Adjuvant use of interferon 2b is not justified in patients with stage IIb/III melanoma

Emilio Bajetta  About the author

Melanoma is the third most common skin cancer worldwide with an incidence rate of 5% per year, and its incidence continues to increase, especially in white populations. Melanoma is the most lethal form of skin malignancy because of its aggressive behavior and its ability to spread to lymphatic and visceral organs. When diagnosed early, melanoma is curable by surgery alone, with 80% of patients relapse-free 10 years after such surgery. When disease has spread to distant lymph nodes or metastasized (stage IV) it becomes refractory to common therapies, and, therefore, incurable.¹

Dacarbazine is currently considered, the best first-line therapeutic approach for metastatic disease, with response rates of 10–20%. The efficacy of this agent is disappointing however, with median overall survival (OS) following treatment being 8–10 months.² The increasing incidence of thinner melanoma skin lesions, the poor survival observed in metastatic disease and the low efficacy of new systemic agents,³ led to the development of various adjuvant therapies in patients with a medium or high risk of recurrence. A wide range of adjuvant regimens, such as chemotherapy, radiotherapy, chemo-immunotherapy and immunotherapy, have been proposed.

The association of primary melanoma regression with lymphoid infiltration or adoptive transfer of tumor-infiltrating lymphocytes, and laboratory reports of antibody and T-cell dependent responses in melanoma created a valid basis for the testing of both nonspecific (e.g. Bacillus Calmette-Guerin, Corynebacterium parvum) and specific (e.g. interferon, vaccines) immunotherapy within clinical trials.

In advanced disease, interferon 2b (IFN-2b) showed similar activity to dacarbazine monotherapy² and for this reason IFN-2b is used with various administration schedules in adjuvant clinical trials; however, the data on IFN-2b are not sufficiently convincing to recommend its use in the clinical setting. Moreover, it is still questionable as to whether even the subgroup of patients considered at high risk of relapse should be treated with this agent.

The first study supporting the use of IFN-2b as adjuvant therapy in patients with stage IIB/III melanoma (E1684) was published in 1996.⁴ This small randomized study showed that in comparison with observation only, treatment with high-dose IFN-2b (HDI) produced an improvement in both median OS (2.78 vs 3.82 years; P = 0.0237) and median relapse-free survival (RFS; 0.98 vs 1.72 years; P = 0.0023). After a median follow-up of 12.6 years; however, the clinical benefit associated with HDI disappeared, although an advantage in terms of longer relapse free survival was still evident. Even though the authors explained the loss of survival benefit over long follow-up as being attributable to most of the patients dying from causes other than melanoma, the final results are not strong enough to support their hypothesis of improved OS with HDI.

In the second trial of HDI, E1690,⁵ the study population was chosen using the same criteria as E1684,⁴ with the patients randomized to HDI or observation only arms. HDI significantly increased RFS compared with observation only, but did not increase OS. The lack of improvement in OS with HDI might be attributable to the cross-over of patients with nodal relapse, but this hypothesis cannot be proven.

The third trial,⁶ E1694, compared HDI with GMK vaccine. This trial was prematurely closed on the basis of an 'ad interim' analysis at 16 months' follow up. Statistically significant benefits were demonstrated for HDI compared with vaccine in terms of both RFS and OS (hazard ratios 1.47; P = 0.0015 and 1.52; P = 0.009, respectively). The absence of an observation arm and the short duration of follow-up limit the conclusions that can be drawn from this study, however, and the results do not, therefore, provide sufficient evidence to recommend HDI as a standard therapy in clinical practice. The results of these three trials indicate that adjuvant HDI might prolong RFS, while producing no clear improvement in terms of OS: this conclusion is supported by the results of one pooled analysis,⁷ an independent review⁸ and a meta-analysis.⁹

Employment of adjuvant HDI is compromised by the high incidence of severe and irreversible adverse events associated with it. These events have a substantial negative impact on patient quality of life (QoL). In the E1684 trial,⁴ 78% of patients experienced severe (grade 3–4) adverse events and only one-third of patients completed the therapy without dose reduction. Severe fatigue was reported in 20–25% of patients and was frequently accompanied by flu-like symptoms, fever and myalgias. The use of the recommended premedication with NSAIDs was often not sufficient to manage these events. These adverse effects are quite common but are generally under-reported in the literature, where only grade 3–4 toxicities tend to be stated.

In addition, mild-to-moderate depression was also experienced by 40–70% of the patients treated with HDI, with suicidal ideation being documented in 5–10% of HDI-treated patients following careful assessment.

HDI therapy can also cause bone marrow suppression and hepatotoxicity, although these events can only be detected through careful monitoring. The detection of these adverse effects requires repeated blood tests with indirect increases in the financial cost of therapy and worsened QoL for the patient. IFN-2b therapy can also induce the production of autoantibodies or clinical manifestations of autoimmune disease such as hypo-hyperthyroidism, antiphospholipid-antibody syndrome, vitiligo, rheumatoid arthritis and lupus erythematosus syndrome. A prospective study reported development of autoantibodies in 25% and an autoimmune disorder in 10% of patients during IFN-2b therapy.¹⁰ On multivariate analysis, presence of autoimmunity markers was considered an independent prognostic factor for improved RFS. In comparison with patients who showed no autoimmunity, patients with detectable autoimmunity markers had markedly longer median RFS (16 months vs not reached) and median OS (37.6 months vs not reached).¹⁰

Autoimmunity, which is caused by blockade of T-cell regulatory machinery by IFN-2b, is a phenomenon with major clinical significance, representing on the one hand a possible surrogate end point to assess the benefit of adjuvant therapy, and on the other hand a potentially chronic life-threatening disease in those patients who will not benefit from HDI.

On the basis of published data, adjuvant HDI therapy does not seem to reduce the risk of death from melanoma in those patients at highest risk of this outcome. It does, however, seem to increase the possibility of worse QoL: 1 year of adjuvant HDI therapy causes an impairment of QoL in 70–80% of cases.

Researchers must try to categorize responsiveness to IFN-2b therapy among patients with melanoma through the use of gene profiling techniques. Additionally, the use of other cytokines, such as interleukin 12,¹¹ should be explored in this setting. Such advancements would enable the individual tailoring of adjuvant treatment regimens to carefully balance the risks and benefits.

Competing interests

The author declared no competing interests.

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