Overview of Studies Attests to Value of Capecitabine/Oxaliplatin Combination in Colorectal Cancer and Liver Metastases

CHICAGO-An overview ofstudies attests to the efficacy and safety ofthe combination of capecitabine (Xeloda)and oxaliplatin (Eloxatin) for the treatmentof colorectal cancer and liver metastasesthat frequently develop afterresection of the primary tumor. Additionalstudies are required, however, todetermine the optimal dosing regimenand address quality of life and other issues.Data and implications from previousand ongoing studies and directions forfuture studies were presented at a symposiumon integrating capecitabine in themanagement of colorectal cancer, sponsoredby Roche and held in conjunctionwith the American Society of ClinicalOncology annual meeting.Charles Blanke, MD, of the OregonHealth Science University in Portland reviewedthe rationale for combining capecitabine and oxaliplatin. "Both drugshave single-agent activity. There is verylittle overlap in the key toxicities," he said."There is evidence of improvement whencombining the drugs in humans. Whenyou add oxaliplatin to fluorouracil(5-FU) and leucovorin (LV), you can improveresponse rate and time to diseaseprogression."Meaningful Response RatesPhase II studies of FOLFOX regimens(fluorouracil [5-FU], leucovorin, oxaliplatin)in previously treated colorectalcancer demonstrate clinical evidence ofsynergy, Dr. Blanke noted. The responseto FOLFOX as second-line therapy in patients who had already failed chemotherapygenerally tended to be quite high."And if we add in the patients withstable disease, then tumor control exceeded90% on a couple of the trials," hereported. "Median survival was also verystriking for second-line therapy, as well.In several studies, patients actually gotoxaliplatin added to the exact same 5-FUdrug regimen they had already failed, andthere was still a meaningful response rate,ranging from 25% to 50%. In the de Gramonttrial (J Clin Oncol 18:2938, 2000),once again the 5-FU regimen was improveddramatically with the addition ofoxaliplatin-the objective response ratedoubled, and progression-free survivalimproved in a superior fashion."Phase II studies tested capecitabineplus oxaliplatin (XELOX) in a every-3-week schedule of capecitabine 1,000mg/m² twice daily for 14 days and oxaliplatin130 mg/m² day 1, or capecitabine1,250 mg/m² twice daily plus oxaliplatin120 mg/m². The objective response ratewas 17% to 55%. Severe toxicities mainlyoccurred at higher doses that would generallynot be used in practice.A phase II Swiss study enrolled 43nontreated patients and 26 fluoropyrimidine-resistant patients. They receivedcapecitabine 1,250 mg/m² twice daily plusoxaliplatin 130 mg/m². "Patients who didnot receive prior therapy had a responserate of about 50%," Dr. Blanke reported."Adding stable disease, about two-thirdsof the patients had control of tumor. Andmedian survival was also remarkable at17 months. With those who had receivedprevious therapy, tumor control was 50%.Median survival was 11.5%."Differing ResultsIn an international phase II trial (TaberneroJ, et al) using XELOX as first-linetherapy in about 100 patients with metastaticcolorectal cancer, capecitabine wasstarted on the evening of day 1 of oxaliplatin,and given through the morning of day 15. "Again the combination was veryeffective," Dr. Blanke said. "Response ratewas the primary objective, and it was 55%;tumor control was 86%; and progressionfreesurvival exceeded 7 months. Responseswere seen in all groups regardless ofprior treatment status, age, and performancestatus. The toxicity profile was fairlymanageable."Interestingly, a US trial by Karmanoswith untreated patients (not yet published)used dosing similar to the internationalstudy mentioned above. The only real differencein this study was that capecitabinewas given at the same time as oxaliplatin-rather than being started later thesame evening. "There was however, unexpectedtoxicity and lowered efficacy in thistrial, " Dr. Blanke said. Then the capecitabine dose was reduced."The objective response rate was lowerthan in other trials," he continued. "Itwas about 40%, but not the 50+% that wasseen in the other trials. Interestingly, evenwith the lower dose, progression-free survivalwas very similar to what we've seenbefore-about 7 months. The toxicity profilewas what we would expect once thediarrhea went away with the lowereddose."Why did the drug work with the Europeanstudy, but not with the Americanstudy? The investigators speculated thatperhaps because capecitabine was startedbefore rather than after oxaliplatin, theremay have been an unexpected direct interactionamong the two drugs; or perhapsEuropean colleagues were more rigorousin dose adjustments or patientmonitoring. Ultimately the investigatorsagreed to use the 1,000 mg/m² twice-dailydose instead of the 750 mg/m² twice-dailydose, but strongly suggested that patientsand hospitalizations be carefully monitored.Need to IncorporateQuality of Life MeasuresCommenting on the direction of futurestudies, Dr. Blanke said, "I think thatcapecitabine could theoretically replaceinfusional 5-FU in combination regimenswith oxaliplatin. It is very likely that it willbe a more convenient regimen than thoseincorporating infusional 5-FU becausepatients have to come in for treatment lessfrequently. There is no need for a centralline or an infusion pump.""However, I would strongly argue atthis point that we don't yet know the bestdosing regimen, and we clearly need phaseIII trials for two reasons: we need to determinethe best dose, and we need to see ifcapecitabine can really replace infusional5-FU. And future trials should incorporatequality of life measures because thatis an important benefit of the capecitabine/oxaliplatin combination."Use in Liver MetastasesAbout half of all patients who developa recurrence after resection of the primarytumor in colorectal cancer go on todevelop a recurrence in the liver. "Thisoccurs in about 50,000 patients each year,"noted Roy Smith, MD, of the NationalSurgical Adjuvant Breast and BowelProject (NSABP), Pittsburgh. "The 5-yearsurvival after surgical resection of one ofthose hepatic metastases is about 37% ifthe patient had one metastasis, 34% if twometastases, and only 14% if there werethree or more metastases. Once a metastasectomyis performed, about 40% ofrecurrences after resection are restrictedto the liver. So it is important that adequatetherapy be developed for patientswho have isolated liver metastases becauseupon recurrence these patients maystill be curable.'Systemic chemotherapy is presently ofuncertain benefit. The rationale for usingliver-directed chemotherapy with floxuridine(FUDR) is that it is 90% extractedby the liver on the first pass. The results ofa series of well-designed clinical trials alsojustify the use of hepatic arterial infusion(HAI) of FUDR. "Newer combinationsseem to have increased the response rate,both at non-liver sites as well as at theliver. These types of observations lead usto reconsider how best to treat patientswith isolated liver metastases," Dr. Smith

"Capecitabine may play a major rolein the future treatment of patients withisolated liver metastases. The use of HAIfor treatment of isolated hepatic metastasesis based on the fact that liver metastases,if greater than 3 mm, are generally fedby the hepatic artery, whereas normal hepaticsites are fed by the portal venoussystem. Therefore, giving HAI can achievehigh concentrations of cytotoxic agents atthe tumor site, while theoretically sparingnormal liver tissue. In addition, beingselective in the type of drug used canachieve high concentrations due to thefirst-pass mechanism, and with total bodyclearance protecting other sites of the bodyfrom cytotoxicity.explained."Systemic TherapyA number of phase II trials have lookedat systemic therapy vs alternatives such asHAI with FUDR, 5-FU, or other drugs."Looking at about 10 studies in total,there does seem to be an improvementover systemic therapy, and there alsoseems to be an improvement with HAI inmedian survival," Dr Smith said."However, there have been two metaanalysesand they draw into questionwhether there has really been any improvementat all, and whether the findings significance. In terms of hepatic progression-free survival, initially there was animpressive difference for HAI, but after 5years of follow-up that advantage haslargely disappeared. The benefit is transient,and needs to be improved upon."The necessity for an hepatic artery catheteris also a disadvantage of HAI andanother reason to look for newer agents."Two agents that may play an importantrole in treatment of this disease are oxaliplatinand capecitabine," said Dr. Smith."Oxaliplatin may play a role for obviousreasons, and capecitabine because it canmimic continuous infusion 5-FU; furthermore,evidence that thymidine phosphorylase(TP) has increased activity in normalliver tissue as well as in colorectalmalignant tissue is an added reason forconsidering this combination. By usingcapecitabine, theoretically we should havea concentration effect in the liver and inthe metastatic disease located within theliver."Twocurrent trials share basic premises."The first premise is that there is a modestadvantage with HAI, and alternating HAIwith another therapy offers a small additionaladvantage. Right now it is FUDRand 5-FU, but it could be something elsein the future," Dr. Smith said. The secondpremise is the demonstrated efficacy oftolerability of combinations of oxaliplatinand capecitabine in the treatment ofmetastatic disease at other sites, as well asin the liver. Increased TP levels in the liverand in metastases may offer an advantagedue to increased concentrations of 5-FUwhen patients are exposed to capecitabine."Third, it may be possible to eliminateHAI from the treatment template," Dr.Smith said. "There is very little evidencethat it prolongs survival. Finally, the identificationand introduction of an innovativesystemic therapy might bring additionalbenefit to what little benefit existswith intrahepatic FUDR."Other Trials ProceedingThe North Central Cancer TreatmentGroup (NCCTG) is conducting two trials,a phase II trial and a randomized phase IIItrial, to evaluate these suppositions. Patientswith resected-liver-only metastasesfrom colorectal cancer are evaluated forsafety, 2-year survival, 2-year recurrencerate, and time to recurrence. The treatmentparadigm is FUDR at 0.2 mg/kg/don days 1 to 14, 1 week rest, then capecitabine/oxaliplatin over the next 14 days(see Figure 1). Over the course of the trial,patients developed significant gastrointestinaltoxicity and for this reason the dose ofcapecitabine has been reduced from 1,000mg/m² to 850 mg/m² twice daily.A NSABP trial with an accrual goal of400 patients will treat patients with eithersurgical resection or some type of ablation,then randomize patients to either atreatment arm that received capecitabineplus oxaliplatin systemically, or an armthat receives capecitabine plus oxaliplatinplus FUDR by HAI. This trial will compareprogression-free interval, overall survival,liver disease-free interval, and treatmenttoxicity, and examine molecularmarkers."We believe that the use of systemicchemotherapy with capecitabine plus oxaliplatinwill improve overall survival andboth hepatic and systemic disease-freesurvivals," Dr. Smith said. "It is also likelythat the addition of regional therapy withFUDR by HAI techniques will furtherimprove hepatic disease control, diseasefreesurvival, and overall survival. Shouldwe find that both arms of the trial havesimilar benefits and adverse event profiles,we can then select the more convenientor cost-effective arm as a templatefor future trials that investigate the treatmentof patients with isolated hepaticmetastases."In summarizing, Dr. Smith remarked,"Patients with resected liver metastasesfrom colorectal cancer have poor survivaland high recurrence rates. HAI with FUDRis marginally better than systemic 5-FU,and even that advantage is debatable. AlternatingHAI with 5-FU and FUDR seemsto be better than 5-FU alone, but thisconclusion is derived from a trial that issorely underpowered."TP is active in normal liver and livermetastases, capecitabine is activated incolorectal cancer tissue, and a capecitabine/oxaliplatin combination appears tobe effective in colorectal cancer, and fairlywell tolerated. Based on these data, theNCCTG and NSABP have undertakenthese two combined projects to try tochange the paradigm in the treatment ofpatients with isolated hepatic metastasesthat have been resected," Dr. Smith concluded.