William G. Kraybill

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.).

Gastrointestinal Stromal Tumors: Current Diagnosis, Biologic Behavior, and Management

Gastrointestinal stromal tumors (GIST) are rare tumors of the gastrointestinal (GI) tract that arise from primitive mesenchymal cells. GISTs occur throughout the GI tract but are usually located in the stomach and small intestine. The majority of GISTs are immunohistochemically positive for c-kit protein (CD117) and CD34. GISTs express a heterogeneous clinical course not easily predicted by standard pathological means. The most important prognostic factors are size >5 cm, tumor necrosis, infiltration and metastasis to other sites, mitotic count >1–5 per 10 high-powered fields, and most recently, mutation in the c-kit gene. Surgical resection remains the mainstay of treatment, as chemotherapy and radiation are ineffective. Long-term follow-up is imperative, as recurrence rates are high.

Phase II Study of Neoadjuvant Chemotherapy and Radiation Therapy in the Management of High-Risk, High-Grade, Soft Tissue Sarcomas of the Extremities and Body Wall: Radiation Therapy Oncology Group Trial 9514

PURPOSE On the basis of a positive reported single-institution pilot study, the Radiation Therapy Oncology Group initiated phase II trial 9514 to evaluate its neoadjuvant regimen in a multi-institutional Intergroup setting. PATIENTS AND METHODS Eligibility included a high-grade soft tissue sarcoma > or = 8 cm in diameter of the extremities and body wall. Patients received three cycles of neoadjuvant chemotherapy (CT; modified mesna, doxorubicin, ifosfamide, and dacarbazine [MAID]), interdigitated preoperative radiation therapy (RT; 44 Gy administered in split courses), and three cycles of postoperative CT (modified MAID). RESULTS Sixty-six patients were enrolled, of whom 64 were analyzed. Seventy-nine percent of patients completed their preoperative CT and 59% completed all planned CT. Three patients (5%) experienced fatal grade 5 toxicities (myelodysplasias, two patients; infection, one patient). Another 53 patients (83%) experienced grade 4 toxicities; 78% experienced grade 4 hematologic toxicity and 19% experienced grade 4 nonhematologic toxicity. Sixty-one patients underwent surgery. Fifty-eight of these were R0 resections, of which five were amputations. There were three R1 resections. The estimated 3-year rate for local-regional failure is 17.6% if amputation is considered a failure and 10.1% if not. Estimated 3-year rates for disease-free, distant-disease-free, and overall survival are 56.6%, 64.5%, and 75.1%, respectively. CONCLUSION This combined-modality treatment can be delivered successfully in a multi-institutional setting. Efficacy results are consistent with previous single-institution results.

Anal sphincter conservation for patients with adenocarcinoma of the distal rectum: long-term results of radiation therapy oncology group protocol 89-02

PURPOSE To assess the outcome of a multi-institutional, national cooperative group study attempting functional preservation of the anorectum for patients with limited, distal rectal cancer. METHODS AND MATERIALS Between September 21, 1989 and November 1, 1992, a Phase II trial of sphincter-sparing therapy was conducted for patients with clinically mobile rectal cancers located below the pelvic peritoneal reflection. Protocol treatment was designed for patients who were, in the judgement of their attending surgeon, unsuitable for anal sphincter conservation in the context of anterior resection, and would have required abdominoperineal resection (APR) as conventional surgical therapy. Primary cancers were estimated to be 4 cm or less in largest clinical diameter, and occupied 40% or less of the rectal circumference. Chest radiography and computerized axial tomography (CT) of the abdomen and pelvis excluded patients with overt lymphatic or hematogenous metastases. Protocol surgery was intended to remove the primary cancer by en-bloc, transmural excision of an ellipse of rectal wall by transanal, transcoccygeal, or trans-sacral technique, while conserving the anal sphincter. Based on tumor size, T classification, grade, and adequacy of surgical margins, patients were allocated to one of three treatment assignments: observation, or adjuvant treatment with 5-fluorouracil (5-FU) and one of two different dose levels of local-regional radiation. After completion of protocol therapy, patients were observed with follow-up that included periodic general physical and rectal examination, determinations of CEA, abdominopelvic CT, chest radiography, and surveillance endoscopy. Sixty-five eligible and analyzable patients were registered. RESULTS With minimum follow-up of 5 years and median follow-up of 6.1 years, 11 patients have failed: 3 patients recurred local-regionally only, 3 patients had distant failure alone, and 5 patients manifested local-regional and distant failure. Eight patients died of intercurrent illness. Local-regional failure correlated with T-category revealed: T1 1/27 (4%), T2 4/25 (16%), and T3 3/13 (23%). Local-regional failure escalated with percentage involvement of the rectal circumference: 2/31 (6%) among patients with cancers involving 20% or less of the rectal circumference, and 6/34 (18%) among patients with cancers involving 21-40% of the circumference. Distant dissemination rose with T-category with 1/27 (4%) T1, 3/25 (12%) T2, and 4/13 (31%) T3 patients manifesting hematogenous spread. Eight patients (12%) required temporary or permanent colostomy. Five of 8 patients with local-regional recurrence achieved local-regional control with management including surgery, although 4 of these patients subsequently developed distant dissemination. Three patients (5%) had persistent, uncontrolled, local disease. Actuarial freedom from pelvic relapse at 5 years is 88% based on the entire study population, and 86% for the less favorable patients treated with adjuvant radiation and 5-FU. CONCLUSION Conservative, sphincter-sparing therapy is a feasible alternative treatment for selected patients with limited cancer involving the middle and lower rectum. Risk of both local and distant failure appears to escalate with increasing T-category (depth of invasion). Results achieved in the multi-institutional, cooperative group setting approximate results reported from single institutions.

Randomized Multicenter Trial of Hyperthermic Isolated Limb Perfusion With Melphalan Alone Compared With Melphalan Plus Tumor Necrosis Factor: American College of Surgeons Oncology Group Trial Z0020

PURPOSE To determine in a randomized prospective multi-institutional trial whether the addition of tumor necrosis factor alpha (TNF-alpha) to a melphalan-based hyperthermic isolated limb perfusion (HILP) treatment would improve the complete response rate for locally advanced extremity melanoma. PATIENTS AND METHODS Patients with locally advanced extremity melanoma were randomly assigned to receive melphalan or melphalan plus TNF-alpha during standard HILP. Patient randomization was stratified according to disease/treatment status and regional nodal disease status. RESULTS The intervention was completed in 124 patients of the 133 enrolled. Grade 4 adverse events were observed in 14 (12%) of 129 patients, with three (4%) of 64 in the melphalan-alone arm and 11 (16%) of 65 in the melphalan-plus-TNF-alpha arm (P = .0436). There were two toxicity-related lower extremity amputations in the melphalan-plus-TNF-alpha arm, and one disease progression-related upper extremity amputation in the melphalan-alone arm. There was no treatment-related mortality in either arm of the study. One hundred sixteen patients were assessable at 3 months postoperatively. Sixty-four percent of patients (36 of 58) in the melphalan-alone arm and 69% of patients (40 of 58) in the melphalan-plus-TNF-alpha arm showed a response to treatment at 3 months, with a complete response rate of 25% (14 of 58 patients) in the melphalan-alone arm and 26% (15 of 58 patients) in the melphalan-plus-TNF-alpha arm (P = .435 and P = .890, respectively). CONCLUSION In locally advanced extremity melanoma treated with HILP, the addition of TNF-alpha to melphalan did not demonstrate a significant enhancement of short-term response rates over melphalan alone by the 3-month follow-up, and TNF-alpha plus melphalan was associated with a higher complication rate.

Nodal basin recurrence following lymph node dissection for melanoma: implications for adjuvant radiotherapy

PURPOSE To analyze patterns of failure in malignant melanoma patients with lymph node involvement who underwent complete lymph node dissection (LND) of the nodal basin. To determine prognostic factors predictive of local recurrence in the lymph node basin in order to select patients who may benefit from adjuvant radiotherapy. METHODS AND MATERIALS A retrospective analysis of 338 patients undergoing complete LND for melanoma between 1970 and 1996 who had pathologically involved lymph nodes was performed. Mean follow-up from the time of LND was 54 months (range: 12-306 months). Lymph node basins dissected included the neck (56 patients), axilla (160 patients), and groin (122 patients). Two hundred fifty-three patients (75%) underwent therapeutic LND for clinically involved nodes, while 85 patients (25%) had elective dissections. Forty-four percent of patients received adjuvant systemic therapy. No patients received adjuvant radiotherapy to the lymph node basin. RESULTS Overall and disease-specific survival for all patients at 10 years was 30% and 36%, respectively. Overall nodal basin recurrence was 30% at 10 years. Mean time to nodal basin recurrence was 12 months (range: 2-78 months). Site of nodal involvement was prognostic with 43%, 28%, and 23% nodal basin recurrence at 10 years with cervical, axillary, and inguinal involvement, respectively (p = 0.008). Extracapsular extension (ECE) led to a 10-year nodal basin failure rate of 63% vs. 23% without ECE (p < 0.0001). Patients undergoing a therapeutic dissection for clinically involved nodes had a 36% failure rate in the nodal basin at 10 years, compared to 16% for patients found to have involved nodes after elective dissection (p = 0.002). Lymph nodes larger than 6 cm led to a failure rate of 80% compared to 42% for nodes 3-6 cm and 24% for nodes less than 3 cm (p < 0.001). The number of lymph nodes involved also predicted for nodal basin failure with 25%, 46%, and 63% failure rates at 10 years for 1-3, 4-10, and > 10 nodes involved (p = 0.0001). There was no significant difference in nodal basin control in patients with synchronous or metachronous lymph node metastases, nor in patients receiving or not receiving adjuvant systemic therapy. Nodal basin failure was predictive of distant metastasis with 87% of patients with nodal basin recurrence developing distant disease compared to 54% of patients without nodal failure (p < 0.0001). On multivariate analysis, number of positive nodes and type of dissection (elective vs. therapeutic) were significant predictors of overall and disease-specific survival. Size of the largest lymph node was also predictive of disease-specific survival. Site of nodal involvement and ECE were significant predictors of nodal basin failure. CONCLUSIONS Malignant melanoma patients with nodal involvement have a significant risk of nodal basin failure after LND if they have cervical involvement, ECE, >3 positive lymph nodes, clinically involved nodes, or any node larger than 3 cm. Patients with these risk factors should be considered for adjuvant radiotherapy to the lymph node basin to reduce the incidence of nodal basin recurrence. Patients with nodal basin failure are at higher risk of developing distant metastases.

Accuracy of pathologic techniques for the diagnosis of metastatic melanoma in sentinel lymph nodes.

Background: Sentinel lymph node (SLN) biopsy can accurately predict the presence of metastatic melanoma (MM) and has been used to identify patients with occult metastases. We present an analysis of the sensitivity and specificity of standard pathological techniques including intraoperative frozen section, permanent section, and immunohistochemistry in diagnosing MM within the SLN.Methods: Sixty-nine consecutive patients with primary malignant melanoma thickness of .1.0 mm or thinner lesions invading the reticular dermis (Clark level IV) who underwent SLN biopsy were reviewed. Lymph nodes were examined intraoperatively by frozen section (FS), permanent section (H&E), and by immunohistochemistry (IH) for S-100 protein and HMB45.Results: MM was found in 14 of 69 cases (20%). Permanent section H&E was performed in all cases, FS in 64 cases, and IH in 65 cases. FS analysis diagnosed MM in 4 of 14 cases (29%), was suspicious in 2 of 14 (14%), and falsely negative (FN) in 8 of 14 (57%) ultimately found to be positive with further workup. Within the FN group, MM was identified on review of the original FS slides in 3 of 8 cases (38%). Furthermore, within the FN group, the remaining 5 cases were identified as positive for MM by either permanent and/or deeper H&E sections and IH. IH alone with permanent H&E sections would have diagnosed MM in only 8 of 10 cases (80%) that were FS negative or suspicious. In no cases was MM identified by IH alone with the permanent and deeper H&E sections being negative. It is noteworthy that no false-positive cases were identified.Conclusions: Intraoperative FS has low sensitivity in identifying MM within the SLN. IH alone does not increase the diagnostic yield. A combination of permanent H&E sections with deeper levels and S-100 and HMB45 IH dramatically increases the overall diagnostic sensitivity of SLN biopsy. Definitive diagnosis should await permanent H&E sections and IH staining.

Vascular endothelial growth factor and soft tissue sarcomas: tumor expression correlates with grade.

Introduction: Vascular endothelial growth factor (VEGF), an endothelial–specific mitogen overexpressed in various epithelial malignancies is thought to be a potent regulator of angiogenesis. We hypothesized that some soft tissue sarcomas, due to their high propensity for hematogenous metastases (1) would overexpress VEGF, (2) that the degree of expression may represent a significant biologic predictor for disease-specific survival, and (3) that recurrent tumor would express as high or higher VEGF compared with the primary tumor.Methods: Selected paraffin-embedded tissue of surgical specimens from 79 patients with soft tissue sarcomas, treated between 1989 and 1995 were stained with a rabbit polyclonal anti-VEGF antibody at a concentration of 2 μg/ml. Slides were assessed for VEGF expression as high or low by two investigators blinded to the clinicopathologic data. Twelve patients had VEGF expression of their primary tumors, and their recurrent tumors were compared. The Fishers’ exact test assessed for differences in VEGF expression; survival analyses were performed according to the methods of Kaplan and Meier.Results: Seventy-eight percent (29 of 37) of patients who died of disease had high VEGF expression. However, VEGF expression was not an independent predictor of either overall or disease-free survival. Tumor grade correlated with VEGF expression significantly. For the low-grade tumors, 7 of 13 expressed low VEGF, whereas for high-grade tumors, 53 of 66 expressed high VEGF (P = .016). Seven of the 12 paired tumor samples expressed identical VEGF immunostaining.Conclusions: The majority of high-grade soft tissue sarcomas in this study have high intensity VEGF expression. This finding may provide useful information on individual soft tissue sarcomas and offer the basis for therapeutic and biologic targeting in high-risk patients using anti-angiogenesis strategies. However, in our analysis, after accounting for tumor grade, VEGF does not seem to be an independent predictor of clinical outcome.

The benefits of adjuvant radiation therapy after therapeutic lymphadenectomy for clinically advanced, high-risk, lymph node-metastatic melanoma.

The objective of this study was to evaluate the impact of adjuvant radiation therapy (RT) on regional recurrence and survival after therapeutic lymphadenectomy (TL) for clinically advanced, lymph node‐metastatic melanoma.

Factors associated with actual long-term survival following soft tissue sarcoma pulmonary metastasectomy

AIMS To identify clinicopathologic and treatment variables associated with long-term overall survival (OS) in soft tissue sarcoma (STS) patients with lung metastases undergoing pulmonary metastasectomy (PM). METHODS Retrospective review of 94 STS PM patients with an actual follow-up > or = 5 years. Data were collected on demographics, tumor features, treatment, and outcome. RESULTS Most primary tumors were intermediate/high grade and the common histopathologies were evenly distributed. Half of the primary tumors were located on the extremities. The mean disease-free interval (DFI) from time of original diagnosis until metastases was 25 months (median 15 months). Eighteen patients had synchronous metastatic disease. Bilateral pulmonary metastases and >1 metastasis were common. The median number of metastases resected was 2.5. Thirty-four patients had extrapulmonary tumor at the time of PM; all extrapulmonary disease was resected. Negative margin resection (R0) PM was performed in 74 patients. Actual 5-year disease-free survival (DFS) and OS for all patients were 5% and 15%, respectively. For the R0 group, actual 5-year DFS and OS were 7% and 18%, respectively. R0 resection and a prolonged DFI were associated with improved OS. Patient characteristics, tumor features, local recurrence, and adjuvant therapy did not affect OS. CONCLUSIONS Less than 20% of STS PM patients will survive 5 years. Complete resection and DFI are the most predictive factors for prolonged survival.