Precision Medicine and Pancreatic Cancer: A Gemcitabine Pathway Approach.

Objectives: There is a need for validated predictive markers of gemcitabine response to guide precision medicine treatment in pancreatic cancer. We previously validated human equilibrative nucleoside transporter 1 as a predictive marker of gemcitabine treatment response using Radiation Therapy Oncology Group 9704. Controversy exists about the predictive value of gemcitabine metabolism pathway biomarkers: deoxycytidine kinase (DCK), ribonucleotide reductase 1 (RRM1), RRM2, and p53R2.

Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection.

Purpose: Surgical resection of gastric cancer has produced suboptimal survival despite multiple randomized trials that used postoperative chemotherapy or more aggressive surgical procedures. We performed a randomized phase III trial of postoperative radiochemotherapy in those at moderate risk of locoregional failure (LRF) following surgery. We originally reported results with 4-year median follow-up.

Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the U.S. Intergroup/RTOG 9704 phase III trial.

Background: The impact of the addition of gemcitabine to 5-fluorouracil (5-FU) chemoradiation (CRT) on 5-year overall survival (OS) in resected pancreatic adenocarcinoma are presented with updated results of a phase III trial.

Methods: After resection of pancreatic adenocarcinoma, patients were randomized to pre- and post-CRT 5-FU versus pre- and post-CRT gemcitabine. 5-FU was provided continuously at 250 mg/m(2)/day, and gemcitabine was provided at 1000 mg/m(2) weekly.

Failure to adhere to protocol specified radiation therapy guidelines was associated with decreased survival in RTOG 9704--a phase III trial of adjuvant chemotherapy and chemoradiotherapy for patients with resected adenocarcinoma of the pancreas.

Purpose: In Radiation Therapy Oncology Group 9704, as previously published, patients with resected pancreatic adenocarcinoma received continuous infusion 5-FU and concurrent radiotherapy (5FU-RT). 5FU-RT treatment was preceded and followed by randomly assigned chemotherapy, either 5-FU or gemcitabine. This analysis explored whether failure to adhere to specified RT guidelines influenced survival and/or toxicity.

The influence of total nodes examined, number of positive nodes, and lymph node ratio on survival after surgical resection and adjuvant chemoradiation for pancreatic cancer: a secondary analysis of RTOG 9704.

Purpose: Lymph node status is an important predictor of survival in pancreatic cancer. We performed a secondary analysis of Radiation Therapy Oncology Group (RTOG) 9704, an adjuvant chemotherapy and chemoradiation trial, to determine the influence of lymph node factors--number of positive nodes (NPN), total nodes examined (TNE), and lymph node ratio (LNR ratio of NPN to TNE)--on OS and disease-free survival (DFS).

Patient And Methods: Eligible patients from RTOG 9704 form the basis of this secondary analysis of lymph node parameters.

Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial.

Context: Among patients with locally advanced metastatic pancreatic adenocarcinoma, gemcitabine has been shown to improve outcomes compared with fluorouracil.

Objective: To determine if the addition of gemcitabine to adjuvant fluorouracil chemoradiation (chemotherapy plus radiation) improves survival for patients with resected pancreatic adenocarcinoma.

Design, Setting, And Participants: Randomized controlled phase 3 trial of patients with complete gross total resection of pancreatic adenocarcinoma and no prior radiation or chemotherapy enrolled between July 1998 and July 2002 with follow-up through August 18, 2006, at 164 US and Canadian institutions.

Synergy between cetuximab and chemotherapy in tumors of the gastrointestinal tract.

Cetuximab is a recently approved monoclonal antibody that targets the epidermal growth factor receptor, a receptor tyrosine kinase involved in the development and progression of colorectal cancer (CRC) and other solid tumors. Cetuximab, as a single agent or in combination with chemotherapy, has demonstrated significant clinical efficacy against CRC. Combinations of cetuximab with chemotherapy have proven to be well tolerated, with minimal overlap of toxicities between agents; and the anticancer synergy between cetuximab and traditional chemotherapy agents has made cetuximab a vital treatment for patients who are no longer responsive to chemotherapy alone.

Phase II trial of infusional fluorouracil, leucovorin, mitomycin, and dipyridamole in locally advanced unresectable pancreatic adenocarcinoma: SWOG S9700.

Purpose: To test the hypothesis that dual biochemical modulation of fluorouracil (FU) in combination with mitomycin improves the survival of patients with pancreas cancer.

Patients And Methods: Eligibility included stage II or III unresectable adenocarcinoma of the pancreas, performance status of 0 to 2, and adequate organ function. Treatment included FU 200 mg/m2/d via continuous intravenous infusion for 4 weeks followed by 1 week of rest; leucovorin 30 mg/m2 administered via intravenous bolus infusion on days 1, 8, 15, and 22, followed by 1 week rest; mitomycin 10 mg/m2 intravenous bolus infusion every 6 weeks for a total of four doses.

Impact of hospital volume on recurrence and survival after surgery for gastric cancer.

Background: Some, but not all, studies using registry data have suggested a small but significant long-term survival advantage following a curative surgical resection of gastric cancer at hospitals where the volume of such surgeries is high. However, because such data may be significantly influenced by the impact of postoperative mortality, and may be imbalanced for factors important to survival, the true nature of this relationship remains uncertain.

Methods: We conducted a nested volume-outcome study in a sample of 448 surgical survivors with stage IB through IV (M0) gastric and gastroesophageal junction adenocarcinoma, previously randomized to adjuvant chemoradiation after surgery or surgery alone, to measure the effect of hospital surgical volume, as assessed by Medicare claims data, on overall survival and gastric cancer recurrence.

Gastric cancer: D2 dissection or low Maruyama Index-based surgery--a debate.

This article provides perspectives on the surgical approaches required optimally to manage patients with respectable gastric adenocarcinoma. The status of techniques of surgical resection in the management of gastric cancer is reviewed. The premise of this approach is that extended gastrectomy with D2 lymph node dissection is good.

ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer.

Purpose: To update the recommendations for the use of tumor marker tests in the prevention, screening, treatment, and surveillance of gastrointestinal cancers.

Methods: For the 2006 update, an update committee composed of members from the full Panel was formed to complete the review and analysis of data published since 1999. Computerized literature searches of Medline and the Cochrane Collaboration Library were performed.

Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144.

Purpose: Adjuvant chemoradiotherapy after or before resection of high-risk rectal cancer improves overall survival (OS) and pelvic control. We studied three postoperative fluorouracil (FU) radiochemotherapy regimens.

Patients And Methods: After resection of T3-4, N0, M0 or T1-4, N1, 2M0 rectal adenocarcinoma, 1,917 patients were randomly assigned to arm 1, with bolus FU in two 5-day cycles every 28 days before and after radiotherapy (XRT) plus FU via protracted venous infusion (PVI) 225 mg/m2/d during XRT; arm 2 (PVI-only arm), with PVI 42 days before and 56 days after XRT + PVI; or arm 3 (bolus-only arm), with bolus FU + leucovorin (LV) in two 5-day cycles before and after XRT, plus bolus FU + LV (levamisole was administered each cycle before and after XRT).

Phase II trial of PN401, 5-FU, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach: a Southwest Oncology Group study.

From February, 2001 to September, 2002, the Southwest Oncology Group (SWOG) accrued 65 patients with advanced gastric adenocarcinoma to a phase II trial of weekly 5-FU, leucovorin, and the orally-administered uridine analog PN401. Of these 65 patients, 57 were assessable for survival and toxicity, which were the endpoints for the study. Treatment consisted of the administration of 1200 mg/m(2) of 5-FU, 500 mg/m(2) of leucovorin, and 6 grams of PN401 every 8 h, beginning 8 h after the completion of the 5-FU infusion, and continuing for a total of 8 doses (48 grams) during each weekly chemotherapy session.

Phase II trial of R115777 (NSC #70818) in patients with advanced colorectal cancer: a Southwest Oncology Group study.

Purpose: The purpose of this Phase II multi-institutional trial was to determine the efficacy and toxicity of R115777 in previously untreated patients with metastatic colorectal carcinoma.

Patients And Methods: Patients were required to have histologically confirmed colorectal cancer with distant metastatic disease that was not surgically curable. They could not have received prior chemotherapy for metastatic disease.

Impact of the year 2000 Medicare policy change on older patient enrollment to cancer clinical trials.

Purpose: A prior analysis by the Southwest Oncology Group (SWOG) showed that women and African American patients were adequately represented on cancer clinical treatment trials but that older patients were substantially underrepresented. Twenty-five percent of patients > or = 65 years old were enrolled onto SWOG trials from 1993 to 1996, whereas 63% of all patients with cancer were > or = 65 years old. Recognition of this under-representation led to a change in Medicare policy in 2000 to include coverage of routine patient care costs of clinical trials.

Colon cancer survival is associated with decreasing ratio of metastatic to examined lymph nodes.

Purpose: Colorectal cancer is the second leading cause of cancer deaths in the United States, with poor survival predicted by regional lymph node (LN) metastasis. The impact of LN ratio (LNR) on survival is unknown in this disease.

Patients And Methods: We analyzed data from Intergroup trial 0089 of adjuvant chemotherapy for stage II and III patients with colon cancer, in which all patients received fluorouracil-based therapy.

Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089.

Purpose: In 1990, fluorouracil (FU) plus levamisole for 1 year became standard adjuvant treatment for patients with high-risk stages II and III colon cancer. Intergroup (INT) 0089 assessed the relative contributions of leucovorin and levamisole in such patients.

Patients And Methods: From 1988 to 1992, 3,794 patients were randomly assigned.

A randomized phase III trial of post-operative adjuvant oral fluoropyrimidine versus sequential paclitaxel/oral fluoropyrimidine; and UFT versus S1 for T3/T4 gastric carcinoma: the Stomach Cancer Adjuvant Multi-institutional Trial Group (Samit) Trial.

Paclitaxel, S1 and their combined sequential administration is proposed to be examined installing UFT as an active control of adjuvant chemotherapy for curatively resected T3-4 gastric cancer in a multicenter Phase III trial. The primary endpoint is disease-free survival and the secondary endpoints are incidence of adverse events, overall survival and compliance. The sample size is 370 per treatment arm (1480 in total) for two hypotheses of the superiority of sequential use of paclitaxel followed by oral fluoropyrimidines to fluoropyrimidines (UFT/S1) alone and the non-inferiority of S1 to UFT to be tested by two-by-two factorial design.

A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest oncology group (SWOG 9924) study.

Ninety per cent of pancreatic adenocarcinomas (PC) contain mutations of the K-Ras proto-oncogene resulting in constitutively activated Ras protein. A critical step in Ras activation is farnesylation of Ras protein. Farnesyl transferase inhibitors are compounds that inhibit farnesylation.

An observational study suggesting clinical benefit for adjuvant postoperative chemoradiation in a population of over 500 cases after gastric resection with D2 nodal dissection for adenocarcinoma of the stomach.

Purpose: The role of adjuvant chemoradiotherapy (CRT) in D2-resected gastric-cancer patients has not been defined yet. We investigated the effect of postoperative chemoradiotherapy on the relapse rate and survival rate of patients with D2-resected gastric cancer.

Methods And Materials: From August 1995 to April 2001, 544 patients received postoperative CRT after curative D2 resection.