CALGB Cancer in Elderly Committee Investigates Therapy, Pharmacokinetics, Low Accrual to Trials

MINNEAPOLIS-The Cancerand Leukemia Group B (CALGB)investigators have undertaken a numberof "provocative" studies, not onlyof cancer therapy in the elderly butalso of pharmacokinetics and barriersto clinical trial participation for oldercancer patients, according to VickiMorrison, MD.The studies are under the directionof the CALGB Cancer in the ElderlyCommittee, an outgrowth of the ElderlyWorking Group formed about adecade ago to address issues specific toolder patients, said Dr. Morrison, associateprofessor of medicine at theUniversity of Minnesota, Minneapolis.Therapy Trials in the ElderlyOne important Committee investigationunderway is CALGB 9793/ECOG-SWOG 4494. This phase IIIintergroup trial compares CHOP (cyclophosphamide[Cytoxan, Neosar]/doxorubicin HCl/vincristine [Oncovin]/prednisone) chemotherapy vsCHOP plus rituximab (Rituxan) instage I to IV non-Hodgkin's lymphomapatients 60 years of age and older.The study includes 632 patients withpreviously untreated diffuse large cellB-cell lymphoma and performance status0 to 3. Following an inductionrandomization to CHOP or CHOPrituximab,responders are further randomizedto maintenance rituximab for6 or 8 cycles (every 6 months for 2years if the IgG level is above 500 units/mL) or observation.Ancillary studies are planned inCALGB 9793, including one that correlatesdose intensity with outcome."There have been series reported overthe years saying older people do morepoorly with this disease because theyare given lower doses of chemotherapy,so that's one aspect that will belooked at," Dr. Morrison said.The CALGB Cancer in the ElderlyCommittee also has an ongoing studyof postoperative therapy for elderlybreast cancer patients. The study,CALGB 49907, compares capecitabine(Xeloda) with CMF (cyclophosphamide[Cytoxan, Neosar], methotrexate, and fluorouracil) or AC (doxorubicinand cyclophosphamide) chemotherapyin women with operablebreast adenocarcinoma. About 110patients have been enrolled in the trialso far.At the 2003 meeting of the AmericanSociety of Clinical Oncology(ASCO), CALGB committee co-chairHyman Muss, MD, reported a breastcancer study of the relationship betweenage and outcome in node-positivewomen who received adjuvanttherapy (ASCO abstract 11). The resultsshow that older patients had moretreatment-related deaths, said Dr.Muss, professor of medicine and associatedirector for clinical research, VermontCancer Center, University ofVermont, Burlington. However, thedata also suggested that older patientswho undergo aggressive chemothera-pyregimens derive a greater benefit vsmore standard regimens, similar towhat is observed in younger patients.Pharmacokinetic TrialsOther of the CALGB trials are assessingthe pharmacokinetics of specificchemotherapeutic agents. Theongoing CALGB 9762 trial (ASCO2001, abstract 265) has been evaluatingclearance and toxicity of paclitaxelwith advancing age. In 2001, after 3years, there were 142 patients 55 yearsof age or older on study receiving paclitaxelas a single agent. Investigatorsfound that with increasing age, therewas a significant decline in total bodyclearance, decrease in white blood cellnadir, and increase in area under thecurve (AUC).Barriers to ClinicalTrial AccrualA third focus of the committee isinvestigating what might be done toimprove accrual of elderly patients toclinical trials. In CALGB 9670, Kornblithet al reported the main barriersto accrual as reported by oncologiststreating breast cancer patients at 10 ofthe group's sites (Cancer 95:989-996,2002). It was the perception of thesephysicians that some elderly patientshave significant comorbidities thatmay affect response to therapy. Othersnoted that there is a concern regardingexcessive toxicity. In addition, elderlypatients do not often meet eligibilitycriteria for trials, and even if they domeet the criteria, their compliance maybe poor because of difficulty in understandingcomplex clinical trial protocols.A subsequently published retro-spective study (J Clin Oncol 21:2268-2275, 2003), noting that 48% of breastcancer patients are at least 65 yearsold, found older breast cancer patientswere significantly less likely to be offereda clinical trial. Among stage IIpatients, 68% of the younger patients(< 65 years old) were offered a clinicaltrial, vs 34% of older patients (> 65years old) (P = .0004). When offered atrial, however, a nearly equal numberof younger and older patients (abouthalf) decided to participate. Investigatorsfound age and stage of diseasewere both predictors of being offereda clinical trial, while the greatest barrierto enrolling older women was thephysician's perceptions about age andtoxicity tolerance.Telephone monitoring and educationalinterventions may reducebarriers to therapy in the elderly. ACALGB study that recently closed accrued180 elderly breast, colorectal,and prostate cancer patients and randomizedthem to a telephone monitoringintervention plus educationalmaterials, or educational materialsalone.Intensive InterventionAlso under study is the hypothesisthat an intensive educational interventionmay increase accrual of elderlycancer patients to clinical trials. InCALGB 36001, patients were randomizedto a control arm or an interventionarm that included didactic symposia,a binder of materials, and emailreminders. An abstract describingthe study is under considerationfor presentation at ASCO 2004.In the future, studies of the Cancerin the Elderly Committee may includeinvestigations of biomarkers (eg,prostate-specific antigen) in the elderly.There are also plans to developtrials in the elderly for malignanciessuch as metastatic lung cancer, particularlyin regard to poor-performancestatuspatients. "In addition," Dr.Morrison said, "there has been somediscussion of looking at chemotherapytoxicities among older patients insome of the recent CALGB studies andcomparing this to older literature onthis topic."