Originally published as JCO Early Release 10.1200/JCO.2005.01.8168 on October 31 2005

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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kirkwood, J. M. Search for Related Content PubMed PubMed Citation Articles by Kirkwood, J. M. Related Articles Related Article

Building Upon the Standard of Care in Adjuvant Therapy of High-Risk Melanoma

University of Pittsburgh, Pittsburgh, PA

Melanoma is the fifth most frequent cancer among males and the sixth most frequent cancer in females.¹ It takes a toll in productive life years that is exceeded only by childhood cancers and testicular carcinoma. Melanoma incidence has increased consistently during the past two generations. However, the depth of primary tumor invasion—the cardinal prognostic factor of localized primary melanoma—has decreased. As a consequence, the case fatality rate has decreased from 50% to less than 10% during the past 50 years.¹ Despite these advances, 8,000 deaths in the United States each year are attributable to melanoma. The death rate has increased 157% in the past decade among older men, a subset of the population who present with thicker lesions ( 4.0 mm) that may have evaded detection or may represent a biologically different process. Against this background, it is daunting that no therapy has ever shown a significant prolongation of survival in large, properly conducted, randomized clinical trials for metastatic disease. Only one, interferon alfa-2b (IFN-2b), has shown a significant benefit in terms of overall and relapse-free survival in multicenter randomized United States cooperative group and intergroup trials.^2,3 These facts suggest that we have much to do in both patient and physician education and in development of better therapies for melanoma.

Richtig et al⁴ report in this issue of the Journal of Clinical Oncology the closure of the European Cooperative Adjuvant Melanoma Treatment Study Group (ECAMTSG) placebo-controlled trial of isotretinoin and low-dose IFN compared with low-dose IFN in patients with resected stage IIA and IIB melanoma. Unfortunately, like many other recent trials of adjuvant therapy for melanoma, this trial was closed and reported early when an interim analysis demonstrated no significant likelihood of reaching the initial study goals (1.3%). With this negative experience, and a series of other negative trials recently reported in the literature or in abstracts, it is time to ask the question, How may progress be accelerated and the pitfalls of past trials avoided in future melanoma studies?

The potential answers to this complex question may be found in our increasing understanding of the requirements of adjuvant clinical trial design and our scientific understanding of tumor progression, along with an analysis of current effective therapies. Only one adjuvant therapy has stood the test of time: the high-dose IFN-2b regimen tested initially in the Eastern Cooperative Oncology Group E1684 trial and reassessed in the United States intergroup E1690 and E1694 trials reported in the Journal of Clinical Oncology in 1996, 2000, and 2001.^2,3,5 These trials have taught us many things, including the importance of prognostic factors for melanoma outcome and the necessity of concurrently randomized controlled trials for rigorous assessment of new interventions. They also point to the large time window between new trial initiation and the return of meaningful answers regarding disease-free and overall survival. The evolution of prognostic factors between trial cohorts, even when trial entry criteria have been relatively consistent in the United States cooperative groups, argues for standardization of major prognostic variables as far as is possible to optimize detection of differences related to experimental interventions. Trials conducted in the recent past have taught us that only robust trials that include sufficient numbers of patients to have the power to arrive at unequivocal conclusions are worthy of our patients' involvement. The design of clinical trials depends on the anticipated rate of relapse and mortality for the population to be treated: the lower the risk of the group selected, the larger the number of patients needed to answer the trial question. Events among patients with resected stage IIIB to IV disease exceed those for stage IIIA and those, in turn, exceed those for stage IIB and IIA. The numbers required for trials designed to detect clinically relevant differences for survival and progression-free interval increase from 600 to 800 for stage IIIB to IV to numbers that may exceed 1,400 for stage IIIA and stage IIA/B disease. The ECAMSTG study was thus underpowered to detect differences that would have been clinically of interest.

What ought to be sufficient scientific or clinical grounds for new adjuvant studies and what comparator regimen is appropriate for future adjuvant studies in intermediate- and high-risk melanoma? Phase III adjuvant clinical trials are long and highly resource-consumptive endeavors. The large drain of resources, time, and effort of patients and physicians alike prompts us to ask whether particular strategies are more likely to be rewarded in the quest for more effective adjuvant therapy. On the grounds that isotretinoin combined with IFN exerts antitumor effects on melanoma cell lines in vitro, the ECAMSTG initiated a phase III trial of isotretinoin and low doses of IFN-2a. This placebo-controlled study enrolled 407 patients from 20 centers over a period of 6 years and required 2 years of therapy to draw a negative conclusion. The history of clinical trials in melanoma suggests that little of relevance to the clinical biology, immunology, or treatment response of melanoma has been learned from cultured cell lines. It is time to dismiss studies of tumor cell lines as a sole basis for pursuit of clinical trials and to demand that new clinical trials be based on studies of the disease as it exists in the human patient, in vivo, or in tumor and other tissues sampled directly ex vivo. Some have argued that only clinical antitumor responses ought to be considered evidence sufficient to prompt new adjuvant trials, but we are entering an era when our understanding of this disease should permit the use of other evidence from the clinic and the laboratory. For example, the prolongation of time to progression or the modulation of immune responses could serve as impetus for new adjuvant trials. Few centers have the systems necessary for acquiring and banking tumor tissues on a regular basis to perform the corollary studies that might optimally guide these efforts. Recourse to fresh, high-quality tumor tissues banked and clinically annotated for modern molecular and immunologic research studies is limited to a few centers at this time, worldwide. Evaluation of the impact of potentially effective new therapies on in-tumor tissue in vivo or ex vivo using quantitative reverse transcriptase polymerase chain reaction and phenotypic/functional immunological assays (ELISPOT, tetramer flow cytometry, and intracellular cytokine staining) and microarray technology are likely to be the source of improved rates of progress.^6-8 Federal and private support of tumor tissue acquisition and proper banking for molecular and immunologic studies are critical to guide and accelerate future progress.

SCIENTIFIC BASIS FOR ADJUVANT THERAPY OF MELANOMA

A fundamental question that requires an answer is, What are the likely mechanisms of therapeutic benefit for agents that are active in melanoma? After years of study, following the precept that cytotoxic or cytostatic effects mediate the benefits of one pleiotropic agent, IFN, the preponderance of new evidence suggests that IFN, like interleukin 2 (IL-2; the only two agents approved for treatment of melanoma in modern times), achieves its therapeutic benefits through immunologic mechanisms. Although it remains to be proven, reasonable evidence suggests that the antitumor effects of IFN studied in advanced metastatic disease^9,10 and in conventional as well as neoadjuvant trials of our cooperative groups and the University of Pittsburgh Cancer Institute Melanoma Program (Pittsburgh, PA)^11,12 are related to immunomodulatory effects. These immunomodulatory effects are now being dissected in terms of the major components of the immunologic system in vivo and suggest a role of IFN in the polarization of dendritic cells¹³ and are correlated with the proportion of circulating blood and tumor-infiltrating CD4 and/or CD8 T-cell numbers.^9,10,14 Effects on antigen-presenting dendritic cells, helper CD4 T cells, and/or effector CD8 T cells suggest that the fulcrum of antitumor actions of IFN is immunologic—and likely to be derived from IFN induction of major histocompatibility and costimulatory molecule expression in melanoma cells that are critical to T-cell recognition and response, as well as immunoregulatory effects on natural killer cells, dendritic cells, and/or regulatory (suppressor) T cells and tumor that have yet to be fully explored.

As the immunologically subversive effects of tumor progression are better understood,^15,16 it is clear that the effects of therapy need to be analyzed in terms of the signaling pathways that contribute to tumor progression. The benefits of both IFN-2b and IL-2 have been correlated with induction of autoimmune responses such as vitiligo-like depigmentation, observed as a corollary of favorable disease more then 22 years ago by Nordlund et al and our group at Yale,¹⁷ and thyroiditis reported 17 years ago by Atkins et al from Beth Israel Deaconess Medical Center (Boston, MA)¹⁸ as a potential surrogate of the antitumor effects of IL-2. After years of searching for markers that may predict therapeutic benefit for these agents, derepression of autoimmunity has emerged as one of the most intriguing findings.¹⁹ The current evidence suggests that it is not cytotoxic and/or cytostatic effects in vitro against tumor cell lines that will add meaningfully to the therapy of melanoma, but the more focused application of the tools of modern immunology and a myriad of new and exciting agents capable of modulating dendritic, T-effector, and T-regulatory cells, in the context of trials against human melanoma.

STUDY DESIGN

Richtig et al⁴ evaluated the combination of isotretinoin and low-dose IFN-2a administered for 24 months TIW. Seven studies performed over the past 20 years, including the United Kingdom Adjuvant Interferon Melanoma-High Risk Trial (AIM-HIGH) reported in the past year, have shown no survival or durable relapse-free interval benefit of low-dose IFN.^5,20-25 As in the AIM-HIGH study of the United Kingdom, the absence of benefit on relapse-free or overall survival led to early termination of the ECAMSTG trial.²⁵ The AIM-HIGH study targeted 1,000 stage III patients to achieve 90% power to detect a 10% difference in relapse or overall survival. It ultimately enrolled 674 patients at futility analysis.²⁶ The ECAMSTG trial targeted stage IIA/B disease, in which relapse risk was lower than the stage III population of the AIM-HIGH study, but with a smaller sample size. With only 201 to 206 patients per trial arm, the power to detect differences that would have been deemed clinically valuable by patients and investigators is limited. The ECAMSTG study used a biased-coin randomization to balance for stage (IIA v IIB), age ( 50 v > 50 years), weight ( 73 v > 73 kg), and study center. The importance of assuring balance for the known important prognostic variables insofar as possible has already been remarked on. The criteria adopted in the American Joint Committee on Cancer sixth edition melanoma staging system incorporated both thickness and ulceration, but these were not used by the ECAMSTG. The most important prognostic factor for this group of patients is nodal status, assessed by sentinel lymph node biopsy (SLNB). SLNB was performed in only 158 of the 407 patients who entered this trial. In trials focused on stage IIA/B disease, it is essential to assure that risk factors are balanced between the trial arms, and the absence of this information in 249 of 407 subjects of the ECAMSTG study raises concern regarding potential imbalances in the assignment of patients with occult nodal disease. Sentinel lymph node status is the only reliable means of nodal assessment for patients with stage II melanoma and was therefore introduced as a requirement for pathologic staging of stage II melanoma in the American Joint Committee on Cancer sixth edition system published in 2000.^27-30 Where SLNB is not available, the factors that bear most significantly on prognosis of stage II patients are the ulceration and Breslow depth of the primary tumor. The ulceration status is not reported at all in this series, and Breslow depth was unavailable in 9% (37 patients). The absence of sentinel node status for 61% of the patients and primary lesion ulceration status for all patients in this small trial pose difficulties in the interpretation of the results.

CURRENT THERAPEUTIC OPTIONS

The current intergroup international trial for resected intermediate-risk stage IIA/B and stage IIIA resected melanoma (E1697) evaluates the efficacy of 1 month of intravenous high-dose induction IFN therapy, derived from the established 1-year E1684 regimen: this trial calls for 1,420 patients to detect a difference in relapse-free survival of 7.5% between the treatment arms. The current intergroup trial for patients with resected higher-risk stage IIIB gross nodal disease compares chemo-biotherapy with 1 year of high-dose IFN and calls for 420 patients (S0008). Finally, for patients with resectable recurrence after IFN, including stage IIIB and IV disease, the intergroup international trial E4697 tests the role of granulocyte-macrophage colony-stimulating factor and multiepitope peptide vaccination in 800 patients. These current trials offer new options for patients and encompass intermediate- and high-risk disease settings and should be prioritized by the oncologic community to answer these important questions.

THE FUTURE

Where should the field now be turning to develop more effective therapeutic approaches to melanoma? The discovery of molecular markers of melanoma progression, including mutations of BRAF in the mitogen-activated protein kinase pathway (BRAF V599E³¹), has been accompanied by the development of potent inhibitors of the mitogen-activated protein kinase pathway that are now being evaluated in the phase III intergroup setting for metastatic disease (E2603). Immunologically, our increasing understanding of the importance of dendritic cells for antigen presentation and immune response polarization and the effects of tumor burden on CD4 T-cell polarization^32,33 has been accompanied by the development of potent means to improve the intensity, durability, and polarization of immune responses to vaccines. These range from the use of peptide vaccines that are capable of stimulating helper CD4 cells and effector CD8 T cells, cytokines like granulocyte-macrophage colony-stimulating factor, IL-12, and IL-18 and represent promising new avenues for more specific immunologic intervention. The so-called Toll-like receptor agonist oligonucleotide immunostimulants CpGs are modern iterations of Coley's toxins, and heat shock proteins that chaperone antigenic signals of the tumor for more effective immunotherapy are already in large phase III trials. These approaches, developed in preclinical systems and currently being evaluated in large clinical trials, offer options for future consideration as adjuvant therapy of melanoma that may become relevant to us all in the near future.

Antibodies, which have achieved a significant role in the therapy of several other solid tumors over the past few years, also have considerable promise for the future in melanoma. There is a resurgence of studies on chimeric humanized antibodies to integrin receptors associated with progression and directed against gangliosides that are well-established targets for cytotoxic complement-mediated tumor lysis as well as antibody-dependent cellular cytotoxicity. Among the most interesting agents for therapy of melanoma to emerge from preclinical tumor immunology are the anti-CTLA4 antibodies, which recognize a T-cell antigen that leads to unbraking of the immune system and elicits autoimmune responses to tumors along with a range of normal tissues, with durable antitumor responses.^34,35 In addition, new agents that act through Toll-like receptors seem to promote autoimmunity as well as antitumor responses.³⁶

RESOLUTIONS

Given this rich and expanding array of new options for systematically improving the therapy of patients with metastatic melanoma, we should resolve to make the larger commitment to pursue only solid leads that have achieved success in human melanoma in vivo or achieved meaningful impact on relevant target end points in tissues studied ex vivo. When trials are undertaken, they should be adequately powered to detect differences in relapse-free and/or overall survival that are clinically meaningful—and that for intermediate-risk stage IIA/B and stage IIIA disease will generally reach 1,400 or more patients to detect incremental benefits on relapse-free survival in the range of 7% to 10%. Clinical corollary laboratory studies ought to accompany these trials wherever possible, to establish proof of concept and provide midcourse corrections for the trials, as well as illuminate prognostic and predictive markers with which we will be able to improve on our successes and more precisely understand our failures. Finally, we should not accept the ad hoc treatment of patients off protocol in 2005, but insist on clinical trials as the state of the art for melanoma, where no currently available agents or combinations have demonstrated significant results in terms of survival in advanced disease or ever been established as effective adjuvant therapies in properly conducted studies after the high-dose IFN-2b regimen.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

Acknowledgment

The University of Pittsburgh Cancer Institute receives industrial trial support from the Schering Plough Corporation, Kenilworth, NJ.

REFERENCES

1. Jemal A, Murray T, Ward E, et al: Cancer Statistics, 2005. CA Cancer J Clin 55: 10-30, 2005[Abstract/Free Full Text]

2. 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]

3. Kirkwood JM, Ibrahim J, 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]

4. Richtig E, Soyer HP, Posch M, et al: Prospective, randomized, multicenter, double-blind placebo-controlled trial comparing adjuvant interferon alfa and isotretinoin with interferon alfa alone in stage IIA and IIB melanoma: European Cooperative Adjuvant Melanoma Treatment Study Group. J Clin Oncol 23: 8655-8663, 2005[Abstract/Free Full Text]

5. 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]

6. Wang E, Miller L, Ohnmacht G, et al: Prospective molecular profiling of melanoma metastases suggests classifiers of immune responsiveness. Cancer Res 62: 3581-3586, 2002[Abstract/Free Full Text]

7. Kirkwood JM., Lee S, Land S, et al: E1696: Final analysis of the clinical and immunological results of a multi-center ECOG phase II trial of multi-epitope peptide vaccination for stage IV melanoma with MART-1 (27-35), gp100 (209-217, 210M), and tyrosinase (368-376, 370D) (MGT) +/–IFNa2b and GM-CSF. Proc Am Soc Clin Oncol 22: 710s, 2004 (abstr 7502)

8. Keilholz U, Weber J, Finke J, et al: Immunologic monitoring of cancer vaccine therapy: Results of a workshop sponsored by the Society for Biological Therapy. J Immunother 25: 97-138, 2002

9. Ernstoff MS, Gooding W, Nair S, et al: Immunological effects of treatment with sequential administration of recombinant interferon gamma and alpha in patients with metastatic renal cell carcinoma during a phase I trial. Cancer Res 52: 851-856, 1992[Abstract/Free Full Text]

10. Hakansson A, Gustafsson B, Krysander L, et al: Tumor-infiltrating lymphocytes in metastatic malignant melanoma and response to interferon alpha treatment. Br J Cancer 74: 670-676, 1996[Medline]

11. Kirkwood JM, Wilson J, Whiteside T, et al: Antitumor and immunomodulatory effects of intradermal picibanil (OK-432): Results of a phase IA trial and status of a phase IB trial in high-risk melanoma. Cancer Invest 10: 20-21, 1992 (suppl 1, abstr 19)

12. Moschos S, Edington H, Rao AR, et al: High dose interferon-alfa 2b (HDI): Toxicity, response, and predictive markers in a trial of neoadjuvant therapy for regional lymph node metastatic melanoma. Proc Am Soc Clin Oncol 23: 714S, 2005 (abstr 7517)

13. Mailliard RB, Wankowicz-Kalinska A, Cai Q, et al: A-type-1 polarized dendritic cells: A novel immunization tool with optimized CTL-inducing activity. Cancer Res 64: 5934-5937, 2004[Abstract/Free Full Text]

14. Clemente CG, Mihm MC Jr, Bufalino R, et al: Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77: 1303-1310, 1996[CrossRef][Medline]

15. Wang T, Niu G, Kortylewski M, et al: Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10: 48-54, 2004[CrossRef][Medline]

16. Gabrilovich D: Mechanisms and functional significance of tumor-induced dendritic-cell defects. Nat Rev Immunol 4: 941-952, 2004[CrossRef][Medline]

17. Nordlund JJ, Kirkwood JM, Forget BM: Vitiligo in patients with metastatic melanoma: A good prognostic sign. J Am Acad Dermatol 9: 689-696, 1983[Medline]

18. Atkins M, Mier JW, Parkinson DR, et al: Hypothyroidism after treatment with interleukin-2 and lymphokine-activated killer cells. N Engl J Med 318: 1557-1563, 1988[Abstract]

19. Tsoutsos D, Ioannovich J, Frangia K, et al: The prevalence and prognostic significance of autoantibodies detected in patients with high risk melanoma receiving adjuvant therapy with high-dose interferon. Proc Am Soc Clin Oncol 23: 714s, 2005 (abstr 7519)

20. Hancock BW, Wheatley K, Harris S, et al: Adjuvant interferon in high-risk melanoma: The AIM HIGH study-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]

21. Moschos SJ, Kirkwood JM, Konstantinopoulos PA: Present status and future prospects for adjuvant therapy of melanoma: Time to build upon the foundation of high-dose interferon alfa-2b. J Clin Oncol 22: 11-14, 2004[Free Full Text]

22. Cameron D, Cornbleet M: Adjuvant interferon alpha 2b in high-risk melanoma: The Scottish Study. Br J Cancer 84: 1146-1149, 2001[CrossRef][Medline]

23. Pehamberger H, Soyer P, 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]

24. Grob JJ, Dreno B, de la Salmonière P, et al: Randomised trial of interferon alfa-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]

25. 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]

26. Hancock BW, Wheatley K, Harrison G, et al: Aim high-adjuvant interferon in melanoma (high risk), a United Kingdom Co-Ordinating Committee on Cancer Res (UKCCR) 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)

27. Balch CM, Buzaid AC, Atkins MB, et al: A new American Joint Committee on Cancer staging system for cutaneous melanoma. Cancer 88: 1484-1491, 2000[CrossRef][Medline]

28. Morton DL: Lympathatic mapping and sentinel lymphadenectomy for melanoma: Past, present, and future. Ann Surg Oncol 8: 22S-28S, 2001 (suppl)

29. Balch CM, Soong S, 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]

30. Gershenwald JE, Thompson W, Mansfield PF, et al: Multi-institutional melanoma lymphatic mapping experience: The prognostic value of sentinel lymph bode status in 612 stage I or II melanoma patients. J Clin Oncol 17: 976-983, 1999[Abstract/Free Full Text]

31. Davies H, Bignell GR, Cox C, et al: Mutations of the BRAF gene in human cancer. Nature 417: 949-954, 2002[CrossRef][Medline]

32. Tatsumi T, Kierstead L, Ranieri E, et al: Disease-associated bias in T helper Type 1 (Th1)/Th2 CD4+ T cell responses against MAGE-6 in HLA-DRB1 0401+ patients with renal cell carcinoma or melanoma. J Exp Med 196: 619-628, 2002[Abstract/Free Full Text]

33. Tatsumi T, Kierstead L, Ranieri E, et al: MAGE-6 encodes HLA-DRB1 *0401-presented epitopes recognized by CD4+ T cells from patients with melanoma or renal cell carcinoma. Clin Cancer Res 9: 947-954, 2003[Abstract/Free Full Text]

34. Topalian SL, Rivoltini L, Mancini M, et al: Human CD4+ T cells specifically recognize a shared melanoma-associated antigen encoded by the tyrosinase gene. Proc Natl Acad Sci U S A 91: 9461-9465, 1994[Abstract/Free Full Text]

35. Sanderson K, Scotland R, Lee P, et al: Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and montanide ISA 51 for patients with resected stages III and IV Melanoma. J Clin Oncol 23: 741-750, 2005[Abstract/Free Full Text]

36. Lang KS, Recher M, Junt T, et al: Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease. Nat Med 11: 138-145, 2005[CrossRef][Medline]

Related Article

• Prospective, Randomized, Multicenter, Double-Blind Placebo-Controlled Trial Comparing Adjuvant Interferon Alfa and Isotretinoin With Interferon Alfa Alone in Stage IIA and IIB Melanoma: European Cooperative Adjuvant Melanoma Treatment Study Group
  Erika Richtig, H. Peter Soyer, Martin Posch, Ulrike Mossbacher, Peter Bauer, Ligia Teban, Gerhard Svolba, Ingrid H. Wolf, Peter Fritsch, Bernhard Zelger, Beatrix Volc-Platzer, Walter Gebhart, Paul Mischer, Andreas Steiner, Wolf Pachinger, Helmut Hintner, Friedrich Gschnait, Klemens Rappersberger, Peter Pilarski, and Hubert Pehamberger
  JCO 2005 23: 8655-8663 [Abstract] [Full Text]

This article has been cited by other articles:

				F. Grange, F. Vitry, F. Granel-Brocard, D. Lipsker, F. Aubin, G. Hedelin, S. Dalac, F. Truchetet, C. Michel, M.-L. Batard, et al. Variations in Management of Stage I to Stage III Cutaneous Melanoma: A Population-Based Study of Clinical Practices in France Arch Dermatol, May 1, 2008; 144(5): 629 - 636. [Abstract] [Full Text] [PDF]

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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kirkwood, J. M. Search for Related Content PubMed PubMed Citation Articles by Kirkwood, J. M. Related Articles Related Article