Robert M. Elashoff

Validation of the Accuracy of Intraoperative Lymphatic Mapping and Sentinel Lymphadenectomy for Early-Stage Melanoma: A Multicenter Trial

OBJECTIVE To evaluate the multicenter application of intraoperative lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection (LM/SL/SCLND) for the management of early-stage melanoma. SUMMARY BACKGROUND DATA The multidisciplinary technique of LM/SL/SCLND has been widely adopted, but not validated in a multicenter trial. The authors began the international Multicenter Selective Lymphadenectomy Trial (MSLT) 5 years ago to evaluate the survival of patients with early-stage primary melanoma after wide excision alone versus wide excision plus LM/SL/SCLND. This study examined the accuracy of LM/SL/SCLND in the MSLT, using the experience of the organizing center (John Wayne Cancer Institute [JWCI]) as a standard for comparison. METHODS Before entering patients into the randomization phase, each center in the MSLT was required to finish a 30-case learning phase with complete nuclear medicine, pathology, and surgical review. Selection of MSLT patients in the LM/SL/SCLND treatment arm was based on complete pathologic and surgical data. The comparison group of JWCI patients was selected using these criteria: primary cutaneous melanoma having a thickness > or =1 mm with a Clark level > or =III, or a thickness <1 mm with a Clark level > or =IV (MSLT criterion); LM/SL performed between June 1, 1985, and December 30, 1998; and patient not entered in the MSLT. The accuracy of LM/SL/SCLND was determined by comparing the rates of sentinel node (SN) identification and the incidence of SN metastases in the MSLT and JWCI groups. RESULTS There were 551 patients in the MSLT group and 584 patients in the JWCI group. In both groups, LM performed with blue dye plus a radiocolloid was more successful (99.1 %) than LM performed with blue dye alone (95.2%) (p = 0.014). After a center had completed the 30-case learning phase, the success of SN identification in the MSLT group was independent of the centers case volume or experience in the MSLT. CONCLUSIONS Lymphatic mapping and sentinel lymphadenectomy can be successfully learned and applied in a standardized fashion with high accuracy by centers worldwide. Successful SN identification rates of 97% can be achieved, and the incidence of nodal metastases approaches that of the organizing center. A multidisciplinary approach (surgery, nuclear medicine, and pathology) and a learning phase of > or =30 consecutive cases per center are sufficient for mastery of LM/SL in cutaneous melanoma. Lymphatic mapping performed using blue dye plus radiocolloid is superior to LM using blue dye alone.

Final Trial Report of Sentinel-Node Biopsy versus Nodal Observation in Melanoma

BACKGROUND Sentinel-node biopsy, a minimally invasive procedure for regional melanoma staging, was evaluated in a phase 3 trial. METHODS We evaluated outcomes in 2001 patients with primary cutaneous melanomas randomly assigned to undergo wide excision and nodal observation, with lymphadenectomy for nodal relapse (observation group), or wide excision and sentinel-node biopsy, with immediate lymphadenectomy for nodal metastases detected on biopsy (biopsy group). Results No significant treatment-related difference in the 10-year melanoma-specific survival rate was seen in the overall study population (20.8% with and 79.2% without nodal metastases). Mean (± SE) 10-year disease-free survival rates were significantly improved in the biopsy group, as compared with the observation group, among patients with intermediate-thickness melanomas, defined as 1.20 to 3.50 mm (71.3 ± 1.8% vs. 64.7 ± 2.3%; hazard ratio for recurrence or metastasis, 0.76; P=0.01), and those with thick melanomas, defined as >3.50 mm (50.7 ± 4.0% vs. 40.5 ± 4.7%; hazard ratio, 0.70; P=0.03). Among patients with intermediate-thickness melanomas, the 10-year melanoma-specific survival rate was 62.1 ± 4.8% among those with metastasis versus 85.1 ± 1.5% for those without metastasis (hazard ratio for death from melanoma, 3.09; P<0.001); among patients with thick melanomas, the respective rates were 48.0 ± 7.0% and 64.6 ± 4.9% (hazard ratio, 1.75; P=0.03). Biopsy-based management improved the 10-year rate of distant disease-free survival (hazard ratio for distant metastasis, 0.62; P=0.02) and the 10-year rate of melanoma-specific survival (hazard ratio for death from melanoma, 0.56; P=0.006) for patients with intermediate-thickness melanomas and nodal metastases. Accelerated-failure-time latent-subgroup analysis was performed to account for the fact that nodal status was initially known only in the biopsy group, and a significant treatment benefit persisted. CONCLUSIONS Biopsy-based staging of intermediate-thickness or thick primary melanomas provides important prognostic information and identifies patients with nodal metastases who may benefit from immediate complete lymphadenectomy. Biopsy-based management prolongs disease-free survival for all patients and prolongs distant disease-free survival and melanoma-specific survival for patients with nodal metastases from intermediate-thickness melanomas. (Funded by the National Cancer Institute, National Institutes of Health, and the Australia and New Zealand Melanoma Trials Group; ClinicalTrials.gov number, NCT00275496.).

Prolongation of survival in metastatic melanoma after active specific immunotherapy with a new polyvalent melanoma vaccine.

A new polyvalent melanoma cell vaccine (MCV) was administered to 136 stage. IIIA and IV (American Joint Committee on Cancer) melanoma patients. Induction of cell-mediated and humoral immune responses to common melanoma-associated antigens present on autologous melanoma cells was observed in patients receiving the new MCV. This was accompanied by increased activation of tumor-infiltrating lymphocytes. Survival correlated significantly with delayed cutaneous hypersensitivity (p = 0.0066) and antibody responses to MCV (p = 0.0117). Of 40 patients with evaluable disease, nine (23%) had regressions (three complete). From our historical database of 126 stage IIIA and 1275 stage IV melanoma patients, there were no significant changes in the natural history of metastatic melanoma during the past 20 years. Univariate and multivariate analyses demonstrated prognostic significance for site of metastases (p = 0.0001) and immunotherapy with the new MCV (p = 0.0001). Overall our new MCV increased the median and 5-year survival of stage IIIA melanoma patients with regional soft tissue metastases twofold (p = 0.00024), and stage IV patients threefold (p = 0.0001) compared with previous immunotherapy and other treatments.

Improved Long-term Survival After Lymphadenectomy of Melanoma Metastatic to Regional Nodes

A review of 1134 patients from the John Wayne Cancer Clinic with melanoma metastatic to regional lymph nodes was carried out to evaluate the importance of various prognostic features after lymphadenectomy. Univariate analysis identified the prognostic significance of clinical stage for lesions with a depth of 0.76 to 4.0 mm (p = 0.0018); number of involved nodes (p = 0.0001); Breslows thickness (p = 0.0487); gender (p = 0.0103); location on an extremity (p = 0.0104); synchronous versus asynchronous detection of nodal metastases (p = 0.0107); age as a continuous variable (p = 0.0670); and unknown primary site (p = 0.088). Multifactorial analysis showed that number of involved nodes (p = 0.0001), extremity location of primary (p = 0.0059), and Breslow thickness (p = 0.0334) maintained their significance, whereas gender (p = 0.0627) and clinical stage (p = 0.0942) were almost significant. The long-term survival of the entire patient population at 5, 10, and 15 years of follow-up was estimated to be 46%, 41%, and 38%. When individual characteristics found to be significant by multivariate analysis were combined into different subsets, there was considerable heterogeneity, with 5-year survival varying from 79% to 14%. To quantify this heterogeneity better, a mathematical model was developed and found to approximate closely the observed survival rates in the heterogenous subsets and in the group as a whole.

Prognostic Significance of Occult Metastases Detected by Sentinel Lymphadenectomy and Reverse Transcriptase–Polymerase Chain Reaction in Early-Stage Melanoma Patients

PURPOSE Detection of micrometastases in the regional tumor-draining lymph nodes is critical for accurate staging and prognosis in melanoma patients. We hypothesized that a multiple-mRNA marker (MM) reverse transcriptase-polymerase chain reaction (RT-PCR) assay would improve the detection of occult metastases in the sentinel node (SN), compared with hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC), and that MM expression is predictive of disease relapse. PATIENTS AND METHODS Seventy-two consecutive patients with clinical early-stage melanoma underwent sentinel lymphadenectomy (SLND). Their SNs were serially sectioned and assessed for MAGE-3, MART-1, and tyrosinase mRNA expression by RT-PCR, in parallel with H&E staining and IHC, for melanoma metastases. MM expression in the SNs was correlated with H&E and IHC assay results, standard prognostic factors, and disease-free survival. RESULTS In 17 patients with H&E- and/or IHC-positive SNs, 16 (94%) expressed two or more mRNA markers. Twenty (36%) of 55 patients with histopathologically negative SNs expressed two or more mRNA markers. By multivariate analysis, patients at increased risk of metastases to the SN had thicker lesions (P =.03), were 60 years of age or younger (P <.05), and/or were MM-positive (P <.001). Patients with histopathologically melanoma-free SNs who were MM-positive, compared with those who were positive for one or fewer mRNA markers, were at increased risk of recurrence (P =.02). Patients who were MM-positive with histopathologically proven metastases in the SN were at greatest risk of disease relapse (P =. 01). CONCLUSION H&E staining and IHC underestimate the true incidence of melanoma metastases. MM expression in the SN more accurately reflects melanoma micrometastases and is also a more powerful predictor of disease relapse than are H&E staining and IHC alone.

A Critical Analysis of the Clinical Use of Incretin-Based Therapies Are the GLP-1 therapies safe?

There is no question that incretin-based glucose-lowering medications have proven to be effective glucose-lowering agents. Glucagon-like peptide 1 (GLP-1) receptor agonists demonstrate an efficacy comparable to insulin treatment and appear to do so with significant effects to promote weight loss with minimal hypoglycemia. In addition, there are significant data with dipeptidyl peptidase 4 (DPP-4) inhibitors showing efficacy comparable to sulfonylureas but with weight neutral effects and reduced risk for hypoglycemia. However, over the recent past there have been concerns reported regarding the long-term consequences of using such therapies, and the issues raised are in regard to the potential of both classes to promote acute pancreatitis, to initiate histological changes suggesting chronic pancreatitis including associated preneoplastic lesions, and potentially, in the long run, pancreatic cancer. Other issues relate to a potential risk for the increase in thyroid cancer. There are clearly conflicting data that have been presented in preclinical studies and in epidemiologic studies. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In the point narrative below, Dr. Butler and colleagues provide their opinion and review of the data to date and that we need to reconsider the use of incretin-based therapies because of the growing concern of potential risk and based on a clearer understanding of the mechanism of action. In the counterpoint narrative following the contribution by Dr. Butler and colleagues, Dr. Nauck provides a defense of incretin-based therapies and that the benefits clearly outweigh any concern of risk. —William T. Cefalu, MD Editor In Chief, Diabetes Care

Treatment of Donor Bone Marrow with Monoclonal Anti-T-Cell Antibody and Complement for the Prevention of Graft-Versus-Host Disease: A Prospective, Randomized, Double-Blind Trial

The effects of ex-vivo depletion of T lymphocytes from donor bone marrow using a monoclonal anti-T-cell antibody (CT-2) and complement on the outcome of allogeneic bone marrow transplantation was evaluated in a prospective, randomized, double-blind study of 40 patients with leukemia. Patients receiving T-cell-depleted bone marrow had a lower incidence of acute graft-versus-host disease than control patients (3 of 20 compared with 13 of 20; p = 0.004), and mortality due to acute graft-versus-host disease was reduced. Five patients in the T-cell-depletion group developed graft failure; all control patients had sustained engraftment (p less than 0.05). Clinically apparent relapse of leukemia occurred in 7 patients from the T-cell-depletion group and in 2 controls (p, not significant). Cytogenetic evidence of residual leukemia was also detected in the 5 patients with graft failure without overt relapse. Infections and overall survival were similar in the two groups. The effects of T-cell depletion on engraftment and recurrence of leukemia require further evaluation.

Bevacizumab and chemotherapy for recurrent glioblastoma A single-institution experience

Objective: Bevacizumab has been shown to be effective in the treatment of recurrent glioblastoma in combination with chemotherapy compared with historic controls but not in randomized trials. Methods: We conducted a retrospective analysis of patients treated for recurrent glioblastoma with bevacizumab vs a control group of patients, comparing progression-free survival (PFS) and overall survival (OS) between the two groups, and performed subgroup analysis based on age and performance status. Expression of vascular endothelial growth factor (VEGF) based on age was examined using DNA microarray analysis. We also evaluated the impact of bevacizumab on quality of life. Results: We identified 44 patients who received bevacizumab and 79 patients who had not been treated with bevacizumab. There was a significant improvement in PFS and OS in the bevacizumab-treated group. Patients of older age (≥55 years) and poor performance status (Karnofsky Performance Status ≤80) had significantly better PFS when treated with bevacizumab, and bevacizumab-treated older patients had significantly increased OS. VEGF expression was significantly higher in older glioblastoma patients (aged ≥55 years). Patients treated with bevacizumab also required less dexamethasone use and maintained their functional status longer than the control group. Conclusions: Bevacizumab in combination with chemotherapy may be a more effective treatment for recurrent glioblastoma and warrants further randomized prospective studies to determine its effect on survival. Bevacizumab also has more effect in those with older age and might reflect biologic differences in glioblastoma in different age groups as seen with the expression of vascular endothelial growth factor. GBM = glioblastoma; HR = hazard ratio; KPS = Karnofsky Performance Status; OS = overall survival; PFS = progression-free survival; VEGF = vascular endothelial growth factor.

A Critical Analysis of the Clinical Use of Incretin-Based Therapies: Are the GLP-1 Therapies Safe? How safe are the GLP-1–based therapies?

There is no question that incretin-based glucose-lowering medications have proven to be effective glucose-lowering agents. Glucagon-like peptide 1 (GLP-1) receptor agonists demonstrate an efficacy comparable to insulin treatment and appear to do so with significant effects to promote weight loss with minimal hypoglycemia. In addition, there are significant data with dipeptidyl peptidase 4 (DPP-4) inhibitors showing efficacy comparable to sulfonylureas but with weight neutral effects and reduced risk for hypoglycemia. However, over the recent past there have been concerns reported regarding the long-term consequences of using such therapies, and the issues raised are in regard to the potential of both classes to promote acute pancreatitis, to initiate histological changes suggesting chronic pancreatitis including associated preneoplastic lesions, and potentially, in the long run, pancreatic cancer. Other issues relate to a potential risk for the increase in thyroid cancer. There are clearly conflicting data that have been presented in preclinical studies and in epidemiologic studies. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In the point narrative below, Dr. Butler and colleagues provide their opinion and review of the data to date and that we need to reconsider the use of incretin-based therapies because of the growing concern of potential risk and based on a clearer understanding of the mechanism of action. In the counterpoint narrative following the contribution by Dr. Butler and colleagues, Dr. Nauck provides a defense of incretin-based therapies and that the benefits clearly outweigh any concern of risk. —William T. Cefalu, MD Editor In Chief, Diabetes Care

Monitoring Dietary Change in a Low-Fat Diet Intervention Study: Advantages of Using 24-Hour Dietary Recalls vs Food Records

OBJECTIVE The purpose of the study was to evaluate two methods of dietary assessment for monitoring change in fat intake in a low-fat diet intervention study. DESIGN The two dietary assessment methods were a 4-day food record (4DFR) and an unannounced 24-hour dietary recall conducted by telephone interview (referred to as a telephone recall [TR]). Subjects were assigned randomly to either a low-fat diet intervention group or a control group that received no counseling about fat intake. Dietary data were collected at baseline, 6 months, and 12 months. SUBJECTS Two hundred ninety postmenopausal women with localized breast cancer were recruited at seven clinical centers in the United States. STATISTICAL ANALYSIS Analysis of variance was used to test for significant differences in mean fat and energy intakes. RESULTS Three sources of error were identified: (a) an instrument effect, suggesting underreporting at baseline of approximately 8% in mean energy intake and 11% in mean fat intake in the TR group compared with the 4DFR group (P = .0001); (b) a repeated measures effect observed for the 4DFR, suggesting underreporting of approximately 7% for energy intake and 14% for fat intake in the control group at 6 and 12 months compared with baseline values (P < .001); and (c) an adherence effect (or compliance bias), suggesting greater compliance to the low-fat intervention diet when subjects were keeping food records than when estimates were based on the unannounced TR. Compared with the TR, the 4DFR overestimated the extent of fat reduction in the low-fat diet intervention group by 41% (P = .08) and 25% (P = .62) at 6 and 12 months, respectively. APPLICATION Multiple days of unannounced 24-hour recalls may be preferable to multiple-day food records for monitoring dietary change in diet intervention studies.