Introduction

Melanoma continues to be a significant public health problem, with 53,600 cases of melanoma diagnosed in the United States in 2002.  Although melanoma can be successfully cured in its early stages, it is the most common fatal form of skin cancer. Although the majority of patients diagnosed with melanoma present with early stage disease that is cured by surgical excision alone, for others presenting with locoregional or distant metastatic disease, the course of disease is not as favorable, with 50% to 100% of patients dying from the disease within 5 years.  The 40th Annual Meeting of the American Society of Clinical Oncology (ASCO) in June 2004 included 75 abstracts in the field of melanoma/skin cancers and represents the most current research worldwide relating to the diagnosis, staging, and treatment of melanoma.  The highlights of the meeting are presented in the following summary.

Epidemiology

The 2002 AJCC melanoma staging system was validated using population data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) cancer registry.  The registry, which includes 36,190 patients with melanoma diagnosed between 1988 and 2000, confirmed that tumor thickness, level, ulceration, age, sex and site were important prognostic factors.  The 10-year survival rates for patients with stage I and II disease from the SEER population (IA – 97.4%, IB - 84%, IIA – 69.2%, IIB – 57.4%) were slightly better than those reported for the 14,670 patients from the AJCC validation population (IA – 87.9%, IB - 80%, IIA – 63.8%, IIB – 53.9%).  The authors emphasized that risk estimates are population specific.[1]

The SEER database was also used in a study to examine risk factors and survival outcomes in pediatric patients with melanoma. In this study, 1,183 patients with melanoma were identified in the group under 20 years of age and 34,165 patients were identified in the young adult group (20-44 years).  Five-year survival in the pediatric group was 94.8% for localized disease, 69.4% for regional disease, and 36.1% for distant disease, which was similar to that seen in young adults.[2] A separate study using SEER data noted that about 8% of cases of melanoma occur in patients under 30 years of age.[3]

The clinical presentation and survival outcomes of melanoma patients with unknown primary sites were examined in a retrospective study.  A total of 71 patients (8.7%) from a cohort of 820 patients with stage III disease were confirmed to have melanoma metastatic to lymph nodes without identified primary tumors.  With a median follow-up of 7.6 years, the overall 5- and 10- year disease-free survival rates were 53% and 41%, respectively.[4]

A prospective study of 227 patients presenting with a first recurrence was reported.   The authors reported that 75% of all recurrences were detected by patients themselves and that the only clinicopathologic factor that predicted recurrence was symptomatology.[5]

Surgical Treatment

The results of sentinel lymph node (SLN) biopsy were examined retrospectively in patients with melanomas £ 1 mm (group A) and > 4 mm (group B) thickness.  A total of 832 patients were identified who underwent SLN biopsy using a combined technetium radiocolloid and blue dye technique between 1996 and 2003.  In the 176 patients with thin melanomas, nodal metastases were noted in 14 patients (7.9%).  In the 223 patients with thick melanomas, nodal metastases were identified in 79 patients (35.4%).  The 5-year overall survival for patients with SLN-positive and SLN-negative in group A was 95% and 93%, respectively.  The 5-year overall survival with SLN-positive and SLN-negative in group B was 31% versus 75%, respectively.[6]

The experience with SLN biopsy for eyelid and conjunctival malignancies was presented (12 patients with melanoma).  In a total of 20 patients, SLNs were identified using a combined technetium Tc-99-m colloid and isosulfan blue dye technique.  There were no complications noted except for mild temporary weakness of the marginal mandibular nerve in 2 patients.  None of the patients had blue tattooing of the conjunctival surface or eyelid.[7]

The utility of SLN biopsy for patients with head and neck melanoma was examined retrospectively.  The analysis, which compared 3 groups of patients (WLE alone versus WLE SLN biopsy versus WLE/SLN biopsy and completion node dissection), noted that there was a decrease in the incidence of local/regional recurrence (6.3% versus 20%) in those patients who had undergone SLN biopsy.[8]

The clinical outcomes for a series of 17 patients who underwent adrenalectomy for metastases between 1987 – 2001 were presented.  The median survival for this group was 19 months.[9]

Therapeutic Vaccines

The highlight of the melanoma sessions were the updates on the status of vaccine therapy.  Two large cooperative group studies were presented.  The Southwest Oncology Group  (SWOG) reported the results from their randomized study of 689 patients with stage II melanoma treated with a melanoma cell lysate vaccine.  In this study, which had a follow-up time of 7.8 years, there was no benefit in 5-year overall survival for patients treated with the vaccine.  However, a subset analysis that examined patients according to HLA type suggested that patients with particular HLA subtypes, specifically HLA-A2 and C3, benefited from vaccine therapy, with 5-year survival of 93% versus 74%.  SWOG is planning a confirmatory trial.[10]

The Eastern Cooperative Oncology Group (ECOG) reported the results of their phase II trial of a multi-epitope peptide vaccine for patients with metastatic (stage IV) melanoma.  This trial of 120 patients was designed so that patients were randomized to one of four treatment arms, which included peptide vaccine alone or in combination with GM-CSF, IFNa, or combination GM-CSF and IFNa.  The outcome measurement for the trial was immune response, which was measured using an ELISPOT assay in the laboratory using patient blood samples (peripheral blood lymphocytes (PBL)).  In this study, 37% of patients had an increased immunologic response to the vaccine, which was not influenced by GM-CSF or IFNa.  Of those patients who demonstrated an immunologic response, the median overall survival was 21.3 months, compared to 13.4 months for patients who did not have an immunologic response.[11]

Another phase II randomized trial of multipeptide vaccines was reported from the University of Virginia.  This study, which included 51 patients with resected high-risk melanoma, included 2 treatment arms, which differed by the number of peptides administered with a helper peptide and GM-CSF.  Immunologic responses were evaluated from peripheral blood samples and a lymph node.  The authors reported that it was safe and feasible to administer multiple peptides as a vaccine.  The most immunogenic peptides administered were tyrosinase, gp100, MAGE-A1, and MAGE-A10.[12]

A strategy for enhancing the response to vaccination was reported that used vaccinia virus expressing costimulatory molecules to enhance the systemic immunologic response.  In this small study of 25 patients, investigators reported that 8 patients exhibited distant tumor responses.[13]

Immunotherapy

A phase 2 trial of Allovectin-7, an agent which induces a local inflammatory response, was reported to induce tumor shrinkage in 12 of 91 patients with infectable cutaneous, subcutaneous, or nodal lesions.  The median duration of response was 6.4 months.[14]

High-dose bolus interleukin-2 (IL-2) was reported to have activity, with objective responses noted in 5 of 26 patients (19%) who had previously been treated with biochemotherapy (combination chemotherapy, infusional IL-2 and IFN-a).[15]

A phase II trial of temozolomide and low-dose pegylated interferon in the treatment of 30 patients with stage IV unresectable melanoma was presented.  The combination was considered to be well tolerated and the median survival of the group was 8.5 months.[16]

Combination Therapies

Biochemotherapy

A systematic review of the literature involving the treatment of patients with metastatic melanoma with biochemotherapy (cytotoxic chemotherapy and immunotherapy including IFN and IL-2) was performed.  Phase II and Phase III trials were included and pooled data was used to estimate response rate, time to progression and overall survival.  The authors identified 9 randomized clinical trials, 8 randomized phase II trials and 39 single-arm phase II trials.  The pooled analysis demonstrated that biochemotherapy was superior to chemotherapy with respect to response rate and time to progression, but not 1-year overall survival.   The authors note that there were increased  toxicities associated with biochemotherapy, which should be considered when prescribing treatment.[17]

The result of biochemotherapy with CVD (DTIC, CDDP and vinblastine) combined with subcutaneous IL-2 was reported.  A total of 39 patients were treated between 1996 – 2003, with acceptable toxicity.  There were 6 complete responses (24%) and 8 partial responses (32%) observed with a median time to progression of 6.5 months.[18]

The result of administration of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, temozolomide, interferon and interleukin-2 was reported.  In 22 patients with assessable metastatic disease, one patient (4.5%) achieved a complete response and 10 patients (45.5%) achieved a partial response.  The median time to disease progression for all patients was 5 months.  Although there were no treatment-related deaths, toxicity for this regimen was noted to be severe.[19] 

Isolated Limb Perfusion (ILP)

The toxicity and survival of 56 patients who underwent ILP using melphalan was reported by a group from the United Kingdom.  The authors reported that a tumor response was detected in 48 patients (92%), with 31 complete responses.  Significant Grade III/IV bone marrow toxicities were reported in 14 patients and other systemic side effects included nausea and vomiting (82%), fever (31%), and hair loss (4%).  Five-year survival for the group of patients who received a therapeutic ILP was 49%.[20]

Radiation and Chemotherapy

A study of radiotherapy (RT) followed by temozolomide (TMZ) in the treatment of patients with melanoma metastatic to the brain was reported.  Among 15 evaluable patients, 5 had stabilization of their disease and 3 partial responses of cerebral sites were noted.  The median survival was 180 days for patients who received both RT and TMZ.[21]

Radiation Therapy

A retrospective review examining adjuvant nodal radiotherapy with head and neck melanoma was presented.  The single institution study noted that the incidence of local (cervical nodal) recurrence was less (25% vs. 43%) in the irradiated group.[22]

Imaging

A prospective study that examined the utility of PET scanning in preoperative melanoma patients was reported from Memorial Sloan-Kettering Cancer Center and Columbia University.  In a total of 103 patients with preoperative stage III and stage IV disease (n = 15), the addition of PET scanning to standard CT imaging led to a change in management in 34 patients, primarily due to the detection of occult metastatic disease.[23]  Another group from John Wayne Cancer Institute reported that the sensitivity of PET imaging could be improved for lesions < 1 cm with a hand-held radiation detection probe system (PET-Probe).  In their study of 26 patients, the PET-Probe was reported to improve intraoperative management by identifying occult tumors. [24]

Sentinel node assessment techniques using in vivo and ex vivo ultrasound, fine needle aspiration cytology and tyrosinase RT-PCR were reported.  The evaluation of 136 sentinel nodes confirmed that ultrasound and fine needle aspiration cannot replace SLN biopsy, but can identify nodal metastases so that patients may directly undergo lymph node dissection.[25]

On the Horizon

There were a number of reports that included small numbers of patients treated with newer agents (Bcl-2 antisense[26] and BAY 43-9006[27],[28]) that target cell death (apoptosis) and retard cell growth (angiogenesis) through specific molecular pathways. Although these agents are generally well tolerated and have demonstrated promise in the laboratory setting, clinical benefits have not yet been observed. 

A melanoma-specific subscale for the Functional Assessment of Cancer Therapy (FACT-Melanoma) quality of life questionnaire was introduced.  The questionnaire is currently undergoing validation in a large prospective study.  It is available for inclusion in clinical trials to examine melanoma-specific quality of life[29]

Conclusion

There is significant ongoing study in the field of melanoma.  As the understanding of tumor biology including molecular mechanisms increases, so will the ability to develop targeted cancer therapies.  Vaccine therapies continue to hold future promise for melanoma treatment. 

References