Utility of a molecular prescreening program in advanced colorectal cancer for enrollment on biomarker-selected clinical trials.

BACKGROUND: Incorporation of multiple enrichment biomarkers into prospective clinical trials is an active area of investigation, but the factors that determine clinical trial enrollment following a molecular prescreening program have not been assessed. PATIENTS AND METHODS: Patients with 5-fluorouracil-refractory metastatic colorectal cancer at the MD Anderson Cancer Center were offered screening in the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) program to identify eligibility for companion phase I or II clinical trials with a therapy targeted to an aberration detected in the patient, based on testing by immunohistochemistry, targeted gene sequencing panels, and CpG island methylation phenotype assays. RESULTS: Between August 2010 and December 2013, 484 patients were enrolled, 458 (95%) had a biomarker result, and 157 (32%) were enrolled on a clinical trial (92 on biomarker-selected and 65 on nonbiomarker selected). Of the 458 patients with a biomarker result, enrollment on biomarker-selected clinical trials was ninefold higher for predefined ATTACC-companion clinical trials as opposed to nonpredefined biomarker-selected clinical trials, 17.9% versus 2%, P < 0.001. Factors that correlated positively with trial enrollment in multivariate analysis were higher performance status, older age, lack of standard of care therapy, established patient at MD Anderson, and the presence of an eligible biomarker for an ATTACC-companion study. Early molecular screening did result in a higher rate of patients with remaining standard of care therapy enrolling on ATTACC-companion clinical trials, 45.1%, in contrast to nonpredefined clinical trials, 22.7%; odds ratio 3.1, P = 0.002. CONCLUSIONS: Though early molecular prescreening for predefined clinical trials resulted in an increase rate of trial enrollment of nonrefractory patients, the majority of patients enrolled on clinical trials were refractory to standard of care therapy. Within molecular prescreening programs, tailoring screening for preidentified and open clinical trials, temporally linking screening to treatment and optimizing both patient and physician engagement are efforts likely to improve enrollment on biomarker-selected clinical trials. CLINICAL TRIALS NUMBER: The study NCT number is NCT01196130.

Improved Survival with Anti-VEGF Therapy in the Treatment of Unresectable Appendiceal Epithelial Neoplasms.

BACKGROUND: Currently, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are accepted treatments for surgically resectable appendiceal epithelial neoplasms. However, for nonsurgical candidates, systemic treatment may be considered. The purpose of this analysis was to determine the benefit of biologic therapy (anti-vascular endothelial growth factor and anti-epidermal growth factor receptor) in addition to systemic chemotherapy in this select patient population. METHODS: The MD Anderson Cancer Center tumor registry was retrospectively reviewed for systemic treatment-naive appendiceal epithelial neoplasm patients registered between January 2000 to July 2007 for prior cytoreductive surgery and hyperthermic intraperitoneal chemotherapy status, histologic grade, signet ring pathology, systemic chemotherapy, biologic therapy, tumor markers (carcinoembryonic antigen, carbohydrate antigen [CA] 125, and/or CA19-9), progression-free survival (PFS), overall survival (OS), and disease control rate. Kaplan-Meier method, log-rank, and Cox proportional hazard regression models were used for statistical analysis. RESULTS: A total of 353 patients were identified; 130 patients met the inclusion criteria. Fifty-nine patients received biologic therapy. The use of the anti-vascular endothelial growth factor (VEGF) agent bevacizumab improved both OS (42 months vs. 76 months, hazard ratio 0.49 [95 % confidence interval 0.25-0.94] P = 0.03) and PFS (4 months vs. 9 months, hazard ratio 0.69 [95 % confidence interval 0.47-0.995], P = 0.047) for all histologic subtypes. Moderately differentiated tumors had an improved PFS relative to well-differentiated tumors, 9 months versus 3 months (P = 0.05). CONCLUSIONS: Bevacizumab in combination with chemotherapy appears to play a role in surgically unresectable appendiceal epithelial neoplasm patients, with an improvement in PFS and OS. Anti-VEGF agents should be strongly considered in the management of patients with higher-grade appendiceal epithelial neoplasms who are suboptimal candidates for surgical resection.

Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer.

BACKGROUND: Src has a critical role in tumor cell migration and invasion. Increased Src activity has been shown to correlate with disease progression and poor prognosis, suggesting Src could serve as a therapeutic target for kinase inhibition. Saracatinib (AZD0530) is a novel selective oral Src kinase inhibitor. METHODS: Metastatic colorectal cancer patients who had received one prior treatment and had measurable disease were enrolled in this phase 2 study. Saracatinib was administered at 175 mg by mouth daily for 28 day cycles until dose-limiting toxicity or progression as determined by staging every 2 cycles. The primary endpoint was improvement in 4 month progression-free survival. Design of Thall, Simon, and Estey was used to monitor proportion of patients that were progression free at 4 months. The trial was opened with plan to enroll maximum of 35 patients, with futility assessment every 10 patients. RESULTS: A total of 10 patients were enrolled between January and November 2007. Further enrollment was stopped due to futility. Median progression-free survival was 7.9 weeks, with all 10 patients showing disease progression following radiographic imaging. Median overall survival was 13.5 months. All patients were deceased by time of analysis. Observed adverse events were notable for a higher than expected number of patients with grade 3 hypophosphatemia (n = 5). CONCLUSION: Saracatinib is a novel oral Src kinase inhibitor that was well tolerated but failed to meet its primary endpoint of improvement in 4 month progression-free survival as a single agent in previously treated metastatic colorectal cancer patients.

The prognostic significance of left ventricular ejection fraction in patients with advanced cancer treated in phase I clinical trials.

BACKGROUND: New targeted agents may cause acute cardiac events. The purpose of our study was to investigate the incidence and the prognostic significance of left ventricular ejection fraction (LVEF) in phase I trials. PATIENTS AND METHODS: Between October 2008 and September 2011, the records of 1166 consecutive patients with advanced cancer treated in the Phase I Clinic who underwent echocardiography were retrospectively reviewed. RESULTS: Most of the patients were White (78%), and the most common tumor types were colorectal cancer and melanoma. Of 1166 patients, 177 (15.2%) patients had an LVEF of <50%. No difference in overall survival (OS) between patients with LVEF ≥ 50% and patients with LVEF < 50% was seen (median OS 7.4 versus 7.0 months, P = 0.84). Patients with LVEF ≤ 35% had shorter survival compared with those with LVEF between 35% and 50% (median 4.2 versus 8.0 months; P = 0.005). In multivariate analysis of patients with LVEF < 50%, independent factors predicting longer survival were LVEF > 35%, ≤2 prior systemic therapies, ≤2 metastatic sites, and normal lactate dehydrogenase and albumin levels. CONCLUSION: Echocardiography would improve patient selection for enrollment in phase I clinical trials. These data suggest that it is safe to treat patients with LVEF between 35% and 50%.

A retrospective study of ampullary adenocarcinomas: overall survival and responsiveness to fluoropyrimidine-based chemotherapy.

BACKGROUND: Whether carcinomas of the ampulla of Vater should be classified with biliary tract tumors and treated in a similar manner remains unknown. We sought to compare the outcomes of similarly staged periampullary adenocarcinomas (AAs) and analyze the chemotherapy responsiveness of AAs. PATIENTS AND METHODS: A total of 905 patients with resected periampullary adenocarcinomas were identified from a prospective surgical registry from 1988 to 2010. A second cohort of 64 metastatic AA patients from 1992 to 2009 who received either front-line fluoropyrimidine-based or gemcitabine-based chemotherapy was also identified. RESULTS: Overall survival (OS) for AAs was similar to survival with duodenal adenocarcinomas, but was significantly different from both extrahepatic biliary and pancreatic adenocarcinomas (P < 0.001 for each comparison). In multivariate analysis, AAs had a significantly improved OS in comparison with extrahepatic biliary adenocarcinomas (HR = 1.97, P = 0.006). Fluoropyrimidine-based as opposed to gemcitabine-based chemotherapy for metastatic AAs resulted in a significant improvement in time to progression (P = 0.001) but only a trend toward benefit for OS (P = 0.07) in multivariate analysis. CONCLUSIONS: Differences in the natural history of ampullary and extrahepatic biliary adenocarcinomas exist. Analyses of metastatic ampullary adenocarcinomas suggest that fluoropyrimidine-based chemotherapy may represent a more appropriate front-line chemotherapy approach.

Systemic chemotherapy and surgical cytoreduction for poorly differentiated and signet ring cell adenocarcinomas of the appendix.

BACKGROUND: Poorly differentiated and signet ring cell adenocarcinomas of the appendix represent a subset with aggressive tumor biology and poor outcomes with few studies evaluating the impact of systemic chemotherapy and cytoreductive surgery (CRS). PATIENTS AND METHODS: A retrospective chart review of patients with either poorly differentiated and signet ring cell appendiceal adenocarcinomas was completed from 1992 to 2010. RESULTS: One hundred forty-two patients were identified. Seventy-eight patients with metastatic disease received chemotherapy. Radiographic response was 44%, median progression-free survival (PFS) was 6.9 months, and median overall survival (OS) was 1.7 years. In multivariate analysis, response to chemotherapy [hazard ratio (HR) 0.5; P = 0.02] predicted improved PFS, and complete CRS (HR 0.3; P = 0.004) predicted improved OS. Patients who underwent complete CRS (n = 26) had a median relapse-free survival (RFS) of 1.2 years and a median OS of 4.2 years. In multivariate analysis for this subset, complete cytoreduction score of 0 was significantly correlated with improved RFS (HR 0.07; P = 0.01) and OS (HR 0.02; P = 0.01). CONCLUSIONS: Systemic chemotherapy appears to be a viable treatment option for patients with metastatic poorly differentiated and signet ring cell appendiceal adenocarcinomas. Complete CRS is associated with improved RFS and OS, though part of this benefit likely reflects the selection of good tumor biology.

Metastatic small bowel adenocarcinoma: role of metastasectomy and systemic chemotherapy.

BACKGROUND: Metastatic small bowel adenocarcinoma (SBA) has a poor prognosis. Due to its rarity, high-quality data are lacking to guide treatment. This retrospective analysis was conducted to help characterize the treatment options for patients with metastatic SBA while providing clinically meaningful prognostic information. PATIENTS AND METHODS: In total, 437 patients who initially presented with or developed metastatic SBA between September 1977 and September 2019 were identified from the MD Anderson Tumor Registry. Clinical data were collected from review of the medical record. Overall response rates (ORR), time to progression (TTP), and overall survival (OS) were assessed across various treatments and treatment lines. RESULTS: The median OS from diagnosis of metastatic disease was 15.9 months [95% confidence interval (CI): 14.3-17.9]. Seventy-five patients (17.1%) underwent metastasectomy, which was associated with a median OS of 34.5 versus 17.1 months among patients who received chemotherapy alone (P < 0.001). Fluoropyrimidine plus platinum (n = 164) was the most common first-line chemotherapy, associated with an ORR of 59% and TTP of 8.1 months. Irinotecan with 5-FU (n = 101) was the most common second-line therapy associated with an ORR of 31% and TTP of 4.0 months. Twenty-two patients received immunotherapy; 5 of 6 patients with deficient mismatch repair (dMMR) responded, while 0 of 16 with proficient mismatch repair (pMMR) responded. Taxane-based chemotherapy was given to 34 patients with an ORR of 21% and a median TTP of 2.4 months. Among 11 patients who received anti-epidermal-growth-factor-receptor (EGFR) monotherapy, the best response was stable disease (SD) in 1 patient. CONCLUSIONS: In well-selected patients with SBA, metastasectomy appears to be associated with improved OS. This improvement was seen across metastasectomy sites, including liver, lung and peritoneal. Anti-programmed cell death protein 1 (PD-1) based immunotherapy was active for dMMR SBA but not pMMR SBA. While taxane-based chemotherapy demonstrates therapeutic activity, the activity of anti-EGFR therapy was limited.

Immunophenotype and molecular characterisation of adenocarcinoma of the small intestine.

BACKGROUND: Despite having a dramatically larger surface area than the large intestine, the small intestine is an infrequent site for the development of adenocarcinoma. To better understand the molecular abnormalities in small bowel adenocarcinoma (SBA), we characterised a number of candidate oncogenic pathways and the immunophenotype of this rare cancer. METHODS: Tissue microarrays were constructed from tumour samples from 54 patients with all stages of the disease. Immunohistochemistry and microsatellite instability (MSI) testing were conducted. RESULTS: The profile of cytokeratin 20 and 7 coexpression was variable, but expression of caudal type homeobox transcription factor 2 (CDX2) was present in 70% of cases. In this young population (median age 54 years), loss of mismatch repair (MMR) proteins occurred in 35% of patients, with confirmed MSI in 100% of tested cases. Expression of vascular endothelial growth factor-A (VEGF-A) and epidermal growth factor receptor (EGFR) was common, occurring in 96 and 71% of patients, respectively. Only one case showed HER2 expression and none showed loss of phosphatase and tensin homologue mutated on chromosome 10 (PTEN). CONCLUSIONS: These results suggest that alterations in DNA MMR pathways are common in SBAs, similar to what is observed in large bowel adenocarcinomas. Furthermore, the high percentage of tumours expressing both EGFR and VEGF suggests that patients with this rare cancer may benefit from therapeutic strategies targeting EGFR and VEGF receptor (VEGFR).

The integration of chemoradiation in the care of patient with localized pancreatic cancer.

The use of chemoradiation for patients with localized pancreatic cancer is controversial. Although some randomized trials have indicated that chemoradiation improves the median survival of patients with locally advanced as well as resected pancreatic cancer, other more recent trials have called into question the role of chemoradiation and have supported the use of chemotherapy. In the adjuvant setting, the high local tumor recurrence/persistence rate in all trials probably reflects the inclusion of patients with incompletely resected tumors, whose prognosis is similar to the prognosis of patients with locally advanced who do not undergo resection, making these trials difficult to interpret. More precise clinical staging and selection of patients appropriate for surgical resection is an important goal. The keys to the successful integration of radiotherapy in the care of patients with localized pancreatic cancer are selection, sequencing and smaller treatment volumes. A strategy of initial chemotherapy followed by consolidation with a well-tolerated chemoradiation regimen both in the adjuvant and locally advanced settings maximizes benefits of both treatment options, which are in fact complementary. Herein, we discuss the rationale for this approach as well as the ongoing investigation of novel radiation approaches designed to enhance outcome through the molecular and physical targeting of disease as well as the investigation of neoadjuvant chemoradiation in radiographically resectable and borderline resectable pancreatic cancer.

A phase II study of UFT with leucovorin administered as a twice daily schedule in the treatment of patients with metastatic colorectal cancer.

Prolonged infusions have been shown to be safer and potentially more effective than bolus regimens of 5-fluorouracil (5-FU) as treatment for metastatic colorectal cancer (mCRC). However, infusional 5-FU requires central venous access and costly infusion pumps. Oral fluoropyrimidines enable longer exposures to 5-FU with increased convenience. Tegafur-uracil (UFT) with leucovorin (LV) given thrice daily has improved safety plus comparable survival and response rates to bolus 5-FU/LV. We conducted a phase II clinical study in 98 patients with mCRC to evaluate if UFT with LV given twice daily provided comparable time to progression (TTP), efficacy and tolerability to that reported for thrice daily in two phase III clinical studies. Secondary objectives included overall response rate (ORR) and overall survival (OS). Median TTP was 3.8 months, when compared with 3.5 months for thrice daily. The ORR (11%) and median OS (12.8 months) with twice daily administration were similar to that of thrice daily administration (12% and 12.4 months). The incidence of grade 3/4 treatment-related diarrhoea was 30% on the twice daily and 21% on the thrice daily schedule. These results suggest that twice daily administration has similar efficacy and tolerability to thrice daily administration and is an acceptable alternative for patients who would benefit from UFT with LV therapy.

Management of bevacizumab-associated bowel perforation: a case series and review of the literature.

BACKGROUND: This study examined the various approaches to the management of perforation and the associated outcomes in patients with bevacizumab-associated bowel perforation at a tertiary cancer center. PATIENTS AND METHODS: Our institutional pharmacy database was searched to identify all patients who had received bevacizumab over a 2-year period (January 2004 to October 2006). Medical records of these patients were examined for reports of confirmed bowel perforation or fistula, associated clinicopathological factors, treatment, and outcomes. RESULTS: We identified 1442 patients who had been treated with bevacizumab over the study period with perforation occurring in 24 (1.7%). The breakdown of these 24 patients by disease site was as follows: ovarian (3 of 50, 6%), gastroesophageal (2 of 38, 5.3%), pancreatic (7 of 141, 5%), unknown primary (1 of 60, 1.7%), lung (1 of 67, 1.5%), colorectal (6 of 478, 1.3%), and renal cell (4 of 269, 1.5%). The majority of patients (n = 19, 79%) were initially managed nonoperatively. Only five (21%) patients ultimately underwent surgical exploration, with a subsequent anastomotic leak developing in one patient. The overall 30-day mortality rate was 12.5%. CONCLUSIONS: Bevacizumab-associated bowel perforation occurs in patients with various malignancies, with an incidence of 1.7%. Nonoperative treatment is a viable approach to management in selected patients.

Neoadjuvant therapy versus upfront surgical strategies in resectable pancreatic cancer: A Markov decision analysis.

BACKGROUND: Neoadjuvant therapy is gaining acceptance as a valid treatment option for borderline resectable pancreatic cancer; however, its value for clearly resectable pancreatic cancer remains controversial. The aim of this study was to use a Markov decision analysis model, in the absence of adequately powered randomized trials, to compare the life expectancy (LE) and quality-adjusted life expectancy (QALE) of neoadjuvant therapy to conventional upfront surgical strategies in resectable pancreatic cancer patients. METHODS: A Markov decision model was created to compare two strategies: attempted pancreatic resection followed by adjuvant chemoradiotherapy and neoadjuvant chemoradiotherapy followed by restaging with, if appropriate, attempted pancreatic resection. Data obtained through a comprehensive systematic search in PUBMED of the literature from 2000 to 2015 were used to estimate the probabilities used in the model. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Of the 786 potentially eligible studies identified, 22 studies met the inclusion criteria and were used to extract the probabilities used in the model. Base case analyses of the model showed a higher LE (32.2 vs. 26.7 months) and QALE (25.5 vs. 20.8 quality-adjusted life months) for patients in the neoadjuvant therapy arm compared to upfront surgery. Probabilistic sensitivity analyses for LE and QALE revealed that neoadjuvant therapy is favorable in 59% and 60% of the cases respectively. CONCLUSION(S): Although conceptual, these data suggest that neoadjuvant therapy offers substantial benefit in LE and QALE for resectable pancreatic cancer patients. These findings highlight the value of further prospective randomized trials comparing neoadjuvant therapy to conventional upfront surgical strategies.

Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma.

PURPOSE: To evaluate the toxicities, radiographic and pathologic responses, and event-free outcomes with combined modality treatment that involves preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and electron-beam intraoperative radiation therapy (EB-IORT) for patients with resectable pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients with radiographically resectable localized adenocarcinoma of the pancreatic head were entered onto a preoperative protocol that consisted of a 2-week course of fluorouracil (5-FU) 300 mg/m2 daily 5 days per week and concomitant rapid-fractionation radiation 30 Gy, 3 Gy daily 5 days per week. Radiographic restaging was performed 4 weeks after chemoradiation, and patients with localized disease underwent pancreaticoduodenectomy with EB-IORT 10 to 15 Gy. RESULTS: Thirty-five patients were entered onto the study and completed chemoradiation, 34 (97%) as outpatients. Three patients (9%) experienced grade 3 nausea and vomiting; no other grade 3 or 4 toxicities were observed. Of the 27 patients taken to surgery, 20 patients (74%) underwent pancreaticoduodenectomy with EB-IORT. All patients had a less than grade III pathologic response to preoperative chemoradiation. At a median follow-up of 37 months, the 3-year survival rate in patients who underwent combined modality therapy was 23%. CONCLUSION: Combined modality treatment with preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and EB-IORT is associated with minimal toxicity and excellent locoregional control. This represents one approach to maximize the proportion of patients who receive all components of combined modality therapy and avoids the toxicity of pancreaticoduodenectomy in patients found to have metastatic disease at the time of restaging.

Preoperative chemoradiation for patients with pancreatic cancer: toxicity of endobiliary stents.

PURPOSE: A recent multicenter study of preoperative chemoradiation and pancreaticoduodenectomy for localized pancreatic adenocarcinoma suggested that biliary stent-related complications are frequent and severe and may prevent the delivery of all components of multimodality therapy in many patients. The present study was designed to evaluate the rates of hepatic toxicity and biliary stent-related complications and to evaluate the impact of this morbidity on the delivery of preoperative chemoradiation for pancreatic cancer at a tertiary care cancer center. PATIENTS AND METHODS: Preoperative chemoradiation was used in 154 patients with resectable pancreatic adenocarcinoma (142 patients, 92%) or other periampullary tumors (12 patients, 8%). Patients were treated with preoperative fluorouracil (115 patients), paclitaxel (37 patients), or gemcitabine (two patients) plus concurrent rapid-fractionation (30 Gy; 123 patients) or standard-fractionation (50.4 Gy; 31 patients) radiation therapy. The incidences of hepatic toxicity and biliary stent-related complications were evaluated during chemoradiation and the immediate 3- to 4-week postchemoradiation preoperative period. RESULTS: Nonoperative biliary decompression was performed in 101 (66%) of 154 patients (endobiliary stent placement in 77 patients and percutaneous transhepatic catheter placement in 24 patients). Stent-related complications (occlusion or migration) occurred in 15 patients. Inpatient hospitalization for antibiotics and stent exchange was necessary in seven of 15 patients (median hospital stay, 3 days). No patient experienced uncontrolled biliary sepsis, hepatic abscess, or stent-related death. CONCLUSION: Preoperative chemoradiation for pancreatic cancer is associated with low rates of hepatic toxicity and biliary stent-related complications. The need for biliary decompression is not a clinically significant concern in the delivery of preoperative therapy to patients with localized pancreatic cancer.

Phase I trial of gemcitabine combined with radiation for the treatment of locally advanced pancreatic adenocarcinoma.

Gemcitabine has modest activity in the treatment of advanced pancreatic cancer and is a potent radiosensitizer. We conducted a Phase I trial to determine the maximum tolerated dose of weekly gemcitabine delivered concurrently with radiation therapy for the treatment of locally advanced adenocarcinoma of the pancreatic head and to assess the treatment-related toxic effects associated with such a regimen. Eighteen patients with pathologically proven, locally advanced adenocarcinoma of the pancreatic head were enrolled in this study. Patients received seven weekly doses of gemcitabine with 3000 cGy of external beam radiation therapy delivered during the first 2 weeks of therapy. Six patients received gemcitabine at 350 mg/m(2)/week, nine at 400 mg/m(2)/week, and three at 500 mg/m(2)/week. Grade 3-4 hematological toxicity was observed in over half the patients treated. Nonhematological toxicities were significant and included fatigue, anorexia, nausea, vomiting, and dehydration. Forty-four % of the patients required admission to the hospital for management of nausea/vomiting and dehydration. The risk of hospitalization appeared to be dose-related; all of the three patients treated at 500 mg/m(2)/week required hospital admission during treatment. Seventeen patients were evaluated for response, and eight patients (47%) had evidence of a local anticancer effect. Four of these eight patients (24%) had a partial response to therapy. The median survival for the entire group was 6 months. The 1-year survival rate for patients with an objective response to therapy was 66%. The clinical responses observed in this group of patients suggest gemcitabine is a clinically relevant radiosensitizer in patients with pancreatic adenocarcinoma. However, the toxic effects are significant, suggesting that until dose and scheduling issues are explored further, concomitant administration of gemcitabine and radiation therapy should still be considered investigational.

"Normothermic range" temperature affects myocardial infarct size.

OBJECTIVES: This study tested the hypothesis that small changes in temperature above the hypothermic range may alter myocardial infarct size after acute coronary occlusion-reperfusion. A secondary hypothesis, that a correlation between temperature and infarct size may be independent of an associated change of heart rate, was also evaluated. METHODS: Eighteen pentobarbitone-anaesthetised, open chest rabbits underwent 30 min coronary artery occlusion and 3 h reperfusion at blood temperatures ranging from 35-42 degrees C, achieved and maintained using surface methods (not paced, group NP). In a second group of 11 animals, heart rate was held constant across the same range of temperatures (paced, group P), before and throughout coronary artery occlusion-reperfusion. Infarct sizes were assessed by the tetrazolium method. RESULTS: Target temperature was effectively controlled over the duration of the experimental protocol to within +/- 0.25 degrees C. Area at risk did not vary with temperature. Infarct size, normalised to area at risk, was correlated with temperature in both groups (infarct size = 7.9 x temp-250.0, r = 0.75, p = 0.0003, group NP; infarct size = 11.7 x temp-404.5, r = 0.88, p = 0.0004, group P). There was no significant difference between the slopes of these two lines (p = 0.18), indicating that the positive correlation between infarct size and temperature is not related to changes of heart rate. CONCLUSION: Temperatures in the range of 35-42 degrees C affect myocardial infarct size significantly, independent of heart rate.

Anaesthetics alter the magnitude of infarct limitation by ischaemic preconditioning.

OBJECTIVE: The aim was to determine whether three commonly used animal anaesthetics alter the magnitude of infarct limitation achieved with ischaemic preconditioning. METHODS: Eighty four anaesthetised non-preconditioned and preconditioned open chest rabbits underwent a 30 min coronary occlusion followed by 3 h reperfusion. Ischaemic preconditioning was achieved with 5 min coronary occlusion beginning 15 min before the 30 min coronary occlusion. The anaesthetics studied were: pentobarbitone (30 mg.kg-1 intravenously +30-50 mg.kg-1.h-1 intravenously), isoflurane (1.5-2.5% end expiratory), and ketamine/xylazine (cocktail of 67 mg ketamine and 6.7 mg xylazine.ml-1, 1 ml.kg-1 intramuscularly +0.3-1.3 ml.kg-1.h-1 intramuscularly). Area at risk was delineated with ZnCdS particles and infarction assessed with tetrazolium. RESULTS: There were no significant differences in area at risk, heart rate, arterial pressure, and temperature between non-preconditioned and preconditioned hearts. Although infarct size was not significantly different among non-preconditioned hearts for each anaesthetic regimen (p = NS), the magnitude of infarct limitation with preconditioning varied with the anaesthetic employed (decrease in infarct size from control values of 81%, 44%, and 33% for pentobarbitone, isoflurane and ketamine/xylazine, respectively, p = 0.0145 for comparison of the three magnitudes, two factor ANOVA). CONCLUSION: Anaesthetic regimens affect the degree of infarct size limitation seen with ischaemic preconditioning.

Neoadjuvant chemoradiation for adenocarcinoma of the pancreas.

Adjuvant 5-fluorouracil and concurrent radiation may improve survival following complete surgical resection in patients with pancreatic adenocarcinoma. However, the morbidity and prolonged recovery associated with pancreaticoduodenectomy frequently prevents the timely delivery of postoperative chemoradiation. Therefore, the University of Texas M.D. Anderson Cancer Center (MDACC) has investigated the use of neoadjuvant chemoradiation in potentially resectable pancreatic cancer. We have incorporated a standardized approach to pretreatment staging, operative technique and pathologic evaluation. Our initial experience suggests that preoperative chemoradiation is well tolerated and may reduce loco-regional recurrence. Patients treated with rapid-fractionation preoperative chemoradiation had a significantly shorter duration of treatment compared with patients who received postoperative chemoradiation or standard-fractionation preoperative chemoradiation. New and more potent radiation-sensitizing agents such as gemcitabine may further enhance local control. Novel therapies directed at specific molecular events involved in pancreatic tumorigenesis may be incorporated into preoperative and postoperative regimens to attempt to reduce systemic relapse.

Combining gemcitabine with radiation in pancreatic cancer: understanding important variables influencing the therapeutic index.

We compared and evaluated available laboratory and clinical data on the use of concurrent gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and radiation in pancreatic cancer to provide guidance for subsequent prospective research initiatives. Preclinical data suggest that the timing of administration of gemcitabine with respect to radiotherapy is important, but this issue has not yet been confirmed by clinical data. Phase I clinical data indicate that the amount of acute toxicity from the combination of gemcitabine and radiotherapy is strongly related to the dose and schedule of administration of gemcitabine, as well as to the radiation field size. There also appears to be an inverse linear relationship between the maximum tolerated gemcitabine dose and radiation dose. Also important, but less clear, is the infusion rate of gemcitabine as it relates to the systemic efficacy of the drug. The combination of additional agents with gemcitabine and radiation appears to be feasible. Finally, the addition of radioprotectors may enable chemotherapy dose escalation, but safe escalation of the radiotherapy dose with newer techniques has not been established. Semin Oncol 28 (suppl 10):25-33.

T4 rectal cancer treated with preoperative chemoradiation to the posterior pelvis followed by multivisceral resection: patterns of failure and limitations of treatment.

PURPOSE: To analyze the overall pattern of treatment failure and sites of pelvic disease recurrence relative to the radiation fields used in treating patients with clinically staged T4 rectal cancer with preoperative chemoradiation followed by multivisceral resection. METHODS AND MATERIALS: Between 1990 and 1998, 45 patients with T4 rectal cancer were treated with preoperative chemoradiation. Clinical staging was according to the system of the American Joint Cancer Committee and was based on endoscopic ultrasonography, chemotherapy (CT), and physical examination. A diagnosis of T4 disease required evidence of invasion of a contiguous structure on CT (n = 31) or endorectal ultrasonography (n = 6), vaginal mucosal involvement on pelvic examination (n = 6), or a combination of these findings (n = 2). Chemoradiation was delivered with 18 MV photons using a 3-field belly-board technique. The median total dose was 45 Gy in all patients (range 45-63). Nine patients received a boost with external beam radiotherapy (EBRT) (n = 5, 1.8-18 Gy), intraoperative RT (n = 3, 10-20 Gy), or interstitial brachytherapy (n = 1, 20 Gy). All patients received concurrent chemotherapy consisting of protracted venous infusion 5-fluorouracil (300 mg/m(2), 5 d/wk). Resection was not performed in 13 (29%) of the 45 patients because of metastases detected before resection or patient refusal. Multivisceral resection and pelvic exenteration was required in 21 (66%) and 11 (34%) of 32 patients, respectively. We compared the location of pelvic disease recurrence with the RT simulation films. The Kaplan-Meier method was used to calculate the 4-year actuarial pelvic and distant recurrent rates and the overall survival rate. RESULTS: The median length of follow-up was 31.0 months for all patients and 40.0 months for patients alive at last follow-up. When only the resected cases were considered, the local recurrence rate was 20%. Distant metastases occurred in 44% of cases; the overall survival rate was 69%. When all patients were considered, the local recurrence rate was similar (24%), but the rate of distant recurrence (51%) was higher and the overall survival rate lower (50%). Pelvic disease was controlled in all 8 patients whose disease responded well to chemoradiation (either a histologically complete response or microscopic residual disease). Three of 4 patients with close or positive margins had pelvic recurrences despite intraoperative RT and brachytherapy. Nine of the 10 pelvic recurrences occurred in the radiation field. Elective external iliac nodal irradiation was not used, and nodal metastases were not seen in that region. In 1 case, marginal recurrence occurred in a common iliac node at the superior edge of the treatment field. CONCLUSIONS: Despite aggressive multimodality therapy including multivisceral resection, a high rate of pelvic and distant disease recurrence occurred in patients with clinically staged T4 disease. Regional disease recurred almost exclusively in the radiation field. The intraoperative RT and interstitial brachytherapy doses used did not prevent pelvic disease recurrence in patients with close or positive margins. Novel strategies such as higher preoperative doses of RT with or without altered fractionation or more effective radiosensitizers are needed to improve locoregional control in patients with T4 disease. Future strategies must also include more effective systemic therapy.