Notification of Publication Correction
Imedex strives to provide accurate information in our publications and correct published errors of fact. The following publication recently required corrections or clarifications.

PUBLICATION TITLE: OncoFacts February 2009 Issue
PUBLICATION TYPE: Online: OncoFacts summaries of abstracts from the 31st Annual San Antonio Breast Cancer Symposium (SABCS) conference
CORRECTION : Abstract 78, paragraph 2, lines 1-2. FEC should have been 5-fluorouracil, epirubicin, and cyclophosphamide, not fludarabine, epirubicin and cyclophosphamide.
The corrected sentence is as follows: 1. 5- fluorouracil, epirubicin, and cyclophosphamide (FEC [500/100/500 mg/m²]) q 3 weeks x 6

This month we will be focusing on data from the recent 2009 Gastrointestinal Cancers Symposium. This multidisciplinary meeting was held in San Francisco in mid-January. The program included a number of didactic presentations as well as 563 abstracts, both oral, poster and published. Nearly 3000 attendees were present at this year’s meeting, including a large international contingent of attendees.

In this issue:

• Esophageal and Gastric Cancers
• Esophagogastric Carcinomas and Pancreatic Cancers
• Colorectal Cancer and Gastrointestinal Cancers
• Additional Colorectal Cancer Data
• Quick Poll

Esophageal and Gastric Cancers

Dr Douglas Corley, a gastroenterologist from the University of California, San Francisco and Kaiser Permanente, presented a discussion of high-risk groups for esophageal cancer screening. He noted the recent trend over the past several decades of decreasing incidence of squamous cell carcinomas and the rising incidence of esophageal adenocarcinoma. Groups at higher risk for squamous cell carcinoma of the esophagus include African American males, persons with a history of upper aerodigestive cancer, persons with underlying esophageal disease, smokers, those who drink alcohol to excess and those with diets low in fruits and vegetables. Squamous cell carcinoma of the esophagus is more common in males of lower socioeconomic status in the US. Factors associated with a higher risk of esophageal adenocarcinoma include male gender, central obesity, gastroesophageal reflux disease (GERD), smoking and diets poor in fruits and vegetables. While helicobacter pylori infection is associated with an increased risk of gastric cancer, its presence seems to reduce the incidence of reflux disease and esophageal adenocarcinoma. White males with central obesity, GERD, and the absence of H. pylori may be a population that should be considered in screening for gastroesophageal adenocarcinoma.

Dr Benjamin Wong from Hong Kong discussed screening and prevention of gastric cancer, noting its high incidence in Asia.
He focused particularly on the role of Helicobacter pylori and the value of effective treatment for H. pylori. He mentioned studies from China that demonstrated the eradication of H. pylori in patients without baseline pre-cancerous lesions leading to significantly reduced risk of subsequent gastric cancer. However, in patients with H. pylori and intestinal metaplasia or dysplasia, similar benefit from eradication of H. pylori was not apparent. Dr Wong is participating in a large ongoing trial in H. pylori positive patients with atrophic gastritis, intestinal metaplasia or dysplasia in Asia. Patients will be randomized to H. pylori treatment versus celecoxib versus H. pylori treatment plus celecoxib versus placebo.

Abstract 2: Epidermal growth factor polymorphism, gastroesophageal reflux disease and risk of esophageal adenocarcinoma
Dr W Y Cheung from the University of Toronto presented some very interesting data regarding the association of polymorphisms in the epidermal growth factor gene and GERD resulting in an increased risk for esophageal adenocarcinoma. The epidermal growth factor (EGF) A61G gene has 3 genotypes: A/A, A/G, and G/G. Epidermal growth factor wild-type (A/A) was compared to EGF gene variants (A/G and G/G). Dr Cheung’s group compared the presence of the EGF A61G gene polymorphisms in patients with esophageal adenocarcinoma (EAC) with its presence in normal controls. Dr Cheung’s group also noted that GERD of greater frequency and longer duration was found more commonly in the EAC group than in the control group. Adjusting for age, gender, smoking-status, pack-years and body mass index (BMI), the odds ratio of EAC in patients with the G/G polymorphism compared to the normal A/A polymorphism was 9.71 in the GERD subset compared to the GERD-free subset. Patients with the G/G variant of the EGF A61G polymorphism who have long standing or severe GERD have a 20-fold greater risk of developing EAC.

Abstract 7: Salvage resection for esophageal adenocarcinoma after failed definitive chemoradiation
Dr Wayne Hofstetter, a thoracic surgical oncologist from M. D. Anderson Cancer Center, presented a retrospective review of 45 patients with esophageal adenocarcinoma who had failed definitive chemoradiation and subsequently underwent salvage esophagectomy. Dr Hofstetter and his colleagues compared this cohort to 300 consecutive patients with EAC who received pre-operative chemoradiation prior to a planned esophagectomy. Salvage esophagectomy was associated with increased morbidity and 30 day mortality with an increased number of anastomotic leaks, admissions to the ICU, and greater lengths of hospital stay. Nonetheless 5-year survival following esophagectomy was similar (47% vs 45%) for the 2 groups. Multivariate regression analysis revealed that pathologic stage, number of resected nodes and age were independent predictive factors for survival, while salvage strategy, location of the tumor, type of resection, presence of a leak, and initial clinical stage were not. Patients who fail definitive chemoradiation might be considered for salvage resection if their disease recurrence is local/regional, and they have a good performance status.

Abstract 8: Multicenter phase III comparison of cisplatin/S-1 with cisplatin/5-FU as first line therapy in patients with advanced gastric cancer (FLAGS)
Dr Jaffer Ajani from M. D. Anderson Cancer Center presented the long awaited results of the First-Line Advanced Gastric Cancer Study (FLAGS). This large phase III trial of 1029 eligible patients with advanced gastric or gastroesophageal (GE) junction adenocarcinoma from the US, Europe and South America randomized patients to cisplatin plus either S-1 (CS) or 5-FU (CF). S-1 is an oral flouropyrimidine which combines tegafur, CDHP, and potassium oxonate in a molar ratio of 1:0.4:1. S-1 is approved in Japan for multiple solid tumor types. Because of single nucleotide polymorphism (SNP) differences in the CYP2A6 gene between Asian and Western populations phase I pharmacokinetic studies were necessary to determine the most appropriate dose of S-1 to combine with cisplatin in Western populations. This data was reported in the Journal of Clinical Oncology in 2005 by Dr Ajani.¹ The current study was an attempt to determine if S-1 could be substituted for 5-FU in the platinum-flouropyrimidine regimens for gastric cancer. The FLAGS trial was powered for superiority with the primary endpoint being overall survival (OS). Seventy-one percent of the patients were male, and 86% were white with a median age of 59. The median number of cycles delivered was 4, and dose intensity for all agents was above 92%. The combination of CS was much better tolerated than CF with significantly less grade 3-4 neutropenia, febrile neutropenia, stomatitis and adverse renal events. However, it should be noted that the dose of cisplatin varied between the 2 arms with a cisplatin dose of 100 mg/m² combined with 5-FU versus a dose of 75 mg/m² combined with S-1. This very likely affected the adverse event profiles. Whether it affected the relative efficacy of the 2 arms is the subject of discussion. The OS for the 2 arms was not significantly different (P = .1983) with a median OS of 8.6 months for the CS arm and 7.9 months for the CF arm. In addition, there were no significant differences in progression-free survival (PFS), time-to-treatment failure (TTF), overall response rate (ORR), or median duration of response (MDR). Dr Robert Mayer discussed this abstract and noted that in the phase II study² the ORR to CS was 51%, compared to approximately 30% in the FLAGS trial, and the OS was 10.9 months in the phase I-II studies compared to 8.6 months in the large FLAGS trial. He concluded that CS was NOT superior to CF, but the data was confounded by the lower dose intensity for cisplatin and the much lower dose of S-1 used in this Western population compared to what is used in Japan.

References:

1. Ajani JA, Faust J, Ikeda K, et. Phase I pharmacokinetic study of S-1 plus cisplatin in patients with advanced gastric carcinoma. J Clin Oncol. 2005;23(28):6957-6965.
2. Ajani JA, Lee FC, Singh DA, et al. Multicenter phase II trial of S-1 plus cisplatin in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol. 2006 Feb 1;24(4):663-667.

Abstract 10: Phase II study of modified docetaxel, cisplatin, fluorouracil, and bevacizumab in patients with metastatic gastroesophageal adenocarcinoma
Dr Manish Shah, presenting for his associate Dr Jhawer, discussed the results of a phase II trial combining a modification of the docetaxel, cisplatin, fluorouracil (mDCF) regimen with bevacizumab. Recall that the DCF regimen was compared to cisplatin and fluorouracil (CF) in the V-325 trial in advanced GE adenocarcinoma. While the ORR, PFS and OS were all significantly increased with DCF, it was associated with significantly greater toxicity. The GI Cancers group at Memorial-Sloan Kettering Cancer Center has attempted to modify the DCF regimen to decrease its toxicity while maintaining its efficacy advantage. They reduced the doses of docetaxel and cisplatin from 75 mg/m² to 40 mg/m² and gave the cisplatin on day 3 instead of day 1. In addition 5-FU was given in a dose and schedule similar to the deGramont regimen. Bevacizumab was given at a dose of 10 mg/m² on day 1. The regimen was repeated every 14 days. Forty-four evaluable patients were reported with an ORR of 67%, a 6-month PFS of 79%, a 1-year OS of 63%, and a median OS of 16.2 months. Grade 3-4 neutropenia was seen in 51% of patients, but febrile neutropenia was only 4%. One concern that was noted was the 31% incidence of venous thromboembolism (VTE). A recent meta-analysis published this past November in JAMA reviewed 15 randomized controlled studies of 7956 patients with advanced solid tumors.³ Compared to the control patients in these trials those receiving bevacizumab had a relative risk of developing VTE of 1.33. The risk was significantly increased for all-grade VTE and for high-grade VTE. The results of the large phase III AVAGAST trial are pending. This trial randomized 760 patients with GE adenocarcinoma to cisplatin-capecitabine with or without bevacizumab.

Reference:

3. Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA. 2008;300(19):2277-2285.

OncoFacts™ Editor:

James Epstein, MD

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