Originally published as JCO Early Release 10.1200/JCO.2009.22.2133 on May 11 2009

This Article 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 Google Scholar Articles by Glaspy, J. Articles by Chmielowski, B. PubMed PubMed Citation Articles by Glaspy, J. Articles by Chmielowski, B. Social Bookmarking                            What's this?

Interferon Alfa in the Postsurgical Management of High-Risk Melanoma: Is It Worth It?

Antoni Ribas

Bartosz Chmielowski

Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine at the University of California-Los Angeles, Los Angeles, California

The incidence of cutaneous malignant melanoma is increasing in the United States. After resection, some patients, primarily those with relatively deep invasion by the primary tumor or regional lymph node involvement, have a substantial risk of future relapse and death from systemic disease.^1,2 Accordingly, there has been a longstanding and growing need for an effective and feasible adjuvant systemic treatment to address micro-metastatic disease to reduce this risk. Despite decades of research resulting in the development of several therapies that initially seemed promising in uncontrolled or historically controlled clinical studies, the only approach that has consistently been shown in randomized controlled trials to have an impact on relapse risk compared with either no treatment or a control treatment believed to be ineffective has been interferon alfa.^3–7 Unfortunately, interferon alfa administered at doses and durations shown to have efficacy as an adjuvant therapy for melanoma has significant toxicity. Moreover, although the improvement in relapse-free survival (RFS) associated with interferon alfa is now clearly established, this benefit is modest and has not been consistently coupled with a significant increase in observed overall survival (OS), even with relatively long follow-up.⁶ This has resulted in an unresolved controversy regarding the utility of adjuvant interferon in this setting and has left the clinician with a difficult dilemma when advising a patient with high-risk melanoma on postsurgical treatment options.

The most frequently used interferon regimen in early-stage melanoma in the United States has been interferon alfa-2b, administered at a dose of 20 x 10⁶ U/m² 5 days a week for 4 weeks, followed by 10 x 10⁶ U/m² 3 days each week for 48 weeks. Because both interferon therapy and melanoma relapse can compromise quality of life, formal utility analyses have attempted to address the question of whether the observed benefit in terms of RFS justifies the toxicity of this schedule. Early on, it was shown that the net impact of high-dose interferon on quality-of-life-adjusted survival (QAS) varied from patient to patient and depended on the relative value placed by individual patients on time without relapse and time with toxicity.⁸ A subsequent study performed in patients with melanoma who were candidates for interferon therapy concluded that the median patient valued a 4% to 10% improvement in 5-year RFS highly enough to offset moderate to severe interferon toxicity.⁹ An analysis of data from the first two randomized trials of this interferon regimen^3,4 concluded that most high-risk melanoma patients will experience an increase in QAS associated with high-dose interferon therapy,¹⁰ a finding consistent with the two previous reports. This study identified specific questions for the clinician to ask patients to identify a subset who would be likely to benefit in terms of QAS from high-dose interferon that remain potentially useful in practice but fall short of providing the validated tool for reliably predicting utility in each individual patient that clinicians really need. Throughout, for the high-dose interferon regimen currently in use in the United States for high-risk melanoma, both the clinical outcomes data (improved RFS without a consistent, statistically significant effect on observed OS) and the quality of life/utility data (effects on QAS that vary depending on an individual patient's values, with many patients having improvements in QAS) have been remarkably consistent. What remains remarkably inconsistent is the conclusion drawn and communicated to patients by individual physicians involved in treating melanoma, caused in part by our desire to practice evidence-based medicine which we believe should result in our determining from the data what the correct treatment should be for all patients with a given specific clinical presentation and then recommending that approach to all patients with that condition. Paradoxically, with high-dose interferon therapy for high-risk melanoma, the evidence has consistently indicated that the correct treatment is not necessarily the same for two patients with identical clinical parameters but different individual values.

All agree that we need a better adjuvant treatment for postsurgical management of high-risk melanoma. Optimally, this therapy would be more efficacious, with profound improvements in RFS and demonstrable increases in OS that stand the test of randomized, controlled trials. The attainment of this grail probably will have to await translation of the recent substantial advances in the molecular biology of melanoma and in basic immunology. In the meantime, some progress can be made by decreasing the toxicities associated with interferon alfa. Meticulous attention to supportive care during high-dose interferon therapy is important.¹¹ It may also be possible to truncate the schedule to 1 month of intravenous therapy, an approach under study for deep, but node-negative, melanomas in ECOG (Eastern Cooperative Oncology Group) E1697.

There has been some evidence that therapy with pegylated interferon alfa, because of its pharmacokinetic profile, might achieve equal efficacy with less toxicity compared with treatment with the unmodified protein. In a recently published randomized trial (European Organisation for Research and Treatment of Cancer [EORTC] 18991) with a median follow-up of 3.8 years, pegylated interferon alfa-2b (peg-IFN--2b) administered weekly with a 2-month induction phase (6 mcg/kg/wk) followed by maintenance (3 mcg/kg/wk) for an intended treatment duration of 5 years was shown to improve RFS, but not OS, in patients with node-positive melanoma compared with observation alone.⁷ The specific toxicities reported were similar to those previously reported with adjuvant high-dose interferon in melanoma, including fatigue, hepatotoxicity, and depression. The frequencies of grade 3 and 4 toxicities were lower than some prior reports using nonpegylated protein, but there are obvious limitations to cross-study comparisons, and ultimately 31% of patients discontinued peg-IFN--2b early because of toxicity; the median duration of treatment with peg-IFN--2b was only 12 months.

In this issue of Journal of Clinical Oncology, Bottomley et al¹² report the findings of their well-executed study of the effects of peg-IFN--2b on quality of life in the EORTC 18991 trial. Patient-reported outcomes were collected at baseline and at 3, 12, 24, and 36 months after enrollment. Results of both functioning and symptom scales were significantly inferior during peg-IFN--2b therapy compared with patients in the observation arm. These data are important but disappointing and do not support a conclusion that using peg-IFN--2b, at least with the schedule used in EORTC 18991, will either greatly improve the tolerability or significantly increase the feasible duration of treatment for adjuvant interferon in high-risk melanoma. It has been pointed out that the follow-up of EORTC 18991 is still early and it is not impossible that, with longer follow-up, this peg-IFN--2b regimen will result in improved outcomes, including even improved survival.¹³ However, for the present, peg-IFN--2b does not seem to better meet the clinical needs of patients with high-risk melanoma.

Key questions remain unanswered. Why has a consistent improvement in RFS for a cancer with a high patient fatality rate not been consistently associated with an observed increase in OS? Is this a trial design and statistical power issue, or does exposure to interferon alfa before relapse somehow negatively affect the duration of survival after relapse? Are there subsets of patients identifiable before or early on during interferon treatment that benefit most from the completion of interferon therapy? The observation that patients who develop autoimmune phenomena during interferon therapy for high-risk melanoma may have a significantly reduced relapse risk¹⁴ is intriguing, but has not been confirmed in other studies and is not currently useful in focusing adjuvant interferon therapy. Similarly, the hypothesis generated by the observation in EORTC 18991, in which the benefit of adjuvant peg-IFN--2b was most evident in patients with nonpalpable nodes (N1),⁷ is recent and has not been confirmed. Will the major advances in this field come from building on high-dose interferon to devise a better treatment for all high-risk melanoma patients or from separating patients into more homogeneous subsets on the basis of molecular markers of pathway addiction and rational therapeutic targeting?

Until the answers are known, enrollment in high-quality clinical trials remains an appropriate choice for patients with high-risk cutaneous melanoma. For those who are not eligible or who decline participation in clinical trials, the treating clinician will continue to face the question: is high-dose interferon worth it? The data indicate that for many patients it has value and is the appropriate approach. In each individual case, the correct answer can only come from an honest and open dialog with that patient.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Manuscript writing: John Glaspy, Antoni Ribas, Bartosz Chmielowski

REFERENCES

1. Manola J, Atkins M, Ibrahim J, et al: Prognostic factors in metastatic melanoma: A pooled analysis of Eastern Cooperative Oncology Group trials. J Clin Oncol 18:3782–3793, 2000.[Abstract/Free Full Text]

2. Balch CM, Soong SJ, Gershenwald JE, et al: Prognostic factors analysis of 17,600 melanoma patients: Validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 19:3622–3634, 2001.[Abstract/Free Full Text]

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. Kirkwood JM, Ibrahim JG, Sosman JA, et al: High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: Results of intergroup trial E1694/S9512/C509801. J Clin Oncol 19:2370–2380, 2001.[Abstract/Free Full Text]

6. Kirkwood JM, Manola J, Ibrahim J, et al: A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma: Mechanisms and management of toxicities associated with high-dose interferon alfa-2b therapy. Clin Cancer Res 10:1670–1677, 2004.[Abstract/Free Full Text]

7. Eggermont AM, Suciu S, Santinami M, et al: Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: Final results of EORTC 18991, a randomised phase III trial. Lancet 372:117–126, 2008.[CrossRef][Medline]

8. 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]

9. Kilbridge KL, Weeks JC, Sober AJ, et al: Patient preferences for adjuvant interferon alfa-2b treatment. J Clin Oncol 19:812–823, 2001.[Abstract/Free Full Text]

10. Kilbridge KL, Cole BF, Kirkwood JM, et al: Quality-of-life-adjusted survival analysis of high-dose adjuvant interferon alpha-2b for high-risk melanoma patients using intergroup clinical trial data. J Clin Oncol 20:1311–1318, 2002.[Abstract/Free Full Text]

11. Kirkwood JM, Bender C, Agarwala S, et al: Mechanisms and management of toxicities associated with high-dose interferon alfa-2b therapy. J Clin Oncol 20:3703–3718, 2002.[Abstract/Free Full Text]

12. Bottomley A, Coens C, Suciu S, et al: Adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma: A phase III randomized controlled trial of health-related quality of life and symptoms by the European Organisation for Research and Treatment of Cancer Melanoma Group. J Clin Oncol 27:2916–2923, 2009.[Abstract/Free Full Text]

13. Sondak VK, Flaherty LE: Adjuvant therapy of melanoma: Is pegylated interferon alfa-2b what we've been waiting for? Lancet 372:89–90, 2008.[CrossRef][Medline]

14. Gogas H, Ioannovich J, Dafni U, et al: Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med 354:709–718, 2006.[Abstract/Free Full Text]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This Article 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 Google Scholar Articles by Glaspy, J. Articles by Chmielowski, B. PubMed PubMed Citation Articles by Glaspy, J. Articles by Chmielowski, B. Social Bookmarking                            What's this?