High-risk Resected Melanoma Research Articles

A phase II trial of N-Acetyl-GM3/VSSP vaccine in high-risk resected melanoma patients (pts). Does vaccination modify melanoma outcome after relapse?

3026 Background: Quantitative and qualitative changes occur in ganglioside expression during the oncogenic transformation. Cellular over-expression and shedding of gangliosides into the interstitial space may play a central role in cell growth regulation, immune tolerance and tumor-angiogenesis, representing an interesting target for anticancer therapy. Methods: Based on previous phase I study (Bitton et al, PASCO 2002, #1376), 38 high risk melanoma pts received N-Acetyl-GM3/VSSP vaccine in an adjuvant setting. Stage III: 8 pts, local-regional and systemic relapsed pts: 30 pts. All patients had no clinical evidence of disease. Five doses of 360 μg were given IM Q14D, 4 doses Q28D and then Q90D up to 2 years of treatment, relapse or unacceptable toxicity. Clinical outcome, humoral and cellular responses (Ig M anti-GM3, Ig G anti VSSP-GM3 and INFγ anti GM3 detected by Elispot) and toxicity (NCIC v2) were evaluated. Results: At a median follow-up of 35m (r: 7- 62 ), 28 pts (74%) relapsed and 23 (62%) are alive, most of them disease-free. One pt was lost at 7m. Median PFS was 8.5m (r:1–62). Median follow-up for alive pts is 49m (r:7–63).The estimated 5-year OS was 56% (95% CI: 34–76, Kaplan-Meier). Remarkably, many of the pts who relapsed were successfully rescued with local and/or systemic treatments, explaining the important gap between PFS and OS. Although serum reactivity to the vaccine (Ig G anti-VSSP-GM3) was observed in all patients, no specific humoral or cellular responses were detected. Mild to moderate local reactions, transient fever and asthenia were the most frequent toxicities observed. Five patients discontinued vaccination due to adverse events: post-vaccination G3 hypotension plus G3 ASAT/ALAT elevation (2); G2 injection site reaction (2); and syncope with uncertain relation to treatment (1). Conclusions: Compared to published data, observed OS was better than expected. N-Acetyl-GM3/VSSP vaccine might impact on the course of the disease through an antitumor effect or modulating responses to following treatments. The lack of specific immune response is probably due to the low immunogenicity of the ganglioside. Toxicity was acceptable. The immunomodulatory properties of GM3/VSSP warrants further investigation. No significant financial relationships to disclose.

Perioperative adjuvant biotherapy in high-risk resected cutaneous melanoma: the results of 5 years of follow-up

A feasibility study was conducted to establish the safety and, to some extent, the effectiveness of a new approach of perioperative adjuvant biotherapy in patients with resected cutaneous melanoma. The candidates for this study included patients with primary cutaneous melanoma greater than 1 mm deep, those with resectable regional lymph node (LN) metastases and patients with resectable distant metastases. Interleukin-2 was administered 1 week before definitive surgery as 22 million IU, and again 1 week after the surgery. This was followed by interferon alpha-2b, 10 million IU three times a week for 4 weeks. Fifty-six patients were studied. The program was well tolerated with low, mainly symptomatic, grade I-II toxicity, occasionally with grade III toxicity. Patients' compliance was good. The 5-year survival data were expressed by Kaplan-Meier analysis, and compared with matched historical controls by the log-rank method. The results suggested an improvement in disease-free survival (P=0.021) and a disease-specific overall survival (P=0.05), but not in overall survival, owing to all causes of death (P=0.089). The consequent administration of low-dose interleukin-2 and interferon, initiated preoperatively on outpatient bases, resulted in several constitutional symptoms that were self-limiting and did not delay surgery. No surgical complications related to this approach were observed. This program was well tolerated in all age groups, and the results suggested some survival benefits when compared with matched historical controls.

7022 POSTER High dose interferon alpha 2b as adjuvant therapy in high-risk resected malignant melanoma: 10 year experience of patients treated in Northern Ireland

7022 POSTER High dose interferon alpha 2b as adjuvant therapy in high-risk resected malignant melanoma: 10 year experience of patients treated in Northern Ireland

GM-CSF Plus Antigenic Peptide Vaccination in Locally Advanced Melanoma Patients

Twenty-four (24) pretreated patients with relapsed high-risk resected The American Joint Committee on Cancer (AJCC) stage IIA-IV melanoma received adjuvant peptide vaccinations derived from the melanosomal antigens MelanA/MART1, MAGE-1, gp100, and tyrosinase, according to patient tumor-associated human leukocyte antigen (HLA) restricted antigen expression, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF). Pretreatment was comprised of surgery (n=23 primary tumor; n=23 metastases), local radiotherapy (n=2), immunotherapy (n=23), chemotherapy (n=10), and chemoimmunotherapy (n=1), respectively. All patients received peptide vaccines in an adjuvant setting. Seven (7) patients were relapse free for 3+ up to 25+ months. Of the patients exhibiting progressive disease (n=17), 13 patients developed metastases during vaccination (9 local, 4 distant), and 4 patients developed metastases (2 local, 2 distant) after finishing vaccine therapy. Two (2)-year local and distant metastases-free survival, 2-year distant metastases-free survival, and 2-year overall survival were calculated as 8.6%, 68%, and 85%, respectively. Vaccine treatment was well tolerated, with no severe side-effects. Twenty (20) of 24 patients developed local delayed-type hypersensitivity (DTH) reactions to synthetic peptide vaccination. Transient fever (n=2) and pain in muscle/bone (n=2) occurred rarely. In conclusion, antigenic peptide vaccination, combined with GM-CSF, is safe and may yield clinical benefits in relapsed high-risk resected melanoma patients.

A randomized phase III trial of 1 month versus 1 year adjuvant high-dose interferon alfa-2b in patients with resected high risk melanoma

8505 Background: High dose IFNa regimen as reported in E1684 was unique for the incorporation of an induction phase of maximally-tolerated dosages of IV therapy for the initial 4 weeks. This is the only trial that has shown prolongation of overall survival and disease-free survival in comparison to observation. Analysis of the hazard curves for DFS and OS in E1684 reveal early and durable separation of the high-dose and observation arms suggesting that the induction phase may represent a critical component of the high-dose regimen, although this has not been tested prospectively. Methods: We conducted a prospective randomized study of IV induction therapy vs a full year of high-dose IFN with primary endpoints of DFS and OS for stage IIB, IIC and III melanoma patients within 56 days of curative surgery. Patients were randomized to receive IFN alfa-2b 15×106 U/m2 IV × 5/7 days weekly × 4 weeks (arm A) versus the same regimen followed by 10×106 U(flat dose) SC 3 times a week for 48 weeks (arm B). The proposed treatment would be considered at least as good as the conventional treatment, if the relapse rate at 3 years from study entry is at most 15% higher in the former arm (power 85%, one-sided test a=0.05, required sample size: 340). Results: Between 1998 and 2004, 364 patients were enrolled (355 eligible: 178 arm A and 177 arm B). Patients′ and tumor characteristics were well balanced between the two arms. At a median follow up of 51 months (95% CI 46–55), the median DFS is 32 months vs 31 months (p=0.836) and the median OS is 61 months vs 63 months (p=0.444). Eleven patients discontinued treatment in arm A and 54 in arm B. The discontinuation rate is significantly higher in group B (p<0.001), possibly due to the longer duration. Reasons for discontinuation were disease progression (69%) and toxicity (19%). Patients in arm B had more grade 3–4 hematologic, constitutional and neurologic toxicity. Conclusions: There are no significant differences in OS and DFS between the regimen of 1 month and 1 year treatment tested. [Table: see text]

Systemic Adjuvant Therapy for Patients With High-Risk Melanoma

Question: What is the evidence that systemic adjuvant therapy is of benefit in patients with high-risk resected melanoma? In their study, Verma et al include patients with thick melanomas (at least 4.0 mm in thickness), Clark level V tumor, primary melanoma with in-transit metastases, primary melanoma with clinically apparent lymphnodeinvolvementorapositivesentinellymphnode biopsyresult,resectedlymphnodediseasewithnoknown primary site, and current American Joint Committee on Cancer (AJCC) 2002 stage IIB, IIC, and III disease.

Multiplex Analysis of Serum Cytokines in Melanoma Patients Treated with Interferon-α2b

Interferon (IFN)-alpha2b is the only Food and Drug Administration-approved treatment for operable high-risk melanoma that has been shown to significantly and durably prolong relapse-free survival (RFS) of patients with stage IIB-III melanoma. Development of reliable serum assays may contribute to the development of methods for earlier detection of melanoma and the selection of patients who may be most susceptible to current available interventions with IFNalpha. A powerful high-throughput xMAP multiplex immunobead assay technology (Luminex Corp., Austin, TX) was used to simultaneously test 29 cytokines, chemokines, angiogenic as well as growth factors, and soluble receptors in the sera of 179 patients with high-risk melanoma and 378 healthy individuals. Serum concentrations of interleukin (IL)-1alpha, IL-1beta, IL-6, IL-8, IL-12p40, IL-13, granulocyte colony-stimulating factor, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, IFNalpha, tumor necrosis factor (TNF)-alpha, epidermal growth factor, vascular endothelial growth factor (VEGF), and TNF receptor II were found to be significantly higher in patients with resected high-risk melanoma compared with healthy controls. Bayesian Network algorithm classification of the data offered 90% sensitivity at 98% specificity with 96.5% of melanoma patients distinguished from healthy individuals. IFN-alpha2b therapy resulted in a significant decrease of serum levels of immunosuppressive and tumor angiogenic/growth stimulatory factors (VEGF, epidermal growth factor, and hepatocyte growth factor) and increased levels of antiangiogenic IFN-gamma inducible protein 10 (IP-10) and IFN-alpha. Pretreatment levels of proinflammatory cytokines IL-1beta, IL-1alpha, IL-6, TNF-alpha, and chemokines MIP-1alpha and MIP-1beta were found to be significantly higher in the serum of patients with longer RFS values of 1 to 5 and >5 years when compared with patients with shorter RFS of <1 year. These data show that multiplexed analysis of serum biomarkers is useful for the evaluation of prognostic markers of clinical outcome and potential predictive markers of response to IFN-alpha2b in patients with high-risk operable melanoma.

Alum with Interleukin-12 Augments Immunity to a Melanoma Peptide Vaccine: Correlation with Time to Relapse in Patients with Resected High-Risk Disease

We attempted to augment immunity to melanoma antigens using interleukin-12 (IL-12) with aluminum hydroxide (alum) for sustained release or granulocyte macrophage colony-stimulating factor (GM-CSF) added to a multipeptide vaccine. Sixty patients with high-risk resected melanoma were randomized to receive melanoma peptides gp100(209-217) (210M), MART-1(26-35) (27L), and tyrosinase(368-376) (370D) with adjuvant Montanide ISA 51 and either IL-12 at 30 ng/kg with alum (group A), IL-12 at 100 ng/kg with alum (group B), or IL-12 at 30 ng/kg with 250 mug GM-CSF (group C). Three patients had stage IIC (5%), 50 had stage III (83%), and 7 had stage IV (12%) melanoma. Most toxicities were grade 1/2 and resolved rapidly. Significant toxicity included grade 3 colitis and visual changes and grade 3 headache resolving after stopping IL-12 but continuing peptide vaccine. A higher rate of post-vaccine 6-month immune response to gp100 and MART-1 was observed in group A (15 of 19) or B (19 of 20) that received IL-12 plus alum versus group C with IL-12/GM-CSF (4 of 21; P < 0.001). Post-vaccine enzyme-linked immunospot response rates to peptide analogues in group B were higher than group A (P = 0.031 for gp100 and P = 0.010 for MART-1); both were higher than group C (P < 0.001 for gp100 and P < 0.026 for MART-1). With a median of 24 months of follow-up, 23 patients have relapsed. Post-vaccine immune response to MART-1 was associated with relapse-free survival (P = 0.012). IL-12 with alum augmented an immune response to melanoma antigens compared with IL-12 with GM-CSF. Immune response was associated with time to relapse.

Phase II trial of extended dose anti-CTLA-4 antibody ipilimumab (formerly MDX-010) with a multi-peptide vaccine for resected stages IIIC and IV melanoma

2510 Background: Ipilimumab is a human anti-CTLA-4 antibody shown to have clinical activity in melanoma and renal cancer that is associated with inflammatory-type adverse events termed immune breakthrough events (IBEs). Methods: 25 patients with resected stages IIIC/IV melanoma received MART-1/gp100/tyrosinase peptides with adjuvant Montanide ISA 51 12 times injected subcutaneously with Ipilimumab at 3 mg/kg intravenously every eight weeks for 12 months. The primary endpoints were toxicity and the achievement of a 40% rate of tolerable IBEs, and 20% or less rate of intolerable adverse events. Immune responses measured by ELISPOT and peptide-tetramer assays, and time to relapse were also assessed. The three melanoma peptides differed from wild type by one amino acid modification to increase HLA binding, and were administered at 1000 mcg/dose each. Results: Median age was 55, with 13 men and 12 women. 15 patients had stage IV, and 10 had stage IIIC resected disease. Thus far, 12/25 (48%) patients had grades 2–3 IBEs; 5 (20%) were dose limiting; 7 had GI toxicity, of which 2 were dose limiting; four had skin toxicity, of which 2 were dose limiting; one patient had hypopituitarism, which was also dose limiting. No patient with dose limiting toxicity required hospitalization and all returned to baseline status with the use of systemic steroids. Serologic assays of IBD-related microbial and auto-antibodies showed that seven of eight patients tested had increases in ANCA IgG or I2 IgA, and 5/8 had increases in ASCA IgA. Four of 25 patients have relapsed with a median of 10 months of follow-up. Two were again rendered NED surgically. The two remaining patients were treated with biochemotherapy, with one CR and one PR. All 25 patients are alive, one with disease. No patient with grade 2–3 IBEs has relapsed. ELISPOT assays showed that 10/11 patients tested responded in fresh PBMC to MART-1 and gp100. Conclusions: These data suggest that IBEs are associated with clinical benefit in patients with resected high-risk melanoma receiving Ipilimumab at 3 mg/kg with a peptide vaccine, and support testing the current regimen in a larger randomized trial. [Table: see text]

High dose Interferon-α2b (HDI): Toxicity, response, and predictive markers in a neoadjuvant trial for regional lymph node metastatic melanoma

7517 Background: High-dose interferon-α2b (HDI) is the only adjuvant therapy to show consistently significant clinical benefit in resected high-risk melanoma, as tested in randomized multicenter cooperative group trials. However, the mechanism of HDI action remains uncertain, and definition of its mechanism and response markers would allow improvement upon this therapy. Neoadjuvant application of interferon may improve surgical resectability, treatment responsiveness, and enable identification of surrogate endpoints for therapy. We investigated neoadjuvant HDI in patients (pts) with palpable regional lymph node positive melanoma (AJCC Stage IIIB and IIIC) to assess the feasibility, efficacy, and molecular-histological predictors of clinical outcome. Methods: Consenting pts with palpable biopsy-proven regional lymph node metastasis received one month of daily intravenous HDI followed by lymphadenectomy and standard maintenance HDI for one year. Responses were assessed clinically, pathologically, and radiographically at day 29. Proteomic and immunohistochemical (IHC) analysis of the pre- and post-treatment biopsies was performed. Results: 17 pts (age: median 57, range 41–76) were enrolled; 11 had regional lymph node recurrence and 6 initial node + presentation. 13 completed 4 weeks of intravenous HDI, and 4 required dose reduction. Response at day 29 was complete in 1, partial in 8, and pathology established complete response in 3, with microscopic residual disease in 4. At median follow up of 14 months (range 2–38 months) there were 4 deaths from metastatic disease, 4 alive with metastatic disease, and 9 have no evidence of disease. Grade 3 and 4 toxicities occurred in 4/17 pts requiring dose reduction in 3 pts and discontinuation of HDI in 1 pt. HDI significantly increased CD4+ cell infiltration of the tumor (p=0.03). Conclusions: Neoadjuvant HDI is well-tolerated and active in stage IIIB-IIIC disease, inducing clinical response in 53% of pts prior to definitive surgery in this study. In pts with clinical response to HDI an increase in CD4+ cell infiltration of tumor by IHC suggests an indirect immunomodulatory mechanism that is currently under intense study. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough Schering-Plough

High-risk surgically resected pediatric melanoma and adjuvant interferon therapy.

Pediatric patients with high-risk surgically resected melanoma are at risk for relapse, yet little is known about these young patients and how they tolerate high-dose interferon therapy. We reviewed medical records of patients (< or =18 years) with high-risk melanoma referred to the University of Michigan Pediatric Hematology-Oncology service between January 1989 and July 2003. Fourteen patients were identified with high-risk resected melanoma. The median age at diagnosis was 8.5 years. The median time to establish diagnosis was 9 months. Primary lesions were diagnosed as unequivocal melanoma, atypical epithelioid melanocytic proliferations, or atypical Spitz tumor with indeterminate malignant potential. Twelve patients had a positive sentinel lymph node (SLN) biopsy or a palpable regional lymph node and underwent regional lymph node dissection (LND). Two patients with unequivocal melanoma with Breslow depth >4 mm had negative SLN biopsies. Twelve patients received adjuvant high-dose interferon. The following toxicities were observed: constitutional symptoms, gastrointestinal symptoms, depression or neuropsychiatric symptoms, myelosuppression, elevated AST or ALT, hypothyroidism, and hypertension. Grade 3 or 4 toxicities were uncommon with exception of neutropenia, resulting in modification of therapy in one patient. All patients are alive and free of disease at follow-up (median 24.5 months). Invasive melanoma can occur in very young children. Despite early signs of malignancy, there is often a delay in diagnosis. Histologically, diagnosis may be difficult because of overlap with Spitz nevi. Pediatric patients tolerated adjuvant high-dose interferon well and may be less likely than adults to require therapy modification secondary to toxicities.

Characterization of long-term effector-memory T-cell responses in patients with resected high-risk melanoma receiving a melanoma Peptide vaccine.

The authors determined whether long-term memory T cells could be detected in patients who received a multipeptide vaccine for high-risk resected melanoma. Five HLA-A*0201 patients received a vaccine that included the gp100(209-217) (210M) peptide with Montanide ISA 51. Peripheral blood mononuclear cells were obtained before therapy, after 6 months of vaccinations, and from 18 months to 36 months later. The presence of gp100 antigen-specific cytolytic T cells was measured by ELISPOT, tetramer and chromium release assays. Tetramer-positive CD8 cells were phenotyped by flow cytometry for markers including CD44, CD45RA, and CCR7. T-cell avidity and its evolution over time were examined in selected patients. Epitope spreading was analyzed by assessment of gp100(280-288) (288V) T cells. All patients exhibited a significant increase in tetramer-positive gp100-specific CD8 T cells that decayed at different rates over 18 to 36 months after vaccinations. Cells from all patients exhibited an effector-memory phenotype and were generally CD45 RA low/CCR7 negative and CD44 positive. Tetramer-positive cells declined over time in four of the five patients, but the proportion of tetramer-positive CD8 cells that secreted gamma-interferon rose, suggesting enrichment for effector cells. Epitope spreading for the gp100(280-288) (288V) epitope was detected. One patient maintained a population of 2.5% circulating gp100 tetramer-positive cells over 36 months. Avidity analysis showed no changes over time after induction of antigen-specific T cells. Vaccination with a heteroclitic melanoma antigen peptide with Montanide ISA 51 generated populations of circulating functional effector-memory T cells that were specific for gp100 and long-lived in the circulation for periods of 18 to 36 months after vaccination.

Immunological results of a phase II randomized trial of multipeptide vaccines for melanoma

7503 Background: To evaluate the immunogenicity of 12 peptides from cancer-testis and melanocyte differentiation proteins, and to assess the feasibility of complex peptide vaccines, a randomized phase II trial was performed in 51 patients with resected high-risk melanoma. Methods: Arm 1 received 4 peptides and arm 2 received 12 peptides. Each vaccine was an emulsion of 4 or 12 peptides (100ug each), a tetanus helper peptide (190ug), Montanide ISA-51 adjuvant (1 ml), and GM-CSF (110 ug). T-cell responses were evaluated in peripheral blood lymphocytes and in a sentinel immunized node by IFNγ ELIspot assay after one in vitro sensitization. Results: All patients have completed treatment; immunologic assessment is complete on 31 patients. Preliminary data from these 31 patients reveal immune responses in 11/14 patients (79%) on arm 1 and 17/17 patients (100%) on arm 2. Responses to 9 of the peptides are shown (Table). Patients on arm 2 responded to an average of 2.8 different peptides, those on arm 1 responded to an average of only 0.9 peptides. By comparing T cell responses to three index peptides in both peptide mixtures, it will be possible to assess whether co-administration of 4 peptides binding the same MHC molecule interferes with immunogenicity of the index peptides. Current results indicate that the median of the best immune responses for index peptides (fold-increase over background) was 9.7 in arm 1 and 11.1 in arm 2. The mean number of responses to index peptides per patient was 0.7 for Group 1, and 1.1 for Group 2. Conclusions: These findings support that (1) the most immunogenic peptides in this study were from tyrosinase, gp100, MAGE-A1, and MAGE-A10; (2) multiple peptides can be administered in combined aqueous mixture with safety and immunogenicity, and (3) immunogenicity is maintained despite peptide competition for binding to MHC. Further investigation of multiple-peptide vaccine mixtures is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration This was funded primarily by the NCI (R01 CA57653), but funding was provided by Immunex for purchase of GMCSF used in the vaccines

Immunological results of a phase II randomized trial of multipeptide vaccines for melanoma

7503 Background: To evaluate the immunogenicity of 12 peptides from cancer-testis and melanocyte differentiation proteins, and to assess the feasibility of complex peptide vaccines, a randomized phase II trial was performed in 51 patients with resected high-risk melanoma. Methods: Arm 1 received 4 peptides and arm 2 received 12 peptides. Each vaccine was an emulsion of 4 or 12 peptides (100ug each), a tetanus helper peptide (190ug), Montanide ISA-51 adjuvant (1 ml), and GM-CSF (110 ug). T-cell responses were evaluated in peripheral blood lymphocytes and in a sentinel immunized node by IFNγ ELIspot assay after one in vitro sensitization. Results: All patients have completed treatment; immunologic assessment is complete on 31 patients. Preliminary data from these 31 patients reveal immune responses in 11/14 patients (79%) on arm 1 and 17/17 patients (100%) on arm 2. Responses to 9 of the peptides are shown (Table). Patients on arm 2 responded to an average of 2.8 different peptides, those on arm 1 responded to an average of only 0.9 peptides. By comparing T cell responses to three index peptides in both peptide mixtures, it will be possible to assess whether co-administration of 4 peptides binding the same MHC molecule interferes with immunogenicity of the index peptides. Current results indicate that the median of the best immune responses for index peptides (fold-increase over background) was 9.7 in arm 1 and 11.1 in arm 2. The mean number of responses to index peptides per patient was 0.7 for Group 1, and 1.1 for Group 2. Conclusions: These findings support that (1) the most immunogenic peptides in this study were from tyrosinase, gp100, MAGE-A1, and MAGE-A10; (2) multiple peptides can be administered in combined aqueous mixture with safety and immunogenicity, and (3) immunogenicity is maintained despite peptide competition for binding to MHC. Further investigation of multiple-peptide vaccine mixtures is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration This was funded primarily by the NCI (R01 CA57653), but funding was provided by Immunex for purchase of GMCSF used in the vaccines

An update on adjuvant interferon for melanoma.

Despite advances in the staging and surgical therapy of melanoma, patients with high-risk resected melanoma still have 5-year recurrence rates of 55% to 80% and 5-year survival rates as low as 25% to 70%. Effective adjuvant therapy is needed for this patient population. The authors review the literature regarding the use of interferon for the adjuvant therapy of resected melanoma. Low-dose adjuvant interferon regimens have not affected overall survival and have had an inconsistent effect on disease-free survival across different stage groupings. High-dose adjuvant interferon improved disease- free and overall survival in the E1684 and Intergroup E1694 trials. High-dose interferon regimens cause significant morbidity, but quality-adjusted years of life are greater with this therapy. Adjuvant high-dose interferon should be considered standard therapy for all high-risk melanoma patients expected to be able to tolerate the interferon and treated off protocol. In addition, this regimen should serve as the active control in future trials of alternative adjuvant therapies for these patients.

Adjuvant therapy of melanoma with interferon-alpha-2b is associated with mania and bipolar syndromes

The use of a high dose regimen of interferon-alpha-2b (IFN) has recently been demonstrated to benefit patients with resected high risk melanoma. The incidence of melanoma is rising rapidly, and the use of this regimen is becoming increasingly common. IFN has been associated with numerous psychiatric side effects. The authors describe four melanoma patients treated with adjuvant IFN who developed a manic-depressive syndrome or mood instability with therapy, and they review the literature on mania and the mixed affective syndromes associated with IFN. The authors suggest that IFN may induce a mixed affective instability, and that patients risk developing hypomania or mania as IFN doses fluctuate or as IFN-induced depression is treated with antidepressants alone. Mania is particularly associated with dose reductions or pauses in IFN treatment. The risk of mood fluctuation continues after treatment with IFN stops, and patients should be monitored for 6 months following completion of therapy. Gabapentin appeared effective as monotherapy for acute mania, as an antianxiety agent, as a hypnotic, and as a mood stabilizer in these individual cases. Mania and mood instability can occur in patients being treated with IFN therapy for melanoma. In this study, gabapentin was an effective mood-stabilizing agent for these patients.

MELANOMA: A Multidisciplinary Approach for the General Surgeon

Advances in the understanding of the biology and treatment of melanoma have moved the care of melanoma patients into an increasingly multidisciplinary environment. Surgeons must understand these advances because they will often be responsible for directing the overall care of these patients. Most patients with melanomas more than 1 mm in diameter and no evidence of metastatic disease should be offered SLNB to more accurately stage them and direct decisions about participation in postoperative adjuvant therapy trials. Until the results of the MSLT are known, the effect of SLNB and ELND on outcome remains unknown. SLNs should be analyzed with serial sectioning and immunohistochemistry to avoid missing micro-metastatic disease. Based on the results of the ECOG-1684 trial, the FDA approved IFN-alpha 2b for the adjuvant treatment of melanoma patients with thick primary tumors (> 4 mm) or resected nodal disease. IFN-alpha 2b treatment is expensive and potentially toxic. The data from ECOG-1684 do not support the use of IFN-alpha 2b in patients with node-negative disease. In light of the ECOG-1690 trial results, the role of high-dose IFN-alpha 2b in the management of patients with resected nodal disease is considerably less clear. Any recommendations for treatment with high-dose IFN-alpha 2b should be made only after weighing the costs, side effects, and potential benefits for individual patients. Numerous, less toxic, promising, adjuvant immunotherapeutic strategies have been developed and are being tested in multicenter, prospective, randomized trials. These strategies include GMK, PMCV, and Melacine. If the results of any of these trials show a survival advantage compared with placebo or equivalent survival compared with IFN-alpha 2b, these immunotherapeutic agents will become the adjuvant treatment of choice for patients with resected high-risk melanoma. RT-PCR detection of tyrosinase in SLNs can identify patients with submicroscopic nodal disease who may be at increased risk for recurrence or death from melanoma. An ongoing, prospective, randomized trial will determine whether patients with histologically negative but RT-PCR-positive SLNs will benefit from lymphadenectomy or adjuvant IFN-alpha 2b therapy. RT-PCR can also identify minimal residual disease in peripheral blood and bone marrow from patients with high-risk melanoma, but RT-PCR analysis of peripheral blood and bone marrow is still experimental, and procedural details need to be standardized and prospectively validated in large patient groups before its use can be considered the standard of care.

Cost-effectiveness assessment of interferon alfa-2b as adjuvant therapy of high-risk resected cutaneous melanoma.

The use of interferon alfa-2b (IFN-alpha 2b) as adjuvant therapy of high-risk resected cutaneous melanoma was recently found to significantly improve relapse-free and overall survival in the Eastern Cooperative Oncology Group trial 1684 (E1684). However, treatment toxicities and costs may limit its widespread use. A cost-effectiveness and cost-utility analysis of this therapy was conducted using a hypothetical cohort of patients as if they had entered E1684. Survival and recurrence rates were calculated at 7 and 35 years for typical 50-year-old melanoma patients based on the clinical results of E1684 and natural history databases. Costs included all treatment-related costs (i.e. drug acquisition and administration, monitoring and treatment-related toxicity) and the costs of treating recurrences. Estimated utility values were assigned based on data from other oncology trials. The model predicted that IFN-alpha 2b provided an extra 0.52 years of life compared with observation at 7 years; however, at 35 years, the survival benefit of IFN-alpha 2b increased almost 4-fold to nearly 2 years. At 7 years, the cost per year of life gained was U.S. $32,600 and the cost per quality-adjusted life-year (QALY) gained was U.S. $43,200. At 35 years, these costs decreased to U.S. $13,700 and $15,200, respectively. These costs are comparable with those of other well-established medical interventions. Although these results require confirmation in a prospective study, it appears that the use of high-dose IFN-alpha 2b for patients with high-risk melanoma is cost-effective.

Systemic adjuvant treatment of high-risk melanoma: the role of interferon alfa-2b and other immunotherapies.

Until recently, the prognosis of patients with deep primary melanomas or regionally metastatic nodal disease has been poor, with 5-year survival rates of 25-50%. The results of the Eastern Cooperative Oncology Group (ECOG) trial 1684 represent the first evidence of effective adjuvant therapy for these patients. Interferon alfa-2b (IFN-alpha 2b) administered at maximally tolerated doses for 1 year significantly improved both relapse-free and overall survival. The impact of interferon therapy was observed early during treatment and the effect was durable. The results of this trial represent a breakthrough in the treatment of high-risk resected cutaneous melanoma and identify the new reference standard for new cytokines, vaccines and combinations. The favourable results provide a strong impetus for redoubled research into immunotherapy for treatment of melanoma. Specifically, ganglioside vaccines have been identified that induce antibody responses and may affect patient outcome and peptide/protein vaccines that are recognised by the T-cell have been identified in large numbers. ECOG and the U.S. Intergroup are conducting a phase III trial (E1694) that compares GM2 vaccine to IFN-alpha 2b and a phase II trial evaluating concurrent or sequential use of interferon and vaccines for patients with resectable melanoma. They are also planning phase II trials of peptides for patients with metastatic unresectable melanoma. Laboratory analyses of the immune responses induced by IFN and the several vaccines are anticipated to reveal the fundamental immune mechanisms that are important for relapse-free survival and immunological control of melanoma.

Interferon-??-2b cost effective in high-risk resected melanoma?

Interferon-??-2b cost effective in high-risk resected melanoma?