Small But Significant Survival Advantage for Dukes’ B Patients on FUFA Regimen

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.

BIRMINGHAM, United Kingdom-In Dukes, B colon cancer, adjuvantchemotherapy based on fluorouracil(5-FU) provides a small butworthwhile survival advantage overobservation, according to the latestanalysis of data in the internationalQUASAR (Quick and Simple and Reliable)study (abstract 3501). The analysisinvolved 3,239 patients with an"uncertain" indication for chemotherapy(primarily stage II/Dukes' B disease)who were randomized to 5-FU/folinic acid (FUFA) or observation.Survival with FUFA was three tofour percentage points higher than inthe observation arm. "I think it is beyonda reasonable doubt now that thereis a small but definite survival benefitfor Dukes' stage B patients," said Ri-chard G. Gray, MS, University of Birmingham,United Kingdom.

Chemotherapy was "inexpensive"at about $4,000 per patient, and welltolerated, with no treatment-relateddeaths among patients who chose tohave chemotherapy. Because of that,investigators believe the benefits ofchemotherapy outweigh the inconvenienceand cost-at least up to 70years of age, at which point the healtheconomics become less favorable, investigatorsdetermined.Preventing Recurrences
Prof. Gray presented results on behalfof the QUASAR CollaborativeGroup, which includes 322 cliniciansfrom 150 centers in 17 countries. Aspart of QUASAR, patients with completeresection but an "uncertain indication"for chemotherapy were randomizedto FUFA (n = 1,622) orobservation (n = 1,617)The main factor leading to uncertaintyabout the indication for chemotherapywas node negativity due tostage II/Dukes' B colorectal cancer(92% of patients). For all patients inthis study, median age was 63 years,and 71% had colon cancer. Medianfollow-up at the time of the analysiswas 4.6 years.Chemotherapy reduced the riskof recurrence, Prof. Gray said. The5-year recurrence was "not terriblydifferent but highly significant" favoringchemotherapy, 22.2% vs 26.2%in the observation arms (relative risk[RR] 0.78, P < .001).The difference persisted out to almost10 years. "All the benefit was inthe first 2 years, and there was no lossof benefit or further gain," said Prof.Gray. "This is very encouraging. Itmeans we are preventing recurrences,not just delaying them."Difference in survival at 5 years was"statistically significant but quitesmall," 80.3% for FUFA vs 77.4% inthe observation group. This nearly3% difference in survival translatedinto a reduction in risk of death ofabout 17%, according to the analysis(RR 0.83).For the 92% of patients with StageII/Dukes' B disease, the difference in5-year survival was significant, with aP value equal to .04. (Specific 5-yearsurvival percentages for FUFA vs observation were not reported. "This isthe first study ever to report a statisticallysignificant benefit in Dukes' Bpatients" for the FUFA regimen, Prof.Gray noted.'Highly Tolerable'
Among the more than 1,600 patientswho received treatment, therewere no chemotherapy-related deaths,suggesting the FUFA regimen usedwas "really very highly tolerable," Prof.Gray said.The QUASAR study evaluated intravenousfluorouracil (370 mg/m2)obandfolinic acid, given according to avariety of schedules (six 5-day, fourweekly,or 30 once-weekly courses),with either high- or low dose folinicacid (175 or 25 mg) and with or withoutlevamisole (Ergamisol). Investigatorshave found that the varyingschedules, varying folinic acid doses,and assignment to levamisole or placebohad no effect on recurrence ratefor patients in QUASAR (Lancet355(9215):1588-1596, 2000; Ann Oncol947-955, 2000).'Peculiar' Finding
One "peculiar" finding was the apparenteffect of age on outcomes, contraryto some other reported studies,Prof. Gray said. While reduction inrecurrence was similar in younger cohorts(up to 69 years), there appearedto be "less or no benefit" from chemotherapyin patients 70 years or older.In addition, a health economicsanalysis showed that the life-yearsgained with chemotherapy, adjustedfor quality of life on chemotherapy,"becomes quite a bit less" at age 70, inpart simply because older patients havefewer life-years left to gain. Assuming1 year on chemotherapy is worth 70%of a normal year, the net gain for a40-year-old is 2 years, while the gainfor a 70-year-old patient was about 6months, according to the analysis (seeFigure 1).'Up to 70 years of age, I think thereis good evidence of benefit, but afterthat, it's a bit more dubious, especiallygiven our finding of less benefit (inrecurrence rate) for the over-70s,"Prof. Gray stated.