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Originally published as JCO Early Release 10.1200/JCO.2004.03.185 on December 9 2003 © 2004 American Society of Clinical Oncology. 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 MelanomaFrom the Yorkshire Cancer Research Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield; Clinical Trials Unit, University of Birmingham, and Skin Oncology Service, Selly Oak Hospital, Birmingham; Clinical Trial Service Unit and Epidemiological Studies Unit, Radcliffe Infirmary, Oxford; Christie Hospital, Withington, Manchester; Salisbury District Hospital, Salisbury, Wiltshire; and Royal Marsden Hospital, Sutton, Surrey, United Kingdom. Address reprint requests to Professor B W Hancock, Academic Unit of Clinical Oncology, The University of Sheffield, Weston Park Hospital, Whitham Rd, Sheffield S10 2SJ, United Kingdom; e-mail: b.w.hancock{at}sheffield.ac.uk
PURPOSE: To evaluate low-dose extended duration interferon alfa-2a as adjuvant therapy in patients with thick (  4 mm) primary cutaneous melanoma and/or locoregional metastases. PATIENTS AND METHODS: In this randomized controlled trial involving 674 patients, the effect of interferon alfa-2a (3 megaunits three times per week for 2 years or until recurrence) on overall survival (OS) and recurrence-free survival (RFS) was compared with that of no further treatment in radically resected stage IIB and stage III cutaneous malignant melanoma. RESULTS: The OS and RFS rates at 5 years were 44% (SE, 2.6) and 32% (SE, 2.1), respectively. There was no significant difference in OS or RFS between the interferon-treated and control arms (odds ratio [OR], 0.94; 95% CI, 0.75 to 1.18; P = .6; and OR, 0.91; 95% CI, 0.75 to 1.10; P = .3; respectively). Male sex (P = .003) and regional lymph node involvement (P = .0009), but not age (P = .7), were statistically significant adverse features for OS. Subgroup analysis by disease stage, age, and sex did not show any clear differences between interferon-treated and control groups in either OS or RFS. Interferon-related toxicities were modest: grade 3 (and in only one case, grade 4) fatigue or mood disturbance was seen in 7% and 4% respectively, of patients. However, there were 50 withdrawals (15%) from interferon treatment due to toxicity. CONCLUSION: The results from this study, taken in isolation, do not indicate that extended-duration low-dose interferon is significantly better than observation alone in the initial treatment of completely resected high-risk malignant melanoma.
Although malignant melanoma is relatively uncommon, its incidence and mortality continue to increase. In patients with very thick primary tumors ( 4 mm Breslow thickness) or who have satellite, in-transit, or regional nodal metastases resected, the 5-year survival rate following radical surgery can be as low as 40% [1]. However, because the progression of malignant melanoma is relatively well understood, if an effective adjuvant treatment could be identified, it should be possible to select those patients most likely to benefit. In several earlier studies [2] of adjuvant chemotherapy and biologic therapy, no statistically significant improvements in overall survival (OS) or disease-free survival (DFS) rates were achieved. However, phase I and II studies in metastatic disease have demonstrated a response rate of approximately 15% with interferon alfa [2]. At the time of planning of the Adjuvant Interferon in Melanoma-High Risk (AIM HIGH) study, there were some early reports of randomized studies using adjuvant interferon alfa for high-risk disease. The Eastern Cooperative Oncology Group (ECOG), using high-dose interferon compared with observation alone, reported (on preliminary analysis) a prolongation of DFS, but, at that stage, no corresponding improvement in OS. Toxicity was, however, a serious problem, with 66% of patients suffering grade 3 or higher toxicity [3]. The WHO also presented preliminary data on 426 assessable patients (444 entered) treated with 3 megaunits three times weekly for 3 years, versus surgery alone [4]. A significant benefit for females younger than 51 years and males older than 50 years, in terms of both DFS and OS, was claimed. The Scottish Melanoma Group adjuvant study of 6 months of low-dose interferon versus no further therapy closed after recruiting only 96 assessable patients and reported no significant difference between the two arms, though the numbers involved were small (M.C. Cornbleet, personal communication, 1995). The European Organization for Research and Treatment of Cancer (EORTC) was currently conducting a four-arm, 12-month therapy study of very low-dose interferon alfa, versus interferon gamma, versus nothing, versus Iscador (Hiscia Laboratories, Arlesheim, Switzerland) after surgery in high-risk primary or lymph node metastatic disease. An interim analysis had not indicated an inferior arm [5]. There was clearly a need for an additional large randomized controlled trial. It was felt that, as yet, there were no compelling data available to recommend the high doses of interferon and that the potential role of therapy with low-dose Interferon remained of considerable interest. We therefore set up this study of low-dose extended duration interferon alfa as adjuvant therapy in patients with completely resected high-risk melanoma. Interferon therapy was to be given until disease recurrence or for 2 years (whichever occurred first).
Study Objectives The primary objective of the study was to determine the effects of interferon alfa-2a on OS and recurrence-free survival (RFS) in patients with malignant melanoma at high risk of recurrence. Secondary objectives were: (1) to test the claim that there is an interaction between the effect of interferon therapy, age, and sex on RFS and OS; (2) to document the side effects associated with prolonged administration of interferon subcutaneously 3 times per week; and (3) to evaluate the economic implications of implementing interferon therapy in this group of patients should it prove clinically effective.
Eligibility
Clinical Assessments
Random Assignment
Statistical Considerations On the advice of the data monitoring committee, the study was terminated after 674 patients had been recruited during 5 years, as it was felt that extending the period of recruitment to enroll more patients was statistically unlikely to change the preliminary analysis, or the contribution of this trial to a future meta-analysis.
Statistical Methods
Recruitment Between October 3, 1995, and December 22, 2000, 674 patients with completely resected high-risk melanoma were enrolled onto the study; 338 patients were allocated to receive interferon alfa-2a and 336 were allocated to observation alone (no further treatment). The arms of the study were well balanced for sex, age, and disease status on entry (Table 1). The median duration of follow-up in 367 survivors, as of July 31, 2002, was 3.1 years (range, 0 to 6.8 years). Two patients dropped out of the trial immediately and had no further follow-up. In all, 18 patients in the interferon-treated arm and 23 patients in the control arm were lost to follow-up.
RFS and OS Four hundred twenty-six patients (63%) suffered disease recurrence (211 interferon-treated v 215 control), and 307 patients (46%) died (151 interferon-treated v 156 control). The Kaplan-Meier estimates of OS and RFS at 5 years for all patients were 44% (SE, 2.6) and 32% (SE, 2.1), respectively. There was no significant difference in OS or RFS between the interferon-treated and control arms (OS: odds ratio [OR], 0.94; 95% CI, 0.75 to 1.18; P = .6; and RFS: OR, 0.91; 95% CI, 0.75 to 1.10; P = .3; Figs. 1 and 2).
Being male (OR, 1.40; 95% CI, 1.12 to 1.75; P = .003) and regional lymph node involvement (test for heterogeneity, P = .0009) were statistically significant adverse features for OS, though age was not (P = .7; Figs. 3, 4, and 5). An analysis comparing patients whose disease status was regionally metastatic at diagnosis or recurrence, with those patients with localized metastatic or localized disease, found that there was a 39% reduction in the risk of death if patients presented with localized metastasis or localized disease (OR, 0.61; 95% CI, 0.48 to 0.78; P < .0001).
Analysis by Subgroup Subgroup analysis for age, sex, and disease stage did not show any conclusive evidence of a difference between the interferon-treated and control groups in either RFS or OS (Figs 6 and 7). In patients younger than 50 years, RFS was significantly better with interferon, with a 30% reduction in the risk of disease recurrence (P = .02), and some evidence of heterogeneity between age groups (P = .03). However, there was no significant benefit for interferon in this age group on OS (P = .10). There was no evidence of heterogeneity of treatment effect between any other subgroups for either RFS or OS.
Toxicity Grade 3 toxicity was seen in 15% of interferon-treated patients (compared with 4% in the observation arm; Table 2). Grade 4 toxicity was seen in five interferon-treated patients (in four cases, hepatic) and in one patient on observation. Only for fatigue was grade 3 or 4 toxicity significantly greater in the interferon-treated group as compared with observed patients (P < .005). One patient in the interferon group reported grade 4 mood toxicity and withdrew because of it. Three patients reported "local" toxicity while on observation. There were no treatment-related deaths.
In total, there were 50 withdrawals (14.8%) from interferon therapy due to toxicity, at a mean of 6.9 months (range, 1 to 21 months). Twenty-four other patients stopped therapy for reasons other than toxicity, recurrence, or death from unrelated causes. Dose reductions for toxicity were recorded for 21 patients (five of whom subsequently withdrew from therapy); 15 patients (three of whom subsequently withdrew) had breaks in therapy due to toxicity. Deterioration in Karnofsky performance status, from presentation to any time during follow-up (Table 3), was significantly greater in interferon-treated compared with observed patients. However, a drop of more than 20 points was seen in only 4% of treated patients (compared with < 2% in the observation arm).
While AIM HIGH was recruiting, several randomly assigned controlled trials of interferon alfa versus controls were reported. In the North Central Cancer Treatment Group study 83-7052, the group randomly assigned 262 patients to either 20 megaunits/m2 three times weekly for 3 months, or observation. They reported no significant difference in DFS or OS [7]. The ECOG EST1684 trial recruited 287 patients who were node-positive or who had a lesion of 4 mm or larger, and who were randomly assigned to either observation or a high-dose interferon alfa regimen (20 megaunits/m2 intravenously daily, for 5 days of 7 for 4 weeks, followed by 10 megaunits/m2 subcutaneously three times per week for 48 weeks). Initially, DFS was significantly better with interferon, as was OS, with a median survival of 3.8 years in the interferon group and 2.8 years in the control group [8], but with longer follow-up, the OS benefit is no longer significant [9]. It was confirmed that this regimen was associated with manageable but significant side effects; two-thirds of patients experienced grade 3 or 4 toxicity [8]. In 1998, two further studies were published. In an Austrian study, 311 patients with resected primary stage II cutaneous melanoma were randomized to either an induction phase of 3 megaunits daily for 3 weeks, followed by 3 megaunits 3 times weekly for 1 year, or observation. This study showed a significant DFS advantage for interferon alfa (72% v 64% at 3 years) [10]. In a French trial, 499 patients with stage II disease were randomized to either 3 megaunits three times weekly for 18 months, or observation. There was a DFS advantage with interferon, and only 10% of patients experienced grade 3 or 4 adverse events [11]. The results from the United States Intergroup trial (E1690/S9111/C9190), evaluating high-dose versus low-dose interferon alfa-2b versus observation, demonstrated an RFS benefit with high-dose interferon as compared with observation [12]. However, there was no OS benefit for either high-dose or low-dose interferon. The EORTC 18871 study involving 830 patients compared 1 megaunit of interferon alfa on alternate days for 1 year with interferon gamma, Iscador, or observation in patients with thick primary tumors or with nodal involvement. At 6 years, the DFS rate was 34% and the OS rate was 42%, and there was no significant difference according to treatment group [13]. These data are, however, immature and should therefore be interpreted with caution. At the American Society of Clinical Oncology meeting of 2001, the preliminary results of EORTC 18952 were reported, comparing two intermediate-dose schedules of interferon alfa (10 megaunits subcutaneously 5 days per week for 4 weeks, followed by either 10 megaunits three times per week for 1 year or 5 megaunits three times per week for 2 years) with observation only in stage IIB or III disease. One year's treatment with high- or intermediate-dose interferon demonstrated no significant effect on the distant metastasis–free interval, whereas longer treatment (2 years) with the intermediate dose of 5 megaunits produced an apparently significant effect [13]. These data are, however, immature and should therefore be interpreted with caution. Also in 2001, the long-term follow-up results of the WHO and Scottish Melanoma Group studies were published. In the WHO 16 study, comparing interferon alfa at 3 megaunits three times weekly for 3 years with surgery alone, the 5-year analysis did not confirm the preliminary reports of significant improvements in DFS, with differences between age and sex subsets. At 5 years, DFS was 28%, and OS was approximately 36% for both interferon-treated and surgery-alone patients [14]. The Scottish Melanoma Study Group recruited 96 patients with both stage IIA and III disease, and randomly assigned them to either low-dose interferon (3 megaunits three times weekly) for 6 months, or observation. At 6 months, there was a DFS benefit, but this was lost at 2 years. There was no significant effect on OS [15]. It was against this background that the preliminary analysis of AIM HIGH was reported [16]. At 4 years, there was no significant difference in OS or RFS between the interferon-treated and control arms. The present updated analysis (at 5 years) confirms this. The acknowledged adverse presenting features of regional lymph node involvement and male patients were again evident; however, age was not a significant factor. The subgroup analysis for age and sex showed no significant heterogeneity between the treatment arms; and this does not confirm the initial WHO report [4], though it is consistent with the latest update [14]. In the earlier WHO report, it was suggested that there was survival benefit with interferon for younger females and older males [4]. Paradoxically, we have actually observed a significant survival benefit (P = .04) in young males. It is, however, probable that such findings are likely to be false-positives, owing to inappropriate subgroup analysis, as since there are multiple end points (24 total) being tested, at least one end point is likely to be statistically significant just by chance. This demonstrates the dangers of subgroup analysis, and therefore, as with all such analyses, these findings should be interpreted with caution, and need confirmation in other studies. Thus, there are now 11 randomized controlled trials in which adjuvant interferon has been compared with no treatment. In AIM HIGH, consistent with most previous studies, there is a suggestion of an initial benefit in RFS, but the curves become superimposed during the third and fourth years of follow-up. However, no trial taken in isolation has shown a persistent significant OS advantage, with the latest update in ECOG EST1684 [9] no longer showing a significant benefit for interferon. However, with the initial positive results from ECOG EST 1684 [8], and influenced by circumstantial evidence, with short follow-up, from the United States Intergroup E1694/F9512/C509801 trial showing high-dose interferon to have a significant survival benefit compared with the GM2-KLH/KS-21 vaccine [17], and pooled analysis data from ECOG or United States Intergroup trials of high-dose interferon alfa-2b in 1,916 patients with high-risk resected cutaneous melanoma [18], high-dose interferon has become the standard of care within the United States. However, the French and Austrian trials showing DFS advantage to low-dose interferon [10,11] have meant that this treatment has been licensed in Europe for thick primary melanomas, and there is less enthusiasm for high-dose interferon, though it is licensed in the United Kingdom for this indication. Such variations may be put down to differences in treatment regimens (interferon dose/duration), chance effects or heterogeneity of tumor behavior. This important factor is recognized in the new American Joint Committee on Cancer melanoma staging system, which demonstrates that the spectrum of survival is wide, particularly for nodal (stage III) disease (depending on the number of metastatic nodes, micro- versus macrometastases, and primary melanoma ulceration) [1]. Such data take into account evolving methods of staging, and in particular, sentinal node biopsy, which was not often employed in many of the earlier studies, including AIM HIGH. A recent systematic review of published randomized controlled trials concluded that there was no clear advantage to interferon therapy [19]. However, a quantitative method to assess treatment effects, which is more informative than qualitative narrative reviews, is meta-analysis. A meta-analysis of randomized trials comparing interferon alfa with control has been performed [20]. A statistically significant benefit from adjuvant interferon alfa was demonstrated for DFS, but the advantage was less obvious for OS. There was no clear evidence that the dose level of interferon affected either end point. Thus at the current time, decisions to use interferon could be based on the perceived relative merits of disease control, quality of life, and financial cost. Quality-of-life data from ECOG EST1684, based on earlier analysis when there was a survival benefit to high-dose interferon, suggest that while toxic effects are severe, clinical benefits of treatment (if these are indeed real) can offset the toxic effects [21]. Health economic assessments indicate that the treatment is as cost-effective as other accepted cancer interventions [22,23], but again, are selectively based on the most positive trial result. The toxicity of low-dose interferon is modest in all reported studies. The data from AIM HIGH confirms this, though 1 in 6 patients on interferon stopped treatment due to toxicity. A preliminary cost benefit analysis in this study showed that despite the high costs of therapy, there are some cost offsets associated with treatment, and that any adverse impact on health-related quality of life appears small [24]. However, there is no evidence of clinical benefit from this study when taken in isolation. The debate on adjuvant interferon in high-risk melanoma continues [2,25-30]. After many years of clinical research, there is good evidence that interferon improves RFS [20], but clear evidence of a survival benefit or of an effect of dose remains lacking, and questions remain as to whether efficacy is sufficient to justify routine use. Both commissioners of care and patients should therefore be given the facts so that they can make an informed decision.
This appendix lists centers and clinicians participating in the study: Manchester (N Thatcher, J Radford); Sheffield (PC Lorigan, BW Hancock); Royal Marsden (M Gore, AW Hutcheon); Birmingham (J Marsden); Salisbury (L Burrows); Southend (A Lamont); Clatterbridge (E Marshall, A Slater, S White, A Jones); Edinburgh (JF Smythe); Addenbrooke's (P Corrie); Aberdeen (M Nicholson, M Hutcheon); Bristol (CGA Price, EC Whipp); Newcastle/South Cleveland (W Taylor, AN Branson); Nottingham (J Carmichael, PJ Woll, DW Fyfe); Cardiff (M Mason); Royal Free (A Jones, S Whittaker); Hull (A Maraveyas), Bournemouth/Poole (T Hamblin, RP Crellin, R Osborne); Bath (ED Gilby); Swansea (D Roberts, KHM Rowley); Leeds (P Selby, PWM Johnston); Leicester (I Peat, K O'Byrne); The Middlesex (MF Spittle, TG Eisen); Exeter/Torbay (A Goodman, A Hong); Kent (RS Colthart,); Guy's (P Harper); Derby (D Otim-Oyet); Plymouth (S Kelly); North Middlesex (TG Eisen); Kings Lynn (J Anderson); Frenchay (P Townsend); Airdale (SM Crawford); Preston (AJ Howcroft); Rhyl/Glan Clwyd (ABW Nethersell); Oxford (B Lavery); Bangor (NS Stuart).
The authors indicated no potential conflicts of interest.
The study was supported by a grant from Roche Products Ltd, who also provided the interferon alfa-2a (Roferon A) for the first 3 years of the study. Lesley Turner and Rachel Hambly assisted with data coordination. We gratefully acknowledge the contribution of the many investigators and patients participating in this trial.
Preliminary results of this study were presented at the annual meeting of the American Society of Clinical Oncology, 2001. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Balch CM, Soong SJ, Gershwald 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 2. Moliffe R, Hancock BW: Adjuvant therapy of malignant melanoma. Crit Rev Oncol Haematol 44:81-102, 2002[Medline]
3. Kirkwood J, Hunt M, Smith T, et al: A randomised controlled trial of high dose interferon 4. Cascinelli N, Bufalino R, Morabito A, MacKie R: Results of adjuvant interferon study in WHO melanoma programme. Lancet 343:913-914, 1994[CrossRef][Medline]
5. Kleeberg UR, Bröcker EB, Lejeune F, et al: Adjuvant trial in melanoma patients comparing rIFN 6. Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Co-operative Oncology Group. Am J Clin Oncol 5:649-655, 1982[Medline] 7. Creagan ET, Dalton RJ, Ahmann DL, Jung SH, et al: Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma. J Clin Oncol 13:2776-2783, 1995[Abstract] 8. Kirkwood JM, Strawderman MH, Ernstoff MS, et al: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Co-operative Oncology Group trial EST1684. J Clin Oncol 14:7-17, 1996[Abstract]
9. Kirkwood JM, Ibrahim J, Manola J: High-dose interferon versus GM2 vaccine in high-risk malignant melanoma. J Clin Oncol 19:4350, 2001
10. Pehamberger H, Soyer HP, Steiner A, et al: Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. J Clin Oncol 16:1425-1429, 1998
11. Grob JJ, Dreno B, Salmoniere P, et al: Randomised trial of interferon
12. Kirkwood JM, Ibrahim JG, Sondak VK, et al: High and low-dose interferon alpha-2b in high risk melanoma: First analysis of Intergroup trial E1690/S9111/C9190. J Clin Oncol 18:2444-2458, 2000 13. Eggermont AMM, Kleeberg UR, Ruiter DJ, et al. European Organisation for Research and Treatment of Cancer Melanoma Group trial experience with more than 2, 000 patients, evaluating adjuvant treatment with low or intermediate doses of interferon alpha-2b, in American Society of Clinical Oncology Educational Book. Alexandria, VA, American Society of Clinical Oncology, 2001, pp 88-93 14. Cascinelli N, Belli F, MackKie 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] 15. 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] 16. 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 (UKCCCR) randomised study of observation versus adjuvant low dose extended duration interferon alpha-2a in high risk resected malignant melanoma. Proc Am Soc Clin Oncol 20:349, 2001 (abstr 1393)
17. Kirkwood JM, Ibrahbim 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 18. Kirkwood JM. Adjuvant therapy of high-risk resected melanoma: Relapse-free and overall survival effects of high-dose Interferon alpha-2b in randomised controlled multicenter trials E1684 and E2696 and Intergroup trials E1690 and E1694, in American Society of Clinical Oncology Educational Book. Alexandria, VA, American Society of Clinical Oncology, 2001, pp 94-101
19. Lens MB, Dawes M: Interferon alpha therapy for malignant melanoma: A systematic review of randomised controlled trials. J Clin Oncol 20:1818-1825, 2002
20. Wheatley K, Ives N, Hancock BW, et al: Does adjuvant interferon
21. 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 Co-operative Oncology Group study. J Clin Oncol 14:2666-2673, 1996
22. Hillner BE, Kirkwood JM, Atkins MB, et al: Economic analysis of adjuvant interferon alfa-2b in high-risk melanoma based of projections from Eastern Co-operative Oncology Group 1684. J Clin Oncol 15:2351-2358, 1997 23. Gonzalez-Larriba JL, Serrano S, Alvarez-Mon M, et al: Cost-effectiveness analysis of interferon as adjuvant therapy in high-risk melanoma patients in Spain. Eur J Cancer 36:2344-2352, 2000 24. Hancock BW, Dixon S, Turner LA, et al: AIM High: adjuvant interferon in melanoma (high risk)—The costs. Br J Cancer 86:27, 2002 (supp 1)[CrossRef] 25. Hancock BW, Harris S, Wheatley K, et al: Adjuvant interferon-alpha in malignant melanoma: Current status. Cancer Treat Rev 26:81-89, 2000[CrossRef][Medline] 26. Agarwala S. Melanoma and Sarcoma, in American Society of Clinical Oncolgy: ASCO Annual Meeting Summaries. Alexandria, VA, American Society of Clinical Oncolgy, 2001, pp 74-76 27. Eggermont AMM: The role interferon-alpha in malignant melanoma remains to be defined. Eur J Cancer 37:2147-2153, 2001 28. Middleton MR, Thatcher N: Adjuvant interferon in melanoma: A resurrection?. Br J Cancer 84:1141-1142, 2001[CrossRef][Medline] 29. Kirkwood JM, Ibrahim JG, Sondak VK, et al: Interferon alfa-2a for melanoma metastases. Lancet 359:978-979, 2002[CrossRef][Medline]
30. Kefford RF. Adjuvant therapy of cutaneous melanoma: The interferon debate. Ann Oncol 14:358-365, 2003 Submitted March 28, 2003; accepted August 1, 2003.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test for toxicities grades 3 to 4 versus lesser (or no) toxicities. Fisher's exact test was used where there was an expected frequency of less than 5 in at least one cell of the 2 x 2 contingency table. Changes in Karnofsky performance status, between baseline and worst scores, were compared using the Mann-Whitney test. All P values are two-tailed. 
2b for high risk melanoma. Proc Am Soc Clin Oncol 12:390, 1993 (abstr 1331)
to Iscador to a control group after curative resection of high risk primary (>3mm) or regional lymph node metastasis (EORTC 18871). Eur J Cancer 35:582, 1999 (abstr 24)
