Adjuvant Therapy of Melanoma

The American Joint Committee on Cancer (AJCC) Melanoma Staging Committee proposed a new staging system for melanoma[1,2]; the final version and validation of this new staging system were published in 2001.[3,4] The new staging system has been approved by the AJCC Executive Committee, the International Union Against Cancer (UICC) TNM Committee, the World Health Organization Melanoma Program, and the European Organization for Research and Treatment of Cancer (EORTC) Melanoma Group, and will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in 2002.

This system represents an important advance in that it identifies significant prognostic variables in patients with melanoma and validates them in an analysis of 17,600 patients, making it possible to precisely determine the patient’s chance for survival. The important prognostic indicators regarding the primary tumor are now identified as thickness and ulceration (level is an important indication only for T1—primary tumors ≤ 1.0 mm in thickness). For patients with nodal involvement, the number of metastatic nodes, whether the tumor burden is microscopic or macroscopic, and ulceration of the primary tumor are important in prognosis. For patients with metastatic disease, the site of metastasis (skin, subcutaneous, and/or lymph node vs lung vs other sites) is relevant, as is whether or not the lactate dehydrogenase (LDH) level is elevated.

The new system takes these factors into account: it incorporates ulceration of the primary as a prognostic indicator (not previously included), includes patients with satellites and in-transit lesions in stage III, includes the number of positive nodes (rather than gross dimensions) and tumor burden in the substaging within stage III, and adds the site of distant metastases and the presence of elevated LDH as a prognostic indicator for patients with stage IV disease.

Under the new staging system, survival curves correlate well with stage of disease (see Figure 1) and subgroupings within each stage allow further refinement of prognosis (see Table 1). This allows the physician to determine with precision which patients are at high risk for recurrence, and to counsel patients about their prognosis and therapeutic options. Based on this important information, the dilemma being faced by the treating physicians and patients at high risk for recurrence is what, if any, surgical adjuvant therapy to choose.

Interferon

Alpha-interferon has direct antitumor activity, and also produces immune modulatory effects. In patients with metastatic disease, the response rate to alpha-interferon is approximately 15% to 20%. It is the only drug approved in the United States for adjuvant therapy of melanoma. It was approved as surgical adjuvant treatment of patients with a T4 primary (> 4.0 mm in thickness) or node-positive (stage III) melanoma by the US Food and Drug Administration (FDA) in 1996. It has not been tested or approved as adjuvant therapy for patients with stage IV disease.

High-Dose Interferon Studies

The Eastern Cooperative Oncology Group (ECOG) completed a prospective randomized controlled study of interferon (IFN) alfa-2b vs observation as surgical adjuvant therapy in 287 patients with melanoma (protocol E1684).[5] The dose used in this study was the maximum tolerated dose: 20 million IU/m²/d intravenously (IV) 5 days per week for 4 weeks followed by 10 million IU/m² three times per week subcutaneously (SC) for 48 weeks. The results showed that there was a significant prolongation of relapse-free survival and overall survival in the group receiving IFN alfa-2b. Patients randomized to treatment with IFN alfa-2b had a 9% improvement in continuous disease-free survival (from 26% to 37%) and an 11% improvement in survival (from 37% to 46%) compared with patients receiving no further treatment.

Dose modification was required in the majority of patients. Toxicity—including constitutional symptoms (fever, chills, flu-like symptoms, fatigue, malaise, diaphoresis), myelosuppression, hepatotoxicity, and neurologic symptoms—was considerable: 67% of the patients had severe (grade 3) toxicity, 9% had life-threatening toxicity, and there were two deaths due to hepatotoxicity. It is important to consider this toxicity in context. These are patients who have had surgical excision of their melanoma and are clinically free of disease. Although they are at high risk for recurrence, some of them may already be cured. This is different from the situation in which one is administering chemotherapy for widespread metastatic disease, where there is no choice and the toxicity must be accepted as part of the treatment.

In follow-up, a large, prospective, randomized trial was done by the same group in a similar patient population (protocol E1690). This study included 642 patients randomized to three arms: high-dose interferon as described above, low-dose interferon, or observation. The results show that time to disease progression was prolonged in the patients receiving high-dose interferon, but overall survival was the same in all three arms, indicating that there was no survival benefit in patients receiving high-dose interferon.[6]

There has also been a third prospectively randomized trial of high-dose interferon as adjuvant therapy of high-risk melanoma. This trial, described below, compared outcome following this therapy with that in patients randomized to receive a therapeutic melanoma vaccine. The vaccine was based on GM2, a ganglioside derived from bovine brain, which is overrepresented on melanoma cells and thus can be used in a vaccine in an effort to stimulate an immune response to melanoma.

A double-blind randomized trial compared a ganglioside vaccine with bacille Calmette-Guérin (GM2/BCG) to BCG alone as adjuvant therapy in 122 patients with stage III melanoma.[7] The results showed improved survival in patients with GM2 antibodies as compared with patients who did not have these antibodies. In a subsequent phase I trial, it was shown that conjugating the GM2 ganglioside with keyhole limpet hemocyanin (KLH) and administering it with the saponin adjuvant QS-21 resulted in serologic responses against GM2 that were strikingly superior, quantitatively and qualitatively, to any seen with previously tested GM2 vaccines.[8]

These results formed the basis for the trial mentioned above, which was conducted in a combined protocol by the Eastern Cooperative Oncology Group (protocol E1694), the Southwest Oncology Group (SWOG, protocol S9512), and Cancer and Leukemia Group B (CALGB protocol C509801). The study included 880 patients who were randomized to either high-dose interferon or the GM2/KLH vaccine with QS-21 (called GMK), 774 of which were eligible for efficacy analysis.[9] The results showed that patients receiving the high-dose interferon enjoyed benefit in overall and disease-free survival as compared to patients who received the vaccine. However, the study has been criticized for several reasons: (1) the median follow-up was short for this patient population (16 months); (2) there was no control group given observation alone; (3) the difference in overall survival in the two arms was not great (78% for IFN alfa-2b and 73% for GMK); and (4) the vaccine regimen was changed between the positive phase II trial and the phase III trial (QS-21 was substituted for BCG). This might have resulted in an adverse effect on the outcome because of resultant increased titers of IgG antimelanoma antibody, which might have had a blocking effect on the cell-mediated immune response to the tumor.

Other groups have also studied interferon as adjuvant therapy of melanoma. The North Central Cancer Treatment Group (NCCTG) compared high-dose IFN alfa-2a (20 million IU/m² intramuscularly three times per week for 12 weeks) vs observation in 262 patients with high-risk melanoma.[10] There was no benefit in the treated group. The World Health Organization (WHO) evaluated IFN alfa-2a in 444 patients with node-positive melanoma using a dose of 3 million IU/d SC three times per week for 3 years and found no impact on disease-free or overall survival.[11]

The EORTC conducted a trial (protocol 18871) in parallel with the German Cancer Society (DKG, protocol 80-1) in which 830 patients with stage II (> 3 mm) or stage III melanoma were randomized to either 1 million IU of IFN alfa-2b SC every other day for 1 year, IFN-gamma, mistletoe extract (Iscador, available in the United States as Iscar), or observation.[12] This is a mature study, with a median follow-up of 5.9 years. The results show no difference in disease-free or overall survival for the patients treated with IFN alfa-2b as compared with observation-only controls (patients treated with Iscador actually had a worse outcome than the controls or interferon-treated patients).

The EORTC has launched a follow-on trial (protocol 18952) in patients with stage IIB or III melanoma.[12] Patients are randomized to either (1) IFN alfa-2b at 10 million IU 5 days/wk for 4 weeks SC, then three times/wk for 1 year; (2) IFN alfa-2b at 10 million IU 5 days/wk for 4 weeks SC, then 5 million IU three times/wk for 2 years; or (3) observation. So far, 1,418 patients have been enrolled in the study. At the 2001 meeting of the American Society of Clinical Oncology, Dr. Eggermont reported that with a median follow-up of 1.9 years, there was an advantage (P = .04) for the 2-year regimen with very little toxicity compared with high-dose interferon. The authors conclude that it is too early to make a determination regarding the impact on overall survival and/or to draw conclusions regarding this important study.