Induction Therapy for Early-Stage Non-Small-Cell Lung Cancer

ABSTRACT: Data from adjuvant trials clearly indicate that one of the most importantproblems in patients with resected non-small-cell lung cancer(NSCLC) is compliance to chemotherapy. In the postoperative setting,significant comorbidities and incomplete recovery after surgery oftenmake it difficult for patients to tolerate or comply with systemic therapy.Therefore, it may be preferable to deliver chemotherapy before surgeryas "neoadjuvant" or "induction" chemotherapy. The rationale for usinginduction chemotherapy is based on evidence that chemotherapymight reduce tumor burden and possess activity againstmicrometastases, resulting in improved results by surgery, radiotherapy,or a combination. Moreover, induction therapy facilitates in vivo assessmentof tumor response or resistance. Potential drawbacks includethe risk of perioperative complications, and the possibility that the tumormass may become unresectable due to disease progression. Duringthe past decade, four phase III randomized trials evaluated the roleof induction chemotherapy in stage IIIA NSCLC. The first three studiesconsistently showed that induction chemotherapy improves survivalcompared with surgery alone. More recently, a large phase III trialperformed by French investigators suggested a survival benefit in stageI/II patients, but not stage IIIA. The high activity of new platinumbasedchemotherapy-based on response rate and 1-year survival inadvanced disease-reinforces the rationale for the use of these newcombinations in early-stage NSCLC, especially for a subset of patientstraditionally treated with surgery alone. Several phase III trials arecurrently evaluating the role of new doublets as induction chemotherapy;these are discussed in the article. The results of these ongoingphase III trials should help clarify the role of induction chemotherapyin early-stage disease.

Despite advances in therapycombined with smoking-cessationprograms, lung cancercontinues to be the leading cause ofcancer death in the United States withan estimated 173,770 new patients diagnosedand 160,440 deaths in2004.[1] For patients with non-smallcelllung cancer (NSCLC), tumor stagingis the most important prognosticfactor and largely determines treatment.Radical surgery alone is thetreatment of choice of early-stageNSCLC. Nevertheless, after surgicalresection for stage I and II NSCLC,the 5-year survival rate without recurrenceis approximately 50% instage I disease and 35% in stage II.The vast majority of patients withstage IIIA disease that is resected forcure relapse, and the majority of thesedevelop systemic spread.In recent years, clinical trials haveattempted to determine whether postoperativetherapy improves the resultsobtained with surgery alone. The firstgeneration of adjuvant trials (ie, thosecarried out in the 1960s through the1970s) used long-term alkylatingagents; the trials with the largest patientpopulations were those of theMedical Research Council[2] and theVeterans Administration.[3,4] Startingin the late 1970s, most trials incorporatedcisplatin-containing chemotherapyregimens into their studydesigns.[5,6] Chemotherapy often includedcyclophosphamide (Cytoxan,Neosar), doxorubicin, and cisplatin.Because of the limited number ofpatients, it was not possible to establishclearly the role of adjuvant chemotherapy in early-stage NSCLC. TheMedical Research Council and InstitutGustave Roussy therefore conducteda large overview using updatedindividual data of all trials, whetherpublished or unpublished.[7] Morethan 9,000 patients from 52 randomizedtrials fulfilled the selection criteria.In the group comparing surgeryalone to surgery followed by adjuvantchemotherapy, 14 trials recordedan overall accrual of 4,357 patients.

In the five trials using long-termalkylating agents, adjuvant chemotherapyshowed a detrimental effect;in the eight trials that used a cisplatinbasedregimen, there was a 13% reductionin the risk of death, suggestingan absolute benefit of 5% with adjuvantchemotherapy at 5 years. Chemotherapywas randomly added tosurgery and radiotherapy in a total of807 patients. This led to a 6% reductionin the risk of death, suggesting a2% absolute benefit at 5 years. Thesefindings constituted the rationale forthe large-scale trials and several adjuvantstudies worldwide using newerregimens that have been initiated.An important conclusion from theEuropean meta-analysis is that survivalbenefits from chemotherapy aresmall, and trial sizes therefore musthave large patient populations to demonstratepatient benefit. The results offour randomized multicentric trialshave been presented recently (Table1).[8-11] Although the results werecontroversial, these studies, particularlythe Japanese study and the InternationalAdjuvant Lung Cancer Trial(IALT), confirmed a small, statisticallysignificant benefit in survivalfor patients receiving adjuvant chemotherapy.[10,11]Data from adjuvant trials clearlyindicate that one of the most importantproblems in patients with resectableNSCLC is compliance tochemotherapy. In the postoperativesetting, significant comorbidities andinsufficient recovery following surgeryoften make it difficult for patientseither to tolerate or comply withsystemic therapy. Therefore, it mightbe preferable to deliver chemotherapybefore surgery ("neoadjuvant" or"induction" chemotherapy).Induction chemotherapy offers severaltheoretical advantages: (1) immediatesystemic therapy in patientsat high risk for relapse with potentialeradication of micrometastases, (2)avoidance of postoperative complicationsand comorbidities that mightpotentially compromise compliance ortolerance, (3) reduction of tumor burdenwith a potential for increases inresectability rates and ease of resection,and (4) in vivo assessment oftumor response or resistance. However,potential drawbacks include riskof perioperative complications andpotential for the tumor to become unresectabledue to disease progression.Induction Chemotherapy WithOlder-Generation RegimensAlthough complete resection forpatients with stage IIIA disease is technicallyfeasible, the 5-year survival isonly 10%, primarily due to the developmentof distant metastases. Severalphase II studies evaluated the role ofinduction chemotherapy in stage IIIANSCLC.[12-15] These studies demonstratedthat induction chemotherapyis feasible, with acceptable toxicity,and capable of inducing an averageoverall response rate ranging from50% to 82%, with complete responsesachieved in less than 10% of thetreated patients. More than 60% ofpatients who responded underwentradical resection, and the combinedmodalityapproach produced an overallmedian survival duration ofapproximately 19 months, with mediansurvival of 27 to 29.7 months inpatients undergoing complete resection.During the 1990s, four phase IIIrandomized trials evaluated the roleof induction chemotherapy in stageIIIA NSCLC (Table 2).[16-19] Thefirst three studies consistently demonstratedthat induction chemotherapyimproved survival compared withsurgery alone.[16-18] Pass et al[16]randomly assigned 27 stage IIIANSCLC patients to receive cisplatin/etoposide chemotherapy followed bysurgery or surgery alone. This smallstudy reported a trend toward improvedsurvival time in the chemotherapygroup.[16]Rosell et al[17] conducted a randomizedphase III study comparingsurgery alone with induction cisplatin/mitomycin (Mutamycin)/ifosfamide(Ifex) for three cycles followed bysurgery. This study was prematurelyclosed based on an interim analysisthat demonstrated a significant benefitin survival for the patients receivinginduction chemotherapy.[17]Median survival was 26 months inthe combined-modality arm comparedto only 8 months in the surgery-onlyarm (P < .001); no patients were aliveat 2 years in the surgery-only arm.Disease-free survival was 20 monthsin the combined modality arm as opposedto 5 months in surgery group(P < .001). Standard therapy yieldedsurvival results much poorer than expected,based on historic data in patientswith initially resectable stageIII disease. (In fact, several retrospectivestudies showed that the 5-yearsurvival for completely resected N2patients is 20% to 30% without chemotherapy.)Moreover, the incidenceof k-ras oncogene mutations was only15% in the chemotherapy arm vs 42%in the surgery-only arm.[17]Roth et al[18] randomly assignedpatients with IIIA disease to undergoeither surgery alone or inductionchemotherapy (cyclophosphamide/cisplatin/etoposide) for three cyclesfollowed by surgery and additionalchemotherapy. Although the completeresection rates were similar in botharms, median survival was significantlyincreased in patients receiving inductiontherapy (64 vs 11 months,P < .008). The estimated 2- and3-year survival percentages were 60%and 56% for the induction chemotherapyarm compared to 25% and15%, respectively, for study patientsundergoing surgery alone.[18] Similarto Rosell et al's decision in theirstudy based on interim results,[17] thistrial prematurely closed with only 60patients accrued rather than the intended130. Moreover, induction chemotherapywas highly toxic, with80% encountering grade 3/4 neutropeniaand 15% with neutropenic fever,with 70% of patients requiringdose reduction.These trials of Rosell et al and Rothand colleagues have demonstrated survivalbenefits for induction chemotherapyin patients with stage IIIANSCLC. Notably, both trials closedearly due to the overwhelming survivalbenefit in the experimentalarms.[17,18] While these trials wereencouraging, the number of accruedpatients was small and contained aheterogeneous population. Moreover,potential, unintentional selection bias,such as the presence of a high percentageof k-ras mutations in the surgery-only arm of the Rosell trial,[17]and the very poor outcome of the standard-therapy arms, preclude a definitiveconclusion regarding inductiontherapy.

Depierre et al[19] recently conducteda randomized phase III trial thatcompared the survival benefit ofNSCLC patients with stage I, II, andIIIA disease receiving two inductioncycles of mitomycin/ifosfamide/cisplatin(the MIP regimen) before resectionwith patients undergoingsurgical resection alone. For patientswith stage IB through IIIA disease, ageneral 11-month improvement in mediansurvival was recorded for patientsreceiving MIP chemotherapy.Importantly, this finding occurred afterthe first 5 months, and survivalbenefit also reached statistical significanceonly in stage I and II-not instage IIIA disease. However, the lackof survival benefit in stage IIIA diseaseobserved in the trial by Depierreand co-workers[19] contrasts with previousdata[16-18] in which a survivalbenefit was reported for stage IIIA patients.A possible area of discrepancymight lie in the study design used byDepierre et al[19]: it was the first studyto include a large number of patients,and possibly, chemotherapy could beless active on bulky disease.Moreover, a recent update of thedata of Roth and co-workers reinforcedan important difference in respectivesurvival difference betweenthe two arms. The investigators reanalyzedthe study data with a mediantime from random allocation to analysisof 82 months, reporting that theincrease in survival conferred by perioperativechemotherapy was maintainedduring the period of extendedobservation.[20]Another important finding in thestudy by Depierre et al[19] was thatthe benefits of preoperative inductionchemotherapy with MIP were delayedfor 5 months because of the high perioperativetoxicity that was associatedwith the combination of chemotherapyand resection. Because this issue ispotentially the most important findingfrom the trial, reducing perioperativetoxicity should be addressed infuture trials and treatment protocols.Induction Chemotherapy WithNewer-Generation RegimensDuring the 1990s, several trialsevaluated the role of new cytotoxicdrugs, such as the taxanes, gemcitabine(Gemzar), and vinorelbine (Navelbine),in combination with aplatinum agent. These studies demonstratedthat combinations of a newdrug with a platinum derivative producedbetter response rates when comparedwith (1) a single agent, (2) anolder two-drug combination, or (3)an older three-drug regimen.[21-30]Thus, the combination of either cisplatinor carboplatin (Paraplatin) witha new cytotoxic evolved into the standardtreatment for patients with advancedNSCLC.Several large phase III trials recentlycompared these new doubletsto determine the ideal treatment regimenfor patients with advancedNSCLC. The trials similarly demonstrateda substantial equivalence ofthe new regimens in terms of efficacyand survival parameters, with differencesonly in toxicity profiles and economics.[31-33] Thus, in early-stageNSCLC, the new doublets are possiblymore active and less toxic thanolder combinations, and these factorsmight contribute toward increased survivalbenefit.

Gemcitabine is one of the mostactive agents in the management ofNSCLC. Phase II trials in patients withunfavorable stage IIIB or stage IVNSCLC demonstrated that the combinationof gemcitabine and cisplatinachieved an objective response rateranging of 52% to 54%.[34,35] Randomizedphase III trials conducted inthe patients with similar-stage diseaseshowed that the gemcitabine/cisplatincombination was more active than cisplatinalone,[23] cisplatin and etoposide,[21] or the MIP regimen.[22]These pivotal data prompted VanZandwijk and the European Organizationfor Research and Treatment ofCancer (EORTC) Lung Cancer CooperativeGroup to initiate a phase IItrial to define further the activity andtoxicity of the gemcitabine/cisplatincombination as induction treatmentin 47 stage IIIA NSCLC patients withN2, mediastinoscopy verified disease.[36] Patients received gemcitabineat 1,000 mg/m² given on days 1,8, and 15, and cisplatin at 100 mg/m²on day 2, every 4 weeks.The response rate was 70%, withmediastinal downstaging in 53% ofpatients. Radical resection was feasiblein 71% of the patients who underwentthoracotomy. Notably, the mediansurvival was 18.9 months, andthe 1-year survival rate was 69%.Grade 3/4 thrombocytopenia was theprimary toxicity (reported in 60% ofpatients), and was commonly associatedwith the 4-week schedule of gemcitabine.Cappuzzo et al recently conducteda large phase II study (N = 129) thatevaluated the safety and efficacyof gemcitabine/cisplatin in patientswith unresectable stage IIIA/IIIBNSCLC.[37] Patients received gemcitabineat 1,000 mg/m² on days 1 and8, and cisplatin at 70 mg/m² on day 2,every 3 weeks, as part of a combinedmodalityapproach. The efficacy datafrom this trial indicated a 70.4% responserate with a 29% complete resectabilityrate. Importantly, using a3-week treatment administrationschedule, toxicity was generally mild,with grade 3/4 thrombocytopenia asthe primary toxicity (27% of patients).The high activity and favorable toxicityprofile of the gemcitabine/cisplatincombination, especially with the3-week schedule, thus reinforced therationale for testing this regimen inearly-stage disease.The Chemotherapy in Early STageNSCLC (ChEST) study is an international,multicenter, randomized phaseIII trial of surgery alone vs preoperativechemotherapy followed by surgeryin early-stage (I, II, IIIA)NSCLC. The experimental arm consistsof three courses of gemcitabineat 1,250 mg/m² given on days 1 and 8and cisplatin at 75 mg/m² day 2 (every-3-week cycle) followed by surgery.Surgery alone is the standardarm. The primary end point of thestudy is progression-free survival,while secondary end points includeoverall survival, sites of relapse, perioperativetoxicity, and response. Thetrial is ongoing and results will beavailable in the near future.Paclitaxel or docetaxel/platinumcombination regimens are establishedstrategies in the management of advancedNSCLC.[31,38] Docetaxel isone of the most effective drugs for thetreatment of advanced NSCLC, andmany also consider platinum/docetaxelcombinations to be very active regimensin the advanced diseasesetting.[31,38] Mattson et al[39] randomlyassigned 274 patients with resectablestage IIIA/IIIB NSCLC toreceive either induction therapy withdocetaxel (n = 134) or no chemotherapy(n = 140) before surgery and curativeintent radiotherapy. Patientsreceived up to three 3-weekly cyclesIV of docetaxel at 100 mg/m². Mediansurvival was 14.8 months in thedocetaxel group vs 12.6 months inthe control group. Although this trendtoward improved survival in the patientswith potentially resectableNSCLC who received induction therapywas not statistically significant,this trial reported the excellent tolerabilityof induction chemotherapywith docetaxel.Betticher and colleagues[40] recentlyevaluated the activity of docetaxel/cisplatin chemotherapy asinduction therapy in NSCLC patientswith previously untreated, potentiallyresectable stage IIIA mediastinoscopicallypN2 disease (N = 90). Patientsin the phase II trial received threecycles of docetaxel at 85 mg/m² givenon day 1 plus cisplatin at 40 mg/m² ondays 1 and 2, with subsequent surgi-cal resection. The investigators reportedan overall response rate of 66%,and pathologic complete responses in19% of patients, demonstrating thatthe docetaxel/cisplatin combinationwas very active. Moreover, the incidenceof perioperative mortality andmorbidity was 3% and 17%, respectively.These encouraging data supportthe use of regimens includingdocetaxel in patients with early-stagedisease.Pisters and the Bimodality LungOncology Team assessed the role ofinduction carboplatin/paclitaxel chemotherapyin mediastinoscopicallynegative early-stage NSCLC.[41] Thechemotherapy regimen consisted ofpaclitaxel at 225 mg/m² given over 3hours, and carboplatin at an area underthe concentration-time curve(AUC) of 6, every 3 weeks. The initial94 patients treated were to receivetwo preoperative and three postoperativechemotherapy cycles. A secondcohort of 41 patients was then treatedto evaluate a treatment strategy ofthree preoperative and two postoperativechemotherapy cycles.Data from the first 94 patientsshowed that induction therapy withcarboplatin/paclitaxel was active andwell tolerated in early-stage NSCLC.The overall response rate was 56%,and 86% of patients were fully resected.The 1-year survival percentagewas reported to be 85%; median survivalhad not yet been reached at thetime of publication. Importantly, 96%of patients received their planned inductionchemotherapy, while postoperativechemotherapy was administeredonly in 45% of patients. Nounexpected chemotherapy- or surgery-related morbidity occurred.Two large phase III trials are currentlyevaluating the role of inductionchemotherapy with carboplatin/paclitaxelin early-stage NSCLC. TheSouthwest Oncology Group (SWOGtrial 9900) is evaluating whether threecycles of induction chemotherapy withcarboplatin/paclitaxel improve survivalcompared with surgery alone inpreviously untreated patients withclinical stage IB, II, and selected IIIANSCLC disease.The Spanish Lung Cancer Group(SLCG) is conducting a large phaseIII study in which untreated NSCLCpatients with stage I, II, IIIA (T3, N1)are randomly assigned to either surgeryalone (standard arm) or two experimentalarms, in which threecourses of carboplatin/paclitaxel chemotherapyare given before (inductionarm) or after (adjuvant arm)surgery. Other randomized trials ofpreoperative chemotherapy in earlystagedisease are ongoing, includingthose conducted by the Lung CancerGroup of the Medical Research Council(trial LU 22), the Dutch Lung CancerStudy Group, and the EORTC(Table 3).The Intergroupe Francophone deCancerologie Thoracique will comparetwo different strategies of inductionchemotherapy. After two cyclesof neoadjuvant chemotherapy, responderswill receive two additionalcycles, either after surgery in one arm,or immediately after the first two cyclesand before surgery in the otherarm. This study design also comparestwo new regimens: paclitaxel/carboplatinand gemcitabine/cisplatin. Theresults of these ongoing trials will helpclarify the role and the optimal schedulingof chemotherapy in the treatmentof patients with early-stageNSCLC.ConclusionsDespite an apparent complete resectionof NSCLC in many patients,death occurs in the majority of patientswho develop recurrent disease.Therapy aimed at eradicating micrometastaticdisease has been the primaryend point of adjuvantchemotherapy. Data from adjuvant trialsindicate that significant comorbiditiesand insufficient recovery aftersurgery are often associated with thepatients' inability to tolerate or complywith systemic therapy. Therefore,it might be preferable to deliver chemotherapybefore surgery. For patientswho present with locally advanceddisease, induction chemotherapy followedby surgery and/or radiotherapyis a candidate for standard therapy.For patients with early-stageNSCLC, data from randomized phaseIII trials that have concluded have notyet produced sufficient evidence toconsider induction chemotherapy asa standard treatment option. However,the published trials have generallyincluded an induction chemotherapyregimen consisting of older-generationregimens, which many consideredless active and more toxic thannewer doublets. Large randomizedstudies are currently evaluating therole of newer-generation combinationsin patients with resectableNSCLC. The results of these trialswill be available in the future, andmay further define the role of inductionchemotherapy in the treatment ofpatients with early-stage disease.

Disclosures:

The authors have nosignificant financial interest or other relationshipwith the manufacturers of any productsor providers of any service mentioned in thisarticle.

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