Originally published as JCO Early Release 10.1200/JCO.2004.10.952 on December 9 2003

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Present Status and Future Prospects for Adjuvant Therapy of Melanoma: Time to Build upon the Foundation of High-dose Interferon Alfa-2b

University of Pittsburgh Cancer Institute, Pittsburgh, PA

Panagiotis A. Konstantinopoulos

State University of New York Upstate Medical Center, Syracuse, NY

Melanoma is the fourth most frequent cancer among males and the second most frequent cancer in females age 25 to 34 years [1]. The distribution of disease at presentation has evolved during the last 50 years, with thin lesions (< 1.0-mm Breslow depth) increasing in both sexes, leading to resultant cure in more than 86% of patients. Despite the reduction in case fatality rate, more than 8,000 deaths per year are still attributable to melanoma in the United States, and the death rate and incidence continue to rise among subpopulations, such as older men with thick lesions ( 4.0-mm) [2], suggesting the need for better detection, secondary chemoprevention, and adjuvant treatment strategies.

The beneficial effect of high-dose interferon alfa-2b (HDI) adjuvant therapy after resection of thick (American Joint Committee on Cancer [AJCC] stage IIB or IIC) or lymph-node-positive (stage III) melanoma was demonstrated a decade ago and has been widely evaluated in rigorous multicenter randomized controlled trials that have shown statistically significant benefits from HDI on relapse-free survival (RFS), an end point in relation to which the impact of HDI has been confirmed and unquestioned in any quarter [3-5]. The statistically significant impact of HDI on overall survival (OS), first observed in the Eastern Cooperative Oncology Group trial comparing HDI with observation (E1684), has been confirmed in the recent Intergroup American trial (E1694), comparing HDI to GM2 vaccine [5]. Although this benefit has been accepted by the United States Food and Drug Administration (FDA) and regulatory agencies worldwide, the impact of HDI on long-term survival has been questioned, partly because of the cost and toxicity of the regimen, and partly to the absence of a survival benefit in another Intergroup trial (E1690) [4]. In this trial, conducted after FDA approval of HDI as adjuvant therapy, crossover treatment with interferon alfa-2b (IFN--2b) at relapse among patients who had been assigned to observation has been put forth as a confounding variable in interpreting the overall survival data [4].

As a consequence of the cost and toxicity of this regimen, trials outside the US have only recently evaluated HDI, with studies performed by the Association of Dermatologic Oncologists in Germany, the Italian Melanoma Intergroup, and the Hellenic Oncology Group in Greece. A number of randomized controlled studies have evaluated lower doses of IFN--2b (LDI) for intermediate- and high-risk resected melanoma (AJCC stages II and III) and have shown no effect in high-risk melanoma, a transient delay in relapse for intermediate-risk melanoma, and no survival benefit in intermediate and high-risk disease [4,6-10]. The results of these trials of LDI led to the AIM HIGH trial in the United Kingdom, reported in this issue of the Journal of Clinical Oncology. AIM HIGH is the seventh negative randomized controlled study of LDI and the largest single study of LDI published to date, with a median follow-up of 6.8 years. Accrual was terminated before reaching the targeted accrual goal because of the early lack of sufficient evidence of benefit in terms of either RFS or OS [11]. This trial might have been the end of LDI adjuvant therapy for melanoma, save for the European Organization for Research and Treatment of Cancer (EORTC) Trial 18952, testing "intermediate" doses of IFN--2b given for 1 or 2 years. At 3 years’ median follow-up, there was neither OS nor RFS benefit for the two "intermediate" dosages of 5 MU three times per week for 2 years (5 MU/m²) and 10 MU three times per week administered subcutaneously (communication by A.M.M. Eggermont to the Milan ESO Melanoma Congress, May, 2003).

Given the unique element of intravenous (IV) induction therapy administered daily for 1 month incorporated in each of the effective HDI regimens, which was absent from all regimens that have not had durable effects, the US Intergroup, together with the National Cancer Institute of Canada and selected Australian sites, have joined a trial in which the initial IV induction component of therapy in E1697 (1 month of IV HDI) is compared with observation alone for patients at intermediate risk, who are generally not considered to be candidates for the conventional HDI regimen (T3 1.5-mm primary melanoma, stage IIA). To test the role of IFN--2b, and interleukin-2 with the cisplatin, vinblastine, and dacarbazine regimen, another Intergroup trial (S0008), led by the Southwestern Oncology Group, is comparing this chemobiotherapy regimen with HDI for patients with palpable nodal involvement (N2 or N3, stage IIIB or IIIC). A variety of non-IFN adjuvant therapies have been evaluated for intermediate-risk and high-risk melanoma, including the bacterial immunostimulants Bacille Calmette-Guerin and Corynobacterium parvum, antihelminthic immunomodulators (eg, levamisole), and specific vaccines prepared from intact autologous or allogeneic melanoma cells, including viral oncolysates, tumor lysates, or shed antigens of cultured melanoma cell lines and chemically defined antigens (gangliosides) of melanoma [12]. Intergroup E4697 is evaluating whether granulocyte-macrophage colony-stimulating factor alone or in combination with a vaccine comprising three lineage antigen peptides (MART-1/Melan-A 27 to 35, gp100 209 to 217[210M] and tyrosinase 368 to 376 [370D]) is effective as adjuvant therapy in patients who have recurrent locoregional melanoma or distant resectable metastases following IFN failure.

The negative results of many previous studies have often been attributed to methodological shortcomings and particularly to insufficient power, poor trial quality, and heterogeneity of risk for the target population. Adjuvant therapy trials for melanoma demand commitment: trials designed to detect a clinically meaningful 5% increase in 5-year event-free rate of 50%, using a two-arm design, with a 3-year accrual period and 5 years of follow-up, require enrollment of approximately 2,500 patients per arm (for an 80% power, two-sided type I error; P = .05). These are daunting considerations for the design of future studies. To overcome the problem of inadequate power in individual adjuvant trials, a meta-analysis has been conducted, providing additional information on the benefits of IFN--2b on disease-free survival that appear to be dose-dependent. Meta-analysis of published HDI data (without the more robust log-rank analysis that was intended in the design of the actual trials) gives evidence of a trend toward benefit in OS (P = .06) [13]. Multiple factors may reduce the power of a study, including inadequate assessment of risk, as in prior intermediate risk trials that have not assessed nodal status, and changing risk patterns, as noted in Australian vaccine trials [14]. In addition, the effect of crossover therapy on OS, as noted in E1690 and, more recently, the Intergroup E1694, has been considered [15]. Updated analysis of E1684 at 12.6 years’ median follow-up has added further questions, because disease-specific, relapse-free curves show stable highly significant long-term reduction in melanoma relapse, but OS data show a diminishing level of statistical significance (P = .02 at 7 years, but .09 at 12.6 years’ median follow-up) [16].

The controversy regarding the benefits of IFN have been both amplified and illuminated through recent advances in the understanding of melanoma pathophysiology, disease staging, and cancer immunobiology. These argue that the results of past trials are to be taken as a building block, not as the final accomplishment in adjuvant of melanoma. We need to move forward, proceeding in new directions, informed by the experience of the past generation of IFN trials.

First, we need to identify more reliable molecular markers for disease prognosis. Ideally, these molecular markers will be assessed in composite immunologic or proteomic/genomic arrays, to define patients who are destined for relapse, to refine and clarify our risk categories as codified in the sixth edition staging system of the AJCC for melanoma. New markers derived from high-throughput analyses to define "molecular fingerprints" of melanoma will potentially enable us to predict both prognosis and response to particular treatments and allow us to identify patient subgroups that may differ from typical stage groupings, according to molecular mechanisms of response to treatment [17,18].

Second, given leading current hypotheses regarding molecular mechanisms of IFN antitumor action in melanoma [19], it is critical that future studies of IFN evaluate specific T-cell responses, and the Th1/Th2 bias of the immune response, as well as the underlying dendritic cell functions that may drive the immune response in relation to disease outcome [20,21]. Correlations between immune responses and disease course, as well as survival, will most likely reveal the basis of benefits from this immunotherapy and pave the way for more intelligent therapies either to combine with IFN, or supplant it, in the future [22].

Third, the steps of malignant transformation from nevocellular nevus to melanoma require more precise delineation, to identify the most relevant targets of new therapy for melanoma. Thus, gene expression profiling of melanomas suggests that decreased expression of cell adhesion molecules is correlated with reduced motility and invasive characteristics [23] and vasculogenic mimicry [24], prompting clinical trials with antibodies against integrins (eg, _vß₃). Recent reports regarding mutations frequently found in B-Raf, both in melanoma and nevi, may prompt a revolution in treatment similar to that which followed the discovery of the Philadelphia chromosome in chronic myelogenous leukemia, culminating in the rational development of imanitib mesylate. Recent reports on the use of the less selective Raf kinase inhibitors (BAY 43-9006) in patients with metastatic melanoma are also promising [25] although the expression of B-Raf in nevi suggests that the evaluation of this intervention in precursor atypical nevi may be more appropriate, especially as selective B-Raf-specific agents become available [26].

Fourth, we need to develop new paradigms for deciding which agents and approaches apply to the adjuvant arena. Clearly, objective responses in gross disease or survival benefits in advanced disease warrant adjuvant evaluation of a new agent. However, no agent or combination adequately evaluated in multicenter controlled trials has yet shown survival benefits in metastatic melanoma. Intermediate end points, such as the modulation of host immune responses or molecular effects on tumor cell targets should be sufficient to prompt the consideration of adjuvant trials, without requiring objective response in metastatic disease. This is one of the most important lessons of HDI, where to date we have no evidence of survival benefits in metastatic disease but clear and durable effects in the adjuvant setting. A variety of vaccination studies in the adjuvant setting or metastatic disease are now underway, testing genetic vaccination with molecules that enhance immune responses against tumor cells using the canarypox virus as an immunization vehicle, or multiepitope peptide vaccination with more conventional oil adjuvants [22], vaccination against gangliosides of melanoma (GM2-KLH/QS21, in a current EORTC adjuvant trial), or vaccination with autologous heat shock protein-peptide complexes (in an EORTC adjuvant trial planned to start in 2003).

What will be the role of interferon in this growing list of potential alternative treatment approaches? HDI remains the standard of care for adjuvant therapy against which any new treatment strategy will ultimately be best compared in randomized controlled trials. The Intergroup S0008 phase III trial of biochemotherapy (v HDI), and trials of allogeneic tumor cell line derived vaccines plus LDI compared with HDI for resected stage III melanoma [27] or autologous haptenated tumor cell vaccines compared with HDI [28] exemplify this design principle. Ideally, IFN may serve as a platform on which other agents may be added [27] Evidence for synergy between vaccination with IFN has been prospectively sought [29,22] and will also be of critical interest in new vaccine trials. Through these efforts, more effective and less toxic approaches may be discovered.

Authors’ Disclosures of Potential Conflicts of Interest

The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: John M. Kirkwood, Schering-Plough Corporation. Performed contract work within the last 2 years: John M. Kirkwood, Schering-Plough Corporation. Received more than $2,000 a year from a company for either of the last 2 years: John M. Kirkwood, Schering-Plough Corporation.

REFERENCES

1. Desmond RA, Soong SJ: Epidemiology of malignant melanoma. Surg Clin North Am 83:1–29, 2003[CrossRef][Medline]

2. Jemal A, Devesa SS, Hartge P, et al: Recent trends in cutaneous melanoma incidence among whites in the United States. J Natl Cancer Inst 93:678–683, 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. Cameron DA, Cornbleet MC, Mackie RM, et al: Adjuvant interferon alpha 2b in high risk melanoma: The Scottish study. Br J Cancer 84:1146–1149, 2001[CrossRef][Medline]

7. Eggermont AMM, Kleeberg UR, Ruiter DJ, et al: The European Organization for Research and Treatment of Cancer Melanoma Group trial experience with more than 2000 Patients, evaluating adjuvant therapy treatment with low or intermediate doses of interferon alpha-2b, in Perry GM (ed): American Society of Clinical Oncology 2001—Educational Book. Alexandria, VA, ASCO, 2001, pp 88–93

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

9. Grob JJ, Dreno B, de la Salmoniere P, et al: Randomized 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]

10. 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 randomized trial. Lancet 358:866–869, 2001[CrossRef][Medline]

11. Hancock BW, Wheatley K, Harris S, et al: AIM HIGH: Adjuvant Interferon in Melanoma (HIGH risk)—United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low dose extended duration interferon alfa 2a in high risk resected malignant melanoma. J Clin Oncol 22:53–61, 2004[Abstract/Free Full Text]

12. Lotze MT, Dallal RM, Kirkwood JM, et al: Cutaneous Melanoma, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer Principles and Practice of Oncology. Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 2012–2056

13. Wheatley K, Ives N, Hancock B, et al: Does adjuvant interferon-alpha for high-risk melanoma provide a worthwhile benefit?. A meta-analysis of the randomized trials. Cancer Treat Rev 29:241–52, 2003[CrossRef][Medline]

14. Hersey P, Coates AS, McCarthy WH, et al: Adjuvant immunotherapy of patients with high-risk melanoma using vaccinia viral lysates of melanoma: Results of a randomized trial. J Clin Oncol 20:4181–90, 2002[Abstract/Free Full Text]

15. Whalen J, Lee S, Sondak VK, et al: Post-adjuvant (salvage) therapy of high-risk melanoma patients following the Intergroup E1694 trial: Proc Am Soc Clin Oncol, 2003 (abstr 2896)

16. Kirkwood JM, Manola J, Ibrahim J, et al: A pooled analysis of ECOG and Intergroup trials of adjuvant high-dose interferon melanoma. Clin Cancer Res (in press)

17. Petricoin EF, Liotta LA: Clinical applications of proteomics. J Nutr 133:2476S–2484S, 2003 (suppl 7)[Abstract/Free Full Text]

18. Lotze MT: The critical need for cancer biometrics: Quantitative, reproducible measures of cancer to define response to therapy. Curr Opin Investig Drugs 4:649–651, 2003[Medline]

19. Brown CK, Kirkwood JM: Targeted therapy for malignant melanoma. Curr Oncol Rep 3:344–352, 2001[Medline]

20. Tatsumi T, Kierstead LS, Ranieri E, et al: Disease-associated bias in T helper type 1 (Th1)/Th2 CD4(+) T cell responses against MAGE-6 in HLA-DRB10401(+) patients with renal cell carcinoma or melanoma. J Exp Med 196:619–628, 2002[Abstract/Free Full Text]

21. Kalinski P, Hilkens CM, Wierenga EA, et al: T-cell priming by type-1 and type-2 polarized dendritic cells: The concept of a third signal. Immunol Today 20:561–567, 1999[CrossRef][Medline]

22. Kirkwood JM, Lee S, Land S, et al: E1696: Phase II trial of multi-epitope peptide vaccination for melanoma with MGT [(MART-1 (27-35), gp100 (209-217, 210M) and tyrosinase (368-376, 370D)] +/- IFN alfa-2b and GM-CSF-immunological and clinical results. Proc Am Soc Clin Oncol 22:709, 2003 (abstr 2850)

23. Bittner M, Meltzer P, Chen Y, et al: Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature 406:536–540, 2000[CrossRef][Medline]

24. Hendrix MJ, Seftor EA, Hess AR, et al: Vasculogenic mimicry and tumour-cell plasticity: Lessons from melanoma. Nat Rev Cancer 3:411–3421, 2003[CrossRef][Medline]

25. Flaherty KT, Lee RJ, Humphries R, et al: Phase I trial of BAY 43-9006 in combination with carboplatin and paclitaxel. Proc Am Soc Clin Oncol 22:710, 2003 (abstr 2854)

26. Pollock PM, Harper UL, Hansen KS, et al: High frequency of BRAF mutations in nevi. Nat Genet 33:19–20, 2003[CrossRef][Medline]

27. Mitchell MS, Abrams J, Kashani-Sabet M, et al: Interim analysis of a phase III stratified randomized trial of melacine + low-dose intron-a versus high-dose intron-a for resected stage III melanoma. Proc Am Soc Clin Oncol 22:709, 2003 (abstr 2851)

28. Berd D: M-Vax: An autologous, hapten-modified vaccine for human cancer. Expert Opin Biol Ther 2:335–342, 2002[CrossRef][Medline]

29. Kirkwood JM, Ibrahim J, Lawson DH, et al: High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: Results of the Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696. J Clin Oncol 19:1430–6, 2001[Abstract/Free Full Text]

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