Douglas R. Murray

Skin-sparing mastectomy. Oncologic and reconstructive considerations.

OBJECTIVE The authors compared skin-sparing mastectomy and traditional mastectomy both followed by immediate reconstruction in the treatment of breast cancer. SUMMARY BACKGROUND DATA Skin-sparing mastectomy is used increasingly in the treatment of breast cancer to improve the aesthetic results of immediate reconstruction. The oncologic and reconstructive outcomes of this procedure have never been analyzed closely. METHODS Institutional experience with 435 consecutive patients who underwent total mastectomy and immediate reconstruction from January 1989 through December 1994 was examined. Mastectomies were stratified into skin-sparing (SSM) and non-skin-sparing (non-SSM) types. RESULTS Three hundred twenty-seven SSMs and 188 non-SSMs were performed. The mean follow-up was 41.3 months (SSM, 37.5 months, non-SSM, 48.2 months). Local recurrences from invasive cancer occurred after 4.8% of SSMs versus 9.5% of non-SSMs. Sixty-five percent of patients who underwent SSMs had nothing performed on the opposite breast versus 45% in the group of patients who underwent non-SSM (p = 0.0002). Native skin flap necrosis occurred in 10.7% of patients who underwent SSMs versus 11.2% of patients who underwent non-SSMs. CONCLUSIONS Skin-sparing mastectomy facilitates immediate breast reconstruction by reducing remedial surgery on the opposite breast. Native skin flap necrosis is not increased over that seen with non-SSM. Skin-sparing mastectomies can be used in the treatment of invasive cancer without compromising local control.

Surgical adjuvant active specific immunotherapy for patients with stage III melanoma: The final analysis of data from a phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial

BACKGROUND A phase III, randomized, double-blind, multicenter trial of active specific immunotherapy (ASI) using vaccinia melanoma oncolysate (VMO) was performed in patients with stage III (American Joint Commission on Cancer) melanoma to determine the efficacy of VMO to increase the disease-free interval (DFI) or overall survival (OS) in these patients. Two interim analyses of data from this trial were performed in May 1994 and June 1995. Although the results from these analyses showed no statistically significant improvement in DFI or OS in all patients using VMO, two subsets-men aged 44-57 years with one to five positive nodes and all patients with clinical stage I and pathologic stage II disease-showed an overall survival advantage with VMO therapy. A final analysis of data from this trial was performed in May 1996 and is reported here. The design of future melanoma vaccine trials is discussed based on information learned from this first randomized, multicenter trial of ASI therapy. STUDY DESIGN A polyvalent VMO was prepared using melanoma cells derived from four melanoma cell lines and vaccinia vaccine virus (V). Patients were accrued from 11 United States institutions and were randomized by the Statistical Center at the University of Alabama, Birmingham. Two hundred fifty patients were randomized to treatment with either VMO (1 U containing 2 mg of total protein derived from 5 x 10(6) melanoma cells and 10(5.6) 50% tissue culture infectious dose of vaccinia virus) or control V (1 U containing 10(5.4) 50% tissue culture infectious dose of vaccinia virus) once a week for 13 weeks and then once every 2 weeks for a total of 12 months, or until recurrence. Patient data were collected by the Statistical Center and analyzed as of May 1996 for DFI and OS using Wilcoxon test and log-rank analysis. RESULTS Two hundred seventeen patients were found to be eligible according to the inclusion criteria. Data from these patients were analyzed for DFI and OS after a median followup of 46.3 months (50.2 months for VMO and 41.3 months for V). This final analysis showed no statistically significant increase in either DFI (p = 0.61) or OS (p = 0.79) of patients treated with VMO (n = 104) compared with V (n = 113). At 2-, 3-, and 5-year intervals, 47.8%, 43.8%, and 41.7% of patients treated with VMO were disease-free, respectively, compared with 51.2%, 44.8%, and 40.4% of patients treated with V. At the same intervals, 70.0%, 60.0%, and 48.6% of patients treated with VMO survived, compared with 65.4%, 55.6%, and 48.2% of patients treated with V. In a retrospective subset analysis, male patients aged 44-57 years (n = 20) with one to five positive nodes showed 18.9%, 26.82%, and 21.3% improvement in survival at 2-, 3-, and 5-year intervals, respectively, after treatment with VMO when compared with V (n = 18) (p = 0.046). CONCLUSIONS This study was a randomized, multicenter, placebo-controlled evaluation of an active specific immunotherapeutic agent to increase the DFI or OS of patients with stage III melanoma in a surgical adjuvant setting. In this trial, ASI with VMO when compared with V showed no difference in either DFI or OS. In a retrospective subset analysis, however, a subset of men with one to five positive nodes, between the ages of 44 and 57 years, showed a survival advantage with VMO. This result suggests that one must include a detailed subset analysis in the design of future trials of ASI for patients with American Joint Commission on Cancer stage III melanoma. An appropriate control arm also must be included in ASI trials.

A phase II study on the postsurgical management of stage II malignant melanoma with a Newcastle disease virus oncolysate

A Newcastle disease virus lysate of malignant melanoma cells was examined for its possible value in delaying the progression of malignant melanoma with palpable regional node disease (Stage II) to disseminated melanoma (Stage III). This Phase II study was carried out in a group of 32 patients following therapeutic lymphadenectomy. The patients were not prospectively randomized. In each patient, the viral oncolysate was administered subcutaneously at regular intervals over 3 years. The cumulated progressions to disseminated disease at 1, 2 and 3 years were 6%, 8% and 12% of the study group, respectively. These experienced losses were considerably lower than in the control group and in similar control groups described by other investigators. The results suggest that an oncolysate prepared with Newcastle disease virus is a helpful adjunct to surgery in the management of Stage II malignant melanoma.

The Amount of Metastatic Melanoma in a Sentinel Lymph Node: Does It Have Prognostic Significance?

Background: The amount of metastatic disease in the sentinel lymph node (SLN) is examined as a prognostic factor in malignant melanoma.Methods: SLN mapping was performed on 592 patients with stage I and II malignant melanoma from March 1, 1994, through December 31, 1999. One hundred four patients were found to have 134 sentinel SLNs containing metastatic melanoma. The slides were reviewed, and the size of the metastatic melanoma in each SLN was measured. The size of the metastatic deposit was defined as macrometastasis (>2 mm), micrometastasis (≤2 mm), a cluster of cells (10–30 grouped cells) in the subcapsular space or interfollicular zone, or isolated melanoma cells (1 to ≥20 individual cells) in subcapsular sinuses.Results: The number of metastases in each SLN was isolated melanoma cells, n = 5 (3.7%); cluster of cells, n = 35 (26.1%); ≤2 mm, n = 45 (33.6%); and >2 mm, n = 49 (36.7%). Seventy-nine patients (76%) had a single positive SLN. The size of the largest nodal metastasis was used to stratify patients with multiple positive SLNs. The overall 3-year survival for patients with SLN micrometastases was 90%, versus 58% for patients with SLN macrometastases (P = .004).Conclusions: The amount of metastatic melanoma in an SLN is an independent predictor of survival. Patients with SLN metastatic deposits >2 mm in diameter have significantly decreased survival.

Local Recurrence After Skin-Sparing Mastectomy: Tumor Biology or Surgical Conservatism?

Background:Long-term follow-up of the use of skin-sparing mastectomy (SSM) in the treatment of breast cancer is presented to determine the impact of local recurrence (LR) on survival.Methods:A total of 539 patients were treated for 565 cases of breast cancer by SSM and immediate breast reconstruction from January 1, 1989 to December 31, 1998. The American Joint Committee on Cancer pathological staging was stage 0 175 (31%), stage I 135 (23.9%), stage II 173 (30.6%), stage III 54 (9.6%), stage IV 8 (1.4%), and recurrent 20 (3.5%). The mean follow-up was 65.4 months (range, 23.7–86.3 months). Five patients were lost to follow-up.Results:Thirty-one patients developed a LR during the follow-up including five who received adjuvant radiation. The distribution of LR stratified by cancer stage was stage 0 1, stage I 5, stage II 17, stage III 6, and recurrent 2. The overall LR was 5.5%. Twenty-four patients (77.4%) developed a systemic relapse and 7 (22.6%) patients remained free of recurrent disease at a mean follow-up of 78.1 months. The cancer stage of those remaining disease free was stage 0 1 (100%), stage I 4 (80%), and stage II 2 (11.8%).Conclusions:LR of breast cancer after SSM is not always associated with systemic relapse.

Sentinel Lymph Node Mapping for Thick (≥4-mm) Melanoma: Should We Be Doing It?

Background: Thick (≥4-mm) primary melanomas are believed to be associated with a high incidence of occult distant metastases. The use of sentinel lymph node (SLN) mapping and biopsy in the treatment lesions has been questioned.Methods: A retrospective review of a computerized database identified 114 patients who underwent successful SLN mapping and biopsy from January 1, 1994, to December 31, 1999. Records were reviewed for clinicopathologic features of the patients and their tumors. Survival curves were constructed from Kaplan-Meier estimates and analyzed with log-rank tests and Cox proportional hazards modeling.Results: There were 75 men and 39 women with a mean age of 57 years (range, 24–85 years). The primary tumor sites were head and neck (n = 29; 25.4%), trunk (n = 44; 38.6%), and extremities (n = 41; 36%). Tumor thickness ranged from 4 to 17 mm (median, 5.2 mm; mean, 6.3 mm). Ulceration was present in 40 (35.1%) tumors. Thirty-seven patients (32.5%) had a positive SLN biopsy, and 18 of these patients (48.6%) had a single tumor-positive lymph node after dissection. The mean follow-up was 37.8 months. The overall 3-year survival for SLN-negative patients was 82%, versus 57% for SLN-positive patients (P = .006). Lymph node status and tumor ulceration were independent predictors of overall survival in multivariate Cox regression analysis.Conclusions:The pathologic status of the SLN in patients with thick melanomas is a strong independent prognostic factor for survival, and SLN mapping should be routinely performed.

A 15-year follow-up of AJCC stage III malignant melanoma patients treated postsurgically with Newcastle disease virus (NDV) oncolysate and determination of alterations in the CD8 T cell repertoire.

BackgroundThe development of effective adjuvant therapies for the treatment of high-risk melanoma patients is critical for the prevention of metastatic disease and improvement of patient survival. Active specific immunotherapy has been tested as an adjuvant treatment in numerous clinical trials with overall limited, but occasionally promising, success rates. Newcastle disease virus (NDV) oncolysate has been utilized as an adjunctive immunotherapeutic agent in the postsurgical management of these patients. A phase II study initiated in 1975 using adjuvant vaccine therapy composed of allogeneic and autologous human melanoma cells infected with live NDV (NDV oncolysate) in patients with AJCC stage III melanoma following therapeutic lymph node dissection has shown >60% survival rate at 10 years with no adverse effects. Continued long-term analysis of trials with promising early results as well as assessment of immunologic responses generated in these patients may result in improved therapeutic decisions for clinical trials in the future.Materials and MethodsWe analyzed the 15-year survival of patients treated postsurgically with NDV oncolysate in the phase II study described above. In an attempt to understand the immunological effects of this treatment, we have also carried out a comprehensive analysis of the peripheral blood T cell repertoire in these patients.ResultsThe overall 15-year survival of this group of patients is 55%. Previous studies have suggested that improved outcome in patients undergoing immunotherapy is correlated with increased numbers of CD8+CD57+ cells. In surviving patients, we observed a striking oligoclonality in the CD8+ T cell population in peripheral blood, which reflects clonal expansions in the CD8+CD57+ subset.ConclusionsThe data suggest that adjuvant vaccination with NDV oncolysates is associated with prolonged survival of patients with lymph node-positive malignant melanoma and that CD8+ T cells may be an important component of therapeutic efficacy.

A ten-year follow-up on stage II Malignant Melanoma patients treated postsurgically with newcastle disease virus oncolysate

Newcastle disease virus oncolysate was examined as an adjunctive immunotherapeutic agent in the postsurgical management of 83 cases of Stage II malignant melanoma. At this time, all the patients have been under observation for at least 10 years, and over 60% are alive and free of recurrent disease. Older studies in the United States report postsurgical survival figures for Stage II cases of 5-15%. More contemporary studies indicate a 33% survival at 10 years. The unusual disease-free survival periods in the present study, including exceptional survivals in 21 patients with head and neck disease and six cases with cerebral metastases, suggest a unique role for the administration of Newcastle disease virus oncolysate in the management of Stage II malignant melanoma patients.

Regional recurrence after negative sentinel lymph node biopsy for melanoma.

Objective:Sentinel lymph node (SLN) biopsy has shown great utility in the management of melanoma. An analysis of regional recurrence in previously mapped negative SLN basins as the first site of relapse is performed. Methods:A retrospective query of a prospective melanoma database from 1994 to 2006 identified 1287 patients who underwent successful SLN biopsy. One thousand sixty patients (82.4%) were SLN negative and 227 (17.6%) patients SLN positive. Clinical variables were examined for the impact on regional recurrence by multivariate analysis. Results:Mean follow-up was 44.3 months (range 3–155 months). Thirty-five patients (3.3%) presented with false-negative (FN) SLN biopsy. Pathologic review of the SLNs harvested from these basins found 7 (20.0%) samples positive for metastatic melanoma. Multivariate analysis found head and neck site [hazard ratio 3.67; 95% confidence interval (CI), 1.77–7.60, P < 0.001] and tumor thickness (hazard ratio 1.16; 95% CI, 1.04–1.30, P = 0.01) to be predictive of FN SLN biopsy. The 5-year melanoma specific survival calculated from the date of the SLN biopsy was 57.6% (95%CI, 35.7–41.9) in the FN group, which was not statistically different than the SLN positive group 60.0% (95% CI, 29.6–40.1; P = 0.14). Conclusions:Head and neck tumor site and tumor thickness are predictors of a FN SLN biopsy. Mechanisms other than pathologic SLN sampling error may contribute to the failure of the SLN biopsy in some patients. Patients with regional recurrence after negative SLN biopsy have a similar 5-year survival compared with patients with positive SLNs.

Immediate breast reconstruction for stage III breast cancer using transverse rectus abdominis musculocutaneous (TRAM) flap

AbstractBackground: The management of stage III breast cancer is challenging; it often includes multimodal treatment with systemic therapy and/or radiation therapy and surgery. Immediate breast reconstruction has not traditionally been performed in these patients. We review the results of immediate transverse rectus abdominis musculocutaneous (TRAM) flap in 21 patients treated for stage III breast cancer. Methods: Data have been collected retrospectively on 21 patients diagnosed with stage III breast cancer between 1987 and 1994. All patients had mastectomy and immediate TRAM reconstruction. Thirteen patients received primary systemic therapy, 10 patients received postoperative consolidation radiotherapy to the operative site, and 3 patients received preoperative radiation. Results: Mean follow-up for the group was 26 months. Two patients died with disseminated disease: neither of them developed local disease recurrence in the operative site; 82% of the patients followed for at least two years are free of disease. Sixty-two percent of the patients received preoperative chemotherapy, the remaining patients received postoperative multiagent chemotherapy and/or radiation therapy. Two of the patients received autologous bone marrow transplants after their adjuvant therapy. Ten patients had postoperative radiotherapy for consolidation; three patients received preoperative radiation. Conclusions: Immediate TRAM reconstruction for stage III breast cancer is not associated with a delay in adjuvant therapy or an increased risk of local relapse. It facilitates wide resection of involved skin without skin grafting. Radiation therapy can be delivered to the reconstructed breast when indicated without difficulty. Breast reconstruction facilitates surgical resection of stage III breast cancer with primary closure and should be considered if the patient desires immediate breast reconstruction.