COX-2: Can Celecoxib Help Capecitabine ‘XCEL’ in Metastatic Colorectal Cancer?

HOUSTON-A retrospective analysis suggests "XCEL" (capecitabine [Xeloda] plus celecoxib(Drug information on celecoxib) [Celebrex]) might improve survival in metastatic colorectal cancer and reduce incidence of hand-foot syndrome related to treatment, according to a research team from The University of Texas M. D. Anderson Cancer Center, Houston, Texas (abstract 3584). The investigators looked through their records and identified 66 patients who received capecitabine(Drug information on capecitabine) for metastatic colorectal cancer and were also taking the COX (cyclo-oxygenase)- 2-specific nonsteroidal anti-inflammatory drug celecoxib for another reason (ie, for arthritis). Half of these patients had also received radiotherapy. Intriguing Benefit
Celecoxib, they found, appeared to delay both the onset and peak of handfoot syndrome caused by capecitabine, and it was associated with reduced incidence of diarrhea. More intriguingly, celecoxib appeared to improve response, survival time, and progression- free survival time over what would be expected with capecitabine alone, said lead investigator Edward H. Lin, MD, assistant professor of medicine in the Department of Gastrointestinal Medical Oncology at M. D. Anderson. While this study is clearly limited by its retrospective design, the findings at least support the hypothesis that COX-2 is a valid therapeutic target in metastatic colorectal cancer, the investigators said. "Experimental data showed that chemotherapy or radiation activates COX-2," Dr. Lin said. "Obviously, if you activate COX-2 in hands and feet, it's a side effect, but if you activate COX-2 in the tumor, it is tumor progression." The researchers believe these observations warrant further investigation. They have planned a randomized phase III trial that will evaluate incidence of capecitabine-related hand-foot syndrome in patients with metastatic breast and colon cancer. Secondarily, the trial will evaluate response, time to progression and survival. Striking Efficacy
Patients in the retrospective analysis had received capecitabine 1,000 mg/ m2 twice daily and were taking celecoxib 200 mg twice daily for pain related to arthritis or tumor. In addition, 33 patients received consolidative or palliative radiation to tumors that can be contained in the radiation portal. The median age was 66 years; 68% were male and 86% had ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1. Fiftyeight percent had colon cancer and 42% had rectal cancer. Most patients (56%) had prior IFL (irinotecan [CPT- 11, Camptosar], fluorouracil(Drug information on fluorouracil) [bolus], leucovorin) or XELIRI (capecitabine, irinotecan(Drug information on irinotecan)), while 36% of patients had no prior therapy. Celecoxib seemed to delay occur- rence of hand-foot syndrome and its peak. Overall, hand-foot syndrome occurred in about 30% of patients (grade 1, 2, and 3 in 13.6%, 15.5%, and 1.5%, respectively). Median time to onset was 3.75 months, and the median time to HFS peak was at 6.21 months. According to Dr. Lin, time to onset and peak would normally be expected to occur within 2 and 3 months, respectively, of starting capecitabine. There were negligible grade 3/4 toxicities, with diarrhea being 6%. Two patients discontinued therapy because of allergic reaction. Most of the toxicities were grade 1/2 and included rash, agitation, and a rise in serum creatinine levels. Response and survival were higher than expected, investigators said. Complete responses were seen in 13 patients (20%), and partial responses were seen in 12 patients (18%). Median progression-free survival time was 8.1 months, and overall survival time was 22 months in all 66 patients 1 to 14 (More than 50% had failed irinotecan- based treatment.) The median overall survival time was 26.9 months and 17 months for chemonaive patients and irinotecan-refractory patients, respectively. The overall survival time was about 7 to 14 months longer than expected with capecitabine monotherapy, although the investigators noted that this study is limited by its retrospective design. Although the investigators did not conduct a formal quality-of-life study, Dr. Lin said they perceived that patients enjoyed a relatively normal lifestyle, with little interruption of their daily lives.