Carboplatin/Gemcitabine Combination in Advanced NSCLC

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Oncology, ONCOLOGY Vol 18 No 8, Volume 18, Issue 8

The treatment of advanced non–small-cell lung cancer (NSCLC)has evolved rapidly over the past few years. Systemic chemotherapy isassociated with both quality of life and modest survival benefit for patientswith advanced NSCLC. Platinum-based doublet combinationsare the “standard of care.” The US Food and Drug Administration(FDA) has approved gemcitabine (Gemzar), a pyrimidine analog, to beused in combination with cisplatin for the treatment of advanced NSCLCin the first-line setting. Randomized clinical trials have established comparableefficacy with improved therapeutic index for the carboplatin/gemcitabine regimen when compared with cisplatin/gemcitabine andother platinum doublets. Nonhematologic toxicities occur at a lowerfrequency with carboplatin/gemcitabine combinations compared withother “standard” platinum-based doublets, whereas dose-limitingthrombocytopenia, the most common toxicity, rarely requires therapeuticintervention. Both the 3- and 4-week schedules of carboplatin/gemcitabine result in similar efficacy and toxicity profiles, but the3-week regimen is preferred. The combination of carboplatin andgemcitabine is an effective regimen with an acceptable toxicity profilefor the treatment of advanced NSCLC. This regimen can also be usedas a foundation for the development of innovative combinations withmolecularly targeted agents.

ABSTRACT: The treatment of advanced non–small-cell lung cancer (NSCLC)has evolved rapidly over the past few years. Systemic chemotherapy isassociated with both quality of life and modest survival benefit for patientswith advanced NSCLC. Platinum-based doublet combinationsare the “standard of care.” The US Food and Drug Administration(FDA) has approved gemcitabine (Gemzar), a pyrimidine analog, to beused in combination with cisplatin for the treatment of advanced NSCLCin the first-line setting. Randomized clinical trials have established comparableefficacy with improved therapeutic index for the carboplatin/gemcitabine regimen when compared with cisplatin/gemcitabine andother platinum doublets. Nonhematologic toxicities occur at a lowerfrequency with carboplatin/gemcitabine combinations compared withother “standard” platinum-based doublets, whereas dose-limitingthrombocytopenia, the most common toxicity, rarely requires therapeuticintervention. Both the 3- and 4-week schedules of carboplatin/gemcitabine result in similar efficacy and toxicity profiles, but the3-week regimen is preferred. The combination of carboplatin andgemcitabine is an effective regimen with an acceptable toxicity profilefor the treatment of advanced NSCLC. This regimen can also be usedas a foundation for the development of innovative combinations withmolecularly targeted agents.

Systemic chemotherapy prolongssurvival and improves qualityof life for patients with advancednon-small-cell lung cancer(NSCLC).[1] Several randomizedclinical trials conducted in the pastfew years have confirmed the efficacyof various platinum-based combination(cisplatin or carboplatin[Paraplatin]) regimens when used asfirst-line therapy for advancedNSCLC patients who have a goodperformance status (Eastern CooperativeOncology Group [ECOG], performancestatus < 2).[2-7] Platinumbaseddoublet regimens are superiorto either single-agent therapy or threedrugcombinations.[6-10]While platinum compounds continueto hold their role as an essentialcomponent of the doublet regimens,the choice of the second agent is variable.Several third-generation chemotherapyagents, such as the taxanes(ie, paclitaxel, docetaxel [Taxotere]),gemcitabine (Gemzar), vinorelbine(Navelbine), and irinotecan (Camptosar),which possess efficacy as singleagents for the treatment ofadvanced NSCLC, have been evaluatedin combination with a platinumcompound for first-line therapy. In fact, randomized trials have demonstratedcomparable efficacy for combinationregimens consisting of aplatinum compound with any of theabove-mentioned third-generationchemotherapy agents for the treatmentof advanced NSCLC.[3,4,11] Thesedata provided the rationale for individualizingtreatment for patientsbased on schedule of therapy, toxicityprofile of the regimen, and cost.The role of the carboplatin/gemcitabinecombination regimen for thetreatment of advanced NSCLC is reviewedin this article.BackgroundCarboplatin therapy results in lowerincidences of nausea, vomiting, ototoxicity,and nephrotoxicity comparedwith cisplatin.[12] However, the incidence of myelosuppression is higherwith the use of carboplatin. Randomizedtrials comparing cisplatin-vs carboplatin-based regimens for thetreatment of advanced NSCLC demonstratedcomparable efficacy for bothplatinum compounds.[13,14] Thus,based on its favorable toxicity profile,carboplatin has become the preferredplatinum compound in theUnited States for the treatment of patientswith advanced NSCLC, althoughcisplatin doublets are stillpreferred across the Atlantic.Gemcitabine is a novel pyrimidineanalog that inhibits the enzyme ribonucleotidereductase that is essentialfor DNA synthesis.[15] Multiplephase II trials have demonstrated theefficacy of gemcitabine as a singleagent for the treatment of advancedNSCLC.[16-19] In a randomized clinicaltrial, the combination of gemcitabineand cisplatin was superior totherapy with cisplatin alone.[6] Subsequently,Schiller et al in the ECOG1594 trial demonstrated comparableefficacy for the cisplatin/gemcitabinecombination when compared with thecontrol arm of cisplatin/paclitaxel.Cisplatin/docetaxel and carboplatin/paclitaxel were the other two arms ofthe ECOG 1594 study.[4]Phase II studies with the carboplatin/gemcitabine regimen demonstratedresponse rates of 25% to 50%with overall median survival of 9.5 to16 months.[20-22] The regimen waswell tolerated, with thrombocytopenia and neutropenia being the majortoxicities; minimal nonhematologicside effects were seen. The efficacywas comparable to other commonlyused doublet regimens and henceformed the basis to evaluate carboplatin/gemcitabine in randomized trialsfor the treatment of advancedNSCLC.

Randomized Trials ofCarboplatin/GemcitabineRudd and colleagues with the LondonLung Cancer Group comparedthe carboplatin/gemcitabine regimenwith the combination of mitomycin(Mutamycin), ifosfamide (Ifex), andcisplatin (MIC) for the treatment ofpatients with advanced NSCLC. Boththe regimens were administered every3 weeks to patients with stageIIIB (pleural/pericardial effusion) orstage IV NSCLC.[10] Patients withan ECOG performance status of 0 to2 were eligible for the study. The studyenrolled 422 patients with previouslyuntreated NSCLC.Although the response rates weresimilar between the two arms, the carboplatin/gemcitabine therapy was associatedwith superior survival overthe MIC regimen (10.2 vs 6.8 months,P = .028). The incidence of grades3/4 nausea (14% vs 5%), vomiting(10% vs 3%), constipation (7% vs2%), and alopecia (9% vs 1%) werehigher with the MIC regimen, whilethrombocytopenia (25% vs 7%) occurred at a higher frequency in studypatients receiving carboplatin/gemcitabine.In another study, the carboplatin/gemcitabine combination was comparedwith therapy using either theMIC regimen or the combination ofmitomycin, vinblastine, and cisplatin.[23] The study included 372chemonaive patients with advancedNSCLC who were not candidates forsurgical resection or definitive radiotherapy.Carboplatin was given at anarea under the concentration-timecurve (AUC) of 5 (day 1) and gemcitabinewas administered at 1,000 mg/m2(days 1, 8, and 15). Treatment cycleswere repeated every 28 days for thecarboplatin/gemcitabine arm and every3 weeks for the control arm. Theresponse rate, median survival, andtime to progression were similar betweenthe two arms. No differenceswere noted between the two treatmentarms in disease-related symptoms orquality-of-life benefit. Fewer inpatientstays were necessary for complicationsamong the carboplatin/gemcitabinetreated group.Grigorescu and colleagues conducteda randomized trial comparingthe regimen of carboplatin/gemcitabinewith cisplatin/vinblastine for patientswith advanced NSCLC.[24] Thestudy included 198 patients who were≤ 70 years old and had an ECOGperformance status of 0, 1, or 2. Theresponse rate (27% vs 15%), mediansurvival (11.6 vs 7.9 months, P =.0001), and 1-year survival rate (36%vs 13%, P < .05) were all significantlysuperior in the carboplatin/gemcitabinearm.The toxicity profiles were comparablebetween the two regimens. The efficacynoted with the carboplatin/gemcitabine combination with all ofthe randomized studies described abovewas comparable to the other "standard"platinum-based doublets used for thetreatment of advanced NSCLC. Furthermore,the carboplatin/gemcitabineregimen was associated with minimalnonhematologic toxicities.Two randomized trials have comparedthe efficacy of the carboplatin/gemcitabine combination with that ofthe cisplatin/gemcitabine regimen (Table1).[25,26] Zatloukal and colleagues randomized patients with advancedNSCLC to treatment with carboplatinat AUC 5, day 1, andgemcitabine, or therapy with cisplatinat 80 mg/m2, day 1, and gemcitabine.The dose of gemcitabine was identicalfor both the arms given at 1,200mg/m2on days 1 and 8. Both the regimenswere administered on a 21-dayschedule. The primary end point ofthe study was to assess toxicity betweenthe two regimens, while thesecondary end points included responserates, overall survival, and timeto progression.The carboplatin arm was associatedwith a lower incidence of grades3/4 nausea and vomiting (3.8% vs16.2%, P = .0224), and a higher incidenceof thrombocytopenia (33% vs16%, P = .0023). The efficacy wascomparable between the two arms withresponse rates of 47% and 48% for thecarboplatin and cisplatin arms, respectively.The median survival was 8.1months for patients on both the arms.In another study, Mazzanti et alrandomized 115 patients to either cisplatin/gemcitabine or carboplatin/gemcitabine therapy.[26] In the cisplatinarm, gemcitabine was administeredat a dose of 1,200 mg/m2 on days 1and 8 while cisplatin was given at80 mg/m2 on day 2. In the carboplatinarm, gemcitabine was given at a lowerdose of 1,200 mg/m2 on days 1 and 8while carboplatin was given at AUC 5on day 2. The study demonstrated alower incidence of nausea and vomitingwith the carboplatin arm, while theoverall survival was similar betweenthe two arms (10 vs 11 months). Thus,the combination of carboplatin/gemcitabineresults in comparable efficacyand a favorable toxicity profilewhen compared with the cisplatin/gemcitabine combination.Carboplatin/Gemcitabine vsSingle-Agent GemcitabineSandler and colleagues demonstratedthe superiority of the gemcitabine/cisplatin combination over singleagent cisplatin in a randomized registrationtrial.[6] However, until recently,it was unclear whether thegemcitabine/platin combination wassuperior to single-agent gemcitabine.Sederholm and the Swedish LungCancer Study Group reported the resultsof a phase III study that comparedthe efficacy of carboplatin/gemcitabine vs gemcitabine alone forthe treatment of patients with advancedNSCLC (Table 2).[27] The study included334 patients with advancedNSCLC who had an ECOG performancestatus of 0, 1, or 2. Patients wererandomized to therapy with gemcitabinealone given at 1,250 mg/m2 ondays 1 and 8, or in combination withcarboplatin at AUC 5 on day 1.The response rate (30% vs 12%,P = .0001), median survival (11 vs 9months, P = .0024), and 1-year survivalrate (44% vs 32%) were superiorwith the doublet combination. Theincidence of nonhematologic toxicitywas comparable between the twoarms. However, hematologic toxicitywas more pronounced in the doubletarm. Grades 3/4 anemia, thrombocytopenia,and leukopenia occurred in5%, 48%, and 32% with the doubletarm, respectively, compared with 2%,4%, and 6% in the single-agent therapyarm, respectively. Thus, two-drug combinations are superior to singleagenttherapy for the treatment of advancedNSCLC, though the benefitcomes with some increase in toxicity.

Carboplatin/Gemcitabine vsNonplatinum CombinationsNonplatinum regimens have beenevaluated for the treatment of advancedNSCLC with the intention ofreducing toxicities associated withplatinum compounds. Studies havedemonstrated a more favorable toxicityprofile with nonplatinum doubletswhen used for the treatment of advancedNSCLC. However, it is unclearif the reduced toxicity comes atthe price of reduction in efficacy. Randomizedtrials conducted to comparethe efficacy of platinum vs nonplatinumdoublets have yielded mixed resultsthus far.[28,29]The Coalition of National CancerCooperative Groups is conducting alarge randomized trial to compare theefficacy of the carboplatin/gemcitabinedoublet with a nonplatinum doubletconsisting of paclitaxel/gemcitabine(Figure 1) in chemonaive patients.The study also includes a thirdtreatment arm receiving carboplatin/paclitaxel. The treatment regimens weregemcitabine at 1,000 mg/m2 on days 1 and 8 plus carboplatin at AUC 5.5 onday 1 vs gemcitabine at 1,000 mg/m2,days 1 and 8, plus paclitaxel at 200mg/m2,, day 1, compared to the control arm of carboplatin at AUC 6.0plus paclitaxel at 225 mg/m2, day 1.All three regimens were administeredas 21-day cycles.

Treat and colleagues recently presentedthe preliminary results of thisstudy (Table 3),[30] with toxicity datafrom 534 accrued patients. The carboplatin/gemcitabine arm was associatedwith a higher incidence ofgrades 3/4 anemia and thrombocytopenia,while the incidence of grade2 alopecia and neurosensory toxicitieswere lower. For the 345 patientsin whom response data were available,comparable efficacy was notedfor all three arms of the study.Carboplatin/Gemcitabine:3- vs 4-Week ScheduleClinical trials performed with thecarboplatin/gemcitabine combinationinitially used a 4-week regimen. Carboplatinwas administered on day 1of each cycle, and gemcitabine wasgiven on days 1, 8, and 15. In thesestudies, it was noted that administrationof the planned dose of gemcitabineon day 15 was limited by theoccurrence of thrombocytopenia. Subsequently,3-week schedules in whichgemcitabine was administered on days1 and 8 of every cycle were evaluated.Phase II studies with the 3-weekregimen demonstrated comparableefficacy with the 4-week schedules.Two recent studies compared the twodifferent schedules using the carboplatin/gemcitabine combination.[31,32]Masters and colleagues performeda randomized phase II trial of 100chemonaive patients with advancedNSCLC (stage IIIB/IV).[32] In the4-week arm, carboplatin at AUC 5was administered on day 8 andgemcitabine at 1,100 mg/m2 was givenon days 1 and 8. In the 3-week arm,carboplatin at AUC 5 was given on day1, and gemcitabine at 1,000 mg/m2 wasadministered on days 1 and 8. Themedian number of chemotherapy cyclesadministered on-study was 4 and6, respectively, for the two arms.The major toxicities were hematologic,and more adverse events occurredwith the 3-week schedule.Grade 3/4 neutropenia occurred in46% of patients on the 3-week schedule,compared with 27% of patients inthe 4-week group. Grade 3/4 thrombocytopeniaoccurred in 50% and 38%of patients, respectively. Grade 3 nausea/vomiting was the major nonhematologictoxicity occurring inapproximately 4% of the patients inthe 3-week group and 19% of patientsreceiving the 4-week regimen. Theincidence of grade 3/4 neutropeniawas lower in the 4-week arm. However,there was no significant differencein the incidence of thrombocytopeniabetween the two arms.There were trends toward increasedresponse rate in patients receiving the3-week regimen (40% vs 23%), butwith decreased median survival (7.3vs 8.7 months) compared to the4-week schedule.In a larger study, Obasaju et alrecently reported the results of thesurveillance trial of 473 patients withadvanced NSCLC treated with eithera 3- or 4-week regimen of carboplatin/gemcitabine.[31] The doses andschedule of treatment were similar tothe study by Masters et al.[32] Bothschedules of chemotherapy were welltolerated by the patients. The incidenceof grade 3/4 thrombocytopeniawas 8% and 14%, respectively,for the 4-week and 3-week arms. Noclinically significant bleeding episodeswere noted in either arms ofthe study. Dose intensity of chemotherapywas similar for both arms.There were also no statistically significantdifferences in efficacy betweenthe two schedules.There was 1 (2%) complete responseand 20 (38%) partial responses,resulting in an overall responserate of 40% for patients receiving the3-week schedule. Patients treated withthe 4-week regimen had no completeresponses and 11 (23%) partial responsesfor an overall response rateof 23%. Progression-free survival was4.9 months with the 3-week regimenand 3.7 months with the 4-week regimenand median overall survival timeswere 7.3 months and 8.7 months, respectively.There were also no statisticallysignificant differences inefficacy between the two schedules.The 3-week schedule of the carboplatin/gemcitabine combination hasthus become the preferred regimen inthe practice setting.

ConclusionsThe combination of carboplatinand gemcitabine is effective for thetreatment of patients with advancedNSCLC. The efficacy reported withthis regimen in randomized trials iscomparable to that reported for othercommonly used combinations for thetreatment of advanced NSCLC. Thecarboplatin/gemcitabine combinationis associated with a relatively low incidenceof nonhematologic toxicities,especially alopecia, whereas thrombocytopeniais dose limiting. The outcomefor patients with advancedNSCLC has improved over the yearswith the availability of several novelcombinations such as carboplatin/gemcitabine.It does appear, however, that anefficacy plateau has been reached withexisting chemotherapy combinations.The role of "maintenance" therapywith single-agent gemcitabine is beingevaluated in a randomized trial inpatients who do not progress after fourinitial cycles of carboplatin/gemcitabine(Figure 2). A second ongoingrandomized study is exploring the valueof immediate docetaxel after carboplatin/gemcitabine vs the sametreatment administered as true second-line therapy at progression (Figure3). The efficacy of the carboplatin/gemcitabine regimen is also beingevaluated in the earlier stages ofNSCLC both in the neoadjuvant andadjuvant settings.Because of its overall tolerabilityand efficacy, the regimen of carboplatin/gemcitabine can be used as abackbone for evaluating novel molecularlytargeted therapies.

Disclosures:

Dr. Belani has receivedresearch support from and acted as aconsultant for Bristol-Myers Squibb and EliLilly.

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