Sequential administration of GM-CSF (Sargramostim) and IL-2 +/- autologous vaccine as adjuvant therapy in cutaneous melanoma: an interim report of a phase II clinical trial.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) are 2 cytokines with distinct mechanisms of action that complement one another in the adjuvant management of melanoma. Forty-five patients with high-risk melanoma were enrolled in an open-label, single-arm, phase II clinical trial to examine the safety, tolerability, and effectiveness of this combination. After potentially curative surgery, each patient received 12 months of GM-CSF 125 microg/m2/d subcutaneously (SC) for 14 days followed by IL-2, 9 million IU/m2/d SC for 4 days (given every other cycle from months 7-12), followed by 10 days of no treatment. In addition, patients who had tumors yielding an adequate number of live cells received autologous melanoma vaccines. For months 13-24, patients received only GM-CSF 250 microg/m2 twice weekly. This is an interim analysis based on the 45 enrolled patients with a median of 15.9 months follow-up (range, 1-50 months). Thirty-two patients are alive: 9 of 13 with stage IV resected melanoma, 16 of 25 with stage III disease, and 7 of 7 with stage II disease. Twelve died of the disease, and one due to stroke. Adjuvant use of sequential GM-CSF and IL-2 +/- autologous vaccine was well tolerated with good patient compliance and seemed to benefit high-risk patients with surgically resected melanoma.

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.

GM-CSF and IL-2 combination as adjuvant therapy in cutaneous melanoma: early results of a phase II clinical trial.

Cytokines have been used in the treatment of patients with cutaneous melanoma. Granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine]) leads to dendritic cell/macrophage priming and activation, and also increases interleukin-2 (IL-2) receptor expression on T. lymphocytes. IL-2 creates lymphokine-activated killer cells and tumor-infiltrating lymphocyte cells. In this open-label, single-arm study of 16 high-risk patients, we combined these two agents to take advantage of their different but complementary functions. All patients underwent potentially curative surgery. Postoperatively, each patient received GM-CSF at 125 microg/m2/d subcutaneously (SC) for 14 days; this was followed by IL-2 at 9 million IU/m2/d SC for 4 days, and then 10 to 12 days of no treatment. In addition, patients who had large tumors that could yield over 100 million live tumor cells received autologous melanoma vaccines. The duration of follow-up ranged from 21 to 42 months (median: 27 months). During follow-up, five patients developed metastases. This program was carried out on an outpatient basis, and no hospitalization was required. It was well tolerated with minimal side effects. The combination treatment regimen of GM-CSF and IL-2 with or without autologous vaccine used adjuvantly appears to benefit high-risk melanoma patients; further clinical testing of this regimen is warranted.

The risk of regional lymph node metastases in patients with melanoma less than 1.0 mm thick: recommendations for sentinel lymph node biopsy.

BACKGROUND: Lymphatic mapping and sentinel lymph node biopsy can upstage patients with intermediate thickness (1.0 to 4.0 mm) melanoma. Currently, there are no strict guidelines for sentinel lymph node biopsy in patients with melanoma <1.0 mm thick. STUDY DESIGN: A retrospective review of our patient database (598 patients treated at two institutions in Baltimore, MD, between January 1970 and June 2002) was performed to identify patients with primary cutaneous melanoma <1.0 mm thick who developed recurrent disease. This cohort of patients with > or =5 years of followup from the date of diagnosis was compared with patients with primary melanoma of similar thickness and similar followup intervals without recurrent disease. RESULTS: A total of 114 patients with primary cutaneous melanoma <1.0 mm thick were identified, 17 of whom developed disease recurrence. In 13 patients, the site of first recurrence was the regional lymph nodes and in 4 patients disease recurred with distant metastases. The median time to lymph node recurrence was 55 months (range 2 to 112) months. Patients with regional lymph node recurrences had a significant (p = 0.02) difference in median primary tumor thickness of 0.80 mm versus 0.45 mm in patients without recurrent disease; there was no association of Clark level of invasion to recurrence (p = 0.42). In all, 35% of patients (7 of 20) presenting with melanoma 0.80 to 0.99 mm thick developed lymph node recurrence a median of 41 months (range 8 to 112 months) after surgical treatment. CONCLUSIONS: Sentinel lymph node biopsy can be justified for patients with melanoma > or =0.8 mm thick provided that the technique would detect metastatic disease years before it becomes clinically evident.