gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma.

BACKGROUND: Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. METHODS: We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209-217(210M) plus incomplete Freund's adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end point was clinical response. Secondary end points included toxic effects and progression-free survival. RESULTS: The treatment groups were well balanced with respect to baseline characteristics and received a similar amount of interleukin-2 per cycle. The toxic effects were consistent with those expected with interleukin-2 therapy. The vaccine-interleukin-2 group, as compared with the interleukin-2-only group, had a significant improvement in centrally verified overall clinical response (16% vs. 6%, P=0.03), as well as longer progression-free survival (2.2 months; 95% confidence interval [CI], 1.7 to 3.9 vs. 1.6 months; 95% CI, 1.5 to 1.8; P=0.008). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months; 95% CI, 11.9 to 25.8 vs. 11.1 months; 95% CI, 8.7 to 16.3; P=0.06). CONCLUSIONS: In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00019682.).

Diversity of stage III melanoma in the era of sentinel lymph node biopsy.

BACKGROUND: Sentinel lymph node (SLN) biopsy for melanoma often detects minimal nodal tumor burden. Although all node-positive patients are considered stage III, there is controversy regarding the necessity of adjuvant therapy for all patients with tumor-positive SLN. METHODS: Post hoc analysis was performed of a prospective multi-institutional study of patients with melanoma ≥ 1.0 mm Breslow thickness. All patients underwent SLN biopsy; completion lymphadenectomy was performed for patients with SLN metastasis. Kaplan-Meier analysis of disease-free survival (DFS) and overall survival (OS) was performed. Univariate and multivariate Cox regression analyses were performed. Classification and regression tree (CART) analysis also was performed. RESULTS: A total of 509 patients with tumor-positive SLN were evaluated. Independent risk factors for worse OS included thickness, age, gender, presence of ulceration, and tumor-positive non-SLN (nodal metastasis found on completion lymphadenectomy). As the number of tumor-positive SLN and the total number of tumor-positive nodes (SLN and non-SLN) increased, DFS and OS worsened on Kaplan-Meier analysis. On CART analysis, the 5-year OS rates ranged from 84.9% (women with thickness < 2.1 mm, age < 59 years, no ulceration, and tumor-negative non-SLN) to 14.3% (men with thickness ≥ 2.1 mm, age ≥ 59 years, ulceration present, and tumor-positive non-SLN). Six distinct subgroups were identified with 5-year OS in excess of 70%. CONCLUSIONS: Stage III melanoma in the era of SLN is associated with a very wide range of prognosis. CART analysis of prognostic factors allows discrimination of low-risk subgroups for which adjuvant therapy may not be warranted.

Metastasectomy for distant metastatic melanoma: analysis of data from the first Multicenter Selective Lymphadenectomy Trial (MSLT-I).

BACKGROUND: For stage IV melanoma, systemic medical therapy (SMT) is used most frequently; surgery is considered an adjunct in selected patients. We retrospectively compared survival after surgery with or without SMT versus SMT alone for melanoma patients developing distant metastases while enrolled in the first Multicenter Selective Lymphadenectomy Trial. METHODS: Patients were randomized to wide excision and sentinel node biopsy, or wide excision and nodal observation. We evaluated recurrence site, therapy (selected by treating clinician), and survival after stage IV diagnosis. RESULTS: Of 291 patients with complete data for stage IV recurrence, 161 (55 %) underwent surgery with or without SMT. Median survival was 15.8 versus 6.9 months, and 4-year survival was 20.8 versus 7.0 % for patients receiving surgery with or without SMT versus SMT alone (p < 0.0001; hazard ratio 0.406). Surgery with or without SMT conferred a survival advantage for patients with M1a (median > 60 months vs. 12.4 months; 4-year survival 69.3 % vs. 0; p = 0.0106), M1b (median 17.9 vs. 9.1 months; 4-year survival 24.1 vs. 14.3 %; p = 0.1143), and M1c (median 15.0 vs. 6.3 months; 4-year survival 10.5 vs. 4.6 %; p = 0.0001) disease. Patients with multiple metastases treated surgically had a survival advantage, and number of operations did not reduce survival in the 67 patients (42 %) who had multiple surgeries for distant melanoma. CONCLUSIONS: Our findings suggest that over half of stage IV patients are candidates for resection and exhibit improved survival over patients receiving SMT alone, regardless of site and number of metastases. We have begun a multicenter randomized phase III trial comparing surgery versus SMT as initial treatment for resectable distant melanoma.

Axillary recurrence rate following negative sentinel node biopsy for invasive breast cancer: long-term follow-up.

OBJECTIVE: Sentinel lymph node (SLN) biopsy has replaced axillary lymph node dissection (ALND) as the definitive nodal staging procedure for breast cancer. SLN biopsy has been proven to cause less morbidity and be more cost effective than complete ALND. Short-term follow-up has shown that lymphatic mapping and SLN have a low false-negative rate, but there is limited data demonstrating long-term outcomes within a large consecutive series of patients. METHODS: Retrospective review of a prospective database of breast cancer patients at our institution was performed. The initial mapping of 1,530 patients with invasive breast cancer who demonstrated a negative sentinel node biopsy and no axillary dissection between January 1995 and June 2003 were collated and reviewed to achieve a long-term follow-up. These 1,530 patients were reviewed for follow-up time, local recurrences, distant metastases, and survival. RESULTS: 1,530 consecutively mapped invasive breast cancer patients had a negative SLN biopsy and no ALND. The mean invasive tumor size was 1.40 cm. Of 1,530 patients, 73% (1,121) underwent lumpectomy and 27% (409) underwent mastectomy. Mean follow-up was 4.92 years (range 0-12.0 years). There have been 4 (0.26%) patients presenting with local axillary recurrences, 54 (3.53%) patients presenting with local recurrences in the ipsilateral breast/chest wall, and 24 (1.57%) presenting with distant metastases. CONCLUSION: These data confirm that SLN biopsy is an effective and safe alternative to ALND for detection of nodal metastases in patients with invasive breast cancer and should be used as the standard tool for nodal staging.

Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer.

CONTEXT: Immunochemical staining of sentinel lymph nodes (SLNs) and bone marrow identifies breast cancer metastases not seen with routine pathological or clinical examination. OBJECTIVE: To determine the association between survival and metastases detected by immunochemical staining of SLNs and bone marrow specimens from patients with early-stage breast cancer. DESIGN, SETTING, AND PATIENTS: From May 1999 to May 2003, 126 sites in the American College of Surgeons Oncology Group Z0010 trial enrolled women with clinical T1 to T2N0M0 invasive breast carcinoma in a prospective observational study. INTERVENTIONS: All 5210 patients underwent breast-conserving surgery and SLN dissection. Bone marrow aspiration at the time of operation was initially optional and subsequently mandatory (March 2001). Sentinel lymph node specimens (hematoxylin-eosin negative) and bone marrow specimens were sent to a central laboratory for immunochemical staining; treating clinicians were blinded to results. MAIN OUTCOME MEASURES: Overall survival (primary end point) and disease-free survival (a secondary end point). RESULTS: Of 5119 SLN specimens (98.3%), 3904 (76.3%) were tumor-negative by hematoxylin-eosin staining. Of 3326 SLN specimens examined by immunohistochemistry, 349 (10.5%) were positive for tumor. Of 3413 bone marrow specimens examined by immunocytochemistry, 104 (3.0%) were positive for tumors. At a median follow-up of 6.3 years (through April 2010), 435 patients had died and 376 had disease recurrence. Immunohistochemical evidence of SLN metastases was not significantly associated with overall survival (5-year rates: 95.7%; 95% confidence interval [CI], 95.0%-96.5% for immunohistochemical negative and 95.1%; 95% CI, 92.7%-97.5% for immunohistochemical positive disease; P = .64; unadjusted hazard ratio [HR], 0.90; 95% CI, 0.59-1.39; P = .64). Bone marrow metastases were associated with decreased overall survival (unadjusted HR for mortality, 1.94; 95% CI, 1.02-3.67; P = .04), but neither immunohistochemical evidence of tumor in SLNs (adjusted HR, 0.88; 95% CI, 0.45-1.71; P = .70) nor immunocytochemical evidence of tumor in bone marrow (adjusted HR, 1.83; 95% CI, 0.79-4.26; P = .15) was statistically significant on multivariable analysis. CONCLUSION: Among women receiving breast-conserving therapy and SLN dissection, immunohistochemical evidence of SLN metastasis was not associated with overall survival over a median of 6.3 years, whereas occult bone marrow metastasis, although rare, was associated with decreased survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003854.

Ulceration as a predictive marker for response to adjuvant interferon therapy in melanoma.

OBJECTIVE: This analysis was performed to investigate the hypothesis that ulceration predicts improved response to adjuvant interferon (IFN) therapy. SUMMARY BACKGROUND DATA: Several studies have demonstrated that adjuvant therapy for high-risk melanoma patients with IFN alfa-2b improves disease-free survival (DFS), although the impact on overall survival (OS) is controversial. Recent data have suggested that IFN therapy may preferentially benefit patients with ulcerated primary melanomas. METHODS: Post hoc analysis was performed by a prospective multi-institutional randomized study of observation versus adjuvant IFN therapy for melanoma. All patients underwent sentinel lymph node biopsy; completion lymphadenectomy was performed for patients with sentinel lymph node metastasis. Patients were stratified by Breslow thickness, ulceration, and nodal status. Kaplan-Meier analysis of DFS and OS was performed and included univariate and multivariate analyses. RESULTS: A total of 1769 patients were analyzed (1311 without ulceration, 458 with ulceration) with a median follow-up of 71 months. Ulceration was associated with significantly worse DFS and OS in both node-negative and node-positive patients. Kaplan-Meier analysis of node-negative and node-positive patients by ulceration status revealed that the only significant impact of interferon was improved DFS in the ulcerated node-positive patients (P = 0.0169). IFN therapy had no significant impact on OS regardless of ulceration status, however. On multivariate analysis, IFN treatment was a significant independent predictor of DFS among ulcerated patients (odds ratio, 0.51; 95% confidence interval, 0.30-0.83; P = 0.0053), but not among patients without ulceration. CONCLUSIONS: These data support the conclusion that ulceration is a predictive marker for response to adjuvant IFN therapy. Future studies to evaluate specifically the differential effect of IFN on patients with ulcerated melanomas may allow us to focus this therapy on patients most likely to benefit from it.

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.

Erratum to: Axillary recurrence rate following negative sentinel node biopsy for invasive breast cancer: long-term follow-up.

OBJECTIVE: Sentinel lymph node (SLN) biopsy has replaced axillary lymph node dissection (ALND) as the staging procedure for breast cancer. SLN biopsy causes less morbidity and is more cost effective than complete ALND. Lymphatic mapping and SLN biopsy have a low false-negative rate, but long-term outcomes in large consecutive series of patients are unavailable. METHODS: Retrospective review of a prospectively accrued institutional breast cancer database was performed. The initial mapping of 1,528 patients with invasive breast cancer that demonstrated negative sentinel node biopsy and no axillary dissection in 1,530 cases between January 1995 and June 2003 were collated and reviewed to achieve a long-term follow-up. These 1,528 patients were reviewed for follow-up time, local recurrences, distant metastases, and survival. RESULTS: A total of 1,530 consecutively mapped invasive breast cancer cases had negative SLN biopsy and no ALND. The mean invasive tumor size of was 1.40 cm. Of patients, 1,212 (79.2%) underwent lumpectomy and 318 (20.8%) underwent mastectomy. Median follow-up was 63 months (range 0.1-144 months). There have been 4 (0.26%) cases presenting with local axillary recurrences, 54 (3.53%) cases presenting with local recurrences in the ipsilateral breast/chest wall, and 24 (1.57%) cases presenting with distant metastases. CONCLUSION: These data confirm that SLN biopsy is an effective and safe alternative to ALND for detection of nodal metastases in patients with invasive breast cancer and validates its use as the standard tool for nodal staging.

Adherence to the National Quality Forum (NQF) breast cancer measures within cancer clinical trials: a review from ACOSOG Z0010.

BACKGROUND: In 2007, the National Quality Forum (NQF) released four performance measures for the treatment of breast cancer. We proposed to study the degree of adherence with these measures among participating institutions in a multi-institutional trial. METHODS: American College of Surgeons Oncology Group (ACOSOG) Z0010 enrolled breast cancer patients onto a phase II trial studying the prognostic significance of bone marrow and sentinel node micrometastases. The current study used chi(2) analyses to determine the degree of adherence with four NQF measures among three institution types: academic, community, and teaching affiliate. RESULTS: The study revealed small but important differences in two measures. Ninety-five percent of patients from teaching affiliated institutions received whole-breast radiation compared to 92% at academic and 91% at community hospitals. Among patients who were underinsured or uninsured, a marked decrease in radiation use was noted in comparison to patients with insurance-85 versus 93%, respectively. The study also revealed a difference among institutional types in patients undergoing excisional biopsy for diagnosis. In teaching-affiliated hospitals, 28.6% underwent excisional biopsy as compared to 36.8 and 37.4% in academic and community hospitals, respectively. There was no statistically significant difference between adherence rates with the remaining two measures. Adjuvant chemotherapy was administered to patients with hormone receptor negative tumors > or =1 cm in size in 79-85% of institutions. Tamoxifen was administered to 79-82% of those patients with hormone receptor-positive cancers. CONCLUSIONS: Among breast cancer patients enrolled onto a multi-institutional clinical trial, we found a high degree of adherence with current consensus standards for adjuvant treatment, despite varied practice environments.

The impact on morbidity and length of stay of early versus delayed complete lymphadenectomy in melanoma: results of the Multicenter Selective Lymphadenectomy Trial (I).

BACKGROUND: Complete lymph node dissection, the current standard treatment for nodal metastasis in melanoma, carries the risk of significant morbidity. Clinically apparent nodal tumor is likely to impact both preoperative lymphatic function and extent of soft tissue dissection required to clear the basin. We hypothesized that early dissection would be associated with less morbidity than delayed dissection at the time of clinical recurrence. MATERIALS AND METHODS: The Multicenter Selective Lymphadenectomy Trial I randomized patients to wide excision of a primary melanoma with or without sentinel lymph node biopsy. Immediate completion lymph node dissection (early CLND) was performed when indicated in the SLN arm, while therapeutic dissection (delayed CLND) was performed at the time of clinical recurrence in the wide excision-alone arm. Acute and chronic morbidities were prospectively monitored. RESULTS: Early CLND was performed in 225 patients, and in the wide excision-alone arm 132 have undergone delayed CLND. The 2 groups were similar for primary tumor features, body mass index, basin location, and demographics except age, which were higher for delayed CLND. The number of nodes evaluated and the number of positive nodes was greater for delayed CLND. There was no significant difference in acute morbidity, but lymphedema was significantly higher in the delayed CLND group (20.4% vs. 12.4%, P = .04). Length of inpatient hospitalization was also longer for delayed CLND. CONCLUSION: Immediate nodal treatment provides critical prognostic information and a likely therapeutic effect for those patients with nodal involvement. These data show that early CLND is also less likely to result in lymphedema.

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.

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.

Sentinel-node biopsy or nodal observation in melanoma.

BACKGROUND: We evaluated the contribution of sentinel-node biopsy to outcomes in patients with newly diagnosed melanoma. METHODS: Patients with a primary cutaneous melanoma were randomly assigned to wide excision and postoperative observation of regional lymph nodes with lymphadenectomy if nodal relapse occurred, or to wide excision and sentinel-node biopsy with immediate lymphadenectomy if nodal micrometastases were detected on biopsy. RESULTS: Among 1269 patients with an intermediate-thickness primary melanoma, the mean (+/-SE) estimated 5-year disease-free survival rate for the population was 78.3+/-1.6% in the biopsy group and 73.1+/-2.1% in the observation group (hazard ratio for recurrence[corrected], 0.74; 95% confidence interval [CI], 0.59 to 0.93; P=0.009). Five-year melanoma-specific survival rates were similar in the two groups (87.1+/-1.3% and 86.6+/-1.6%, respectively). In the biopsy group, the presence of metastases in the sentinel node was the most important prognostic factor; the 5-year survival rate was 72.3+/-4.6% among patients with tumor-positive sentinel nodes and 90.2+/-1.3% among those with tumor-negative sentinel nodes (hazard ratio for death, 2.48; 95% CI, 1.54 to 3.98; P<0.001). The incidence of sentinel-node micrometastases was 16.0% (122 of 764 patients), and the rate of nodal relapse in the observation group was 15.6% (78 of 500 patients). The corresponding mean number of tumor-involved nodes was 1.4 in the biopsy group and 3.3 in the observation group (P<0.001), indicating disease progression during observation. Among patients with nodal metastases, the 5-year survival rate was higher among those who underwent immediate lymphadenectomy than among those in whom lymphadenectomy was delayed (72.3+/-4.6% vs. 52.4+/-5.9%; hazard ratio for death, 0.51; 95% CI, 0.32 to 0.81; P=0.004). CONCLUSIONS: The staging of intermediate-thickness (1.2 to 3.5 mm) primary melanomas according to the results of sentinel-node biopsy provides important prognostic information and identifies patients with nodal metastases whose survival can be prolonged by immediate lymphadenectomy. (ClinicalTrials.gov number, NCT00275496 [ClinicalTrials.gov].).

The number of lymph nodes involved with metastatic disease does not affect outcome in melanoma patients as long as all disease is confined to the sentinel lymph node.

BACKGROUND: In melanoma, a direct relationship exists between the number of nodes involved with metastatic disease and prognosis. This study was undertaken to determine whether an individual with metastatic disease confined to the sentinel lymph nodes (SLNs) would have a better prognosis than individuals with metastatic disease that has spread to the non-SLNs, regardless of the number of nodes involved. METHODS: The study group consists of 229 melanoma patients with a positive SLN who underwent regional nodal dissection. Cox proportional hazard regression models were used to assess association of the number of SLNs and non-SLNs involved with disease with overall survival (OS) and disease-free survival (DFS). RESULTS: DFS and OS were unchanged regardless of how many SLNs were positive, as long as all disease was confined to SLNs. Among 183 patients without involvement of non-SLNs, OS remained the same despite an increasing number of SLNs involved (P = .59). This was true after controlling for ulceration, Breslow depth, age, sex, and adjuvant treatment. Once disease was present beyond the SLN, DFS and OS were negatively affected. Among patients with involvement of non-SLNs, there was no statistically significant association between the number of positive SLNs and survival. The risk of mortality increased with the number of non-SLNs involved with metastatic disease (P < .001). CONCLUSIONS: The number of regional nodes involved with metastatic disease does not affect DFS and OS if disease is confined to the SLNs. Consideration should be given to specifying SLN versus non-SLN involvement in the American Joint Committee on Cancer staging manual.

Full-thickness grafts procured from skin overlying the sentinel lymph node basin; reconstruction of primary cutaneous malignancy excision defects.

BACKGROUND: Radical excision of a cutaneous malignancy may require skin-graft closure. The skin overlying the sentinel lymph node (SLN) basin may be procured as a full-thickness skin graft (FTSG), eliminating a problematic and painful third wound, the donor site. However, the potential for implantation of malignant cells transferred from the nodal basin to the primary site, resulting in increased perigraft recurrence rates with the FTSG technique, has not been evaluated. METHODS: We retrospectively reviewed all patients with a cutaneous malignancy who underwent SLN biopsy and skin-graft closure to evaluate the outcomes of full-thickness sentinel node basin procured skin grafts compared with partial-thickness grafts (PTSG). RESULTS: Fifty-seven patients underwent FTSG reconstruction, and 39 patients had PTSG placed at the time of wide excision and SLN biopsy. Eighty-five percent of patients had melanoma; median melanoma thickness for FTSG patients (N = 53) was 2.0 vs. 2.8 mm (N = 29) for the PTSG group (P = .0007). Positive sentinel nodes were identified in nine of 57 patients (16%) and 11 of 39 patients (28%) in the FTSG and PTSG groups, respectively. Perigraft recurrence rates were not significantly different (5 vs. 10%) between the two groups. Graft take rate for the FTSG group was slightly higher than the PTSG group (median = 88% vs 80%, P = .008). FTSG cosmetic results were generally excellent. CONCLUSIONS: This FTSG closure method eliminates a painful third wound and often results in a better cosmetic outcome. Perigraft recurrences do not appear to be increased with FTSG. This technique should be in the armamentarium of surgeons who treat cutaneous malignancy.

Regional node dissection for melanoma: techniques and indication.

Because virtually all microscopic nodal disease left untreated in melanoma patients will progress to clinically apparent macroscopic nodal disease, there is worse prognosis with macroscopic nodal disease, and ineffective systemic treatment currently exists, one must be cautious in favoring an observation approach to the regional basin in patients with a positive sentinel lymph node (SLN) in the hopes of avoiding the potential morbidity of a therapeutic node dissection. In the few patients with untreated microscopic nodal disease, the prognosis will be significantly worsened. Until further data are available, melanoma patients with a positive SLN by H&E analysis should proceed to a complete lymph node dissection.

Phase III Randomized Study of 4 Weeks of High-Dose Interferon-α-2b in Stage T2bNO, T3a-bNO, T4a-bNO, and T1-4N1a-2a (microscopic) Melanoma: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E1697).

Purpose To test the efficacy of 4 weeks of intravenous (IV) induction with high-dose interferon (IFN) as part of the Eastern Cooperative Oncology Group regimen compared with observation (OBS) in patients with surgically resected intermediate-risk melanoma. Patients and Methods In this intergroup international trial, eligible patients had surgically resected cutaneous melanoma in the following categories: (1) T2bN0, (2) T3a-bN0, (3) T4a-bN0, and (4) T1-4N1a-2a (microscopic). Patients were randomly assigned to receive IFN α-2b at 20 MU/m2/d IV for 5 days (Monday to Friday) every week for 4 weeks (IFN) or OBS. Stratification factors were pathologic lymph node status, lymph node staging procedure, Breslow depth, ulceration of the primary lesion, and disease stage. The primary end point was relapse-free survival. Secondary end points included overall survival, toxicity, and quality of life. Results A total of 1,150 patients were randomly assigned. At a median follow-up of 7 years, the 5-year relapse-free survival rate was 0.70 (95% CI, 0.66 to 0.74) for OBS and 0.70, (95% CI, 0.66 to 0.74) for IFN ( P = .964). The 5-year overall survival rate was 0.83 (95% CI, 0.79 to 0.86) for OBS and 0.83 (95% CI, 0.80 to 0.86) for IFN ( P = .558). Treatment-related grade 3 and higher toxicity was 4.6% versus 57.9% for OBS and IFN, respectively ( P < .001). Quality of life was worse for the treated group. Conclusion Four weeks of IV induction as part of the Eastern Cooperative Oncology Group high-dose IFN regimen is not better than OBS alone for patients with intermediate-risk melanoma as defined in this trial.

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.

Is incisional biopsy of melanoma harmful?

BACKGROUND: In the era of sentinel lymph node (SLN) biopsy, there has been concern that manipulation, injection, and massage of intact primary melanomas (after incisional or shave biopsy) could lead to an artifactual increased rate of SLN micrometastases or an actual increased risk of recurrence. The aim of this study was to evaluate the difference in the incidence of SLN metastasis, locoregional recurrence (LRR), disease-free survival (DFS), distant disease-free survival (DDFS), or overall survival (OS) for patients who undergo excisional versus incisional versus shave biopsy. METHODS: Analysis of database from a multicenter prospective randomized study from centers across the United States and Canada. Eligible patients were 18 to 71 years old, with cutaneous melanoma > or = 1.0 mm Breslow thickness. All patients underwent SLN biopsy using blue dye and radioactive colloid injection. SLNd were evaluated by serial histological sections with S100 immunohistochemistry. Statistical analysis was performed using univariate and multivariate analyses with a significance level of P < .05; survival analysis was performed by the Kaplan-Meier method with the log-rank test. RESULTS: A total of 2,164 patients were evaluated; 382 patients were excluded for lack of biopsy information. Positive SLNs were found in 220 of 1,130 (19.5%), 58 of 281 (20.6%), and 67 of 354 (18.9%) of patients with excisional, incisional, or shave biopsy, respectively (no significant difference). There were significant differences among the 3 biopsy types in ulceration (P = .018, chi2) and regression (P = .022, chi2); there were no differences in age, gender, Breslow thickness, Clark level, lymphovascular invasion, tumor location, or histologic subtype. Biopsy type did not significantly affect LRR, DFS, DDFS, or OS. CONCLUSIONS: The concern that incomplete excision of primary melanomas may result in an increased incidence of SLN micrometastases, artifactual or real, is unfounded. Similarly, there is no evidence that biopsy type adversely affects locoregional or distant recurrence. Although shave biopsy is generally discouraged because it may lead to inaccurate tumor thickness measurements, it does not appear to affect overall patient outcome.

Worldwide experience with lymphatic mapping for invasive breast cancer.

Lymphatic mapping and sentinel lymph node (SLN) biopsy have changed the standard of surgical care for women with invasive breast cancer. The rate of successful axillary SLN identification varies from 90% to 99%. Recurrence rates after a negative SLN biopsy have been remarkably low. Internal mammary node drainage has been noted in 8% to 22% of cases, but whether to harvest these extra-axillary sites of drainage remains controversial. Because of the low morbidity associated with the lymphatic mapping procedure, all women with invasive breast cancer should be considered as candidates for this more accurate staging technique.