 60% v IFN2b + IL-2 therapy, 75%), with 80% power and a (one-sided) type I error of 5%. For survival analyses of the eligible patients, the Kaplan-Meier estimates were used and compared by the log-rank test. The principal analysis was carried out on an intent-to-treat basis.

The distribution of continuous variables was compared between the treatment arms using Student’s t test, and categorical factors were tested by ² test or Fisher’s exact test, as appropriate. In addition, a Cox regression analysis was applied to adjust for the effect of individual centers and known prognostic factors. Calculations were performed using SPSS version 9.0 software (SPSS Inc, Chicago, IL).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Study Population
Figure 2 summarizes the profile of the study. Two of 225 patients originally randomly assigned to the study and who were assigned to the observation arm were not found to be eligible as a result of missing basic and follow-up data. Thus, 223 patients were eligible and assessable for the study and for long-term follow-up (median, 79.4 months). Major prognostic factors for primary melanoma (sex, site of melanoma, tumor thickness, Clark level, and histologic subtype) showed a similar distribution between treated and untreated study patients (Table 1). Slight differences regarding primary site, subtype, and Clark level in favor of the observation group were not statistically significant.

View larger version (23K): [in this window] [in a new window]   Fig 2. Study profile.

View larger version (12K): [in this window] [in a new window]   Fig 3. Kaplan-Meier estimates of the event-free proportion of patients treated with IFN2b plus IL-2, as compared with untreated control patients, in terms of (A) disease-free survival, (B) time to distant metastasis, and (C) overall survival.

A similar analysis was performed comparing the time to distant metastasis in treated patients with that of untreated controls. There was no significant difference between the groups based on either the intention-to-treat population (Fig 3B) or after excluding the patients (n = 9) who had early treatment withdrawal (data not shown).

Overall Survival
Twenty-six patients (23%) in the group treated with IFN2b plus IL-2 died during the observation period. In the control group, 28 deaths (25.5%) were recorded. In the study group, one patient died as a result of pulmonary embolism; in the observation group, two patients died as a result of myocardial infarction; and one patient each died as a result of metastatic bladder carcinoma and immunocytoma, respectively. Thus, tumor-related death occurred in 25 treated patients (22.1%) and in 24 patients under close observation alone (21.8%; Table 2). No treatment-related deaths occurred. Figure 3C illustrates the survival plots with respect to all patients included in the study (intention-to-treat analysis). No difference in overall survival was detectable between the two arms of the study (log-rank: P = .93).

The results were unaffected by an analysis excluding patients with treatment discontinuation (n = 9). No statistically significant differences were obtained for patients treated according to schedule as compared with control patients (data not shown).

Analysis of Prognostic Covariates
To further explain the influence of potential cofactors, a Cox regression analysis was performed, including sex, age, melanoma subtype, site of primary tumor, Clark level of invasion, tumor thickness, study center, and study arm. The only significant variable in this multivariate model was the invasion depth of the primary tumor (P < .001). None of the other factors, including adjuvant treatment with IFN2b plus IL-2, had significant influence on DFS, the time to distant metastasis, or overall survival.

Tolerability
Low-dose IFN2b and IL-2 treatment was given to 113 patients. At the follow-up visits, all patients were monitored for adverse events during treatment. Furthermore, we received data from the patient’s diary. Frequent low-grade (WHO grade 1 and 2) adverse effects included flue-like symptoms, weight loss, hair loss, cutaneous erythema, leukopenia, and lymphopenia. In 9 out of 113 patients (8%) treatment discontinuation was documented. Therapy had to be stopped because of adverse events according to the protocol in one patient with WHO grade-3 liver toxicity, and in another patient with severe depression. Reasons for withdrawal from the study on the patient’s request (WHO grade 1 and 2) included persistent fever (n = 1), chronic fatigue (n = 2), weight loss (n = 2), and hair loss (n = 1). All patients with treatment discontinuation recovered fully from the adverse reactions within 6 weeks. We did not notice long-term adverse effects.

Of the 113 treated patients, 104 received more than 90% of the scheduled dose of IFN2b and IL-2. Prolonged dose reductions were not necessary in these patients, though all patients reported mild to moderate flu-like symptoms at the initiation of IFN2b treatment and during the weeks of IL-2 application. Regarding IL-2, tachyphylaxia was not reported by the majority of our patients. Life-threatening adverse events or treatment-related deaths did not occur.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Although previous trials with adjuvant low-dose IFN alone have shown an impact on DFS in patients with malignant melanoma, they have not achieved satisfactory results in terms of overall survival benefit.^5,6 Since IFN and IL-2 have been reported to exhibit synergistic immunologic effects,²¹ we combined IFN and IL-2 in an adjuvant setting to treat patients with primary malignant melanoma.

High-dose interleukin-2 has demonstrated significant effects in terms of remission rates (16%) and long-term survival in advanced metastatic melanoma patients.²² However, high-dose bolus IL-2 seems far too toxic to be transferred into an adjuvant setting with long-term treatment in potentially cured patients.²³ Low-dose interleukin-2 administered subcutaneously has been used in combination regimens for metastatic melanoma and renal cell carcinoma with a favorable safety profile and thus appears to be an attractive candidate for immunoaugmentation of IFN2b.^10,13,15 Since it is completely unclear whether low-dose IL-2 is effective as a monotherapy for patients with melanoma , we chose a combination regimen, which could be performed by the patient at home without impairing his or her social functions or working capabilities.

Our results show that IFN2b plus IL-2 treatment in the given setting does not affect DFS or overall survival. Whereas an interim report on our study published in 1998 demonstrated a trend for extended survival in patients treated with IFN2b plus IL-2, as compared with untreated controls,²⁴ the final statistical evaluation showed virtually identical survival curves. Since the relapse rates in our study population were apparently lower than originally expected, one can argue that the study is underpowered in terms of the sample size. However, even for a larger sample size, it would seem unlikely to expect a clinically meaningful effect from low-dose IFN2b and IL-2 treatment on the basis of our results.

A lack of synergistic effects from combined IFN2b plus IL-2 treatment is further evidenced by three recent studies that failed to detect favorable effects of combining IL-2 with IFN2a alone,¹⁶ IFN2a with cisplatin,¹⁷ or IFN with dacarbazine (DTIC)¹⁵ in the treatment of advanced metastatic melanoma.

Today, there are three prospective-randomized studies with a patient population and eligibility criteria comparable to those of our study. Grob et al⁵ published results pertaining to an 18-month treatment regimen with low-dose IFN2a alone, which revealed a prolongation of DFS. Pehamberger et al⁶ showed that 12.75 months of low-dose IFN2a (induction phase: 3 MU/m²/d; 3 times weekly thereafter) improved DFS as compared with observation alone. In a third trial on low-dose interferon, the Scottish Melanoma Group observed an apparent improvement in DFS and overall survival in patients receiving 6 months of low-dose IFN2b (3 MU/m²/d, 3 times weekly), though the study sample size was small.⁷ Taken together, low-dose IFN has shown an impact on DFS in all three studies. It does not seem likely that the duration of treatment is an important issue, because patients in these three studies were treated for rather different time ranges. With its 11 months of treatment, our study protocol was well within this range, but nevertheless, it is clear we failed to confirm the effect of low-dose IFN on DFS. However, one should be cautious in drawing conclusions from our study data about the inefficacy of low-dose IFN2b in the adjuvant treatment of melanoma, since it is clear that the actual type II error is larger than originally planned.

It remains to be discussed whether the addition of low-dose IL-2 to the IFN2b treatment might have diminished the potential positive effects of the IFN2b in our study, but so far, there is no evidence to support such a hypothesis.

Encouraging results from high-dose IFN2b were obtained in melanoma patients with tumor thickness greater than 4.0 mm, or with lymph-node metastasis only.^2–4 Remarkably, the results from an early report on the first positive study, EST 1684,³ could not fully be confirmed by the long-term results, and the issue of adjuvant interferon treatment in malignant melanoma is still controversial.²⁵ Regarding intermediate-risk melanoma (tumor thickness, 1.5 to 4.0 mm) studies are still underway to elaborate on the effects of high-dose IFN2b. In this group of patients, the risk of recurrence is moderate, and the possible benefits have to be carefully outweighed against the substantial toxicity and risks of high-dose interferon therapy.

In this prospective multicenter study, we failed to demonstrate any effect of low-dose IFN2b and IL-2 administered for 48 weeks. In the meantime, we conducted two further prospective randomized studies in patients with intermediate- and high-risk primary melanoma with tumor thickness greater than 1.5 mm. The first study will elaborate upon the usefulness of a high-dose IFN2b induction phase before a low-dose regimen; a subsequent trial compares an 18 months to 60 months low-dose IFN2a treatment in a multi-institutional setting.

Unless better data on the optimal dosage and duration of IFN treatment are available, it is preferable that patients with intermediate- and high-risk melanoma be treated within controlled clinical trials.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Names of additional investigators at different participating centers: Augsburg: H.-J. Hagspiel, J. Seldmaier; Berlin/Mannheim: C. Schadendorf, A. Maleki; Düsseldorf: Th. Ruzicka, H.C. Schuppe; Hamburg: W.N. Meigel, A. Plettenberg, C. Pohl; Heidelberg/Homburg: D. Petzoldt, S. Seiter, V. Waldmann; Kiel: G. Lott, C. Petres-Dunsche; Lübeck: W. Achtelik, P. Grotmann, M. Tronnier; Würzburg: E.B. Bröcker, W. Müller; Zürich: T. Maier.

	ACKNOWLEDGMENTS

 
We thank Tilo Henseler, MD, PhD, Department of Dermatology, University of Kiel, Kiel, Germany, for his help with the statistical evaluations from 1994 to 1998.

	NOTES

 
Supported by grants from Essex Pharma GmbH (Munich, Germany) and Chiron Therapeutics (Ratingen, Germany).

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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3. 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]

4. Kirkwood JM, Ibrahim JG, Sondak VK, et al: High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18:2444–2458, 2000[Abstract/Free Full Text]

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

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9. Lindsey KR, Rosenberg SA, Sherry RM: Impact of the number of treatment courses on the clinical response of patients who receive high-dose bolus interleukin-2. J Clin Oncol 18:1954–1959, 2000[Abstract/Free Full Text]

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11. Rosenberg SA: Interleukin-2 and the development of immunotherapy for the treatment of patients with cancer. Cancer J Sci Am 6:S2–S7, 2000 (suppl 1)

12. Eton O, Legha SS, Bedikian AY, et al: Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol 20:2045–2052, 2002[Abstract/Free Full Text]

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15. Hauschild A, Garbe C, Stolz W, et al: Dacarbazine and interferon alpha with or without interleukin 2 in metastatic melanoma: a randomized phase III multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG). Br J Cancer 84:1036–1042, 2001[CrossRef][Medline]

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Submitted July 18, 2002; accepted May 5, 2003.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hauschild, A. Articles by Dummer, R. Search for Related Content PubMed PubMed Citation Articles by Hauschild, A. Articles by Dummer, R. Social Bookmarking                            What's this?