Final Results of the Sunbelt Melanoma Trial: A Multi-Institutional Prospective Randomized Phase III Study Evaluating the Role of Adjuvant High-Dose Interferon Alfa-2b and Completion Lymph Node Dissection for Patients Staged by Sentinel Lymph Node Biopsy.

PURPOSE: The Sunbelt Melanoma Trial is a prospective randomized trial evaluating the role of high-dose interferon alfa-2b therapy (HDI) or completion lymph node dissection (CLND) for patients with melanoma staged by sentinel lymph node (SLN) biopsy. PATIENTS AND METHODS: Patients were eligible if they were age 18 to 70 years with primary cutaneous melanoma ≥ 1.0 mm Breslow thickness and underwent SLN biopsy. In Protocol A, patients with a single tumor-positive lymph node after SLN biopsy underwent CLND and were randomly assigned to observation versus HDI. In Protocol B, patients with tumor-negative SLN by standard histopathology and immunohistochemistry underwent molecular staging by reverse transcriptase polymerase chain reaction (RT-PCR). Patients positive by RT-PCR were randomly assigned to observation versus CLND versus CLND+HDI. Primary end points were disease-free survival (DFS) and overall survival (OS). RESULTS: In the Protocol A intention-to-treat analysis, there were no significant differences in DFS (hazard ratio, 0.82; P = .45) or OS (hazard ratio, 1.10; P = .68) for patients randomly assigned to HDI versus observation. In the Protocol B intention-to-treat analysis, there were no significant differences in overall DFS (P = .069) or OS (P = .77) across the three randomized treatment arms. Similarly, efficacy analysis (excluding patients who did not receive the assigned treatment) did not demonstrate significant differences in DFS or OS in Protocol A or Protocol B. Median follow-up time was 71 months. CONCLUSION: No survival benefit for adjuvant HDI in patients with a single positive SLN was found. Among patients with tumor-negative SLN by conventional pathology but with melanoma detected in the SLN by RT-PCR, there was no OS benefit for CLND or CLND+HDI.

Surveillance after surgical treatment of melanoma: futility of routine chest radiography.

BACKGROUND: Current recommendations by the National Comprehensive Cancer Network and other groups suggest that follow-up of cutaneous melanoma may include chest radiography (CXR) at 6- to 12-month intervals. The aim of this study was to determine the clinical efficacy of routine CXR for recurrence surveillance in melanoma. METHODS: Post hoc analysis was performed on data from a prospective, randomized, multi-institutional study on melanoma ≥1.0 mm in Breslow thickness. All patients underwent excision of the primary melanoma and sentinel node biopsy with completion lymphadenectomy for positive sentinel nodes. Yearly CXR and clinical assessments were obtained during follow-up. Results of routine CXR were compared with clinical disease states over the course of the study. RESULTS: A total of 1,235 patients were included in the analysis over a median follow-up of 74 months (range, 12-138). Overall, 210 patients (17.0%) had a recurrence, most commonly local or in-transit. Review of CXR results showed that 4,218 CXR were obtained in 1,235 patients either before, or in the absence of, initial recurrence. To date, 88% (n = 3,722) CXR are associated with no evidence of recurrence. Of CXR associated with recurrence, only 7.7% (n = 38) of surveillance CXR were read as "abnormal." Overall, 99% (n = 4,180) of CXR were read as either "normal" or found to be falsely positive (read as "abnormal," but without evidence of recurrence on investigation). Only 0.9% (n = 38) of all CXR obtained were true positives ("abnormal" CXR, with confirmed first known recurrence). Among these 38 patients with true positive CXR, 35 revealed widely disseminated disease (multiorgan or bilateral pulmonary metastases); only 3 (0.2%) had isolated pulmonary metastases amenable to resection. Sensitivity and specificity for surveillance CXR in detecting initial recurrence were 7.7% and 96.5%, respectively. CONCLUSION: The routine use of surveillance CXR provides no clinically useful information in the follow-up of patients with melanoma. CXR does not detect recurrence at levels sufficient to justify its routine use and, therefore, cannot be recommended as part of the standard surveillance regimen for these patients.

Second primary melanomas: incidence and outcome.

The objective of this study was to determine the incidence of multiple primary melanomas (MPM) and other cancers types among patients with melanoma. Factors associated with development of MPM were assessed in a post hoc analysis of the database from a multi-institutional prospective randomized trial of patients with melanoma aged 18 to 70 years with Breslow thickness 1 mm or greater. Disease-free survival (DFS) and overall survival (OS) were evaluated by Kaplan-Meier analysis. Forty-eight (1.9%) of 2506 patients with melanoma developed additional primary melanomas. Median follow-up was 66 months. Except in one patient, the subsequent melanomas were thinner (median, 0.32 mm vs. 1.50 mm; P < 0.0001). Compared with patients without MPM, patients with MPM were more likely to be older (median age, 54.5 vs. 51.0 years; P = 0.048), to have superficially spreading melanomas (SSM) (P = 0.025), to have negative sentinel lymph nodes (P = 0.021), or to lack lymphovascular invasion (LVI) (P = 0.008) with the initial tumor. On multivariate analysis, age (P = 0.028), LVI (P = 0.010), and SSM subtype of the original melanoma (P = 0.024) were associated with MPM. Patients with MPM and patients with single primary melanoma had similar DFS (5-year DFS 88.7 vs. 81.3%, P = 0.380), but patients with MPM had better OS (5-year OS 95.3 vs. 80.0%, P = 0.005). Nonmelanoma malignancies occurred in 152 patients (6.1%). Ongoing surveillance of patients with melanoma is important given that a significant number will develop additional melanoma and nonmelanoma tumors. With close follow-up, second primary melanomas are usually detected at an early stage.

The prognostic significance of nonsentinel lymph node metastasis in melanoma.

BACKGROUND: We hypothesized that metastasis beyond the sentinel lymph nodes (SLN) to the nonsentinel nodes (NSN) is an important predictor of survival. MATERIALS AND METHODS: Analysis was performed of a prospective multi-institutional study that included patients with melanoma ≥ 1.0 mm in Breslow thickness. All patients underwent SLN biopsy; completion lymphadenectomy was performed for all SLN metastases. Disease-free survival (DFS) and overall survival (OS) were computed by Kaplan-Meier analysis; univariate and multivariate analyses were performed to identify factors associated with differences in survival among groups. RESULTS: A total of 2335 patients were analyzed over a median follow-up of 68 months. We compared 3 groups: SLN negative (n = 1988), SLN-only positive (n = 296), and both SLN and NSN positive (n = 51). The 5-year DFS rates were 85.5, 64.8, and 42.6% for groups 1, 2, and 3, respectively (P < 0.001). The 5-year OS rates were 85.5, 64.9, and 49.4%, respectively (P < 0.001). On univariate analysis, predictors of decreased OS included: SLN metastasis, NSN metastasis, increased total number of positive LN, increased ratio of positive LN to total LN, increased age, male gender, increased Breslow thickness, presence of ulceration, Clark level ≥ IV, and axial primary site (in all cases, P < 0.01). When the total number of positive LN and NSN status were evaluated using multivariate analysis, NSN status remained statistically significant (P < 0.01), while the total number of positive LN and LN ratio did not. CONCLUSIONS: NSN melanoma metastasis is an independent prognostic factor for DFS and OS, which is distinct from the number of positive lymph nodes or the lymph node ratio.

Factors associated with false-negative sentinel lymph node biopsy in melanoma patients.

INTRODUCTION: Some melanoma patients who undergo sentinel lymph node (SLN) biopsy will have false-negative (FN) results. We sought to determine the factors and outcomes associated with FN SLN biopsy. METHODS: Analysis was performed of a prospective multi-institutional study that included patients with melanoma of thickness > 1.0 mm who underwent SLN biopsy. FN results were defined as the proportion of node-positive patients who had a tumor-negative sentinel node biopsy. Kaplan-Meier survival analysis and univariate and multivariate analyses were performed. RESULTS: This analysis included 2,451 patients with median follow-up of 61 months. FN, true-positive (TP), and true-negative (TN) SLN results were found in 59 (10.8%), 486 (19.8%), and 1,906 (77.8%) patients, respectively. On univariate analysis comparing the FN with TP groups, respectively, the following factors were significantly different: age (52.6 vs. 47.6 years, p = 0.004), thickness (mean 2.1 vs. 3.1 mm, p = 0.003), lymphovascular invasion (LVI; 3.7 vs. 13.7%, p = 0.037), and local/in-transit recurrence (LITR; 32.2 vs. 12.4%, p < 0.0001); these factors remained significant on multivariate analysis. Overall 5-year survival was greater in the TN group (86.7%) compared with the TP (62.3%) and FN (51.3%) groups (p < 0.0001); however, there was no significant difference in overall survival comparing the TP and FN groups (p = 0.32). CONCLUSIONS: This is the largest study to evaluate FN SLN results in melanoma, with a FN rate of 10.8%. FN results are associated with greater patient age, lower mean thickness, less frequent LVI, and greater risk of LITR. However, survival of patients with FN SLN is not statistically worse than that of patients with TP SLN.

Lumpectomy margins are affected by tumor size and histologic subtype but not by biopsy technique.

OBJECTIVE: The effect of the type of biopsy (needle vs. excisional) on lumpectomy margin status has not been well established. The objective of this study was to determine whether needle biopsy is associated with a higher positive margin rate at time of lumpectomy. METHODS: We evaluated this hypothesis in the setting of a prospective multi-institutional study. A total of 3975 patients were enrolled in the University of Louisville Breast Cancer Sentinel Lymph Node Study from May 7, 1998 to June 3, 2003. Patients who underwent lumpectomy at the time of their sentinel lymph node biopsy were the focus of this analysis. Patients with clinical stage T1 N0 and T2 N0breast cancer were eligible; 29 patients were found to have T3 tumors on final pathology. Pathologists at each institution defined margin positivity, and tumor at the inked margin of resection was the study guideline. RESULTS: Median patient age was 59 years, and median tumor size was 1.5 cm. A total of 2658 patients underwent lumpectomy with the following results. The cancer of 1515 patients was diagnosed by fine-needle or core-needle biopsy and of 821 patients was diagnosed by excisional biopsy; in 322 patients the method of diagnosis was unknown. The type of previous biopsy did not significantly affect the positive-margin rate at the time of lumpectomy (13.3% vs. 11.0% for needle and excisional biopsy, respectively, P = 0.107). However, patients with larger tumors were more often found to have a positive margin (11.4% vs. 13.9% vs. 27.6% for T1, T2, and T3 tumors, respectively; P = 0.010). No difference was found in margin status after excision of palpable versus nonpalpable tumors (10.6% vs. 10.9%, respectively, P = 0.743). Histologic subtype, however, did affect margin status (15.8% vs. 9.8% positive margins for lobular vs. ductal type, respectively, P = 0.003). CONCLUSIONS: In this multi-institutional study, increasing tumor size and lobular histologic subtype were associated with a greater likelihood of a positive margin. The type of biopsy, needle or excisional, had no effect on the ability to achieve negative margins.

Correlation between prognostic factors and increasing age in melanoma.

BACKGROUND: Age of patients with melanoma varies directly with mortality and inversely with the presence of sentinel lymph node (SLN) metastasis. To gain further insight into this apparent paradox, we analyzed the relationship between age and other major prognostic factors. METHODS: The Sunbelt Melanoma Trial is a prospective, randomized study with 79 institutions involving SLN biopsy for melanoma. Eligible patients were 18 to 70 years old with melanoma of > or = 1.0-mm Breslow thickness and clinically N0 regional lymph nodes. SLNs were evaluated by serial histological sections and immunohistochemistry for S-100 protein. RESULTS: A total of 3076 patients were enrolled in the study, with a median follow-up of 19 months. Five age groups were examined: 18 to 30, 31 to 40, 41 to 50, 51 to 60, and 61 to 70 years. Trends between age and several key prognostic factors was identified: as age group increased, so did Breslow thickness (analysis of variance; P <.001), the incidence of ulceration and regression, and the proportion of male patients (each variable: chi2, P <.001). The incidence of SLN metastasis, however, declined with increasing age (chi2; P <.001). CONCLUSIONS: As age increases, so does Breslow thickness, the incidence of ulceration and regression, and the proportion of male patients-all poor prognostic factors. However, the frequency of SLN metastasis declines with increasing age. It is not known whether this represents a decreased sensitivity (higher false-negative rate) of the SLN procedure in older patients or a different biological behavior (hematogenous spread) of melanomas in older patients.