Adding Chemotherapy To Chemoradiation And Surgery For Pancreatic Cancer Has Limited Benefit

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Main Category: Pancreatic Cancer
Also Included In: Radiology / Nuclear Medicine;  Cancer / Oncology
Article Date: 14 Mar 2008 - 0:00 PDT

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Adding gemcitabine with chemoradiation to the treatment of patients who have had surgery for pancreatic cancer has been associated with a slight but not statistically significant survival benefit, as announced in a study released on March 5, 2008 in JAMA.

Pancreatic cancer is perhaps one of the most acute forms of cancer in Western populations, and it has a poor prognosis, with complete remission being very rare. While surgical removal of a tumor in the pancreas has many potential benefits, there are many complications, even in the aftermath of such treatment. For instance, there is a 50-85% rate of local relapse associated liver and intra-abdominal failure, and the five year survival rate is less than 20%. The high frequency and regular pattern of failure makes investigation of postoperative treatment, including chemotherapy and radation, an important one.

In the past, the drug gemcitabine as shown to be more effective than the drug fluorouracil in treatment of such tumors. Both of these drugs are nucleoside analogs, which replace interfere with nucleotide incorporation during DNA replication, thus halting the reproduction of cancerous cells and promoting apoptosis.

To investigate the potential behind various postoperative treatments, William F. Regine, M.D., of the University of Maryland Medical Center, Baltimore, and colleagues collected data to assess the benefits of addition of gemcitabine to a treatment regimen already involving fluorouracil chemoradiation, a combination of chemotherapy and radiation. The study was performed on patients who had, as treatment for pancreatic cancer, removed a part of their pancreas surgically. They received chemotherapy with either fluorouracil or gemcitabine for three weeks before receiving fluorouracil chemoradiation therapy and for 12 weeks after. The randomized, controlled, phase 3 trial had 451 subjects, enrolled between July 1998 and July 2002 at 164 U.S. and Canadian institutions, and follow-up was performed through August 2006.

It was found that patients with a tumor in the pancreatic head treated with gemacitabine had a median survival rate of 20.5 months, while 31% survived 3 years (36 months.) In the fluorouracil group, the median survival was 16.9 months and 22% of the subjects survived 3 years. Hematologic toxicity, which involves abnormal blood count, was evaluted for grade 4 toxicity, yielding 1% in the fluorouracil group and 14% in the gemacitabine group. There was no difference in frequency in neutropenia  between the two groups, nor were there differences in their abilities to complete chemotherapy or radiation therapy. The authors write: "The addition of gemcitabine to [supplemental] fluorouracil-based chemoradiation was associated with a survival benefit for patients with resected pancreatic cancer, although this improvement was not statistically significant."

In comparison with other studies done in the past, the patients in this study had the lowest rate of recurring cancer in the original location. In 23% of patients, it came back in the same place -- in contrast, other studies had 40-60% recurrence. However, at least 70% of the patients in this study experienced systemic metastasis, in which the cancer moves to other parts of the body.

The authors conclude with future directions for research. "Laboratory correlative studies from [this trial] are ongoing and are evaluating molecular genetic alterations that promote local and systemic relapse. Future trials should emphasize novel systemic treatments to reduce systemic metastases and modern image-guided radiation to prevent local recurrence while reducing radiation-related toxic effects."

Editorial: Adjuvant Therapy for Surgically Resected Pancreatic Adenocarcinoma

James L. Abbruzzese, M.D., of the University of Texas M. D. Anderson Cancer Center, Houston, wrote an accompanying editorial, in which he offers suggestions on how to improve ultimate outcomes for pancreatic cancer patients with surgical resection.

"First, the lessons regarding the optimal selection of patients for surgical resection need to be exported more effectively into the high-surgical volume setting.

"Second, further work is needed to determine which patients are most likely to benefit from chemoradiation and, if this modality is going to evolve, further emphasis should be placed on the development of more effective radiation sensitizers.

"Third, based on interindividual differences in drug metabolism and DNA repair, it appears that patients who are more likely to benefit from current chemotherapy and chemoradiation strategies can be defined prospectively. These individualized approaches should be examined in prospective clinical trials.

"Finally, and most importantly, efforts must be redoubled to develop a new generation of promising therapeutics, and the commitment must be increased to understand and test them in prospectively defined patient subsets�"not the means to detect marginal or incremental improvements in clinical trials of large numbers of unselected patients."

Fluorouracil vs Gemcitabine Chemotherapy Before and After Fluorouracil-Based Chemoradiation Following Resection of Pancreatic Adenocarcinoma: A Randomized Controlled Trial
William F. Regine; Kathryn A. Winter; Ross A. Abrams; Howard Safran; John P. Hoffman; Andre Konski; Al B. Benson; John S. Macdonald; Mahesh R. Kudrimoti; Mitchel L. Fromm; Michael G. Haddock; Paul Schaefer; Christopher G. Willett; Tyvin A. Rich
JAMA. 2008;299(9):1019-1026.
Click Here For Abstract

Adjuvant Therapy for Surgically Resected Pancreatic Adenocarcinoma
James L. Abbruzzese
JAMA. 2008;299(9):1066-1067.
Click Here For Abstract

Written Anna Sophia McKenney
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