Gemcitabine-Containing Regimens vs Others in First-Line Treatment of NSCLC

ABSTRACT: Standard first-line chemotherapy regimens in advanced non-smallcelllung cancer (NSCLC) include carboplatin (Paraplatin)/paclitaxel,cisplatin/docetaxel (Taxotere), cisplatin/gemcitabine (Gemzar), andcisplatin/vinorelbine (Navelbine). An informal meta-analysis of 13 randomizedtrials of these regimens in NSCLC indicates no marked differencesin terms of response rates or survival, but toxicity advantageswith cisplatin/gemcitabine and cisplatin/vinorelbine regimens. An informalmeta-analysis to assess the feasibility of substituting carboplatinfor cisplatin in combination with gemcitabine or docetaxel shows nomarked differences in efficacy between cisplatin- and carboplatincontainingregimens, although a slight trend favoring carboplatin/gemcitabine treatment may be observed; comparison of toxicity profilesamong carboplatin-based regimens suggests advantages forcarboplatin/gemcitabine treatment. A formal meta-analysis of 13 trialscomparing gemcitabine/platinum combinations with other platinumbasedregimens in NSCLC indicates significant improvements inprogression-free survival and overall survival with gemcitabine/platinum treatment. On balance, available data suggest that carboplatin/gemcitabine may be the first-line option with the best therapeutic index.

Results of randomized clinicaltrials have established carboplatin(Paraplatin)/paclitaxel,cisplatin/gemcitabine (Gemzar), cisplatin/docetaxel (Taxotere), and cisplatin/vinorelbine (Navelbine) asstandard first-line treatments for advanced/metastatic non-small-cell lungcancer (NSCLC). To address the relativemerits of these regimens, an informalmeta-analysis of efficacy andtoxicity findings in randomized trialsevaluating these regimens was performed.Similarly, an informal meta-analysiswas performed to compare carboplatin-containing regimens withcisplatin-containing regimens to assessthe potential merits of replacingcisplatin with carboplatin in combinationwith gemcitabine or docetaxel.In addition, a formal meta-analysis oftrials comparing gemcitabine/platinumregimens with other platinumbasedregimens in NSCLC has beenperformed with regard to progressionfreesurvival and overall survival.Informal Meta-analysis ofStandard First-Line RegimensOur informal meta-analysis included13 major randomized trials ofcarboplatin/paclitaxel, cisplatin/gemcitabine,cisplatin/docetaxel, or cisplatin/vinorelbine as first-lineregimens in advanced NSCLC; 12 ofthe trials had enrollment greater than150 patients. Select results from thesetrials-consisting of objective responserate, median and 1-year survival,and major toxicities-wereweighted for patient accrual, mathematicallyaveraged, and compared.The 18 treatment arms included in theanalysis are shown in Table 1.[1-12]The comparison of efficacy outcomesis shown in Table 2. Objectiveresponse rates were similar for thefour regimens, ranging from 24% to30%. Survival outcomes also showedlittle difference among regimens, withmedian duration of survival rangingfrom 8.6 to 9.1 months and 1-yearsurvival ranging from 37% to 39%.These findings are consistent withthose reported by Schiller et al in theEastern Cooperative Oncology Group(ECOG) 1594 trial, which showed nosignificant differences in overall survival(and nearly superimposed survivalcurves) with cisplatin/paclitaxel,cisplatin/gemcitabine, cisplatin/docetaxel,and carboplatin/paclitaxel[3]and with the Southwest OncologyGroup comparing carboplatin/paclitaxelto cisplatin/vinorelbine.[2]

The comparison of toxicities isshown in Table 3. The lowest rate ofgrade 4 granulocytopenia is seen withcarboplatin/paclitaxel (15%) and thehighest with cisplatin/docetaxel(35%). Rates of febrile neutropeniaranged from 1% to 2% with carboplatin/paclitaxel and cisplatin/gemcitabineand from 4% to 5% withcisplatin/ docetaxel and cisplatin/vinorelbine.The highest rate of grade 4thrombocytopenia is observed withcisplatin/gemcitabine. It is importantto note, however, both that this thrombocytopeniais characteristically transientand does not result in seriousbleeding complications and that thesix cisplatin/gemcitabine arms includedin the analysis reflect use of gemcitabineon a schedule of days 1, 8,and 15 every 28 days. (Note that thecisplatin dose of 100 mg/m² in someof trials was higher than what is normallyused in actual practice; cisplatindoses > 80 mg/m² only add incrementallymore toxicity without efficacy.)With regard to the latter, hematologictoxicity is markedly reducedwith no loss of efficacy when gemcitabineis given in the now-standardschedule of day 1 and 8 every 21days. For example, a comparison ofgemcitabine at 1,000 mg/m² on days1, 8, and 15 every 28 days or 1,000mg/m² on days 1 and 18 every 21days plus cisplatin at 70 mg/m² onday 2 with both gemcitabine regimensshowed that treatment with the 21-day schedule was associated with anincrease in dose intensity of both drugs(due to improved delivery), a reductionin neutropenia (25% vs 35%), areduction in thrombocytopenia (7%vs 40%), an increase in anemia (10%vs 0%, due to more frequent dosingof cisplatin), reduced nonhematologictoxicity (25% vs 33%), and a numericbut nonsignificant improvementin response rate (55% vs 40%).[13]With regard to nonhematologictoxicities, grade 3/4 neurologic toxicityis most common with carboplatin/paclitaxel, likely reflecting the increasedrisk with paclitaxel given ona 21-day schedule, with rates for thecisplatin-containing combinations reflectingthe usual 6% to 10% rate ofgrade 3 neurologic toxicity seen withcisplatin. The rate of grade 3/4 arthralgias/myalgias is also highest withcarboplatin/paclitaxel, likely reflectingthe generally self-limiting andmanageable toxicity that occurs ondays 3 to 5 after paclitaxel administration,and lowest with cisplatin/gemcitabine.Alopecia of any grade is farmore common with taxane-containingregimens than with cisplatin/gemcitabineor cisplatin/vinorelbine.Cisplatin-induced nephrotoxicity andgastrointestinal toxicity have also beenreported in clinical trials.

Informal Meta-analysis: CanCarboplatin Replace Cisplatinin Combination WithGemcitabine or Docetaxel?It is unclear whether cisplatin-containingcombinations with docetaxelor gemcitabine are superior to carboplatin-containing combinations. Thefindings of the TAX 326 trial, whichshowed a survival advantage of cisplatin/docetaxel over cisplatin/vinorelbineand no difference in this regardbetween cisplatin/vinorelbine and carboplatin/docetaxel regimens, aresometimes interpreted to indicate anadvantage of cisplatin/docetaxel overcarboplatin/docetaxel.[9] However, anumber of trials have shown no differencebetween cisplatin- and carboplatin-containing regimens, includinga trial comparing cisplatin/gemcitabineand carboplatin/gemcitabine,[14]with many data indicating that carboplatin-containing regimens are bettertolerated.

We performed a meta-analysis of13 trials involving 17 arms of firstlinetreatment with carboplatin/paclitaxel, cisplatin/gemcitabine, carboplatin/gemcitabine, cisplatin/docetaxel,and carboplatin/docetaxel(Table 4).[1-10,14-16] Therapeuticoutcome comparisons show nomarked difference between cisplatin/gemcitabine and carboplatin/gemcitabinetreatments, with perhaps someindication of trends favoring the latter(Table 5). There appears to belittle difference between cisplatin/docetaxel and carboplatin/docetaxelin terms of patient survival. Comparisonof toxicities for carboplatin incombination with paclitaxel, gemcitabine,or docetaxel-the three mostwidely used carboplatin-containingregimens in the United States-showsadvantages of the carboplatin/gemcitabineregimen over one or bothother regimens in terms of granulocytopenia,neurologic toxicity, arthralgias/myalgias, and alopecia(Table 6).

ConclusionsThe use of two-drug platinumbasedregimens have improved survivalin advanced NSCLC. Ourinformal meta-analysis of trials evaluatingcarboplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/docetaxel,and cisplatin/vinorelbine indicatescomparable efficacy of the regimensin terms of response rate, time to diseaseprogression, and survival, withsome advantages in terms of toxicityaccruing to the regimens not containingtaxanes. It also appears that carboplatincould be substituted forcisplatin in combination with gemcitabineor docetaxel without loss of effectivenessand with advantages interms of toxicity and ease of drugadministration. In this regard, the datamay be particularly strong in favor ofthe carboplatin/gemcitabine combination,which appears to have the besttherapeutic index of the platinumbasedcombinations.A recent formal meta-analysis indeedsuggests that there are efficacyadvantages to gemcitabine/platinumcombinations compared with otherplatinum-based regimens in the treatmentof NSCLC. Le Chevalier et alperformed a meta-analysis of overallsurvival and time to disease progressionin randomized trials comparingcombinations of gemcitabine with carboplatinor cisplatin against a platinum-based regimen.[17] Thirteentrials were identified for the analysis,representing a total population of4,556 patients.A total of 17 comparators wereidentified, including 12 platinumbaseddoublets (6 cisplatin/vinorelbine,2 cisplatin/paclitaxel, 2carboplatin/paclitaxel, 1 cisplatin/docetaxel,and 1 cisplatin/etoposide), 4platinum-based triplets (mitomycin/vinorelbine/cisplatin or mitomycin/ifosfamide/cisplatin), and 1 singleagentcisplatin regimen. Hazard ra-tios were calculated using a fixedeffectsmodel, with statistical heterogeneitybeing addressed using arandom-effects model when appropriate,and absolute treatment benefit at1 year was estimated.For overall survival, there was asignificant reduction in mortality infavor of the gemcitabine-platinumarms versus platinum-based comparatorarms; the hazard ratio for gemcitabine-based treatment was 0.90 (95%confidence interval [CI] = 0.84-0.96,P < .001), and the absolute survivaladvantage at 1-year was 3.9%. Therewas also a significant improvement intime to disease progression in favorof gemcitabine regimens; the hazardratio was 0.87 (95% CI = 0.82-0.93,P < .001), and the absolute improvementin progression-free survival at1-year was 4.2%.Although the superiority of any oneof the currently accepted regimens forfirst-line treatment of advancedNSCLC has not been clearly definedby individual clinical trials, analysisof available data in aggregate suggeststhat there may indeed be differencesin effectiveness, tolerability, andtoxicity among these regimens. Onthe basis of informal meta-analysesand the formal meta-analysis conductedby Le Chevalier et al,[17] it wouldappear that gemcitabine/platinum regimenspose an advantage in terms oftherapeutic response and that gemcitabine/carboplatin may be consideredthe preferred regimen on the basis of itsoverall efficacy and toxicity profiles.

Disclosures:

The author has no significantfinancial interest or other relationshipwith the manufacturers of any productsor providers of any service mentioned in thisarticle.

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