Induction Chemotherapy for Resectable Non–Small-Cell Lung Cancer

November 1, 2004

Recent advances in molecularclassification and the adventof noncytotoxic molecularlytargeted therapies have offered increasedhope of improving the diagnosis,treatment, and prognosis forpatients with non–small-cell lung cancer(NSCLC).[1] Yet the use of chemotherapyin NSCLC has continuedto evolve over recent years with theappearance of newer cytotoxic agentsthat have improved the outcome forpatients. Doublet combination chemotherapyhas become the standardof care for patients with advanceddisease and good performance status.Prolongation of survival has also beenshown with second-line chemotherapyfor patients whose tumors are refractoryto first-line agents.[1]

Recent advances in molecularclassification and the adventof noncytotoxic molecularlytargeted therapies have offered increasedhope of improving the diagnosis,treatment, and prognosis forpatients with non-small-cell lung cancer(NSCLC).[1] Yet the use of chemotherapyin NSCLC has continuedto evolve over recent years with theappearance of newer cytotoxic agentsthat have improved the outcome forpatients. Doublet combination chemotherapyhas become the standardof care for patients with advanceddisease and good performance status.Prolongation of survival has also beenshown with second-line chemotherapyfor patients whose tumors are refractoryto first-line agents.[1]The value of combined-modalitytherapy in locally advanced stage IIIBdisease has been unquestionably provendespite the limitation that concurrenttherapy imposes on the doses ofsystemic agents used in the combinedconcurrent setting.[2] Recent evidenceindicates that systemic therapy addedto a definitive surgical approach offersa modest increase in survival in patientswith resectable disease.[3] Thesemodest advances seen with the use ofcytotoxic therapy force a reexaminareexaminationof the role of systemic therapy inresectable disease, ultimately redefiningoptimal care for the minority ofpatients presenting with resectableclinical stage I, II, and IIIA disease.Adjuvant Chemotherapy
Patients with stage I to IIIA NSCLCtreated with lobectomy or pneumonectomyand node sampling have a5-year survival ranging between 67%for stage IA to as low as 23% forresected stage IIIA disease.[4] Previousmeta-analysis showed that postoperativecisplatin-based chemotherapymay improve the absolute survivalat 5 years by 5%.[5] The samplesizes in the individual trials were toosmall, however, to draw any firm conclusions.Since then, a number of largeradjuvant chemotherapy trials havebeen completed.The Adjuvant Lung Project Italy(ALPI) trial randomized 1,209 stage Ito IIIA patients to adjuvant systemictherapy with MVP (mitomycin [Mutamycin],vindesine, cisplatin). The timeto progression favored the chemotherapyarm with a nonsignificant difference.[6] The UK trial assigned the samegroup of patients to one of four cisplatin-based chemotherapy regimens aftera complete resection. The study wasunderpowered and showed no differencein survival.[7] The InternationalAdjuvant Lung Cancer Trial (IALT)was a larger similarly designed studythat enrolled 1,867 patients. It showeda statistically significant absolute increaseof 4.1% in the 5-year survivalrate (P = .03).[3]The National Cancer Institute ofCanada (NCIC) and Cancer and LeukemiaGroup B (CALGB) trials usedmore up-to-date chemotherapy combinationsand helped clarify the degreeto which toxicity from systemictherapy contributed to increased deathin the previous trials, providing survivalbenefits of 5% to 10% withcombinations of vinorelbine (Navelbine)and cisplatin,[8] or paclitaxeland carboplatin (Paraplatin).[9] Bothstudies showed a survival advantageof 5% to 10% for adjuvant chemotherapy.Value of Induction Therapy
Extrapolating from data in breastand colon cancer, it seems appropriateto offer systemic adjuvant therapyto patients with resected stages I toIIIA NSCLC with good performancestatus. The appropriate sequencing ofchemotherapy with surgery and therole of induction therapy in resectableNSCLC patients is the topic ofreview in the paper by Patel et al. Thevalue of induction therapy has beenextensively studied in other malignanciesincluding breast and colorectalcancer. In breast cancer, thebeneficial role of induction therapyhas clearly been shown in terms oforgan preservation.[10] However, investigatorshave yet to show evidenceof improved outcome measured interms of survival for patients receivingthis modality vs the more standard adjuvantapproach. To a certain extent,the same applies to rectal cancer.[11]It appears reasonable to examinethe question of induction chemotherapyand its potential benefits in lungcancer, as a large proportion of recurrencesafter surgical resection of stages Ito IIIA are extrathoracic. Potentialadvantages of induction therapy wouldinclude the targeting of micrometastaticsites.[12] In addition, as arguedby Patel et al, decreasing tumor sizemay improve the chance and ease ofadequate resection. Higher responsesand resectability rates have been notedwith induction therapy in patients withstage IIIA/IIIB disease,[13] and overallsurvival was improved and maintainedwith chemotherapy for patientswith stage IIIA disease.[14,15]Study Results
Based on the successes observedin stage IIIA disease, numerous phase IItrials evaluating the role of inductionchemotherapy in earlier stages (IB andII) as well as in stage IIIA were initiated.These trials showed some increasein postoperative morbidity inthe combined arms with no differencein local recurrence rates, yet a low incidenceof distant metastatic sites favoringchemotherapy.[16]The phase III French study comparinginduction with mitomycin, ifosfamide(Ifex), and cisplatin to surgeryalone for patients with stage IB, II, orIIIA disease had a median survivalfavoring chemotherapy (37 vs 26months, P = .15) with a significantprolongation in disease-free survival(P = .033).[17] Of note in this studyare the apparent inaccuracies in clinicalstaging despite the use of mediastinoscopyand CT scanning, as therewas only a 16% correlation betweenclinical and postsurgical pathologicstage, and 36% more extensive diseasethan predicted, raising the questionof whether a more elaboratestaging approach is needed. There wasno significant difference in the rate ofresectability and survival.The Intergroup randomized trialcomparing three cycles of inductionpaclitaxel and carboplatin (SouthwestOncology Group [SWOG] 9900) tosurgery alone in stages T2, N0; T1/2,N1; and T3, N0/1 NSCLC is expectedto randomize 600 patients, and itsresults are anxiously awaited.Conclusions
Can induction therapy be recommendedfor patients with resectableNSCLC? Similar uncertainties existwhen the question of adjuvant therapyin NSCLC is raised. First and foremostis the need to define whichpatients would clearly benefit fromsuch therapy. It seems more appropriateto reserve it for those with goodperformance status.The appropriate choice of inductionregimens and their duration isalso an area that needs clarification.A plethora of cytotoxic agent combinationsis available without provensuperiority in advanced disease. Anydoublet of active agents (eg, paclitaxel,docetaxel, vinorelbine, gemcitabine[Gemzar]) could be considered forfurther investigation. Prolonged therapiesof more than four cycles havenot produced increased benefit inmore advanced disease,[18] whichmakes two to four cycles of therapyseem appropriate in the inductionphase.Will the inclusion of additional adjuvantchemotherapy lead to bettersurvival? Is the addition of radiationtherapy beneficial, or does it lead toincreased morbidity and complications,and who should receive it? Morestudies are obviously needed to clarifyall these issues.Finally, one could not tackle thequestion of adjuvant or induction therapyin NSCLC without a closer lookat the area of most active research inlung cancer today-that is, molecularlytargeted therapies, used alone,in combination with cytotoxics, orwith other targeted agents. One challengein this area is the need to definethe most appropriate subset of patientsfor a certain targeted therapy.The time when the choice of inductionor adjuvant therapy is dictatedby a genotype of a certain tumor maynot be very far off. Until this isachieved, a better definition of therole of induction and adjuvant therapyshould be better answered by thenext generation of clinical trials inNSCLC.

Disclosures:

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

References:

1.

Khuri FR, Herbst RS, Fossella FV: Emerging therapies innon-small-cell lung cancer. Ann Oncol 12:739-744, 2001.

2.

Albain KS, Scott CB, Rusch VR, et al: Phase III comparisonof concurrent chemotherapy plus rdiotherapy (CT/RT) andCT/RT followed by surgical resection for stage IIIA (pN2) nonsmallcell lung cancer (NSCLC): Initial results from the intergrouptrial 0139 (RTOG 93-09) (abstract 2497). Proc Am SocClin Oncol 22:621, 2003.

3.

Arriagada R, Bergman B, Dunant A, et al: Cisplatin-basedadjuvant chemotherapy in patients with completely resected nonsmallcell lung cancer. N Engl J Med 350:351-360, 2004.

4.

Mountain CF: Revisions in the international system for staginglung cancer. Chest 111:1710-1717, 1997.

5.

Non-Small Cell Lung Cancer Collaborative Group: Chemotherapyin non-small cell lung cancer: A meta-analysis using updateddata on individual patients from 52 randomized clinical trials.BMJ 311:899-909, 1995.

6.

Scagliotti G, Fossati R, Torri V, et al: Randomized studyof adjuvant chemotherapy for completely resected stage I, II orIIIA non-small cell lung cancer. J Natl Cancer Inst 95:1453-1461, 2003.

7.

Waller D, Peake MD, Stephens RJ, et al: Chemotherapyfor patients with non-small cell lung cancer: The surgical settingof the Big Lung Trial. Eur J Cardiothorac Surg 26:173-182, 2004.

8.

Winton TL, Livingston R, Johnson D, et al: A prospectiverandomized trial of adjuvant vinorelbine (VIN) and cisplatin (CIS)in completely resected stage IB and II non-small cell lung cancer(NSCLC) Intergroup JBR.10 (abstract 7018). Proc Am Soc ClinOncol 23:619, 2004.

9.

Strauss GM, Herndon J, Maddaus MA, et al: Randomizedclinical trial of adjuvant chemotherapy with paclitaxel andcarboplatin following resection in stage IB non-small cell lungcancer (NSCLC): Report of Cancer and Leukemia Group B(CALGB) protocol 9633 (abstract 7019). Proc Am Soc Clin Oncol23:619, 2004.

10.

Newman LA, Washington TA: New trends in breast conservationtherapy. Surg Clin North Am 83:841-883, 2003.

11.

Crane CH, Skibber J: Preoperative chemoradiation for locallyadvanced rectal cancer: Rationale, technique, and results oftreatment. Semin Surg Oncol 21:265-270, 2003.

12.

Feld R, Rubinstein LV, Weisenberg TH: Sites of recurrencesin resected stage I non-small cell lung cancer: A guide forfuture studies. J Clin Oncol 2:1352-1358, 1984.

13.

Rusch VW, Albain KS, Croley JJ, et al: Surgical resectionof stage IIIA and stage IIIB non-small cell lung cancer after concurrentinduction chemoradiotherapy. J Thorac Cardiovasc Surg105:97-104, 1993.

14.

Rosell R, Gomez-Codina J, Camps C, et al: A randomizedtrial comparing preoperative chemotherapy plus surgery with surgeryalone in patients with non-small cell lung cancer. N Engl JMed 330:153-158, 1994.

15.

Roth JA, Atkinson EN, Fossella F, et al: A randomizedtrial comparing perioperative chemotherapy and surgery with surgeryalone in resectable stage IIIA non-small cell lung cancer. JNatl Cancer Inst 86:9, 1994.

16.

Pisters KM, Ginsberg RJ, Giroux DJ, et al: Induction chemotherapybefore surgery for early-stage lung cancer: A novelapproach. Bimodality Lung Oncology Team. J Thorac CardiovascSurg 119:429-439, 2000.

17.

Depierre A, Milleron B, Moro-Sibilot D, et al: Preoperativechemotherapy followed by surgery in resectable stage I (exceptT1N0), II, and IIIA non-small cell lung cancer. J Clin Oncol20:247-253, 2002.

18.

Socinski MA, Schell MJ, Peterman A, et al: Phase IIItrial comparing a defined duration of therapy versus continuoustherapy followed by second-line therapy in advanced stage IIIB/IV non-small cell lung cancer. J Clin Oncol 20:1335-1343,2001.