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Northern California Melanoma Center, San Francisco - 2008

We have prepared this document in an effort to provide useful information to physicians caring for patients with melanoma. The suggestions contained herein are intended to be helpful in providing some guidance regarding patient care; the individual situation will be different for each patient and the suggestions should be modified accordingly. A manuscript entitled "Value of Alpha Interferon in Adjuvant Therapy for Melanoma: The Case Against" and a second manuscript entitled "Non-interferon Based Alternatives for Adjuvant Therapy of Melanoma" has been published.

Surgical adjuvant treatment of melanoma may be considered when a patient is clinically free of disease following surgery but is at high risk for recurrence. Patients falling into this category include patients with high-risk primary melanoma (AJCC Stage II), lymph node metastasis (Stage III), or hematogenous dissemination of melanoma surgically excised (Stage IV). Work-up to determine if the patient is clinically free of disease may include history and physical examination, complete blood count (CBC), chemistry panel including lactic dehydrogenase (LDH), and computerized tomography (CT) scans of the chest and abdomen. CT scan of the pelvis may be included in patients who have had a high-risk primary of the lower extremity. A single-sequence magnetic resonance imaging (MRI) scan of the brain with gadolinium may be included in patients with Stage III and Stage IV disease. A positron emission tomography (PET) scan is more sensitive than the CT scan and may be helpful in patients who are at very high risk for residual disease. A bone scan is not recommended except in special circumstances; bone metastases of melanoma are relatively rare, and the incidence of false positive results on the bone scan is high.


Approved by the FDA for adjuvant therapy of patients with Stage III melanoma:

  1.    • High-dose alpha interferon

Agents which are currently under evaluation (details follow):

  1.    • Macrophage activator (GM-CSF)
  2.    • Tumor vaccines
  3.    • Alpha interferon
  4.    • Chemotherapy
  5.    • Biochemotherapy
Agents which have been tested in large prospective randomized trials and reported to be of no benefit:
  1.    • Melanoma vaccine
    1.   > Vaccinia Melanoma Oncolysate (VMO)
    2.   > Vaccinia Melanoma Cell Lysate (VMCL)
    3.   > GMK melanoma vaccine (GM2-KLH, QS 21)
    4.   > Melacine
    5.   > Canvaxin in patients with Stage III disease
    6.   > Canvaxin in patients with Stage IV disease
  2.    • Chemotherapy with single agent DTIC
  3.    • BCG
  4.    • Levamisole
Agents which have been dropped:
  1.    • Isoprinosine


Standard therapy for melanoma patients following surgery consists of careful follow up. We suggest an interval history and physical examination with laboratory tests including a CBC, chemistry panel with LDH, and chest x-ray. These may be done every three months for two years after the surgery, every six months for another two years, and annually thereafter. For patients with a primary melanoma less than 1 mm in thickness and no features suggesting increased risk, the follow-up frequency could be decreased to every 6 months during the first four years and annually thereafter.

A PET or PET/CT scan may be done at baseline for patients at high risk for recurrence and may be repeated every 3 months for the first 2 years to monitor for recurrence.

We also suggest that an MRI of the brain, single-sequence with gadolinium, be done every three to six months in patients with Stage III and Stage IV disease (depending on risk category). Recommendation of the only FDA approved therapy, interferon alpha, as therapy for patients with Stage III melanoma is controversial because of conflicting trial outcomes and high toxicity, as described below.

Agents currently under evaluation:

1. Leukine (Macrophage Activator, GM-CSF)

Activated macrophages distinguish tumor cells from normal cells and will kill only the tumor cells.1 Leukine (granulocyte macrophage colony stimulating factor, GM-CSF, Sargramostim), which is approved for marketing for hematopoietic reconstitution and reversal of iatrogenic neutropenia, also has activity as a macrophage activator. It has been reported that Leukine stimulates peripheral blood monocytes in vitro to become cytotoxic for human melanoma cells.2,3 It has further been shown in clinical trials that in vivo administration of Leukine at low doses also results in monocyte activation as shown by enhanced cytotoxicity.4,5 Finally, Leukine causes release of an angiogenesis inhibitor by the macrophages.7

At the Northern California Melanoma Center, we conducted a trial of a Leukine as surgical adjuvant treatment of patients at very high risk for recurrence of melanoma. The multicenter study was done in conjunction with investigators at Massachusetts General Hospital in Boston, MA and the Dartmouth Hitchcock Medical Center in Lebanon, NH. The patient population included patients with Stage III disease with more than four positive nodes or a > 3 cm mass, or with Stage IV disease, surgically excised. Treatment with Leukine commenced within 60 days of the patient’s being rendered clinically tumor-free and continued until recurrence or until the patient had been tumor-free for one year. Patients who had a treatable recurrence could elect to continue treatment with Leukine. The median survival was prolonged over three-fold in patients who received Leukine to 34.3 months compared to matched historical controls (median survival 10.2 months).8,9 The observed 2-year survival was 64% in the study patients vs. 15% in the controls, (p < 0.001). Toxicity was minimal, the major side effect being mild fatigue; there were no reports of Grade 4 toxicity or serious adverse events.

Because of these encouraging results, we have initiated a new study of Leukine at the Northern California Melanoma Center in order to offer this therapy to a larger group of patients with malignant melanoma who are at high risk for recurrence. All patients with Stage II (T4), Stage III (node positive) or Stage IV melanoma are were eligible if they had have surgery and/or other treatment and are were free of demonstrable disease by clinical, laboratory, and radiologic parameters. An interim analysis of this trial was presented at the 6th International Conference on Admuvant Therapy of Melanoma in Stockholm in 2006 and the 5th International Conference on Adjuvant Therapy of Melanoma in Athens in March, 2004. This interim analysis supports the results of the earlier trial and suggests that Leukine improves survival in this patient population.

In addition, a consortium of cooperative study groups, led by the Eastern Cooperative Oncology Group, has initiated a Phase III prospective randomized trial to further evaluate this therapy (E4697). Accrual of 800 patients has been completed, but many patients are still undergoing follow-up evaluation and results of this study will not be known for several years. Finally, we are currently conducting a trial to gather additional information about efficacy of this treatment and to determine the immunologic effects of GM-CSF in patients with melanoma.


Tumor vaccines have been tried since the turn of the century and have consistently shown modest clinical benefit. Recently, the availability of better defined antigens and improved adjuvants have re-stimulated interest in the development of tumor vaccines.

A number of Phase II studies using historic controls have suggested potential benefit of tumor vaccines in the surgical adjuvant setting. There have been 6 prospectively randomized trial Phase III of a tumor vaccine in the surgical adjuvant setting, and of these, all were negative studies i.e. there was no improvement in survival in patients who received the vaccine as compared to patients who received placebo. 10,11 Wallack, M.K., et al conducted a prospective randomized trial of vaccinia virus allogeneic melanoma cell lysates versus vaccinia as adjuvant therapy in 217 patients with high risk melanoma. There was no difference in disease-free survival or survival in the treated group.10 Hersey, P. et al conducted a prospective randomized trial of vaccinia melanoma cell lysates (VMCL) in 700 patients with Stage IIb and III melanoma and found no significant difference in outcome between the patients treated with the melanoma vaccine and the control subjects.

Livingston has studied vaccines for therapy of melanoma based on gangliosides derived from bovine brain. These gangliosides are over-represented 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 was conducted of a ganglioside vaccine with bacille Calmette-Guerin (GM2/BCG) versus BCG alone as adjuvant therapy in 122 patients with stage III melanoma.12 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 and administering it the QS-21 as adjuvant resulted in serological responses against GM2 that were strikingly superior, quantitatively and qualitatively, to any seen with previously tested GM2 vaccines.13 These results formed the basis for a prospectively randomized trial of the vaccine as adjuvant treatment for patients with high risk melanoma. This trial was conducted in a combined protocol by both the Eastern Cooperative Oncology Group (ECOG, E 1694) and the Southwest Oncology Group (SWOG, S9512) and a third group (C509801). The study included 880 patients who were randomized to high-dose interferon or to the GM2/KLH vaccine with QS 21. The results have been reported to show that patients receiving the high-dose interferon showed benefit in overall survival and disease-free survival as compared to patients who received the vaccine.14

Another vaccine that has been extensively studied as therapy of melanoma is called Melacine and consists of 2 lysed allogeneic melanoma cell lines, administered with an adjuvant called Detox. In a Phase III trial in patients with Stage IV melanoma, in which the drug was compared with 4-drug chemotherapy (the Dartmouth regimen), the survival in the two groups was similar, but the quality of life was better in the patients who received the vaccine. On the basis of these findings, Melacine had been approved in Canada for therapy of disseminated melanoma. Melacine was also evaluated in a Phase III trial in patients with Stage II melanoma (primary tumors 1-4 mm in thickness, surgically excised) conducted by the Southwestern Oncology Group (S 9035). Patients were randomized to receive the vaccine or observation (control population). Six hundred eighty nine (689) patients were randomized but 89 were found to be ineligible, leaving 300 eligible patients per arm. There was no significant improvement in disease-free survival in the eligible patients randomized to receive the vaccine but there was a statistically significant improvement for the entire randomized population.15

Another promising approach at the present time involves the use of autologous tumor cells in the preparation of the vaccine. Improved results have been reported recently with a vaccine consisting of autologous tumor cells conjugated to dinitrophenol (DNP) as compared to a vaccine using autologous unconjugated cells, both vaccines being given with BCG.16,17 The survival of patients given the conjugated vaccine was reported to be 70% versus 30% for patients given the unconjugated vaccine. One problem with this approach is that it often is not possible to offer this treatment to patients; it required that a large tumor specimen is available and that arrangements be made before surgery for proper preservation of the tumor for preparation of the vaccine. Tumors handled in the usual fashion at surgery (ie placing them in a preservative such as formalin) cannot be used for preparation of a tumor vaccine.

Morton et. al. reported clinical benefit in patients given a polyvalent vaccine derived from allogeneic cell lines combined with BCG.18 The control group consisted of a historic control population. They further reported that benefit was correlated with the development of immune responses. This vaccine, called Cancervax, was tested in 2 multicenter multinational Phase III randomized trials. In one study, 1,160 patients with Stage III melanoma were randomized to receive vaccine or placebo. In a second Phase III trial, 496 patients with Stage IV disease who had been rendered clinically disease-free by surgery were randomized to vaccine or placebo. The results of these studies have now been reported. Not only were the studies negative, but the patients receiving placebo (Bacillus Calmette-Guerin, BCG) fared significantly better for almost every endpoint than did the patients who were randomized to vaccine!

There have also been encouraging reports in a study of a polyvalent melanoma antigen vaccine consisting of shed antigens19 and of a synthetic peptide vaccine administered with interleudin-2 (IL-2).20 A number of other vaccines for adjuvant therapy of melanoma are in earlier stages of testing. While the results are encouraging, none of these vaccines is approved for marketing in the United States and they are generally not available outside of clinical trials.

In summary, there is current enthusiasm for the potential of vaccines for adjuvant therapy of melanoma, but the six large-scale, prospective, randomized, placebo-controlled studies reported to date have been negative. The failure of the studies with Cancervax to show clinical benefit are particularly disappointing because they were large studies, based on promising previous data and patients receiving the vaccine did not fare as well as the patients receiving placebo.


Alpha interferon has direct anti-tumor activity and also produces immune modulatory effects. In patients with metastatic disease, the response rate to alpha interferon is approximately 15 - 20%.

The Eastern Cooperative Oncology Group (ECOG) completed a prospective randomized controlled study of interferon alfa-2b (IFNa -2b) versus observation as surgical adjuvant therapy in 287 patients with melanoma (E 1684).21 The dose used in this study was the maximum tolerated dose: 20 MU/m2/d intravenously (IV) five days per week for four weeks followed by 10 MU/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 IFNa -2b. Patients randomized to treatment with IFNa -2b had a 9% improvement in continuous disease-free survival (from 26% to 37%) and a 9% improvement is survival (from 37% to 46%) compared with patients receiving no further treatment. The benefit of treatment was greatest among the patients with Stage III disease (node positive). Toxicity was considerable; 67% of the patients had severe (Grade 3) toxicity and 9% had life-threatening toxicity. The toxicity ncluded constitutional symptoms (fever, chills, and flu-like symptoms: fatigue, malaise, diaphoreses), myelosuppression, hepatotoxicity (2 deaths), and neurologic symptoms. Dose modification was required in the majority of the patients. The treatment is also costly. On the basis of the ECOG study, interferon was approved as surgical adjuvant treatment of melanoma by the FDA in 1996. The North Central Cancer Treatment Group (NCCTG) compared high-dose interferon alfa-2a (20 MU/m2 intramuscularly three times per week for 12 weeks) versus observation in 262 patients with high-risk melanoma.22 There was no benefit in the treated group.

In follow-up, a large, prospective, randomized trial was done by the same group in a similar patient population (E 1690). This study included 642 patients randomized to three arms: patients received high-dose interferon, as described above, low-dose interferon, or observation. The results show that there the time to disease progression was prolonged in the patients receiving high-dose interferon, but the overall survival was the same in all three arms, indicating there was no survival benefit in patients receiving high-dose interferon.23 As discussed above under "Vaccines", there now has been a third trial of high-dose interferon as adjuvant therapy of high-risk melanoma and this study showed that patients receiving the interferon had benefit in terms of progression-free and overall survival as compared to patients who received vaccine.14

Other investigators have also studied low-dose alfa interferon as surgical adjuvant treatment for melanoma. Low-dose alfa interferon was evaluated in a large, randomized study in adjuvant therapy in 499 patients with Stage II melanoma (primary melanoma greater than 1.5 mm. in thickness with clinically negative nodes).24 Results in this patient population are promising even though the low-dose regimen does not seem effective in higher risk patients; there was significant benefit in progression-free survival in the patients randomized to low-dose interferon. In a second randomized trial of low-dose interferon in 311 patients with resected primary Stage II melanoma, prolonged disease-free survival was also demonstrated.25 The World Health Organization (WHO) conducted a trial of low-dose interferon alfa-2a (3 MU SC three times per week for 3 years) versus observation as adjuvant therapy in 427 patients with high-risk melanoma.26 There was no difference in the disease free survival or survival in the patients receiving interferon.

In summary, while interferon is the only approved agent for adjuvant therapy of patients at high risk for recurrence of melanoma, the benefit, if any, is marginal for patients with node-positive disease and side effects are significant. For patients with Stage II disease, there have been two large randomized trials with encouraging results using a low-dose regimen and one negative study. The low-dose regimen has been evaluated in at least 3 studies in patients with positive nodes and has not been shown to be of benefit. Patients with positive nodes must weigh the risks and potential benefits of the high-dose interferon regimen; patients with Stage II disease might consider the low-dose regimen.


The hypothesis for the use of chemotherapy in the surgical adjuvant therapy setting is that one might be able to eliminate residual disease and to provide benefit in terms of a prolonged disease free survival. Prospective, randomized studies with single agent chemotherapy with DTIC have not shown adjuvant chemotherapy to be beneficial.27-30 More recently, a regimen of combination chemotherapy and biotherapy has been described which appears to have a higher response rate than single agent or combination regimens previously described.31 This combination includes cisplatin, vinblastine, and DTIC (CVD), in combination with interferon alfa-2a (IFN-alpha) and interleukin-2 (IL-2). It is hoped that this regimen of biochemotherapy might be effective in the surgical adjuvant setting even though previous trials of DTIC alone have been negative. The combination is now being used in the surgical adjuvant setting even though it is associated with substantial toxicity. Downsides of the use of biochemotherapy in the adjuvant setting are that it is a toxic regimen, requires hospitalization, it is unknown whether or not it will be effective, and use of the regimen in the adjuvant setting precludes it’s use later if metastases develop.


Surgical adjuvant treatment of melanoma has been the subject of intense investigation for over twenty years. Studies using historic controls suggested benefit in patients who received agents which modulate the immune response. The most notable and widely evaluated of these was BCG, where encouraging results were reported from several well recognized centers. Subsequent appropriately controlled, randomized trials demonstrated no benefit, and BCG is now recognized to be ineffective in delaying recurrences and prolonging survival in melanoma. The only agent which has been approved by the FDA for adjuvant therapy of Stage III melanoma is high-dose alpha interferon, but the efficacy has been challenged by the reports of negative trials and toxicity is considerable. A macrophage activator (GM-CSF), tumor vaccines, and chemobiotherapy may also be effective, but the efficacy of these agents will remain unknown until appropriate clinical trials of these agents are completed. Clearly we need to find agents for adjuvant therapy of melanoma that have greater efficacy and less toxicity than interferon. For this reason, consideration of participation in clinical trials to find better agents is warranted.

The Northern California Melanoma Center Consulting Panel believes that it is imperative to find more effective and less toxic agents for adjuvant therapy of melanoma and therefore recommends it is preferable for patients to participate in approved clinical trials.


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