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

September 1, 2004

The 30 reports in this special supplement to Oncology News International represent highlights of ongoing major clinical trials and new research presented at ASCO 2004 regarding state-of-the-art chemotherapeutic management of gastrointestinal and other cancers. Important developments in capecitabine as adjuvant therapy, novel targeted agents, and new combinations are discussed.

HOUSTON-A retrospectiveanalysis suggests "XCEL" (capecitabine[Xeloda] plus celecoxib [Celebrex])might improve survival in metastaticcolorectal cancer and reduceincidence of hand-foot syndrome relatedto treatment, according to a researchteam from The University ofTexas M. D. Anderson Cancer Center,Houston, Texas (abstract 3584).The investigators looked throughtheir records and identified 66 patientswho received capecitabine formetastatic colorectal cancer and werealso taking the COX (cyclo-oxygenase)-2-specific nonsteroidal anti-inflammatorydrug celecoxib for anotherreason (ie, for arthritis). Half ofthese patients had also received radiotherapy.Intriguing Benefit
Celecoxib, they found, appeared todelay both the onset and peak of handfootsyndrome caused by capecitabine,and it was associated with reducedincidence of diarrhea. More intriguingly,celecoxib appeared to improveresponse, survival time, and progression-free survival time over whatwould be expected with capecitabinealone, said lead investigator EdwardH. Lin, MD, assistant professor ofmedicine in the Department of GastrointestinalMedical Oncology atM. D. Anderson.While this study is clearly limitedby its retrospective design, the findingsat least support the hypothesisthat COX-2 is a valid therapeutic targetin metastatic colorectal cancer, theinvestigators said."Experimental data showed thatchemotherapy or radiation activatesCOX-2," Dr. Lin said. "Obviously, ifyou activate COX-2 in hands and feet,it's a side effect, but if you activateCOX-2 in the tumor, it is tumor progression."The researchers believe these observationswarrant further investigation.They have planned a randomizedphase III trial that will evaluateincidence of capecitabine-relatedhand-foot syndrome in patients withmetastatic breast and colon cancer.Secondarily, the trial will evaluate response,time to progression andsurvival.Striking Efficacy
Patients in the retrospective analysishad received capecitabine 1,000 mg/m2 twice daily and were taking celecoxib200 mg twice daily for pain relatedto arthritis or tumor. In addition,33 patients received consolidativeor palliative radiation to tumors thatcan be contained in the radiation portal.The median age was 66 years; 68%were male and 86% had ECOG (EasternCooperative Oncology Group)performance status of 0 or 1. Fiftyeightpercent had colon cancer and42% had rectal cancer. Most patients(56%) had prior IFL (irinotecan [CPT-11, Camptosar], fluorouracil [bolus],leucovorin) or XELIRI (capecitabine,irinotecan), while 36% of patients hadno prior therapy.Celecoxib seemed to delay occur-rence of hand-foot syndrome and itspeak. Overall, hand-foot syndrome occurredin about 30% of patients (grade1, 2, and 3 in 13.6%, 15.5%, and 1.5%,respectively). Median time to onsetwas 3.75 months, and the median timeto HFS peak was at 6.21 months. Accordingto Dr. Lin, time to onset andpeak would normally be expected tooccur within 2 and 3 months, respectively,of starting capecitabine.There were negligible grade 3/4 toxicities,with diarrhea being 6%. Twopatients discontinued therapy becauseof allergic reaction. Most of the toxicitieswere grade 1/2 and included rash,agitation, and a rise in serum creatininelevels.Response and survival were higherthan expected, investigators said.Complete responses were seen in 13patients (20%), and partial responseswere seen in 12 patients (18%). Medianprogression-free survival time was8.1 months, and overall survival timewas 22 months in all 66 patients 1 to 14(More than 50% had failed irinotecan-based treatment.) The medianoverall survival time was 26.9 monthsand 17 months for chemonaive patientsand irinotecan-refractory patients,respectively. The overall survivaltime was about 7 to 14 months longerthan expected with capecitabinemonotherapy, although the investigatorsnoted that this study is limited byits retrospective design. Although theinvestigators did not conduct a formalquality-of-life study, Dr. Lin said theyperceived that patients enjoyed a relativelynormal lifestyle, with little interruptionof their daily lives.