Adjuvant Therapy For Melanoma Research Articles

172 INVITED New developments in adjuvant therapy in melanoma

Schwann cells and the glial cells of peripheral nerves arise from the neural crest. They develop through multiple stages, including Schwann cell precursor and immature Schwann cell, before undergoing terminal differentiation. The underlying changes in gene expression are elicited by stage- or cell-specific transcription factors. Sox10 is required for Schwann cell specification, whereas Pax3, FoxD3, Sox2, and cJun help to maintain the undifferentiated and immature state. Eventually, nuclear factor-κB, Oct6, Brn2, and Krox20 act in a defined order to drive the terminal differentiation of myelinating Schwann cells.

Interferon-α as adjuvant therapy for melanoma: An individual patient data meta-analysis of randomised trials

8526 Background: Many randomised trials have evaluated the role of adjuvant interferon-a (IFN) in high-risk melanoma, some suggesting benefit and others not. To assess the totality of current evidence, an individual patient data (IPD) meta-analysis of all available trials was performed. Methods: Standard IPD meta-analysis methods were used to assess event-free (EFS) and overall survival (OS), with odds ratios (OR) and 95% confidence intervals (CI) calculated. Trials were divided by dose of IFN - high (20 MU/m2), intermediate (5–10 MU), low (3 MU) and very low (1 MU). Subgroup analyses by patient age, gender and disease characteristics were also performed. Results: IPD was provided for 10 of 13 reported trials of IFN vs. no IFN (for the other 3 trials published data were used). 6067 patients (IPD available for 85%) were included in the analysis, with over 3,700 and 3,000 events for EFS and OS. There was statistically significant benefit for IFN for both EFS (OR=0.87, CI=0.81–0.93, p=0.00006) and OS (0.9, 0.84–0.97, p=0.008). There was no evidence of differences according to dose (Table 1; trend p>0.1) or duration of IFN. This proportional survival advantage translates into an absolute benefit of about 3% (CI 1%-5%) at 5 years. The effect of IFN did not differ with age, gender, tumor site, Breslow thickness, clinical nodes or disease stage. Only for ulceration was there some evidence of an interaction (p=0.03); patients with ulcerated tumors had greater benefit from IFN (EFS: OR=0.76, OS: OR=0.77) than those with no ulceration (EFS: OR=0.94, OS: OR=0.98). Conclusions: This meta-analysis provides evidence that adjuvant IFN significantly reduces the risk of relapse and improves overall survival, although the absolute survival benefit is relatively small. This analysis does not however, clarify the optimal (high, intermediate or low) dose of IFN. Given the large number of subgroup analyses performed, the apparent increased benefit in patients with ulceration requires confirmation. No significant financial relationships to disclose.

A simplified staging system in cutaneous melanoma to select patients for adjuvant trials

19003 Background: Most clinical trials with adjuvant therapy in melanoma concentrate on high-risk patients including those with metastases to regional lymph nodes (LN), stage III and locally advanced T4, i.e., stage IIB and IIC. These trials may be missing the advantageous results in the relatively earlier stages. Methods: We reviewed the new American Joint Committee on Cancer (AJCC) for cancer staging of cutaneous melanoma and Balchs’ data for the prognostic factors. The data was correlated to patients’ survival expressed by the natural history of the disease. Results: We grouped the reported survival data into 3 risk groups, excluding patients with distant metastases. Group 1: 2–4mm deep primary with ulceration, >4mm deep primary without ulceration, micrometastases to 1–3 LN, primary not ulcerated; Group 2: >4mm deep primary with ulceration, micrometastases to 1–3 LN ulcerated primary, macrometastases to 1–3 LN, primary not ulcerated intransit metastases/satellitosis, without LN metastases; Group 3: macrometastases to 1–3 LN, ulcerated primary, metastases to 4 or more LN, matted LN, and/or intransit, metastases/satellitosis with LN metastases. The table summarizes the results. Conclusions: 1. Over one-third of the patients in group 1 died of disease in the first 5 years. They should be considered at intermediate risk and should receive adjuvant therapy. 2. Patient prognosis should determine the intensity of target therapy utilized in the adjuvant arena. While anti-CTLA-4 may be sufficient for group 1, the addition of anti-kinases may be required in group 2 and more so in group 3. [Table: see text] No significant financial relationships to disclose.

Recombinant interferon α-2b and coenzyme Q10 as a postsurgical adjuvant therapy for melanoma: a 3-year trial with recombinant interferon-α and 5-year follow-up

Early surgical intervention remains the most successful therapy for melanoma. Despite better outcomes observed in soft tissue and lymph node metastases, the results of pharmacological therapies are still disappointing. Currently, there is no standard adjuvant therapy for melanoma. Low concentrations of coenzyme Q10 have been demonstrated in melanoma cell lines and in sera of melanoma patients. These data and the results of clinical trials of patients with other advanced cancers prompted this study of the long-term administration of an optimized dose of recombinant interferon alpha-2b and coenzyme Q10 to patients with stage I and II melanoma. A 3-year trial envisaging uninterrupted treatment with low-dose recombinant interferon alpha-2b (9 000 000 000 IU weekly) administered twice daily and coenzyme Q10 (400 mg/day) was conducted in patients with stage I and II melanoma (American Joint Committee on Cancer criteria 2002) and surgically removed lesions. Treatment efficacy was evaluated as incidence of recurrences at 5 years. All patients completed the treatment and the follow-up. Significantly different rates of disease progression were observed in the interferon+coenzyme Q10 and the interferon group for both stages. No patient withdrew from the study owing to side effects. Long-term administration of an optimized dose of recombinant interferon alpha-2b in combination with coenzyme Q10 seemed to induce significantly decreased rates of recurrence and had negligible adverse effects. A survival study could not be undertaken owing to the small patient sample and the short duration of follow-up.

Adjuvant Therapy of Melanoma

The purpose of this article was to review the current state of knowledge regarding the efficacy of adjuvant therapy for melanoma. We reviewed the published literature, focusing on randomized clinical trials. There have been no meaningful trials addressing adjuvant chemotherapy in melanoma because all trials have been underpowered. Adjuvant interferon-alpha has been tested both at high dose and at lower doses. None of the trials have shown a reproducible benefit in survival, although the high-dose trials and some of the low-dose trials have shown improvement in time to relapse. These experiences raise the question of whether chronic administration is more important than dose. An adjuvant pegylated interferon-alpha trial using a 5-year treatment period is currently under investigation. At least 7 randomized adjuvant vaccine trials have been published, but none have shown a beneficial effect on relapse-free or overall survival except in subset analyses. To date, no adjuvant therapy has resulted in improved overall survival. To be attractive as an adjuvant therapy, experience from other tumor types indicates that a chemotherapy regimen should have a response rate of at least 20% in metastatic melanoma. Currently, biochemotherapy is being tested as an adjuvant treatment but other, less toxic, regimens should be sought. Once such a regimen with acceptable toxicity is identified, it would be reasonable to test it as an adjuvant therapy in a properly powered randomized trial. High-dose interferon-alpha for 1 year remains the only U.S. Food and Drug Administration-approved adjuvant therapy for melanoma, but long-term chronic dosing of interferon-alpha may prove more effective than short-term dose schedules. Development of melanoma vaccines remains an appealing and important goal. New technologies and understanding of the immune response against melanoma are leading to novel vaccine strategies designed to break immunologic tolerance against melanoma.

INV 23 Granulocyte-macrophage colony-stimulating factor (GM-CSF) as adjuvant therapy of melanoma

Oxford Radcliffe Hospitals, Cancer Research UK Medical Oncology Unit, Churchill Hospital, Oxford, UK Email: [email protected] Abstracts of the Sixth International Conference on the Adjuvant Therapy of Malignant Melanoma

P-10 Effects of silencing of flotillin-2 by siRNA in human melanoma cells

Regional Reference Center for ‘Locoregional Perfus’, Department of Medical and Surgical Critical Care – University, Florence, Italy Email: [email protected] Abstracts of the Sixth International Conference on the Adjuvant Therapy of Malignant Melanoma

INV 34 Clinical trials with sorafenib in melanoma: is there evidence to support adjuvant trials?

The Institute of Cancer Research, Signal Transduction Team, 237 Fulham Road, London, UK Email: [email protected] Abstracts of the Sixth International Conference on the Adjuvant Therapy of Malignant Melanoma

INV 13 Sentinel node biopsy in melanoma: a house of cards?

Instituto Nazionale Tumori, Milano, Italy Abstracts of the Sixth International Conference on the Adjuvant Therapy of Malignant Melanoma

INV 7 Primary melanomas with metastatic potential

Cancer Research UK Carcinogenesis Group, University of Manchester, Christie Hospital, Paterson Institute for Cancer Research, Manchester, UK Email: [email protected] Abstracts of the Sixth International Conference on the Adjuvant Therapy of Malignant Melanoma

INV 30 Melanocytic differentiation antigens and humoral immune responses

Istituto Nazionale Tumori, Unit of Immunotherapy of Human Tumors, Milan, Italy Email: [email protected] Abstracts of the Sixth International Conference on the Adjuvant Therapy of Malignant Melanoma

P-02 NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing

Department of Biotechnology, AlbaNova University Center, Royal Institute of Technology, Stockholm, Sweden Email: [email protected] Abstracts of the Sixth International Conference on the Adjuvant Therapy of Malignant Melanoma

INV 19 Role of chemotherapy in advanced melanoma

St Eriks Eye Hospital, Stockholm, Sweden Email: [email protected] Abstracts of the Sixth International Conference on the Adjuvant Therapy of Malignant Melanoma

P-12 Metastatic melanoma cell FGF2 binding, signaling and angiogenesis are modulated by heparanase

UTMD Anderson Cancer Center, Dermatology, Houston, USA Email: [email protected] Abstracts of the Sixth International Conference on the Adjuvant Therapy of Malignant Melanoma

INV 27 Phase I trial of sorafenib (BAY 43-9006) combined with dacarbazine (DTIC) in patients with metastatic melanoma

Marseilles, France Email: [email protected] Abstracts of the Sixth International Conference on the Adjuvant Therapy of Malignant Melanoma

INV 11 Sentinel node biopsy: a mini-invasive procedure to plan surgical treatment of stage IB and II melanoma patients

Oncology Centre, Cromwell Hospital, London, UK Email: [email protected] Abstracts of the Sixth International Conference on the Adjuvant Therapy of Malignant Melanoma

INV 26 DeCOG (Dermatologic Cooperative Oncology Group) melanoma trials in the adjuvant setting

Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, USA Email: [email protected] Abstracts of the Sixth International Conference on the Adjuvant Therapy of Malignant Melanoma

INV 31 How effective will TRAIL be in treatment of melanoma?

Germany Abstracts of the Sixth International Conference on the Adjuvant Therapy of Malignant Melanoma

INV 16 Metastatic uveal melanoma

MD Anderson Cancer Centre, Houston, Texas, USA Abstracts of the Sixth International Conference on the Adjuvant Therapy of Malignant Melanoma

Interferon therapy discussed at the Sixth International Conference on the Adjuvant Therapy of Malignant Melanoma, Stockholm, Sweden, 15???17 June 2006

Interferon therapy discussed at the Sixth International Conference on the Adjuvant Therapy of Malignant Melanoma, Stockholm, Sweden, 15???17 June 2006