Peter W.T. Pisters

Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities

PURPOSE To identify specific independent adverse clinicopathologic factors for event-free survival in a cohort of consecutively treated patients with extremity soft tissue sarcomas. PATIENTS AND METHODS Prospectively collected data from a population of 1,041 adult patients with localized (American Joint Committee on Cancer [AJCC] stage IA to IIIB) extremity soft tissue sarcomas were analyzed. Patients were treated at a single institution between 1982 and 1994. Patient, tumor, and pathologic factors were analyzed by univariate and multivariate techniques to identify independent prognostic factors for the end points of local recurrence, distant recurrence, disease-specific survival, and post-metastasis survival. RESULTS The 5-year survival rate for this cohort of patients was 76%, with a median follow-up time of 3.95 years. Significant independent adverse prognostic factors for local recurrence were age greater than 50 years, recurrent disease at presentation, microscopically positive surgical margins, and the histologic subtypes fibrosarcoma and malignant peripheral-nerve tumor. For distant recurrence, intermediate tumor size, high histologic grade, deep location, recurrent disease at presentation, leiomyosarcoma, and nonliposarcoma histology were independent adverse prognostic factors. For disease-specific survival, large tumor size, high grade, deep location, recurrent disease at presentation, the histologic subtypes leiomyosarcoma and malignant peripheral-nerve tumor, microscopically positive surgical margins, and lower extremity site were adverse factors. For post-metastasis survival, only large tumor size ( > 10 cm) was an adverse prognostic factor. CONCLUSION The independent adverse prognostic factors for distant recurrence and disease specific survival differ from those identified for subsequent local recurrence. Patients with microscopically positive surgical margins or patients who present with locally recurrent disease are at increased risk for subsequent local recurrence and tumor-related mortality. Specific histopathologic subtypes are associated with increased risks for local failure and tumor-related mortality.

Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial

BACKGROUND Gastrointestinal stromal tumour is the most common sarcoma of the intestinal tract. Imatinib mesylate is a small molecule that inhibits activation of the KIT and platelet-derived growth factor receptor alpha proteins, and is effective in first-line treatment of metastatic gastrointestinal stromal tumour. We postulated that adjuvant treatment with imatinib would improve recurrence-free survival compared with placebo after resection of localised, primary gastrointestinal stromal tumour. METHODS We undertook a randomised phase III, double-blind, placebo-controlled, multicentre trial. Eligible patients had complete gross resection of a primary gastrointestinal stromal tumour at least 3 cm in size and positive for the KIT protein by immunohistochemistry. Patients were randomly assigned, by a stratified biased coin design, to imatinib 400 mg (n=359) or to placebo (n=354) daily for 1 year after surgical resection. Patients and investigators were blinded to the treatment group. Patients assigned to placebo were eligible to crossover to imatinib treatment in the event of tumour recurrence. The primary endpoint was recurrence-free survival, and analysis was by intention to treat. Accrual was stopped early because the trial results crossed the interim analysis efficacy boundary for recurrence-free survival. This study is registered with ClinicalTrials.gov, number NCT00041197. FINDINGS All randomised patients were included in the analysis. At median follow-up of 19.7 months (minimum-maximum 0-56.4), 30 (8%) patients in the imatinib group and 70 (20%) in the placebo group had had tumour recurrence or had died. Imatinib significantly improved recurrence-free survival compared with placebo (98% [95% CI 96-100] vs 83% [78-88] at 1 year; hazard ratio [HR] 0.35 [0.22-0.53]; one-sided p<0.0001). Adjuvant imatinib was well tolerated, with the most common serious events being dermatitis (11 [3%] vs 0), abdominal pain (12 [3%] vs six [1%]), and diarrhoea (ten [2%] vs five [1%]) in the imatinib group and hyperglycaemia (two [<1%] vs seven [2%]) in the placebo group. INTERPRETATION Adjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with placebo after the resection of primary gastrointestinal stromal tumour. FUNDING US National Institutes of Health and Novartis Pharmaceuticals.

Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma.

PURPOSE This trial was performed to evaluate the impact of adjuvant brachytherapy on local and systemic recurrence rates in patients with soft tissue sarcoma. PATIENTS AND METHODS In a single-institution prospective randomized trial, 164 patients were randomized intraoperatively to receive either adjuvant brachytherapy (BRT) or no further therapy (no BRT) after complete resection of soft tissue sarcomas of the extremity or superficial trunk. The adjuvant radiation was administered by iridium-192 implant, which delivered 42 to 45 Gy over 4 to 6 days. The two study groups had comparable distributions of patient and tumor factors, including age, sex, tumor site, tumor size, and histologic type and grade. RESULTS With a median follow-up time of 76 months, the 5-year actuarial local control rates were 82% and 69% in the BRT and no BRT groups (P = .04), respectively. Patients with high-grade lesions had local control rates of 89% (BRT) and 66% (no BRT) (P = .0025). BRT had no impact on local control in patients with low-grade lesions (P = .49). The 5-year freedom-from-distant-recurrence rates were 83% and 76% in the BRT and no BRT groups (P = .60), respectively. Analysis by histologic grade did not demonstrate an impact of BRT on the development of distant metastasis, despite the improvement in local control noted in patients with high-grade lesions. The 5-year disease-specific survival rates for the BRT and no BRT groups were 84% and 81% (P = .65), respectively, with no impact of BRT regardless of tumor grade. CONCLUSION Adjuvant brachytherapy improves local control after complete resection of soft tissue sarcomas. This improvement in local control is limited to patients with high-grade histopathology. The reduction in local recurrence in patients with high-grade lesions is not associated with a significant reduction in distant metastasis or improvement in disease-specific survival.

Preoperative Gemcitabine-Based Chemoradiation for Patients With Resectable Adenocarcinoma of the Pancreatic Head

PURPOSE We conducted a phase II trial to assess the outcomes of patients who received preoperative gemcitabine-based chemoradiation and pancreaticoduodenectomy (PD) for stage I/II pancreatic adenocarcinoma. PATIENTS AND METHODS Eligible patients with pancreatic head/uncinate process adenocarcinoma and radiographically defined potentially resectable disease received chemoradiation with 7 weekly intravenous (IV) infusions of gemcitabine (400 mg/m(2) IV over 30 minutes) plus radiation therapy (30 Gy in 10 fractions over 2 weeks). Patients underwent restaging 4 to 6 weeks after completion of chemoradiation and, in the absence of disease progression, were taken to surgery. RESULTS The study enrolled 86 patients. At the time of restaging, disease progression or a decline in performance status precluded 13 patients from surgery. Seventy-three (85%) of 86 patients were taken to surgery, extrapancreatic disease was found in nine, and 64 (74%) of 86 underwent a successful PD. Median overall survival (86 patients) was 22.7 months with a 27% 5-year survival. Median survival was 34 months for the 64 patients who underwent PD and 7 months for the 22 unresected patients (P < .001). The 5-year survival for those who did and did not undergo PD was 36% and 0%, respectively. CONCLUSION Preoperative gemcitabine-based chemoradiation followed by restaging and evaluation for surgery separated the study population into two different subsets: patients likely to benefit from PD (n = 64) and those in whom surgery would be unlikely to provide clinical benefit (n = 22). Furthermore, the encouraging overall survival observed in this large trial supports the continued investigation of gemcitabine-based preoperative therapy in resectable pancreatic cancer.

Borderline Resectable Pancreatic Cancer: Definitions, Management, and Role of Preoperative Therapy

With recent advances in pancreatic imaging and surgical techniques, a distinct subset of pancreatic tumors is emerging that blurs the distinction between resectable and locally advanced disease: tumors of “borderline resectability.” In our practice, patients with borderline-resectable pancreatic cancer include those whose tumors exhibit encasement of a short segment of the hepatic artery, without evidence of tumor extension to the celiac axis, that is amenable to resection and reconstruction; tumor abutment of the superior mesenteric artery involving <180° of the circumference of the artery; or short-segment occlusion of the superior mesenteric vein, portal vein, or their confluence with a suitable option available for vascular reconstruction because the veins are normal above and below the area of tumor involvement. With currently available surgical techniques, patients with borderline-resectable pancreatic head cancer are at high risk for a margin-positive resection. Therefore, our approach to these patients is to use preoperative systemic therapy and local-regional chemoradiation to maximize the potential for an R0 resection and to avoid R2 resections. In our experience, patients with favorable responses to preoperative therapy (radiographical evidence of tumor regression and improvement in serum tumor marker levels) are the subset of patients who have the best chance for an R0 resection and a favorable long-term outcome.

Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas.

PURPOSE The effects of preoperative versus postoperative fluorouracil (5-FU)-based chemotherapy and irradiation on treatment toxicity, duration of treatment, tumor recurrence, and survival were compared in patients who underwent potentially curative therapy for adenocarcinoma of the pancreatic head during a 5-year period. METHODS From July 1990 to July 1995, 142 patients with localized adenocarcinoma of the pancreatic head deemed resectable on the basis of radiographic images were treated with curative intent using a multimodality approach involving either preoperative or postoperative chemoradiation. Patients with biopsy confirmation of adenocarcinoma and a low-density mass in the pancreatic head identified by computed tomography (CT) received preoperative chemoradiation. Patients without a mass on CT or in whom the preoperative biopsy was negative underwent pancreaticoduodenectomy with planned postoperative chemoradiation. Protocol-based preoperative chemoradiation consisted of external-beam irradiation at a dose of 50.4 Gy (standard fractionation; 1.8 Gy/d, 5 d/wk) or 30 Gy (rapid fractionation; 3 Gy/d, 5 d/wk) combined with continuous infusion 5-FU (300 mg/m2/d, 5 d/wk). Postoperative chemoradiation combined 50.4 Gy of external-beam irradiation (standard fractionation) with continuous-infusion 5-FU. RESULTS No patient who received preoperative chemoradiation experienced a delay in surgery because of chemoradiation toxicity, but six of 25 eligible patients (24%) did not receive postoperative chemoradiation because of delayed recovery after pancreaticoduodenectomy. No significant differences in toxicities from chemoradiation were observed between groups. Patients treated with rapid-fractionation preoperative chemoradiation had a significantly (P < .01) shorter duration of treatment (median, 62.5 days) compared with patients who received postoperative chemoradiation (median, 98.5 days) or standard-fractionation preoperative chemoradiation (median, 91.0 days). At a median followup of 19 months, no significant differences in survival were observed between treatment groups. No patient who received preoperative chemoradiation and pancreaticoduodenectomy experienced a local recurrence; peritoneal (regional) recurrence occurred in 10% of these patients. Local or regional recurrence occurred in 21% of patients who received pancreaticoduodenectomy and postoperative chemoradiation. CONCLUSION Delivery of preoperative and postoperative chemoradiation in patients who underwent potentially curative pancreaticoduodenectomy for adenocarcinoma of the pancreatic head resulted in similar treatment toxicity, patterns of tumor recurrence, and survival. Rapid-fractionation preoperative chemoradiation ensured the delivery of all components of therapy to all eligible patients with a significantly shorter duration of treatment than with standard-fractionation chemoradiation given either before or after pancreaticoduodenectomy. Prolonged recovery after pancreaticoduodenectomy prevents the delivery of postoperative adjuvant chemoradiation in up to one fourth of eligible patients.

Borderline Resectable Pancreatic Cancer: The Importance of This Emerging Stage of Disease

BACKGROUND Patients with borderline resectable pancreatic adenocarcinoma (PA) include those with localized disease who have tumor or patient characteristics that preclude immediate surgery. There is no optimal treatment schema for this distinct stage of disease, so the role of surgery is undefined. STUDY DESIGN We defined patients with borderline resectable PA as fitting into one of three distinct groups. Group A comprised patients with tumor abutment of the visceral arteries or short-segment occlusion of the Superior Mesenteric Vein. In group B, patients had findings suggestive but not diagnostic of metastasis. Group C patients were of marginal performance status. Patients were treated initially with chemotherapy, chemoradiation, or both; those of sufficient performance status who completed preoperative therapy without disease progression were considered for surgery. RESULTS Between October 1999 and August 2006, 160 (7%) of 2,454 patients with PA were classified as borderline resectable. Of these, 125 (78%) completed preoperative therapy and restaging, and 66 (41%) underwent pancreatectomy. Vascular resection was required in 18 (27%) of 66 patients, and 62 (94%) underwent a margin-negative pancreatectomy. A partial pathologic response to induction therapy (< 50% viable tumor) was seen in 37 (56%) of 66 patients. Median survival was 40 months for the 66 patients who completed all therapy and 13 months for the 94 patients who did not undergo pancreatectomy (p < 0.001). CONCLUSIONS This is the first large report of borderline resectable PA and includes objective definitions for this stage of disease. Our neoadjuvant approach allowed for identification of the marked subset of patients that was most likely to benefit from surgery, as evidenced by the favorable median survival in this group.

Pancreaticoduodenectomy With Vascular Resection: Margin Status and Survival Duration

Major vascular resection performed at the time of pancreaticoduodenectomy (PD) for adenocarcinoma remains controversial. We analyzed all patients who underwent vascular resection (VR) at the time of PD for any histology at a single institution between 1990 and 2002. Preoperative imaging criteria for PD included the absence of tumor extension to the celiac axis or superior mesenteric artery (SMA). Tangential or segmental resection of the superior mesenteric or portal veins was performed when the tumor could not be separated from the vein. As a separate analysis, all patients who underwent PD with VR for pancreatic adenocarcinoma were compared to all patients who underwent standard PD for pancreatic adenocarcinoma. A total of 141 patients underwent VR with PD. Superior mesenteric-portal vein resections included tangential resection with vein patch (n = 36), segmental resection with primary anastomosis (n = 35), and segmental resection with autologous interposition graft (n = 55). Hepatic arterial resections were performed in 10 patients, and resections of the anterior surface of the inferior vena cava were performed in 5 patients. PD was performed for pancreatic adenocarcinoma in 291 patients; standard PD was performed in 181 and VR in 110. Median survival was 23.4 months in the group that required VR and 26.5 months in the group that underwent standard PD (P = 0.177). A Cox proportional hazards model was constructed to analyze the effects of potential prognostic factors (VR, tumor size, T stage, N status, margin status) on survival. The need for VR had no impact on survival duration. In conclusion, properly selected patients with adenocarcinoma of the pancreatic head who require VR have a median survival of approximately 2 years, which does not differ from those who undergo standard PD and is superior to historical patients believed to have locally advanced disease treated nonoperatively.

Impact of resection status on pattern of failure and survival after pancreaticoduodenectomy for pancreatic adenocarcinoma

Objective:To better understand the impact of a microscopically positive margin (R1) on patterns of disease recurrence and survival after pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma. Summary Background Data:A positive resection margin after PD is considered to be a poor prognostic factor, and some have proposed that an R1 margin may be a biologic predictor of more aggressive disease. The natural history of patients treated with contemporary multimodality therapy who underwent a positive margin PD has not been described. Methods:We analyzed our experience from 1990 to 2004, which included the prospective use of a standardized system for pathologic analysis of all PD specimens. All patients who underwent PD met objective computed tomographic criteria for resection. Standard pathologic evaluation of the PD specimen included permanent section analysis of the final bile duct, pancreatic, and superior mesenteric artery (SMA) margins. First recurrences (all sites) were defined as local, regional, or distant. Survival and follow-up were calculated from the date of initial histologic diagnosis to the dates of first recurrence or death and last contact, respectively. Results:PD was performed on 360 consecutive patients with pancreatic adenocarcinoma. Minimum follow-up was 12 months (median, 51.9 months). The resection margins were negative (R0) in 300 patients (83.3%) and positive (R1) in 60 (16.7%); no patients had macroscopically positive (R2) margins. By multivariate analysis (MVA), high mean operative blood loss and large tumor size were independent predictors of an R1 resection. Patients who underwent an R1 resection had a median overall survival of 21.5 months compared with 27.8 months in patients who underwent an R0 resection. After controlling for other variables on MVA, resection status did not independently affect survival. By MVA, only lymph node metastases, major perioperative complications, and blood loss adversely affected survival. Conclusions:There was no statistically significant difference in patient survival or recurrence based on R status. However, this series is unique in the incorporation of a standardized surgical technique for the SMA dissection, the prospective use of a reproducible system for pathologic evaluation of resection margins, the absence of R2 resections, and the frequent use of multimodality therapy.

Hilar Cholangiocarcinoma: patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system.

OBJECTIVES To determine the resectability rate for hilar cholangiocarcinoma, to analyze reasons for unresectability, and to devise a presurgical clinical T-staging system. METHODS Ninety patients with hilar cholangiocarcinomas seen between March 1, 1991, and April 1, 1997, were evaluated. Accurate patterns of disease progression and therapy were evaluable. Disease was staged in 87 patients using extent of ductal tumor involvement, portal vein compromise, and liver atrophy. RESULTS In 21 patients, disease was deemed unresectable for cure at presentation. In 39 patients, disease was found to be unresectable at laparotomy, 23 secondary to nodal (N2) or distant metastases. Unresectability was the result of metastases in 52% and of locally advanced disease in 28%. Thirty patients (33%) had resection of all gross disease, and 25 of these (83%) had negative histologic margins. Twenty-two patients underwent partial hepatectomy. The 30-day mortality rate was 7%. Projected survival is greater than 60 months in those with a negative histologic margin, with a median follow-up of 26 months. A presurgical T-staging system allows presurgical selection for therapy, predicts partial hepatectomy, and offers an index of prognosis. CONCLUSIONS In half the patients, unresectability is mainly the result of intraabdominal metastases. Presurgical imaging predicts unresectability based on local extension but is poor for assessing nodal metastases. In one third of patients, disease can be resected for cure with a long median survival. Curative resection depends on negative margins, and hepatic resection is necessary to achieve this. The T-staging system correlates with resectability, the need for hepatectomy, and overall survival.