What is the optimal adjuvant interferon therapy for melanoma?

High-dose interferon α-2b (IFN α-2b) was approved by the US Food and Drug Administration in 1995 for the treatment of patients with high-risk melanoma who are free of disease but at high risk of recurrence.¹ However, numerous questions surround the use of IFN α-2b, including concerns that adjuvant IFN may not significantly improve overall survival in patients. Other questions surround ideal treatment duration and dosages. In addition, trials are just beginning to shed light on which specific melanoma stages may best respond to adjuvant treatment. More recently, the availability of pegylated IFN α-2b offers the possibility of extending the duration of IFN therapy to as long as 5 years while also allowing greater weekly exposure to IFN. So in aggregate, patients and physicians have more choices in terms of dose, duration, and formulation of IFN adjuvant therapy than ever, but with little or no comparative clinical trial results to guide decision-making.

Relapse-free Survival and Overall Survival

Numerous studies have consistently established that IFN-α2b improves relapse-free survival (RFS) in high-risk melanoma patients. For example, the E1684 trial analyzed RFS and overall survival (OS) in 287 patients with stage IIB and III melanoma treated with adjuvant high-dose IFN (HDI) for 1 year. Patients were randomized to adjuvant HDI (20 million units [MU]/m intravenously [IV] 5 days per week for 4 weeks, followed by 10 MU/m 3 days per week subcutaneously [SC] for 48 weeks) or observation. At 5 years, patients in the HDI arm were found to have an RFS rate of 37% and an OS rate of 46%, while the patients in the observation arm had an RFS rate of 26% and an OS rate of 37%.² After a median follow-up of 6.9 years, the median RFS was 1.72 years in the HDI arm vs. 0.98 years in the observation arm (P = .0023), and the median OS in the HDI and observation arms were 3.82 years and 2.78 years (P = .0237), respectively. Updated Kaplan-Meier estimates of RFS for patients enrolled in E1684 were calculated at a median follow-up of 12.6 years, and demonstrated that the significant clinical benefit of HDI compared with observation was still evident (hazard ratio [HR], 1.38; P₂ = .02; Figure 1). Therefore, the benefit of a 1-year HDI regimen with respect to RFS remains stable over time.³On the other hand, the improvement in OS at a median follow-up of 12.6 years had diminished, which may be explained by some deaths from causes other than metastatic melanoma.

Figure 1. E1684: One-year HDI, Relapse-free Survival, Extended Follow-up

The benefit of a 1-year HDI regimen remains stable over time.
Key: HDI — high-dose interferon
Source: Kirkwood JM, et al. Clin Cancer Res. 2004;10:1670-1677.

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Another prospective randomized trial, E1694, evaluated the efficacy of HDI for 1 year compared with vaccination with GM2 coupled to keyhole limpet hemocyanin (KLH) and combined with the QS-21 adjuvant ganglioside vaccine (GMK) for 96 weeks (weekly for 4 weeks, then every 12 weeks). Among the 774 patients with resected stage IIB/III melanoma who were eligible for efficacy analysis, HDI led to significant improvements in both OS (HR, 1.52; P = .009) and RFS (HR, 1.47; P = .0015) compared with GMK (Figure 2). Interestingly, the greatest benefit was observed in the node-negative subset. The study was terminated early because of the inferiority of the GMK vaccine.⁴ Results of this study were questioned because the study compared HDI with the GMK vaccine and not observation. Whether the vaccine was actually causing harm or had effects similar to placebo could not be known.

Figure 2. E1694: Overall Survival

In E1694, HDI led to significant improvements in overall survival compared with the GMK vaccine.
Source: Kirkwood JM, et al. J Clin Onc. 2001;19:2370-2380.

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However, in another randomized phase 3 trial, the European Organisation for Research and Treatment of Cancer (EORTC) 18961 study, the GMK vaccine was compared with observation in 1,314 patients with stage II melanoma. Patients were randomized to either be observed or receive the vaccine SC once-weekly for weeks 1 to 4, every 3 months from week 12 for first 2 years, and every 6 months during third year (total of 14 vaccinations). Results indicated that there was no difference in RFS (HR, 1.03; 95% confidence interval [CI], 0.84-1.25; P = .81), OS (HR, 1.16; 95% CI, 0.90-1.51; P = .25), or distant metastasis-free survival (DMFS) (HR, 1.11; 95% CI, 0.88-1.40; P = .36) between the 2 arms of the trial.⁵ These results indicate that the vaccine did not cause additional harm to patients with melanoma, and therefore support the beneficial effects of HDI observed in E1694.

While E1684 and E1694 have demonstrated that HDI leads to improvements in both RFS and OS, other studies did not find that IFN significantly improved OS, which has led to debate regarding the use of this agent. For example, in the E1690 trial, 642 patients were randomized into 3 arms: HDI, low-dose interferon (LDI), or observation. Results indicated that neither HDI nor LDI were associated with an improvement in OS compared with observation. However, RFS rates for the HDI, LDI, and observation arms were 44%, 40%, and 35%, respectively.⁶ The HR for the intent-to-treat analysis of HDI vs. observation was 1.28 (P₂ = .05); for LDI vs. observation, it was 1.19 (P₂ = .17). By Cox analysis, the impact of HDI on RFS achieved significance (P₂ = .03). Of note, however, is that during the conduct of this trial, the positive results of the prior E1684 trial showing a significant benefit of both RFS and OS for the HDI regimen became available, leading to the approval of this regimen by the US FDA. This led to some patients who were randomized to the LDI and observation arms who experienced local regional relapse being “crossed over” to the HDI treatment, which might have confounded any effect on OS.⁶

A meta-analysis that included 14 randomized controlled trials involved 8,122 patients, 4,362 of which were allocated to the IFN-α arm. IFN-α alone was compared with observation in 12 of the 14 trials, and 17 comparisons (IFN-α vs. comparator) were generated in total. IFN-α treatment was associated with a statistically significant improvement in RFS in 10 of the 17 comparisons (HR for disease recurrence, 0.82; 95% CI, 0.77-0.87; P < .001) and improved OS in 4 of the 14 comparisons (HR for death, 0.89; 95% CI, 0.83-0.96; P = .002). Adjuvant IFN (various doses and durations) not only improved RFS by 18% in almost every study, but also improved OS by 11%.⁷ No optimal IFN-α dose or duration was identified using subgroup analysis and meta-regression. Moreover, a subset of patients that were clearly more responsive to adjuvant therapy was not identified.

Interestingly, a less well-known 2006 meta-analysis examined 2-year survival rates for patients on HDI vs. observation. This meta-analysis analyzed HDI in patients with high-risk, resected melanoma based on data from the 3 aforementioned randomized trials (E1684, E1690, and E1694). The data suggested that patients were 15% more likely to survive 2 years with HDI compared with observation, as in E1684 and E1690, or the ganglioside vaccine, as in E1694 (relative risk [RR], 0.85; 95% CI, 0.93-0.99; P = .03).⁸ These results are promising, as considerable scientific progress can occur in 2 years, and if more patients are kept alive for an additional 2 years, they may be able to be treated with therapies that are developed or optimized within this time period. Furthermore, these results may prompt physicians treating patients with melanoma to question whether an improvement in overall survival is still the sine qua non in the decision to use an adjuvant therapy, or should health care providers focus on delaying relapse, while current treatments are being optimized and more effective ones are being developed? Although OS is an important consideration in determining treatment for patients, RFS should not be underestimated, as patients who have more time before they relapse have a chance to take advantage of treatment advances.

Dose and Duration of Therapy

The optimal dose and duration of IFN therapy is also a subject of debate. Regarding dosage, results of the E1690 trial demonstrated that HDI led to a significant improvement in RFS compared with observation, while LDI did not.⁶ On the other hand, no optimal dose or duration could be identified in the meta-analysis by Mocellin and colleagues.⁷ The benefit of an extended duration of LDI was examined in a prospective, randomized, multicenter trial of approximately 850 patients with resected cutaneous melanoma of at least 1.5 mm tumor thickness who were clinically lymph node-negative.⁹ Patients were followed for a median number of 4.3 years, and were randomly assigned to receive 3 MU IFN α-2a 3 times a week subcutaneously for either 18 months (arm A) or 60 months (arm B). Results demonstrated no significant differences in RFS (75.6% vs. 72.6%; P = .72; HR, 1.05; 95% CI, 0.80-1.39), DMFS (81.9% vs. 79.7%; P = .56; HR, 1.10; 95% CI, 0.80-1.52), or OS (85.9% vs. 84.9%; P = .86; HR, 1.03; 95% CI, 0.71-1.50) between the 2 treatment groups (Figure 3). Thus, in this trial, prolongation of conventional LDI therapy from 18 to 60 months showed no incremental clinical benefit in patients with intermediate and high-risk primary melanoma.

Figure 3. Is Longer Better? Low-dose IFN 18 vs. 60 months (n = 840), RFS

No significant differences in RFS were observed between IFN treatment regimens of 18 months and 60 months.
Key: IFN — interferon; RFS — relapse-free survival
Source: Hauschild A, et al. J Clin Oncol. 2010;28:841-846. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.

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Other studies have investigated whether 1 month of IV HDI is as effective as the currently accepted 1-year duration of HDI. However, the E1697 trial concluded that 4 weeks of HDI in relation to RFS and OS did not show statistically significant differences compared with observation (Figure 4).¹⁰ The 5-year OS rate for the observation group was 0.85 (95% CI, 0.81-0.89; n = 535) compared with 0.82 (95% CI, 0.78-0.86; n = 556) for the IFN group. The median RFS was 7.8 months (95% CI, 5.8-9.8) in the observation group and 7.3 months (95% CI, 7.0-9.5) in the 1-month IFN group. Five-year RFS rates were approximately 60% in both groups. Thus, these data from approximately 1,000 patients do not support using only 1 month of IV IFN at the present time and the 1-year regimen that is approved for high-risk patients should not be abbreviated to 1 month of therapy.

Figure 4. Is 1 Month of IV IFN Enough? E1697: 1 Month vs. Observation (n = 975), RFS

Four weeks of HDI did not lead to significant improvements in RFS compared with observation.
Key: IFN — interferon; Obs — observation; RFS — relapse-free survival
Source: Agarwala SS, et al. Presented at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL; Abstract 8505. http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=77947. Accessed September 9, 2011.

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The results of E1697 contrast with those from a smaller prospective randomized trial conducted by the Hellenic Group that compared 1-month IV IFN to 1-year IFN and found no differences in OS and RFS (Figure 5).¹¹ In this study, patients were randomly assigned to receive IFN α-2b 15 x 10⁶ U/m² IV x 5/7 days weekly x 4 weeks (arm A) vs. the same regimen followed by IFN α-2b 10 x 10⁶ U (flat dose) administered SC 3 times a week for 48 weeks (arm B). At a median follow-up of 63 months (95% CI, 58.1-67.7), the median RFS was 24.1 months in arm A vs. 27.9 months in arm B (P = .9) and the median OS was 64.4 months in arm A vs. 65.3 months in arm B (P = .49). Five-year RFS rates were 37% in arm A and 35% in arm B. However, the study included a relatively small number of patients (353 eligible: arm A, n = 177; arm B, n = 176), decreasing the power to detect a small but clinically meaningful difference between the 2 regimens. In addition, the trial did not test commonly accepted IFN dosages and the maintenance treatment of 10 MU flat dose TIW used in this trial has been shown to be ineffective as compared with observation,^12,13 which means that the Hellenic trial compared induction to induction with no effective maintenance therapy. Therefore it is not surprising that the outcome of therapy was not different between the 2 arms.¹³

Figure 5. Is 1 Month of Interferon Enough? 1 vs. 12 Months (n = 373), RFS

In this trial, no differences in RFS between 1-month and 1-year interferon were observed.
Key: Group A — 1-month interferon; Group B — 1-year interferon; RFS — relapse-free survival
Source: Pectasides D, et al. J Clin Oncol. 2009;27(6):939-944. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.

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An interesting trial described a multiple-dose IV regimen. The control group in this trial was IV IFN plus maintenance IFN for 1 year. In that study, 3 to 4 months of interferon was as effective as 12 months of interferon. However, it is still not known how much benefit or how much toxicity is associated with IV administration.¹⁴

Summary

The individual trials with significant improvement in survival almost all involve 1 year of HDI. Meta-analysis data, however, suggest consistent survival impact for all IFN regimens that have been tested that last at least 1 year. Additional comparative trials are needed. Based on available results, the IV IFN only for 1 month cannot be recommended. Adjuvant IFN has an important role to play, even in an era of new treatments that improve survival in patients with stage IV melanoma.

Health care providers still need to determine which adjuvant regimen is ideal and for which patient populations. Today, death and relapse risk in patients with melanoma are still accurately predicted by microscopic analysis of the primary and the sentinel node biopsy. Adjuvant treatment is indicated for patients with melanoma who are at high risk, defined as those with primary melanoma greater than 4 mm or with positive lymph nodes. However, some studies are exploring whether other types of patients, particularly those with ulcerated intermediate thickness primary melanoma, might benefit from adjuvant treatment.^12,15

In the future, new adjuvant therapies will play important roles regardless of their toxicity. Novel adjuvant therapies that only improve RFS will also play a role depending on their toxicity. Moreover, therapies with reliable pretreatment predictors of benefit or resistance will take precedence over therapies where all patients are treated and only few can benefit. Meanwhile, adjuvant therapy remains the best bridge between treatment of the primary tumor and stage IV disease.

Improved prognostic markers to identify patients at risk of relapse, especially in the sentinel node-negative population, are needed. Enhanced understanding of the efficacy of adjuvant therapy in molecularly-defined subsets of patients is also crucial. Finally, as more potential adjuvant therapy options become available, predictors of efficacy and resistance will become increasingly important.

References

Lawson DH. Choices in adjuvant therapy of melanoma. Cancer Control. 2005;12(4):236-241.
Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14(1):7-17.
Kirkwood JM, Manola J, Ibrahim J, Sondak V, Ernstoff MS, Rao U; Eastern Cooperative Oncology Group. A pooled analysis of Eastern Cooperative Oncology Group and Intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res. 2004;10(5):1670-1677.
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. 2001;19(9):2370-2380.
Eggermont AM, Suciu S, Rutkowski P, et al. Randomized phase III trial comparing postoperative adjuvant ganglioside GM2-KLH/QS-21 vaccination versus observation in stage II (T3-T4N0M0) melanoma: Final results of study EORTC 18961. Presented at: American Society of Clinical Oncology Annual Meeting; June 4-8, 2010; Chicago, IL. Abstract 8505. http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=50930. Accessed September 5, 2011.
Kirkwood JM, Ibrahim J, Sondak V, et al. High- and low-dose interferon alfa-2b in high-risk melanoma: First analysis of Intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000;18(12):2444-2458.
Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: A systematic review and meta-analysis. J Natl Cancer Inst. 2010;102(7):493-501.
Verma S, Quirt I, McCready D, Bak K, Charette M, Iscoe N. Systematic review of systemic adjuvant therapy for patients at high risk for recurrent melanoma. Cancer. 2006;106(7):1431-1442.
Hauschild A, Weichenthal M, Rass K, et al. Efficacy of low-dose interferon {alpha}2a 18 versus 60 months of treatment in patients with primary melanoma of ≥ 1.5 mm tumor thickness: Results of a randomized phase III DeCOG trial. J Clin Oncol. 2010;28(5):841-846.
Agarwala SS, Lee SJ, Flaherty LE, et al. Randomized phase III trial of high-dose interferon alfa-2b (HDI) for 4 weeks induction only in patients with intermediate- and high-risk melanoma (Intergroup trial E1697). Presented at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL. Abstract 8505. http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=77947. Accessed September 9, 2011.
Pectasides D, Dafni U, Bafaloukos D, et al. Randomized phase III study of 1 month versus 1 year of adjuvant high-dose interferon alfa-2b in patients with resected high-risk melanoma. J Clin Oncol. 2009;27(6):939-944.
Eggermont AM, Suciu S, MacKie R, et al; EORTC Melanoma Group. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet. 2005;366(9492):1189-1196.
Agarwala SS, Gray RJ, Wong MK. Duration of high-dose interferon alpha-2b regimen for resected high-risk melanoma. J Clin Oncol. 2009;27(25):e82-e83.
Chiarion-Sileni V, Guida M, Romanini A, et al. Intensified high-dose intravenous interferon alpha 2b (IFNα2b) for adjuvant treatment of stage III melanoma: A randomized phase III Italian Melanoma Intergroup (IMI) trial [ISRCTN75125874]. Presented at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL. Abstract 8506. http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=80361. Accessed September 27, 2011.
Eggermont AM, Suciu S, Santinami M, et al. EORTC 18991 phase III trial: Long-term adjuvant pegylated interferon-α2b (PEG-IFN) versus observation in resected stage III melanoma: Long-term results at 7.6-years follow-up. Presented at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL. Abstract 8506b. http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=83141. Accessed September 5, 2011.