Xeloda Combination Therapy in Esophagogastric Cancer Highlighted in New England Journal of Medicine

- Study Demonstrates Oral Xeloda Combination is a Comparable Alternative to All-Intravenous Therapy -

NUTLEY, N.J., January 07, 2008 /PRNewswire/ -- Data published in this week's New England Journal of Medicine show that oral Xeloda(R) (capecitabine) and oxaliplatin in combination with epirubicin is a comparable alternative to infused fluorouracil (5-FU) and cisplatin with epirubicin in patients with previously untreated, advanced esophagogastric cancer.

In the study, median survival time was longer and one-year survival was higher among patients taking the Xeloda, epirubicin and oxaliplatin combination compared to the standard treatment, epirubicin, cisplatin and 5- FU.

Gastric and esophageal cancers are the second and sixth most common causes of cancer-related deaths worldwide, respectively, according to global cancer statistics published in the peer-reviewed journal of the American Cancer Society, CA: A Cancer Journal for Clinicians.

"Our research suggests that oral Xeloda and oxaliplatin can provide patients with a valuable option over the standard regimen of infused fluorouracil and cisplatin in combination with epirubicin as a first-line therapy for esophagogastric cancer," stated lead investigator Professor David Cunningham, M.D., F.R.C.P., Head of the Gastrointestinal and Lymphoma Units of the Royal Marsden Hospital National Health Service Foundation Trust of Surrey and London.

"These results are an important advance for this hard-to-treat patient population which has no other treatment option other than a lengthy, infusion- based treatment that can be inconvenient and associated with complications."

A survey of U.S. oncologists showed that 82 percent stated that their key consideration in selecting an oral chemotherapy agent was efficacy at least equivalent to IV alternatives.(1)

"The REAL-2 study results support the growing body of evidence on the role of Xeloda as the cornerstone of combination chemotherapy," said Lars Birgerson, M.D., PhD, Vice President, Global Head Medical Affairs at Roche. "Roche remains committed to the ongoing research and evaluation of Xeloda as an effective treatment option beyond its current indications."

About the Study

The Phase III REAL 2 study was conducted in 1002 advanced esophagogastric cancer patients from 61 centers mainly in the United Kingdom. The study aimed to establish the potential use of Xeloda and oxaliplatin in previously untreated patients, and the primary endpoint was non-inferiority in overall survival in patients who received capecitabine compared to those who received fluorouracil and for those who took oxaliplatin compared to cisplatin.

Patients were randomized to one of four regimens: ECF, EOF, ECX or EOX.

The primary comparison was overall survival between the Xeloda and 5-FU containing arms (ECX + EOX versus ECF + EOF) and the oxaliplatin and cisplatin containing arms (EOF + EOX versus ECF + ECX). An additional comparison was survival between all four regimens.

Study participants were limited to patients, aged 18 and older, who had a histologically proven adenocarcinoma, squamous-cell carcinoma or undifferentiated carcinoma of the esophagus, gastroesophageal junction, or stomach that was locally advanced (inoperable) or metastatic.

Patients received eight three-week cycles of one of the four triplet treatment regimens. On day one, every patient received an intravenous bolus of epirubicin (50 mg/m2); cisplatin (60 mg/m2) was given intravenously with hydration in the ECF and ECX groups, and oxaliplatin (130 mg/m2) was administered intravenously during a 2-hour period in the EOF and EOX groups. Fluorouracil (200 mg/m2) and twice-daily capecitabine (625 mg/m2) were given throughout the treatment in the respective patient groups.

Median survival times in the ECF, ECX, EOF and EOX groups were 9.9 months, 9.9 months, 9.3 months, and 11.2 months, respectively; one-year survival rates were 37.7 percent, 40.8 percent, 40.4 percent and 46.8 percent, respectively. In a secondary analysis, overall survival was statistically significantly longer with EOX than with ECF, with a hazard ratio of 0.80 in the EOX group (95 percent CI; P=0.02). Progression-free survival and response rates were higher for capecitabine treated patients than those treated with 5-FU, but those differences were not statistically different.

Adverse events between capecitabine and fluorouracil appeared similar. As compared to cisplatin, oxaliplatin was associated with lower incidences of grade 3 or 4 neutropenia, alopecia, renal toxicity and thrombembolism, but with slightly higher incidences of grade 3 or 4 diarrhea and neuropathy.

About Xeloda

Xeloda is the only FDA-approved oral chemotherapy for both metastatic breast cancer and adjuvant and metastatic colorectal cancer. Inactive in pill form, Xeloda is enzymatically activated within the body; when it comes into contact with a naturally occurring protein called thymidine phosphorylase, or TP, Xeloda is transformed into 5-FU, a cytotoxic (cell-killing) drug. Because many cancers have higher levels of TP than does normal tissue, more 5-FU is delivered to the tumor than to other tissue.

A clinically important drug interaction between Xeloda and warfarin has been demonstrated; altered coagulation parameters and/or bleeding and death have been reported. Clinically significant increases in prothrombin time (PT) and INR have been observed within days to months after starting Xeloda, and infrequently within one month of stopping Xeloda. For patients receiving both drugs concomitantly, frequent monitoring of INR or PT is recommended. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.

Xeloda is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil, and in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. Xeloda is contraindicated in patients with severe renal impairment. For patients with moderate renal impairment, dose reduction is required.

The most common adverse events (greater than or equal to 20%) of Xeloda monotherapy were diarrhea, nausea, stomatitis and hand-foot syndrome. As with any cancer therapy, there is a risk of side effects, and these are usually manageable and reversible with dose modification or interruption.

About Roche

Hoffmann-La Roche Inc. (Roche), based in Nutley, N.J., is the U.S. pharmaceuticals headquarters of the Roche Group, one of the world's leading research-oriented healthcare groups with core businesses in pharmaceuticals and diagnostics. For more than 100 years in the U.S., Roche has been committed to developing innovative products and services that address

prevention, diagnosis and treatment of diseases, thus enhancing people's health and quality of life. An employer of choice, in 2007 Roche was named Top Company of the Year by Med Ad News and one of the Top 20 Employers (Science magazine).

In 2006, Roche was ranked the No. 1 Company to Sell For (Selling Power), and one of AARP's Top Companies for Older Workers, and in 2005, Roche was named one of Fortune magazine's Best Companies to Work For in America.

Posted: January 2008

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