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Journal of Clinical Oncology, Vol 25, No 15 (May 20), 2007: pp. 2078-2085 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.1709 Randomized Trial of an Allogeneic Melanoma Lysate Vaccine With Low-Dose Interferon Alfa-2b Compared With High-Dose Interferon Alfa-2b for Resected Stage III Cutaneous Melanoma
From the University of California, San Diego, School of Medicine and Cancer Center, San Diego; University of California, San Francisco, School of Medicine and Cancer Center, San Francisco; University of California, Irvine Medical School and Cancer Center, Irvine, CA; Karmanos Cancer Institute; Karmanos Cancer Institute, Wayne State University, Detroit; Van Elslander Cancer Center, St John Medical Center, Grosse Pointe Woods, MI; University of Washington School of Medicine, Seattle, WA; Moffitt Cancer Center, University of South Florida, Tampa, FL; Yale Comprehensive Cancer Center, New Haven, CT; Beth Israel Medical Center, Harvard Medical School; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; The Melanoma Center of St. Louis, St Louis, MO; Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Hanover, NH; University of Illinois at Chicago, Chicago; Oncology Specialists, Park Ridge, IL; Huntsman Cancer Center, University of Utah, Salt Lake City, UT; Lone Star Oncology, Austin, TX; Maine Center for Cancer Medicine, Scarborough, ME; and the University of Minnesota, Minneapolis, MN Address reprint requests to Malcolm S. Mitchell, MD, University of Texas-El Paso, 500 University Ave, El Paso, TX 79968; e-mail: malcolmsmitchell{at}yahoo.com
Purpose To compare the overall survival (OS) of patients with resected stage III melanoma administered active specific immunotherapy and low-dose interferon alfa-2b (IFN-  -2b) with the OS achieved using high-dose IFN--2b.
Patients and Methods An Ad Hoc Melanoma Working Group of 25 investigators treated 604 patients from April 1997 to January 2003. Patients were stratified by sex and number of nodes and were randomly assigned to receive either 2 years of treatment with active specific immunotherapy with allogeneic melanoma lysates and low-dose IFN- Results Median follow-up time was 32 months for all patients and 42 months for surviving patients. Median OS time exceeds 84 months in arm 1 and is 83 months in arm 2 (P = .56). Five-year OS rate is 61% in arm 1 and 57% in arm 2. Estimated 5-year relapse-free survival (RFS) rate is 50% in arm 1 and 48% in arm 2, with median RFS times of 58 and 50 months, respectively. The incidence of serious adverse events as a result of treatment was the same in both arms, but more severe neuropsychiatric toxicity was seen in arm 2.
Conclusion OS and RFS achieved by active specific immunotherapy and low-dose IFN-
Patients with thin primary melanomas have a good prognosis for survival after resection. Once melanoma has metastasized to viscera, survival is approximately 7 months. After melanoma has reached regional lymph nodes, there is a 40% to 80% likelihood of distant recurrence and death depending on the number and extent of involvement of tumor-containing lymph nodes. The only US Food and Drug Administration–approved treatment for stage III melanoma is high-dose interferon alfa (IFN- ) based on the Eastern Cooperative Oncology Group (ECOG) 1684 and 1690 trials.1,2 Treatment with high-dose IFN--2b (Intron-A; Schering-Plough, Kenilworth, NJ) for 1 year elicited a 7-month improvement in relapse-free survival (RFS) that was sustained for at least 4 years. It is controversial whether there is an improvement in overall survival (OS) versus untreated controls,3,4 with only ECOG 1684 showing a significant difference. An alternative form of adjunctive (adjuvant) treatment for residual microscopic disease is active specific immunotherapy (vaccines). Melacine (active specific immunotherapy; Corixa-Montana, Hamilton, MT), a vaccine comprising lyophilized melanoma cell lysates and the adjuvant Detox PC (Corixa-Montana), was approved in Canada in 1999 for metastatic disease, where Corixa reported a median OS time for Melacine of 18 months versus an unexpected OS time of 15 months for chemotherapy.5 A Southwest Oncology Group study of resected intermediate-thickness stage II disease found that Melacine prolonged RFS and OS in patients expressing HLA-A2 or HLA-C3, confirming our findings in stage IV disease.6-8 In resected stage III disease, 44 patients administered Melacine for 48 weeks had long median RFS and OS times,9 supporting a larger controlled study.
A Melacine plus IFN-
Our goal in this multicenter, randomized controlled clinical trial was to compare OS elicited by 2 years of Melacine and low-dose IFN-
Materials Melacine is composed of lyophilized melanoma lysates from two melanoma cell lines and the complex adjuvant Detox. Cell lines were MSM-M-1, American Type Culture Collection (ATCC) CRL-9822 and MSM-M2, ATCC CRL-9823. MSM-M-1 was amelanotic, slow growing, and nearly tetraploid (modal chromosome number, 80 to 95) with 11q and 22 greatly amplified. It expressed HLA-A2, HLA-B12, HLA-B62, HLA-C3, HLA-DR4, DR10, DRw53, and DQ8. MSM-M-2 was highly pigmented, fast growing, and nearly diploid with a small percentage of hypodiploid cells (modal chromosome number, 45) and with trisomy at chromosome 7. It expressed HLA-A28, HLA-A31, HLA-B51, HLA-B60, HLA-C2, and HLA-C6, with serologically absent HLA-II. Lysates contained melanoma antigens gp100, GD2 and GD3, Melan-A/MART 1, MAGE-1-3, tyrosinase, TRP-1, TRP-2, HMW-MAA, and MG 50.12,13 Detox PC comprised 250 µg of mycobacterial cell wall skeletons from Mycobacterium phlei, 25 µg of Salmonella minnesota monophosphoryl lipid A, squalane, Tween-80 emulsifier, and phosphoryl choline; 0.25 mL/2 mL was admixed with lysates immediately before injection (see Treatment Protocol).
Study Plan
Eligibility.
Eligibility criteria included the following: histologically confirmed cutaneous melanoma, lymph node–positive, American Joint Committee on Cancer (AJCC; 1988) stage III disease, including positive lymph node(s) with an unknown primary melanoma (in transit metastases alone were insufficient); definitive resection of all macroscopic disease within the past 90 days; no evidence of disease by physical examination within 14 days of entry, computed tomography (CT) scans of chest and abdomen within 6 weeks, and magnetic resonance imaging of the brain within 6 weeks; Karnofsky performance status of
Ineligibility.
Exclusion criteria included the following: medical or psychological impediment to compliance; history of clinical depression; severe renal, hepatic, cardiac, or other visceral dysfunction (serum creatinine > 2 mg/100 mL, serum bilirubin > 2 mg/100 mL, AST > 3x normal, and myocardial infarction within 6 weeks); pregnancy or lactation; prior malignancy, except adequately treated basal cell or squamous cell skin carcinoma, in situ cervical cancer, or other cancer for which the patient had been disease free for 5 years; ocular or mucosal melanoma; previous treatment with a melanoma vaccine or IFN-
Statistical Methods
Melanoma patients were stratified by sex and number of nodes (one, two to four, or > four nodes) at a central location and were randomly assigned to receive either Melacine plus low-dose IFN-
Treatment Protocol
Arm 2.
Patients received IFN-
Dose Modification
Follow-Up Accrual was begun on April 10, 1997, and completed on January 21, 2003. An early analysis of toxicity and survival was performed after 20 patients had been entered to assess safety. Because life-threatening toxicity was not observed, 604 patients were treated. Statistical analyses were based on intent to treat, including all randomly assigned patients. Final analysis of the data was performed in September 2006.
Data Collection
Demographics and Study Parameters Six hundred four patients were enrolled at 25 sites (Appendix). Two patients were deemed ineligible by the clinical site, and two other patients were never randomly assigned. Thus, the cohort analyzed by intent to treat included 600 patients (Fig 1).
Median follow-up time was 32 months for all participants and 42 months for patients still alive. No follow-up information is available for nine eligible participants (four on arm 1 and five on arm 2); seven of the nine patients were never treated. Treatment arms were comparable with respect to sex, race, age, and histologic subtype (Tables 1 and 2). Two thirds of participants were male, nearly all were white, and the mean age at start of treatment was approximately 48 years. There was confirmatory histologic information and information about node size for 478 participants (80%); 15% of participants lacked information about nodes, 5% lacked information about histology, and less than 1% (two patients) lacked information on both. There was no difference between arms in the proportion of patients missing confirmatory histologic information (20 of 299 patients on arm 1, 7%; and 12 of 302 patients on arm 2, 4%; P = .14); all were presumed to have melanoma. There was also no difference between arms in the proportion of patients missing information about nodes (15% and 16% in arms 1 and 2, respectively). In arms 1 and 2, 53% and 56% of patients, respectively, had one positive lymph node; 27% and 26% of patients, respectively, had two to three nodes; and 18% and 16% of patients, respectively, had four or more nodes (P = .59, Kruskal-Wallis test).
Intent-to-Treat Analysis The intent-to-treat analysis included all 600 eligible participants who were randomly assigned to a treatment and had adequate follow-up information. Seventeen individuals were not included in the analysis of OS. Four patients each on arms 1 and 2 who were never treated lacked follow-up data. One individual in each arm who was treated also lacked follow-up information, whereas seven patients (one on arm 1 and six on arm 2) had invalid follow-up dates. These 17 individuals were censored at 0.5 months for the analysis of OS and RFS. One patient randomly assigned to arm 2 but never treated had an invalid date of relapse and was censored for RFS at 0.5 months. OS. Ninety-seven deaths occurred in arm 1, and 102 deaths occurred in arm 2. Five-year OS rates for arms 1 and 2 are 61% and 57%, respectively (Table 3). Median OS time has not been reached in arm 1 and is 83 months in arm 2 (95% CI, 60 months to not reached), with no significant difference between treatment arms (P = .57; Fig 2A). Both OS times are significantly higher than expectations from previous historical data.18,19
RFS. In arms 1 and 2, 131 and 134 patients experienced treatment failure in arm 1, 34 and 32 patients experienced relapse without death, and 97 and 102 patients died, respectively. Median RFS time was 58 months for arm 1 and 50 months for arm 2 (P = .61). Five-year RFS rate is 50% in arm 1 and 48% in arm 2 (P = .80; Fig 2B). Multivariable proportional hazards analyses, with adjustment for possible differences between arms in demographic and disease characteristics, yielded the same conclusions.
Per-Protocol Analysis There is no significant difference in either OS (P = .91) or RFS (P = .91; Fig 2C). Median OS time has not been reached in arm 1 and is 84 months in arm 2. The corresponding median RFS times are estimated at 66 months in both arms (Fig 2D).
Analysis by Lymph Node Palpability
By proportional hazards analysis, we found no evidence that the effectiveness of either treatment differs between patients with microscopic and palpable lymph nodes (P = .68). There is no difference in OS between treatment arms among patients with microscopic nodes (P = .98) or palpable nodes (P = .56), and there is also no difference in RFS between these two groups (P = .71 and P = .48, respectively).
Toxicity
Neuropsychiatric problems were more severe in arm 2, with suicide attempt in one patient, delusions and/or suicidal ideation in six patients, severe confusion in two patients, and severe mental status changes in three patients, including one patient each with a psychotic break and profound short-term memory loss. Expressive dysphasia was also noted in one patient. In arm 1, one patient committed suicide, but the patient had had antecedent depression and a recent divorce, and a recurrence of melanoma was suspected. Depression and impotency and a seizure episode were also noted in one patient each.
This multicenter clinical trial comparing Melacine and low-dose IFN- -2b with standard high-dose IFN--2b found no significant differences in RFS or OS, although the number of patients was insufficient to demonstrate either equivalency or small differences. To our knowledge, this represents the first time a randomized large-scale trial of a vaccine regimen has demonstrated such activity. The only other direct comparison of a vaccine (alone) with IFN- found that the vaccine—ganglioside GM2 conjugated to hemocyanin + QS21 adjuvant—produced significantly shorter survival times.20 Here, both arms achieved survival times far exceeding those reported for stage III melanoma, such as in ECOG 1684.1,19 Historically, the RFS time is 18 to 24 months, and the OS time is 36 to 42 months,18,19 although longer survival times were reported in ECOG 1690.2 Approximately 70% of our patients were still alive at those times. Comparison of patients treated with vaccinia virus–modified allogeneic melanoma vaccine with untreated controls in 700 patients also showed extended survival in both groups, causing statistically insignificant differences. OS time was 151 months in the vaccine-treated arm and 88 months in the control arm (95% CI, 0.64 to 1.02; P = .068)21. This CI, which barely reached unity, did not rule out important gains from treatment. Significantly, two thirds of patients had palpable nodes. In our study, the prolonged survivals were probably principally a result of the high proportion of patients with microscopically positive lymph nodes who were admitted as sentinel node mapping became common. We used AJCC 1988 staging criteria because new criteria were not yet approved. The 2002 AJCC staging system, applied prospectively to other patients,22 yielded a 5-year OS rate in stage III patients ranging from 70% (stage IIIA) to 24% (stage IIIC). Our OS rates of 61% and 57% in arms 1 and 2, respectively, are consistent with skewing towards stage IIIA. Twelve percent fewer patients with palpable nodes lived for 5 years compared with patients with microscopic nodes, regardless of treatment. We defined relapse as local, nodal, or visceral recurrence. Because the site of relapse was not always recorded, it is possible that fewer visceral recurrences also explains the longevity.
Without untreated controls, we could not determine whether either treatment improved OS, but our decision to omit controls still seems appropriate ethically and scientifically given the then-recent results of ECOG 1684 and the logistical impossibility of performing a three-arm study. Thus, we cannot distinguish between the antipodal possibilities that the arms were equally effective or ineffective. Nevertheless, if arm 1 was effective, low-dose IFN-
The incidence of neuropsychiatric SAEs was similar in each arm, but neuropsychiatric SAEs were of higher intensity in arm 2. Patients in arm 2 had more severe events, including suicidal ideation and suicide attempts, forcing withdrawal from study in nine instances. Such problems have been reported with IFN- HLA typing was optional because only a few centers could perform it routinely. Thus, although we recognized the association of certain HLA-I phenotypes and response to Melacine in advanced and stage II melanoma,7-11 information was insufficient for stratification or correlation.
We hypothesized that Melacine plus low-dose IFN-
Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Mohammed Kashani-Sabet, Schering-Plough; Michael B. Atkins, Schering-Plough; Marc S. Ernstoff, Schering-Plough; Frank G. Haluska, Schering-Plough Stock: N/A Honoraria: Mohammed Kashani-Sabet, Schering-Plough; Eric Whitman, Schering-Plough; Marc S. Ernstoff, Schering-Plough Research Funds: Malcolm S. Mitchell, Schering-Plough; Judith Abrams, Schering-Plough; John A. Thompson, Schering-Plough; Eric Whitman, Schering-Plough; Marc S. Ernstoff, Schering-Plough; Frederick R. Aronson, Schering-Plough Testimony: Frank G. Haluska, Schering-Plough Other: N/A
Conception and design: Malcolm S. Mitchell, John A. Thompson, Mohammed Kashani-Sabet, Ronald C. DeConti, Wen-Jen Hwu, Eric Whitman, Marc S. Ernstoff, Frank G. Haluska, James G. Jakowatz, Tapas K. Das Gupta, Wolfram E. Samlowski, Frederick R. Aronson Administrative support: Malcolm S. Mitchell Provision of study materials or patients: Malcolm S. Mitchell, Judith Abrams, John A. Thompson, Mohammed Kashani-Sabet, Ronald C. DeConti, Wen-Jen Hwu, Michael B. Atkins, Eric Whitman, Marc S. Ernstoff, Frank G. Haluska, James G. Jakowatz, Tapas K. Das Gupta, Jon M. Richards, Wolfram E. Samlowski, John J. Costanzi, Frederick R. Aronson, Albert B. Deisseroth, Arkadiusz Z. Dudek, Vicky E. Jones Collection and assembly of data: Malcolm S. Mitchell, Judith Abrams, John A. Thompson, Mohammed Kashani-Sabet, Ronald C. DeConti, Wen-Jen Hwu, Michael B. Atkins, Eric Whitman, Marc S. Emstoff, Frank G. Haluska, James G. Jakowatz, Tapas K. Das Gupta, Jon M. Richards, Wolfram E. Samlowski, John J. Costanzi, Frederick R. Aronson, Albert B. Deisseroth, Arkadiusz Z. Dudek, Vicky E. Jones Data analysis and interpretation: Malcolm S. Mitchell, Judith Abrams, John A. Thompson, Michael B. Atkins, Marc S. Ernstoff, Wolfram E. Samlowski, Frederick R. Aronson, Arkadiusz Z. Dudek Manuscript writing: Malcolm S. Mitchell, Judith Abrams, John A. Thompson, Mohammed Kashani-Sabet, Ronald C. DeConti, Wen-Jen Hwu, Michael B. Atkins, Eric Whitman, Marc S. Ernstoff, Frank G. Haluska, James G. Jakowatz, Jon M. Richards, Wolfram E. Samlowski, Frederick R. Aronson, Arkadiusz Z. Dudek Final approval of manuscript: Malcolm S. Mitchell, Judith Abrams, John A. Thompson, Mohammed Kashani-Sabet, Ronald C. DeConti, Wen-Jen Hwu, Michael B. Atkins, Eric Whitman, Marc S. Ernstoff, Frank G. Haluska, James G. Jakowatz, Tapas K. Das Gupta, Jon M. Richards, Wolfram E. Samlowski, John J. Costanzi, Frederick R. Aronson, Albert B. Deisseroth, Arkadiusz Z. Dudek, Vicky E. Jones
Other participants who contributed patients to this study were P. Savage, MD, T. Cosgriff, MD, B. Rosenbloom, MD, R. Hart, MD, G. Militello, MD, K. Charney, MD, T. Dobbs, MD, J. Atkins, MD, and S. Del Prete, MD.
Supported by Integrated Therapeutics, Schering-Plough. An interim analysis was presented at the 36th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. 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] 2. 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 3. 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 4. 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 randomised trials. Cancer Treat Rev 29: 241-252, 2003[CrossRef][Medline] 5. Von Eschen KB, Mitchell MS: Phase III trial of Melacine melanoma theraccine versus combination chemotherapy in the treatment of stage IV melanoma. Melanoma Res 1: S51, 1997 (suppl 1) 6. Sosman JA, Sondak VK: Melacine: An allogeneic melanoma tumor cell lysate vaccine. Expert Rev Vaccines 2: 353-368, 2003[CrossRef][Medline] 7. Sosman JA, Unger JM, Liu PY, et al: Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: Impact of HLA class I antigen expression on outcome. J Clin Oncol 20: 2067-2075, 2002 8. Mitchell MS, Harel W, Groshen S: Association of HLA phenotype with response to active specific immunotherapy of melanoma. J Clin Oncol 10: 1158-1164, 1992[Abstract] 9. Mitchell MS: Allogeneic melanoma vaccines, in Morse MA, Clay TM, Lyerly HK (eds): Handbook of Tumor Immunology. Totowa, NJ, Humana, 2003, pp 397-414 10. Mitchell MS, Jakowatz J, Harel W, et al: Increased effectiveness of interferon alfa-2b following active specific immunotherapy for melanoma. J Clin Oncol 12: 402-411, 1994[Abstract] 11. Vaishampayan U, Abrams J, Darrah D, et al: Active immunotherapy of metastatic melanoma with allogeneic melanoma lysates and interferon alpha. Clin Cancer Res 8: 3696-3701, 2002 12. Mitchell MS, Harel W, Kan-Mitchell J, et al: Active specific immunotherapy of melanoma with allogeneic cell lysates: Rationale, results, and possible mechanisms of action. Ann N Y Acad Sci 690: 153-166, 1993[Medline] 13. Mitchell MS, Kan-Mitchell J, Minev B, et al: A novel melanoma gene (MG50) encoding the interleukin 1 receptor antagonist and six epitopes recognized by human cytolytic T lymphocytes. Cancer Res 60: 6448-6456, 2000 14. Schoenfeld D: Partial residuals for the proportional hazards regression model. Biometrika 69: 239-241, 1982 15. Mitchell MS, Darrah D, Stevenson L: Therapy of melanoma with allogeneic melanoma lysates alone or with interferon-alfa. Cancer Invest 20: 759-768, 2002[CrossRef][Medline] 16. Dean GE, Spears L, Ferrell BR, et al: Fatigue in patients with cancer receiving interferon alpha. Cancer Pract 3: 164-172, 1995[Medline] 17. Sondak VK, Liu PY, Tuthill RJ, et al: Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: Overall results of a randomized trial of the Southwest Oncology Group. J Clin Oncol 20: 2058-2066, 2002 18. Hersey P: Evaluation of vaccinia viral lysates as therapeutic vaccines in the treatment of melanoma. Ann N Y Acad Sci 690: 167-177, 1993[CrossRef][Medline] 19. Verma S, Quirt I, McCready D, et al: Systematic review of systemic adjuvant therapy for patients at high risk for recurrent melanoma. Cancer 106: 1431-1442, 2006[CrossRef][Medline] 20. 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 21. 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: 4181-4190, 2002 22. Ben-Porat L, Panageas KS, Hanlon C, et al: Estimates of stage-specific survival are altered by changes in the 2002 American Joint Committee on Cancer staging system for melanoma. Cancer 106: 163-171, 2006[CrossRef][Medline] 23. Eggermont AM, Punt CJ: Does adjuvant systemic therapy with interferon-alpha for stage II-III melanoma prolong survival? Am J Clin Dermatol 4: 531-536, 2003[CrossRef][Medline] 24. Ascierto PA, Scala S, Ottaiano A, et al: Adjuvant treatment of malignant melanoma: Where are we? Crit Rev Oncol Hematol 57: 45-52, 2006[Medline] 25. Valentine AD, Meyers CA: Neurobehavioral effects of interferon therapy. Curr Psychiatry Rep 7: 391-395, 2005[Medline] 26. Raber J, Sorg O, Horn TF, et al: Inflammatory cytokines: Putative regulators of neuronal and neuro-endocrine function. Brain Res Brain Res Rev 26: 320-326, 1998[CrossRef][Medline] 27. Hanisch UK, Neuhaus J, Quirion R, et al: Neurotoxicity induced by interleukin-2: Involvement of infiltrating immune cells. Synapse 24: 104-114, 1996[CrossRef][Medline] 28. Caraceni A, Gangeri L, Martini C, et al: Neurotoxicity of interferon-alpha in melanoma therapy: Results from a randomized controlled trial. Cancer 83: 482-489, 1998[CrossRef][Medline] Submitted November 30, 2006; accepted February 20, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
70%; age 
2 tests compared treatment arms with respect to categoric prognostic variables, and t tests compared treatment arms with respect to continuous prognostic variables. Data were examined for missing data patterns and anomalous values. Log-rank tests assessed OS and RFS between arms, whereas Cox proportional hazards models analyzed simultaneous effects of treatment and demographic or disease characteristics. Proportional hazards assumptions were verified graphically and analytically with Schoenfeld's test.
grade 1. The dose was then reduced to half the previous level. Failure to tolerate a level of 2.5 MU/m2 required discontinuation of IFN-
