Faculty Publications

PURPOSE: To correlate changes in 2-deoxy-2-[18F]fluoro-d-glucose (18-FDG) positron emission tomography (PET) (18-FDG-PET) uptake with response and disease-free survival with combined modality neoadjuvant therapy in patients with locally advanced rectal cancer. METHODS AND MATERIALS: Charts were reviewed for consecutive patients with ultrasound-staged T3x to T4Nx or TxN1 rectal adenocarcinoma who underwent preoperative chemoradiation therapy at Fox Chase Cancer Center (FCCC) or Robert H. Lurie Comprehensive Cancer Center of Northwestern University with 18-FDG-PET scanning before and after combined-modality neoadjuvant chemoradiation therapy . The maximum standardized uptake value (SUV) was measured from the tumor before and 3 to 4 weeks after completion of chemoradiation therapy preoperatively. Logistic regression was used to analyze the association of pretreatment SUV, posttreatment SUV, and % SUV decrease on pathologic complete response (pCR), and a Cox model was fitted to analyze disease-free survival. RESULTS: A total of 53 patients (FCCC, n = 41, RLCCC, n = 12) underwent pre- and postchemoradiation PET scanning between September 2000 and June 2006. The pCR rate was 31%. Univariate analysis revealed that % SUV decrease showed a marginally trend in predicting pCR (p = 0.08). In the multivariable analysis, posttreatment SUV was shown a predictor of pCR (p = 0.07), but the test results did not reach statistical significance. None of the investigated variables were predictive of disease-free survival. CONCLUSIONS: A trend was observed for % SUV decrease and posttreatment SUV predicting pCR in patients with rectal cancer treated with preoperative chemoradiation therapy. Further prospective study with a larger sample size is warranted to better characterize the role of 18-FDG-PET for response prediction in patients with rectal cancer.

Patients and methods: CTCs were enumerated with immunomagnetic separation from the blood of 430 patients with mCRC at baseline and on therapy. Patients were stratified into unfavorable and favorable prognostic groups based on CTC levels of >= 3 or < 3 CTCs/7.5 ml, respectively. Subgroups were analyzed by line of treatment, liver involvement, receipt of oxaliplatin, irinotecan, or bevacizumab, age, and Eastern Cooperative Oncology Group performance status (ECOG PS). Results: Seventy-one percent of deaths have occurred. Median follow-up for living patients is 25.8 months. For all patients, progression-free survival (PFS) and overall survival (OS) for unfavorable compared with favorable baseline CTCs is shorter (4.4 versus 7.8 m, P = 0.004 for PFS; 9.4 versus 20.6 m, P < 0.0001 for OS). In all patient subgroups, unfavorable baseline CTC was associated with inferior OS (P < 0.001). In patients receiving first- or second-line therapy (P = 0.003), irinotecan (P = 0.0001), having liver involvement (P = 0.002), >= 65 years (P = 0.0007), and ECOG PS of zero (P = 0.04), unfavorable baseline CTC was associated with inferior PFS. Conclusion: Baseline CTC count is an important prognostic factor within specific subgroups defined by treatment or patient characteristics.

Purpose: To correlate changes in 2-deoxy-2-[18F]fluoro-D-glucose (18-FDG) positron emission tomography (PET) (18-FDG-PET) uptake with response and disease-free survival with combined modality neoadjuvant therapy in patients with locally advanced rectal cancer. Methods and Materials: Charts were reviewed for consecutive patients with ultrasound-staged T3x to T4Nx or TxN1 rectal adenocarcinoma who underwent preoperative chemoradiation therapy at Fox Chase Cancer Center (FCCC) or Robert H. Lurie Comprehensive Cancer Center of Northwestern University with 18-FDG-PET scanning before and after combined-modality neoadjuvant chemoradiation therapy. The maximum standardized uptake value (SUV) was measured from the tumor before and 3 to 4 weeks after completion of chemoradiation therapy preoperatively. Logistic regression was used to analyze the association of pretreatment SUV, posttreatment SUV, and % SUV decrease on pathologic complete response (pCR), and a Cox model was fitted to analyze disease-free survival. Results: A total of 53 patients (FCCC, n = 41, RLCCC, n = 12) underwent pre- and postchemoradiation PET scanning between September 2000 and June 2006. The pCR rate was 31 %. Univariate analysis revealed that % SUV decrease showed a marginally trend in predicting pCR (p = 0.08). In the multivariable analysis, posttreatment SUV was Shown a predictor of pCR (p = 0.07), but the test results did not reach statistical significance. None of the investigated variables were predictive of disease-free survival. Conclusions: A trend was observed for % SUV decrease and posttreatment SUV predicting pCR in patients with rectal cancer treated with preoperative chemoradiation therapy. Further prospective study with a larger sample size is warranted to better characterize the role of 18-FDG-PET for response prediction in patients with rectal cancer. (C) 2009 Elsevier Inc.

BACKGROUND: For patients with borderline resectable pancreatic cancer, preoperative chemoradiation and standalone chemotherapy may allow for R0 resection and improved survival. METHODS: A retrospective review of patients with borderline resectable pancreatic cancer treated with preoperative chemoradiation and standalone chemotherapy was undertaken. Clinical variables, including disease-free and overall survival, were collected. Univariate analysis was used to identify factors impacting survival. RESULTS: Thirteen patients with borderline resectable pancreatic cancer were treated with preoperative chemoradiation and chemotherapy. Morbidity and mortality were 38% and 0. There were 2 R1 and 11 R0 resections. Nine patients are alive with a median follow-up of 20 months. Five patients recurred at a median of 4 months. Tumor fibrosis < or = 60% was associated with recurrence and poor survival. CONCLUSIONS: Preoperative chemoradiation and chemotherapy allow a select group of patients with borderline resectable pancreatic cancer to undergo an R0 or R1 resection with acceptable morbidity and mortality. Tumor response may be associated with survival.

Purpose: The combination of capecitabine and oxaliplatin has clinical benefit in a variety of gastrointestinal malignancies. The proteasome inhibitor bortezomib enhances the cytotoxic activity of fluoropyrimidines and platinum agents in vivo, and targeting of NF-kappa B may overcome chemotherapy resistance. Thus, we performed this phase I study to document the safety and obtain preliminary efficacy data for the combination of capecitabine, oxaliplatin, and bortezomib. Patients and Methods: Patients with advanced solid tumors were treated with oxaliplatin 130 mg/m(2) intravenously on day 1, capecitabine 750-900 mg/m(2) twice daily orally for 14 days, and bortezomib 1.0, 1.3, or 1.6 mg/m(2) intravenously on days 1 and 8 of 21 day cycles. CT scans were repeated every 2 cycles. Results: Thirteen patients received 45 cycles of treatment (median, 2; range, 1-8). No dose-limiting toxicities were noted at all bortezomib dose levels when administered with full dose capecitabine and oxaliplatin. The most common grade 3 nonhematologic toxicities during any cycle of therapy included elevated transaminases (3), vomiting, diarrhea, and dehydration (2 each). Only one patient experienced grade 3 peripheral neuropathy in cycle 8. Three objective tumor responses were noted (squamous cell of anus, adenocarcinoma of unknown primary, adenocarcinoma of rectum). Conclusions: Weekly bortezomib can be safely combined with full doses of capecitabine and oxaliplatin. As 1.6 mg/m(2) weekly of bortezomib is the maximum tolerated dose in single-agent studies, no further dose escalation was performed in this study. Preliminary evidence of antitumor activity is demonstrated. The further evaluation of this combination in diseases for which capecitabine and oxaliplatin have efficacy should be considered.

BACKGROUND: Absence of major arterial tumor involvement has generally been regarded as a major criterion for resectability of pancreatic tumors. We hypothesize that resection of a tumor-involved hepatic artery (HA) or celiac artery (CA) with reconstruction may offer a survival benefit to patients whose tumors were traditionally regarded as unresectable. METHODS: All patients with pancreatic adenocarcinoma treated between 1996 and 2007 were reviewed. Patients were included if they underwent resection of the HA or CA during pancreatectomy. Survival was analyzed by Kaplan-Meier survivor functions, Cox proportional hazard models, and the log rank test. RESULTS: Twelve patients (six men and six women) with adenocarcinoma underwent pancreatectomy with resection of a tumor-involved HA (n = 2) and/or CA (n = 10). Median age at diagnosis was 62 years (range, 53-73 years). All patients completed neoadjuvant chemoradiotherapy with or without full dose chemotherapy before resection. Procedures performed were six extended pancreaticoduodenectomies, two proximal subtotal pancreatectomies, two distal pancreatectomies, and two total pancreatectomies. Ten cases involved celiac resections, and two had isolated HA resections. The 60-day mortality was 17% (2 of 12). Median survival after diagnosis was 20 months (range, 6-41 months). Median survival after resection was 17 months (range, 1-36 months). Survival was not statistically significantly related to age, sex, margin status, or preoperative CA19-9 level. The 3-year survival was 17%. There were no 5-year survivors. CONCLUSIONS: Resection of the HA or CA with reconstruction may prolong survival for selected patients who undergo pancreatic resection after neoadjuvant therapy. However, this aggressive approach did not result in any long-term survivors in our series.

Fox Chase Cancer Center Partners (FCCCP) is a community hospital/academic partnership consisting of 25 hospitals in the Delaware Valley. Originally created in 1986, FCCCP promotes quality community cancer care through education, quality assurance, and access to clinical trial research. An important aspect of quality assurance is a yearly medical oncology audit that benchmarks quality indicators and guidelines and provides a roadmap for quality improvement initiatives in the community oncology clinical office setting. Each year, the FCCCP team and the Partner Medical Oncologists build disease site- and stage-specific indicators based on National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Concordance with multiple indicators is assessed on 20 charts from each community practice. A report for each FCCCP medical oncology practice summarizes documentation, screening recommendations, new drug use, and research trends in a particular disease site. Descriptive statistics reflect indicators met, number of new cases seen per year, number of disease site cases from tumor registry information, and clinical trial accrual total. Education and documentation tools are provided to physicians and oncology office nursing staff. The FCCCP Clinical Operations Team, consisting of medical oncologists and oncology-certified nurses, has conducted quality audits in medical oncology offices for 7 years using NCCN-derived indicators. Successful audits comprising gastric, colorectal, and breast cancer have been the focus of recent evaluations. For the 2005 stage II/III breast cancer evaluation, mean compliance per parameter was 88%, with 15 of 16 practices achieving mean compliance greater than 80%. A large-scale quality assurance audit in a community cancer partner network is feasible. Recent evaluation of localized breast cancer shows high compliance with guidelines and identifies areas for focused education. Partnership between academic and community oncologists produces a quality review process that is broadly applicable and adaptable to changing medical knowledge.

Gastrointestinal cancers remain a significant cause of morbidity and mortality. While increasing therapeutic options have improved outcomes for many patients, they have also complicated treatment decision-making. Unfortunately, most patients with advanced gastrointestinal malignancies die from their disease. Prognostic and predictive markers could improve treatment significantly by identifying patients who may or may not require a given therapy, and determining those most likely to benefit from a therapy. Candidates for such markers include blood antigens and circulating tumor cells, tumor enzyme and gene expression, and pharmacodynamic endpoints. In this review, we summarize reported and ongoing research to define and validate prognostic and predictive markers in gastrointestinal malignancies, with an emphasis on colorectal cancer and brief overview of pancreatic and neuroendocrine tumors.

Purpose: Development of targeted therapeutic agents in colorectal cancer (CRC) is impeded by the lack of a noninvasive surrogate of drug effect. This pilot study evaluated the ability of immunomagnetic separation to isolate circulating tumor cells (CTCs) and of the fluorescent microscope system and flow cytometry to enumerate and characterize CTCs from patients with metastatic CRC. Patients and Methods: Fifty patients with metastatic CRC contributed 50 mL of blood at treatment initiation and disease evaluation timepoints. Fresh tumor specimens were obtained from 17 patients for comparison of circulating and in situ tumor cell characteristics. Epithelial cells were magnetically isolated from whole blood targeting the antiepithelial cell adhesion molecule (EpCAM). Circulating tumor cells were defined as EpCAM isolated, cytokeratin positive, nuclear stain positive, and CD45 negative. Total RNA was isolated from EpCAM-enriched CTCs and multigene reverse-transcriptase polymerase chain reaction analyses were performed. Results: The median number of CTCs detected by flow cytometry was 2/7.5 mL blood. Mean change in cell count was significantly different for patients with tumor progression versus nonprogression (+6.7 vs. +0.2/7.5 mL; P = 0.001). A correlation was noted between mean fluorescence intensity (flow cytometry) of cytokeratin in CTC and matched tumor specimens (r = 0.79, P = 0.06). Nearly 80% (15 of 19) of samples with >= 2 CTCs expressed >= 1 epithelial marker gene (CK19, CK20, carcinoembryonic antigen, or epidermal growth factor receptor). Conclusion: Isolating and characterizing CTCs from patients with metastatic CRC is feasible. Change in the CTC number might reflect clinical status, and flow cytometric and gene expression data suggest similarity of circulating and in situ tumor cells. Further evaluation of CTCs for pharmacodynamic and clinical monitoring in patients with CRC is warranted.

SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA

Purpose: The median survival time of patients with locally advanced adenocarcinoma of the pancreas is 8-10 months. Radiation therapy has been used to improve local control and palliate symptoms. This randomized study was undertaken to determine whether the addition of 5-fluorouracil (5-FU) and mitomycin-C (MMC) to radiation therapy improves outcome in this patient population. Patients and Methods: One hundred fourteen patients were randomized to receive 59.4 Gy external beam radiotherapy in 1.8 Gy fractions alone or in combination with 5-FU (1,000 mg/m2/day for 4 days by continuous infusion Days 2-5 and 28-31) and MMC (10 mg/m2 on Day 2). Results: One hundred four patients were evaluable for efficacy. Hematologic and nonhematologic toxicities were more common in the combination arm. The response rates were 6% in the radiation therapy arm and 9% in the combination arm. There were no differences in median disease-free survival time (DFS) or overall survival time (OS) between the combination and radiation therapy alone arms: 5.1 vs. 5.0 months, respectively, for DFS (p = 0.19) and 8.4 vs. 7.1 months, respectively, for OS (p = 0.16). Conclusion: The addition of 5-FU and MMC to radiotherapy increased toxicity without improving DFS or OS in patients with locally advanced pancreatic cancer. Alternative drugs for radiosensitization may improve outcome. © 2005 Elsevier Inc.