Gemcitabine, Anthracycline, and Taxane Combinations for Advanced Breast Cancer

December 1, 2003

In patients with advanced breast cancer, treatment with paclitaxeland doxorubicin has been shown to produce impressive overall responserates (up to 94%) and to prolong overall survival significantly over acombination of fluorouracil (5-FU), doxorubicin, and cyclophosphamide(Cytoxan, Neosar) in one prospective phase III clinical study.

ABSTRACT: In patients with advanced breast cancer, treatment with paclitaxeland doxorubicin has been shown to produce impressive overall responserates (up to 94%) and to prolong overall survival significantly over acombination of fluorouracil (5-FU), doxorubicin, and cyclophosphamide(Cytoxan, Neosar) in one prospective phase III clinical study. Theseresults have been challenged, however, by other data demonstrating nosurvival advantage for taxane-based therapies. In addition, the combinationof paclitaxel and doxorubicin has repeatedly been shown to becomplicated by the development of treatment-related congestive heartfailure, when cumulative doxorubicin doses exceed 300–360 mg/m2.Consequently, attempts have been made to increase the complete remissionrate and overall survival resulting from first-line treatment ofmetastatic breast cancer without compromising patient safety.Gemcitabine (Gemzar)-a relatively effective, well-tolerated and partiallynon–cross-resistant antitumor compound with limited toxicity-represents an attractive alternative to paclitaxel/anthracycline combinations.Initial studies of combination therapy with gemcitabine andpaclitaxel have produced an average response rate of 52%, with time toprogression ranging between 7.0 and 14.5 months. Three-drug regimenscontaining gemcitabine, an anthracycline, and paclitaxel havebeen tested in phase II studies and have produced impressive responserates of 82.9% with gemcitabine, doxorubicin, and paclitaxel and 92%with gemcitabine, epirubicin (Ellence), and paclitaxel (GET). The CentralEuropean Cooperative Oncology Group has evaluated the GETregimen vs a regimen containing 5-FU, epirubicin, and cyclophosphamide(FEC) in a randomized, prospective phase III study. Interim toxicityanalysis showed that the GET regimen was well tolerated but producedmore grade 4 neutropenia (64% vs 42%, P = .084) and significantlymore grade 4 thrombocytopenia (12% vs 0%; P The treatment of advanced breastcancer remains a formidablechallenge for the oncologycommunity, as few therapeutic modalitieshave been developed that prolongoverall survival. Nevertheless, theintroduction of anthracyclines in the1980s and taxanes in the 1990s producedsignificant advances in the treatmentof the disease. Polychemotherapyprotocols that include ananthracycline (doxorubicin orepirubicin [Ellence]) and a taxane(paclitaxel or docetaxel [Taxotere])have contributed to prolonged cumulativesurvival in cohort analyses atThe University of Texas M. D. AndersonCancer Center over the past 2 decades.[1]Paclitaxel/AnthracyclineCombinationsThe combination of paclitaxel anddoxorubicin has produced an overallresponse rate of 94%, with a 41%complete response rate (95% confidenceinterval [CI] = 24%-59%) anda 53% partial response rate in 32 patients.[2] These favorable results,however, were complicated by congestiveheart failure, which occurred

in more than 20% of treated patients.The combination of paclitaxel anddoxorubicin also proved to be superiorto a regimen of fluorouracil (5-FU), doxorubicin (Adriamycin), andcyclophosphamide (Cytoxan, Neosar),or FAC, as first-line therapy for metastaticbreast cancer by producing asignificantly better overall responserate (68% vs 55%, P = .032), significantlylonger time to disease progression(8.3 vs 6.2 months, P = .034),and significantly longer overall survival(23.3% vs 18.3%, P = .013).The incidence of cardiotoxicity wascomparable, as a similar percentageof patients in each treatment groupexperienced a decrease in left ventricularejection fraction. Grade 3/4neutropenia occurred significantlymore often in the paclitaxel/doxorubicinarm than in the FAC arm (89%vs 65%, P < .001). The incidence offebrile neutropenia was comparablein both treatment arms.[3]These data were challenged by theresults of other studies showing that acombination of paclitaxel and doxorubicinwas not significantly betterthan sequential monotherapy withboth drugs,[4] or polychemotherapywith either doxorubicin and cyclophosphamide[5] or epirubicin and cyclophosphamide.[6] Thus, althoughpaclitaxel/anthracycline combinationshave shown considerable efficacy interms of response rates, the numberand percentage of complete remissionsremain low, and efficacy translated intoimproved overall survival in only onestudy. Furthermore, the combinationof paclitaxel and anthracyclines maybe complicated by the occurrence ofcongestive heart failure due to the reducedclearance of anthracyclines andtheir metabolites following exposureto paclitaxel.[7] Finally, analysis of otherstudies strongly suggests that survivalrates may be confounded by theswitch from a nontaxane to a taxanecontainingregimen.[8] Thus, it remainsto be determined whether it is possibleto increase rates of complete remissionand overall survival by first-line treatmentwithout compromising safety.Gemcitabine/PaclitaxelCombinationsTo pursue this goal, a variety ofnewer antitumor drugs have been evaluatedin combination with paclitaxelas potential replacements for anthracyclines.Due to its low toxicity andfavorable results in 10 separate phaseII studies, gemcitabine (Gemzar) hasemerged as one of the major candidatesin this endeavor. Among 280patients recruited into these 10 studies,overall response rates rangingfrom 12.5% to 42% were achievedwith gemcitabine as either first-[9-11] or second-line therapy.[12-16] Ofnote, gemcitabine has been shown toproduce responses even when used asthird-line treatment in patients previouslyexposed to anthracyclines andtaxanes.[13,17,18] The quest for improvedefficacy with low toxicity ledto phase II trials combining gemcitabinewith paclitaxel as either firstlineor salvage therapy in a total of159 patients with advanced or metastaticbreast cancer.[19-21] Responserates as high as 52% were achieved,with time to disease progression rangingfrom 7.0 to 14.5 months. Gemcitabinehas also been shown not tointerfere with the pharmacokineticsor pharmacodynamics of either paclitaxelor epirubicin, suggesting a favorabletoxicity profile whencombined with these agents.[7]Gemcitabine/AnthracyclineCombinationsTwo phase II studies have beenreported that combined gemcitabinewith doxorubicin[22] and epirubicin[23] in women with advanced ormetastatic breast disease. Overall responserates were 75% with gemcitabine/doxorubicin and 60% withgemcitabine/epirubicin. Both regimenswere associated with lowtreatment-related toxicity. These observationsand the favorable outcomesreported with gemcitabine/paclitaxelregimens led to the idea of combininggemcitabine with both an anthracyclineand paclitaxel.

Three-Drug RegimensContaining GemcitabineTwo different three-drug regimenshave been evaluated in patientswith metastatic breast cancer. Oneregimen consists of gemcitabine at2,500 mg/m2, doxorubicin at30 mg/m2, and paclitaxel (Taxol) at135 mg/m2 (GAT).[24] The other regimenincorporates gemcitabine at1,000 mg/m2, epirubicin at 90 mg/m2,and paclitaxel at 175 mg/m2(GET).[25,26] The GAT regimen administeredat 14-day intervals producedan overall response rate of82.9% (95% CI = 67.9%-92.8%), includinga 43.9% complete response rate and a 39% partial response rate,as well as an impressive response ratein patients with visceral metastases(lung metastases, 72%; liver metastases,50%). The median duration of responsewas 14.1 months, median timeto disease progression 13.9 months;and median overall survival 26.2months.[27] Significant toxicity(grades 3/4) included neutropenia,which occurred in 10% of all cyclesin 44% of patients, and thrombocytopenia,which occurred in 1% of cyclesin 7% of patients.In the GET regimen, gemcitabineis administered on days 1 and 4, epirubicinon day 1, and paclitaxel onday 1 every 21 days.[25,26] The GETregimen led to a 31% complete remissionrate and a 61% partial remissionrate, resulting in an overall responserate of 92% (95% CI = 77.5%-98.2%)in 36 patients. Six courses of GETwere followed by high-dose chemotherapyin 25 patients who respondedto primary treatment resulting in conversionto a better response in 39% ofpatients. Ultimately, complete remissionsoccurred in 58% of 36 patients,and the overall response rate increasedto 96%.[26]CECOG Study BM1Based on the favorable resultsachieved with the GET regimen, theCentral European Cooperative OncologyGroup (CECOG) initiated a controlled,prospective, randomized,multicenter phase III trial of GET vs athree-drug regimen containing 5-FU,epirubicin, and cyclophosphamide(FEC) in October 1999. The GET regimenwas administered as describedabove; the FEC regimen consisted of5-FU at 500 mg/m2, epirubicin at 90mg/m2, and cyclophosphamide at 500mg/m2, all given on day 1 of a 21-daycycle. FEC was chosen as the comparator arm owing to its response rateof 45% to 54%, response duration of11 to 14 months, time to disease progressionof 9 to 11 months, and overallsurvival of 15 to 20 months.[28-30]These results have led to the acceptanceof FEC as standard treatmentfor advanced breast cancer in manyparts of the world, including countriesin eastern and southeastern Europe.The first interim toxicity analysisof the trial was presented in 2001.[31]The final data are scheduled for presentationat the annual meeting of theAmerican Society of Clinical Oncologyin 2003.[32]A total of 260 patients were recruitedbetween October 1999 andFebruary 2002 by the clinical investigatorslisted in the Appendix. Inclusioncriteria consisted of the following:histologically confirmed metastaticbreast cancer, prior adjuvant chemotherapyrestricted to non-anthracycline-containing regimens, the presenttreatment constituted first-line chemotherapyfor metastatic disease (previoushormonal treatment waspermitted), presence of measurabledisease, patient age between 18 and75 years, an Eastern Cooperative OncologyGroup performance status of0 to 1, life expectancy exceeding 12weeks, and adequate hematologic, renal,and cardiac function.The primary objective of the studyis time to disease progression; secondaryobjectives include responserate, survival, quality of life, and treatmenttoxicity. An interim toxicityanalysis was performed in February2001 after the recruitment of 123 patients,57 of whom were randomizedto GET and 66 to FEC. At that time,84 patients whose dose intensity exceeded95% in both treatment arms ofthe study were evaluable. The favorableresults achieved in this interimtoxicity analysis (Table 1) encouragedcontinued patient recruitment until theoriginal goal of 260 patients had beenachieved. By the time 117 more patientswere recruited, 52 had completedtreatment. Thirty-nine patientsinterrupted treatment for various reasons,including study drug toxicity(n = 8), disease-related death (n = 3),death due to a non-disease-relatedcause (n = 1), the physician's decision(n = 10), the patient's decision(n = 8), loss to follow-up (n = 4), orother reasons (n = 5).As of this writing, demographicdata on 260 patients ranging in agefrom 29 to 74 years are available.[32]All but three patients allocated to GETor FEC treatment (98.8%) took at leastone dose of the study drug. Medianfollow-up time was 11.48 months forpatients in the GET arm and 10.30months for those in the FEC arm (P =.702). Fifty-eight patients (22.66%),including 24 (19.35%) on GET and34 (25.76%) on FEC, died during thestudy. Demographic analysis of allincluded patients showed a balanceddistribution between treatment arms(GET, 124 patients; FEC, 135 [P =.573]), as well as the distribution ofother variables in patients allocated tothe two treatment arms, including initialpathologic diagnosis and diseasestage (P = .632 and P = .230, respectively),duration of disease-free interval(P = .938), hormone-receptorstatus (estrogen receptors, P = .836;progesterone receptors, P = .825),ECOG performance status (P = .411),distribution of metastases to visceralorgans including liver and lung(P = .111), and prior treatment (hormonaltherapy, P = .252; adjuvantchemotherapy, P = .619). A slightimbalance in distribution was foundin menopausal status, in that fewerpremenopausal patients were randomizedto the GET arm (14.52%) than tothe FEC arm (28.15%; P = .035). Detaileddemographic data are presentedin Table 2. Data on the primaryand secondary end points of the studywill be presented shortly.[32]ConclusionsBased on currently available data,we can conclude that the toxicity profileof either the GET or FEC regimenis acceptable and that both are welltolerated. Myelotoxicity and peripheralpolyneuropathy represented majorside effects of GET, although bothwere of limited clinical relevance. Interimtoxicity analyses showed thatthe vast majority of patients completedtreatment within the framework ofthe CECOG trial, with toxicity constitutinga rare reason for treatment interruption. While the final data ofthis phase III study are expected shortly,it appears that the inclusion of gemcitabinein a triple-drug chemotherapyregimen offers potentially promisingefficacy as first-line treatment withlimited toxicity in patients with advancedor metastatic breast cancer.AppendixInvestigators of the GET vs FECstudy (CECOG BM1), listed accordingto the number of recruited patients:Mrsic Zrinka, MD, Departmentof Medical Oncology, University Hospital,Zagreb, Croatia; Semir Beslija,MD, Institute of Oncology, Sarajevo,Bosnia; Jacek Jassem, MD, Departmentof Oncology and Radiotherapy,Medical University of Gdansk, Poland;Christoph Wiltschke, MD, ClinicalDivision of Oncology, Departmentof Medicine I, University Hospital,Vienna, Austria; Zsuzsanna Kahan,MD, Onkotherapias Klinika, Szeged,Hungary; Mislav Grgic, MD, UniversityHospital Rebro, Zagreb, Croatia;Valentina Tzekova, MD, UniversityHospital "Queen Joanna," Sofia, Bulgaria;Moshe Inbar, MD, OncologyDepartment, Sourasky Medical Center,Tel Aviv, Israel; Jozica Cervek,Institute of Oncology, Ljubljana, Slovenia;Constanta Timcheva, MD, NationalOncologic Center, Sofia,Bulgaria; Janos Szanto, MD, Instituteof Oncology, Debrecen Medical University,Debrecen, Hungary; MariaWagnerova, MD, Fakultna NemocnicaLuisa Pasteura, Kosice, Slovakia;Stanislav Spanik, MD, Nemocnica Sv.Alzbety, Narodny Onkologicky Ustav,Bratislava, Slovakia; Nicolae Ghilezan,MD, Institutul Oncologic Cluj,Cluj-Napoca, Romania; Janusz Pawlega,MD, Klinika Onkologii CMUJ,Krakow, Poland; Damir Vrbanec, MD,Department of Pathophysiology, UniversityHospital, Zagreb, Croatia;Tamas Pinter, MD, Petz Aladar CountyHospital, Gyr, Hungary; JerzyZaluski, MD, Department of Chemotherapy,Great Poland Cancer Center,Poznan, Poland; Antoaneta Tomova,MD, Regional Dispensary for Oncology,Plovdiv, Bulgaria; Nil MolinasMandel, MD, Department of MedicalOncology, Cerrahpa A MedicalSchool, Istanbul University, Turkey;Jerzy Tujakowski, MD, Regional OncologyCenter, Bydgoszcz, Poland;Ivan Koza, MD, National Cancer Institute,Bratislava, Slovakia; MilanKuta, MD, Department of Oncologyand Radiotherapy, Hospital Chomutov,Czech Republic; Nazan Gnel,MD, Department of Medical Oncology,Faculty of Medicine, Gazi University,Ankara, Turkey; OsmanManavoglu, MD, Faculty of Medicine,Uludag University, Bursa, Turkey;Lubos Petruzelka, MD, Department ofOncology, Charles University, Prague,Czech Republic; Adi Shani, MD,Oncology Institute, Kaplan MedicalCenter, Rehovot, Israel; Yilmaz Ugur,MD, Department of Medical Oncology,Faculty of Medicine, Universityof Izmir, Turkey; and Erikisi Melek,MD, Faculty of Medicine, CukurovaUniversity, Adana, Turkey. CECOGHead Office: Christoph C. Zielinski,MD, Coordinator; Thomas Brodowicz,MD, Co-Coordinator; Irmgard Resch,MD, Clinical Research Associate; MargitLandsgesell, Administrative Director;and Dagmar Just, AdministrativeAssistant. CRO: Dr. R. Kobelt, Innopharm.Contacts: cecog@akhwien.ac.at, www.cecog.org

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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