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Adjuvant Therapy of Melanoma

Adjuvant Therapy of Melanoma

ABSTRACT: In 2001, the American Joint Committee on Cancer Melanoma Staging Committee proposed and created a new staging system for melanoma. This new system will become official in 2002, with the publication of the sixth edition of the AJCC Cancer Staging Manual. The new system 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. In light of physicians’ ability to determine with more precision which patients are at high risk for melanoma recurrence, they face the dilemma of which, if any, surgical adjuvant therapy to choose. Alpha-interferon is the only agent approved for adjuvant therapy of melanoma in the United States, but its questionable benefits and substantial side effects make it hard to justify recommending it to patients. Discussion of trials of high- and low-dose interferon is presented here. The author’s group has conducted trials of granulocyte-macrophage colony-stimulating factor (GM-CSF [Leukine]) as surgical adjuvant treatment of patients at high-risk for melanoma recurrence. One of the most important activities of GM-CSF is its ability to activate macrophages and cause them to become cytotoxic for human melanoma cells, at doses low enough to avoid the toxicity associated with other cytokines. The author presents promising trial results, discusses GM-CSF in other malignancies, and includes discussion of tumor vaccines, biochemotherapy, and other agents being studied as adjuvant therapy of melanoma. It is hoped that these newer approaches will result in therapies that are more effective and less toxic than interferon. [ONCOLOGY 16(Suppl 1):40-48, 2002]

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.

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