Lung cancer remains the leading cause of cancer death in Americanmen and women. Non–small-cell lung cancer (NSCLC) accountsfor 85% of these cases. Although surgery is the best curative approachfor resectable NSCLC, long-term survival for patients with operabledisease remains poor. More than half of patients who initially presentwith stage I to IIIA disease experience relapse of metastatic disease.Postoperative adjuvant therapy has been evaluated in several randomizedtrials, and provides a survival benefit. It appears reasonable tolook to induction chemotherapy, or preoperative chemotherapy, to providea similar improvement in survival with early treatment ofmicrometastatic disease. Multiple trials of induction therapy have beencarried out with encouraging results. The use of various induction regimenswith chemotherapy alone or chemotherapy combined with radiotherapyfor stage IIIA NSCLC is under investigation. Randomized trialsare under way to better define the role of induction therapy in themultimodality treatment of NSCLC.
ABSTRACT: Lung cancer remains the leading cause of cancer death in Americanmen and women. Nonâsmall-cell lung cancer (NSCLC) accountsfor 85% of these cases. Although surgery is the best curative approachfor resectable NSCLC, long-term survival for patients with operabledisease remains poor. More than half of patients who initially presentwith stage I to IIIA disease experience relapse of metastatic disease.Postoperative adjuvant therapy has been evaluated in several randomizedtrials, and provides a survival benefit. It appears reasonable tolook to induction chemotherapy, or preoperative chemotherapy, to providea similar improvement in survival with early treatment ofmicrometastatic disease. Multiple trials of induction therapy have beencarried out with encouraging results. The use of various induction regimenswith chemotherapy alone or chemotherapy combined with radiotherapyfor stage IIIA NSCLC is under investigation. Randomized trialsare under way to better define the role of induction therapy in themultimodality treatment of NSCLC.An estimated 173,000 men andwomen in the United Stateswill develop lung cancer in2004, of whom 160,000 will die.[1]Non-small-cell lung cancer (NSCLC)accounts for approximately 85% ofthese cases. Despite advances in therapyand attempts at prevention throughsmoking cessation programs, limitedadvertising, and restricted publicsmoking, lung cancer continues to bethe leading cause of cancer death inthe United States.Unfortunately, the majority of patientswith NSCLC will present withadvanced, incurable disease. At presentation,approximately 30% of patientswill have stage I or II diseasethat is potentially curable by surgery,and an additional 25% to 30% of patientswill have locally advanced disease(stage III) that is generally treatedwith combined-modality therapy.[2]Treatment BackgroundStandard Surgical Treatment
For patients with early-stageNSCLC (clinical stage I/II), lobectomyor pneumonectomy with mediastinalsampling or lymphadenectomyis the optimal treatment modality forthe potential cure of patients and mayresult in a 5-year survival ranging from67% in patients with pathologic T1,N0 disease to 38% in patients withpathologic T3, N0 disease.[3] Clinicalstaging often understages NSCLC,particularly if newer modalities suchas positron-emission tomography(PET) scanning are not utilized. As aresult, patients with disease at a givenclinical stage fare much worse thanthose at the corresponding pathologicstages (Table 1).[2]The majority of patients with stage IIINSCLC evaluated for resection havea disease extent that precludes immediatecurative surgery. However, evenin patients who are immediately resectable,those with pathologic T1-3,N2 disease (stage IIIA) have a 5-yearsurvival of only 23%.[3] Moreover,when bulky mediastinal involvementis noted on chest radiography, 3-yearsurvival is dismal-less than 10%.[4]Although in all of these patients diseaseis confined to the chest at onsetand can be removed surgically, thevast majority suffer from recurrentNSCLC and ultimately die of metastaticdisease.
Adjuvant Approaches
In order to improve on the disappointingresults of surgery alone,investigators have focused on chemotherapyand radiotherapy in additionto surgery. The majority of historicalclinical trials examining adjuvant (ie,postoperative) therapy have not foundunequivocal, reproducible evidence ofefficacy for adjuvant chemotherapy.[5-7] However, a meta-analysis of14 trials including over 4,000 patientsand comparing postoperative chemotherapywith no further therapy demonstrateda survival advantage forchemotherapy regimens containingcisplatin.[8] More recently, a largerandomized study showed that cisplatin-based adjuvant chemotherapyimproves survival by 4% at 5 years.[9]More recently, two trials in early-stagehomogeneous populations demonstratedsignificant survival benefits inpatients treated with platin-based adjuvantchemotherapy. [10, 11]Induction Therapy
Given this uncertainty, chemotherapyprior to surgery, or induction ther-apy,has been the subject of ongoinginvestigations. Induction therapy hasbeen attractive to clinicians becauseregression of the primary tumor to chemotherapyserves as a surrogate markerfor the control of clinically undetectablemetastases. In fact, consistentlyhigher response rates and better tolerabilityhave been noted in locally advanceddisease than in metastaticNSCLC.[12-14] Notably, a completepathologic response rate of 13% hasbeen reported in early clinical studiesof induction chemotherapy.[15]Thus, chemotherapy given beforesurgery has the potential to allow forassessment of tumor response to chemotherapy,to treat micrometastaticdisease early, to facilitate the completeeradication of lesions, and toprovide better dose delivery with fewertreatment interruptions. Additionally,decreasing tumor size mayimprove resectability and decrease themorbidity of resection.Resectable NSCLCPatients with stage I/II NSCLC cangenerally undergo immediate surgerywith curative intent. Although patientswith stage III disease have no evidenceof distant metastases and areviewed as potentially curable, theirprognosis is generally poor, and theoverwhelming majority die of theirdisease. Stage IIIA encompasses patientsfor whom extended surgery canremove all known sites of disease.Patients with stage IIIB disease arefrequently considered unresectable,because of contralateral mediastinallymph node involvement (N3) or extensivetumor invasion (T4) that requiresspecialized surgical techniquesto accomplish complete resections. Acarefully selected subset of patientswith T4 disease may be suitable forsurgical resection.The basic division between stage IIIAand IIIB NSCLC was established inthe 1980s.[3] However, in the 1997revision of the International StagingSystem, patients with T3, N0 diseasewere reclassified as having stage IIBbecause their survival was almostidentical to patients with T2, N1 tumors.This grouping complicates interpretationof stage III trials before1997, because treatment groups withT3, N0 patients have improved outcomes.Futhermore, within stage IIIAdisease there is significant variabilitythat can have an impact on prognosis.Larger tumors and multiple involvedlymph node stations result in worsesurvival.[16-19]Staging NSCLCComputed Tomography
Patients with potentially resectableNSCLC, especially those with stage IIIdisease, benefit from rigorous stagingevaluation prior to therapy. Computedtomography (CT) scanning is criticalin evaluating the location andextent of the primary tumor. CT scans,however, may under- or overestimatemediastinal lymph node involvement.Normal-sized lymph nodes (generallyconsidered to be < 1 cm in the shortaxis) can contain tumor cells, and enlargedlymph nodes do not alwayscontain metastatic tumor. Lymph nodemetastases become more likely withincreasing nodal size.[20]In one meta-analysis of 29 studiesinvolving 2,226 patients utilizing CTscans for the detection of mediastinalnodal metastases, the mean sensitivityand specificity were 60% and 77%,with a positive predictive value of50% and a negative predictive valueof 85%. An enlarged mediastinallymph node detected by CT scanning,therefore, only contains cancer 50%of the time, and 15% of normal-sized(< 1 cm) lymph nodes contain tumorcells.[21]Positron-Emission Tomography
PET with 18F-fluorodeoxyglucoseis a newer staging technique that usesthe relatively increased metabolic activityof cancer cells to differentiatethem from normal cells. In the aforementionedmeta-analysis, data from14 studies involving 514 patients wereexamined, and the authors found thatthe mean sensitivity and specificityfor PET were 79% and 91%, respectively,with a positive predictive valueof 90% and a negative predictivevalue of 93%.[21]Pieterman et al reported their experiencein 102 patients with resectableNSCLC with preoperative PETscanning and found sensitivity andspecificity of 91% and 86%, respectively.[22] However, in this group ofpatients, the positive predictive valueof PET was 74%. Therefore, 26% ofpatients with increased uptake on PEThave no evidence of nodal disease onhistopathology. Furthermore, evenlymph nodes that are positive by CTand PET require histopathologic proofof involvement. The negative predictivevalue of both a negative PET andCT scan of 97% was excellent in thisseries, and many surgeons feel thatPET scans can reliably rule out N2disease but that surgical staging is necessaryto confirm its presence.Mediastinoscopy
In many centers, mediastinoscopyis routinely performed to stage patientswith lung cancer who arecandidates for surgical resection. Mediastinoscopyis used to detect N3disease for which surgical therapywould not be advised and to detectN2 disease for which induction therapyprior to definitive surgery wouldbe warranted. Because not all lymphnodes can be sampled, cervical mediastinoscopyprovides sensitivity between72% and 89%.[23-25] Cervicalmediastinoscopy allows access to theright and left paratracheal lymphnodes and subcarinal lymph nodes.The aorticopulmonary window andsubaortic lymph nodes are not accessiblevia cervical mediastinoscopy andrequire anterior mediastinotomy.Combined Modalities
Appropriate staging procedures forpatients with resectable NSCLC,therefore, include a CT scan not onlyto assess the primary tumor and mediastinumbut also to evaluate for evidenceof metastatic disease withinthe lung, liver, and adrenal glands.All patients with mediastinal lymphnodes that are greater than 1 cm byCT imaging or are positive by PETscan should have mediastinal diseaseconfirmed histopathologically. In patientswith normal mediastinal lymphnodes by CT scan, a negative PETscan may obviate the need for mediastinoscopy.Mediastinoscopy, however,may identify patients withmicrometastatic lymph node involvementnot apparent on imaging modalitieswho may benefit from inductiontherapy.Detecting Brain Metastases
The incidence of brain metastasesin the initial staging of patients withprimary lung cancer has been reportedto between 12% and 18%.[26,27]Asymptomatic brain metastases occurmore frequently in patients withmore advanced stages of disease, withrates as high as 30% at 2 years instage II/III patients. Higher stage andnonsquamous histology have beenidentified as risk factors for brain metastases.[28,29] In asymptomatic patients,gadolinium-enhanced magneticresonance imaging (MRI) of the brainis superior for the detection of occultbrain metastases.A recent study randomized 332patients with potentially operableNSCLC, but without neurologicsymptoms, to brain CT or MRI inorder to detect occult brain metastasisbefore lung surgery.[30] MRI showeda trend toward a higher preoperativedetection rate than CT (P = .069),with an overall detection rate of approximately7% from pretreatment to12 months after surgery. In patientswith stage I/II disease, the detectionrate was 4% (8 of 200), whereas forindividuals with stage III disease, therate was 11.4% (15 of 132).Whether the improved detectionrate of brain metastases by MRI translatesinto improved outcome remainsunknown. Brain imaging is currentlyrecommended as a part of the initialevaluation for all patients with potentiallycurable locally advancedNSCLC. Finally, reevaluation of diseaseafter induction chemotherapy andprior to thoracotomy is recommendedto exclude disease progression. Theability of noninvasive tests to predictpathologic response has thus far beensuboptimal.Induction Chemotherapy TrialsInitial Observations
Several clinical trials have testedcombination chemotherapy prior tosurgery to improve the outcome of patientswith resectable NSCLC. Initialstudies using older chemotherapy regimenssuggested that preoperative chemotherapymay be beneficial.[31,32]Martini demonstrated that otherwiseresectable patients with ipsilateral mediastinallymphadenopathy as theirsole site of distant spread can have3-year survivals of 43%, and 5-yearsurvivals of 24%, if both the primarytumor and ipsilateral mediastinalnodes were completely resected andfollowed by mediastinal irradiation.[33,34] These same studies revealedthat individuals with bulkyipsilateral mediastinal lymphadenopathyhad only an 8% 3-year survival.Based on these observations, a preoperativecombination chemotherapyprogram with MVP (mitomycin [Mutamycin],vinca alkaloids, and highdosecisplatin [Platinol] at 120 mg/m2)was developed at Memorial Sloan-Kettering Cancer Center for use instage IIIA patients with clinical N2disease.[15] In a group of 136 patients,the objective major responserate to MVP was 77%, with a 10%complete response rate. Overall, 65%of patients underwent complete resections;14% had achieved a pathologiccomplete response at surgery.The median survival was 19 monthsfor all patients. The 3-year survivalfor completely resected patients was41%-a significant improvement overthe prior surgery-only experience,where the 3-year survival for thisgroup was 8% (P = .001).[15] Particularlynoteworthy was that a pathologiccomplete response was observedin approximately 12% of advancedNSCLC patients who received preoperativeMVP chemotherapy, with survivalestimates in this population of54% at 5 years.[35]The Cancer and Leukemia GroupB (CALBG) conducted a second similarlydesigned trial. A total of 74 patientswith surgically staged IIIA (N2)NSCLC were treated with two cyclesof preoperative cisplatin and vinblastine.[36] Patients who underwent resectionwere then treated with twocycles of adjuvant cisplatin and vinblastinefollowed by thoracic radiation.Approximately 64% of patientsachieved a radiographic response orstable disease, and 62% underwent acomplete resection. Operative mortalitywas 3% (2 deaths). Median survivalwas 15 months.Elias and investigators at the Dana-Farber Cancer Institute treated 34 patientswith pathologically confirmedN2 disease, using infusional cisplatin,fluorouracil (5-FU), and leucovorinplus postoperative radiotherapy to 54-60 Gy.[37] The radiographic responserate to this regimen was 65%. Thoracotomywas performed in 82% of patients.No operative mortality wasnoted, and 18% of patients achieved apathologic complete response. Mediansurvival was 18 months. The authorsnoted that few local recurrencesoccurred and that 15% of first relapseswere solely in the brain.Randomized Studies
Following these initial observationsthat suggested promising results withinduction therapy, a number of randomizedstudies aimed at establishingthe role of induction therapy wereconducted.
Early-Stage Disease
Taken together, the four small, randomizedstudies described above demonstrateda potential benefit with theaddition of induction chemotherapy instage IIIA NSCLC. Studies have sincebeen designed to evaluate the role ofinduction chemotherapy before surgeryin even earlier-stage NSCLC.
Newer Chemotherapy Regimens
Despite the often impressive resultswith induction chemotherapy,one-quarter or more of patients do notrespond to current primary chemotherapyregimens. Also, the majorityof patients who initially respond andhave complete surgical resectionseventually relapse. Two-thirds of therelapses are systemic. It appearsunreasonable to look to further advancesin surgery or radiation to substantiallyimprove survival. The abilityof a locoregional therapy modalitysuch as radiotherapy to control systemicrelapse is inherently limited.Based on the accumulated resultsand relapse patterns, improvementsin primary chemotherapy regimens aremost likely to result in improvementsin overall outcome. However, whileresponse rates to chemotherapy arehigh in stage III patients, clinical andpathologic complete response rates aregenerally less than 20%. Because individualswith complete pathologicresponses have the highest resectionand survival rates, the completepathologic response rate can serve asa surrogate for patient outcome inthe development of novel inductionregimens.
Induction Chemoradiotherapy
It is postulated that chemotherapydecreases the distant failure rate ofsurgery by eradication of micrometastaticdisease, whereas radiation canreduce the bulk of the primary tumorand nodal disease, thereby increasingthe rate of complete pathologic response-arguably the most importantpredictor of long-term survival. Therefore,investigators have attempted tointegrate chemotherapy and radiationtherapy into induction therapy for resectabledisease.
Phase II Trials
Phase III Trial
Based on the promising results ofthe SWOG phase II trial, a phase III,randomized trial of the North AmericanIntergroup (0139) was initiated.The goal of the study was to evaluatethe need for surgical resection afterchemoradiotherapy. Patients withstage IIIA pathologically proven N2NSCLC were randomized to fullcoursechemotherapy with cisplatinand etoposide plus radiotherapy to61 Gy, or to induction chemoradiationwith the same regimen to 45 Gyfollowed by surgical resection. Dueto slow accrual, the study was closedafter 429 patients (411 of whom wereeligible) were enrolled.[61]In a preliminary analysis of 392patients after a median follow-up of69 months, progression-free survivalwas significantly improved in the surgicalvs the nonsurgical arm (29% vs19%,
P
= .02), but overall survivalwas similar between the two arms(38% vs 34%). Although more earlynoncancer deaths occurred in the surgicalarm-primarily postoperatively(12 of 14 deaths occurred in patientsundergoing pneumonectomy)-thesurvival curves crossed at the medianof 22 months and showed an absolutebenefit of approximately 5% for surgeryat 3 years. Importantly, patientswho achieved a pathologic completeresponse in the mediastinal lymphnodes achieved 50% 3-year overallsurvival.The results of this study challengethe role of surgery in traditionally resectablestage IIIA NSCLC. Concurrentchemoradiotherapy alone maybe sufficient therapy for resectablestage IIIA NSCLC. It is likely that theimpact of postoperative mortality observedin the surgical arm obscured apotential survival advantage resultingfrom surgical resection. Final resultsof this Intergroup study are awaited.
Other Small Trials
The addition of radiotherapy to preoperativeprograms deserves furtherevaluation. Two small studies presentedin abstract form only have comparedinduction chemotherapy tochemoradiotherapy in potentially resectablestage III NSCLC. A studyfrom Brazil[62] demonstrated a significantimprovement in resectionrates, freedom from progression, and2-year survival in patients receivinginduction chemoradiotherapy vs chemotherapyalone before surgery. Thelong-term results of this study havenot been published; it therefore remainsto be seen whether these datawill hold up over time.A study from France in 92 patientswith stage IIIA/IIIB NSCLC evaluatedinduction MVP chemotherapyalone vs induction MVP followed by5-FU and cisplatin plus split-courseradiation to 40 Gy.[63] Higher resectionrates were noted in the inductionchemoradiotherapy arm, but this didnot translate into improved survivalover induction chemotherapy alone.Surgical complications were increasedin the chemoradiotherapy arm.The use of both induction chemotherapywith carboplatin and gemcitabinefollowed by concurrentchemoradiotherapy and then surgeryin patients with stage III NSCLC hasalso been investigated.[64] This studyenrolled 39 patients, 19 of whom ultimatelyunderwent surgical resection(16 with stage IIIA disease and 3 withselected T4 tumors). The pathologiccomplete response rate was 16% (42%in the mediastinal lymph nodes), andthe 3-year overall survival rate in surgicallytreated patients was 51%. Furtherinvestigation of this approach iswarranted.
Importance of Patient Selection
A potential advantage of inductionchemoradiotherapy may be that ahigher proportion of pathologic completeresponses is achieved comparedto the use of induction chemotherapyalone. However, postoperative morbidityand mortality appears to besomewhat higher with inductionchemoradiotherapy compared to inductionchemotherapy. Thus, ifsurgery is to be performed afterchemoradiotherapy, careful patient selectionis paramount. Patients withcompromised performance status orborderline cardiopulmonary reserveare unsuitable for this approach. Futuretrials need to address whether theaddition of radiotherapy to inductionchemotherapy translates to a survivaladvantage in patients with resectableNSCLC.
Surgical ConsiderationsAfter Induction Therapy
Although multiple studies havedemonstrated the safety of surgicalresection after induction therapy, severalissues make interpretation of thedata difficult. First, many studies involveheterogeneous populations thatinclude patients with both stage IIIAtumors with nodal involvement andstage IIIB tumors that are locally advanced.Resection of peripheral tumorswith nodal disease is associatedwith significantly lower complicationrates than extended resections for locallyadvanced disease.Additionally, patients who ultimatelyundergo surgical resection area selected group often without comparablecontrols. They are fit enoughfor surgical resection and have tumorswith demonstrated sensitivity toinduction chemotherapy. These patientshave better nutritional status,immunocompetency, and overallfunction, and therefore, an overall betterprognosis than those unable to toleratechemotherapy or who may not becandidates for multimodality therapy.Finally, many studies are retrospective,involve few subjects, and includevariable induction regimens such aschemotherapy alone and inductionchemoradiotherapy. Despite the limitationsof the available data, some conclusionsabout the risks and benefitsof surgical resection after inductiontherapy can be made.
Tumor and Host Responses
Induction therapy causes tumor andhost responses that have both advantagesand disadvantages in terms ofsurgical resection. Large, bulky tumorsmay be downsized, permittingeasier intraoperative visualization andmanipulation. Induction therapy mayalso result in tumor shrinkage awayfrom vital structures making significantlymore radical resection unnecessary.However, the inflammatoryresponse and fibrosis resulting frominduction therapy can make resectionmore difficult.This is particularly true when tryingto determine whether "close" marginsare clear of tumor. Becauseintraoperative frozen sections showfibrosis around treated tumor, the trueextent of the original tumor cannotbe established. Resection of all fibrosismay require a substantially moreradical operation, but incomplete resectionrisks leaving microscopic depositsof tumor. This issue is nottrivial, as patients with incompletelyresected tumor invariably have poorprognoses. Tumor fibrosis also obscuresthe normal anatomic planes,making dissection around vessels, airways,and the esophagus more difficult.Repeat mediastinoscopy afterprevious mediastinoscopy and inductiontherapy is generally considered arisky procedure and is frequently inadequate.[65]Physical conditioning and immunefunction are weakened by inductiontherapy such that patient tolerance ofperioperative complications may bereduced. Induction therapy likely impairslymphatic drainage of the lungand pleural space and causes parenchymalchanges that alter lung elasticrecoil and healing. These factors maycontribute to postoperative air leaks andpleural space problems. Most studieshave focused only on major complicationrates and mortality. Important althoughless significant difficulties withpostoperative recovery after inductiontherapy may be underreported.
Surgical Mortalityand Complications
Surgical mortality for most resectionsappears comparable to that forresections without induction therapy.However, pneumonectomy, particularlyright-sided, is associated withincreased risk of mortality. A reportfrom Memorial Sloan-Kettering CancerCenter by Martin et al examined470 patients with stage I-IV NSCLCreceiving a variety of regimens, butprimarily MVP. These investigatorsshowed a high rate of surgical mortalityafter right pneumonectomy (24%)compared to an overall rate of surgicalmortality of 4% after inductionchemotherapy.[66] Preoperative chemotherapywas otherwise not foundto be a risk factor for morbidity ormortality in multivariate analysis.Most studies report complicationrates of 15% to 40% in patients undergoingpostinduction therapy resections.With the previously mentionedcaveats, authors report rates equalto[66-70] or above[71-73] those forstandard resections. Most complicationsare pulmonary, such as bronchopleuralfistula, pneumonia,postresectional pulmonary edema,adult respiratory distress syndrome(ARDS), and atelectasis. A retrospectiveanalysis from Vanderbilt Universityreported an increase in morbidityand mortality after induction chemotherapy.[74] This single-institutionexperience from 1997 to 1999 included34 patients with early-stage disease(IB-IIIA) receiving carboplatinand paclitaxel for three cycles comparedwith 67 patients undergoing resectionwithout prior systemic therapy.They observed significant increasesin life-threatening complications (27%vs 3%), major complications (47% vs19%), and reintubation (18% vs 3%)in patients receiving chemotherapy.No hospital mortality was observed.A Spanish case-control study examinedpostoperative morbidity andmortality in 42 patients receiving inductionchemotherapy (74 % clinicalstage III or IV) compared with 42matched controls (all clinical stage I)undergoing surgery alone.[67] Nopostoperative mortality was recorded.Although the authors concludedthat there was no significant influenceof chemotherapy on postoperativecomplication rates (26% in thechemotherapy arm vs 43% in controls),the complication rate in the controlswas unusually high.Depierre et al reported a trendtoward increased mortality and morbiditywhen surgery followed a cisplatin-based induction regimen,compared to a surgery-alone arm.[45]In a large multicenter study, Albain etal observed a surgical mortality rateof 5% in patients who underwentthoracotomy postchemoradiotherapy.[61] Most deaths were due to pulmonarycomplications in patientsundergoing pneumonectomy. Inmulticenter phase II studies with inductioncarboplatin and paclitaxel inearly-stage NSCLC, postoperativemortality has been acceptable, ie, 1%to 6%.[46,48]Extended resections that includebronchoplastic or tracheoplastic reconstructionsprobably have highercomplication rates in the setting ofinduction therapy. This is most likelyto be the case when radiotherapy isinvolved. Macchiarini and colleaguescompared two groups of patients withT4 disease.[71] Induction chemotherapyalone was administered to 11patients, and 12 patients received combinedchemoradiotherapy with 40 Gyto the lesion, mediastinum, and ipsilateralsupraclavicular fossa. Majorcomplication rates were 42% in thechemoradiation group vs 9% in thechemotherapy-alone group. Similarly,bronchial stump breakdown maybe more common in the setting ofradiotherapy.[75]In conclusion, it appears that inductiontherapy, especially chemoradiotherapy,may slightly increasesurgical complications, with a minimal,perhaps negligible, increase insurgical mortality. This potential detrimentaleffect is likely to be outweighedby the potential survivalbenefit from the use of induction therapy.A number of ongoing randomizedcomparisons with a surgicalcontrol arm is expected to provideadditional data on the safety of contemporaryinduction chemotherapyregimens (Table 2).
Incorporation of Novel Agents
Recent years in lung cancer researchhave been an exciting time,with the identification of targetedagents such as gefitinib (Iressa) anderlotinib (Tarceva), which inhibit theepithelial growth factor receptor(EFGR) tyrosine kinase, and bevacizumab(Avastin), a monoclonal antibodyagainst the vascular endothelialgrowth factor (VEGF). Some of thesedrugs, eg, gefinitib and erlotinib, havebeen combined with cytotoxic chemotherapyin the advanced diseasesetting without significantly improvingoutcome.Investigators, however, are look-ing at the induction setting in an effortto understand why a fraction ofpatients does benefit from theseagents. For example, the MemorialSloan-Kettering Cancer Center groupis currently conducting one such trialof gemcitabine and cisplatin plus intermittenterlotinib as induction therapyin patients with locally advanceddisease. In these studies, the availabilityof posttreatment tissue mayhelp further elucidate mechanisms ofaction of novel agents.Another trial, reported by Altorkiet al, included patients with stage IBto IIIA NSCLC.[76] A total of 29patients were treated with the combinationof paclitaxel, carboplatin, andcelecoxib (Celebrex). The addition ofcelecoxib to chemotherapy normalizedlevels of PGE
2
found in NSCLCpatients after treatment with chemotherapy.The authors felt that the additionof celecoxib enhanced theresponse to preoperative therapy.
The Optimal Therapy
There are no validated criteriaavailable that can be used to determinewhether a patient with potentiallyresectable, locally advancedNSCLC should be treated with inductionchemotherapy followed by surgicalresection, chemoradiotherapyalone, or chemoradiotherapy followedby surgery. In general, patients withnonbulky, mobile lymphadenopathytend to be offered induction chemotherapy,and patients with more extensivemediastinal disease are treatedwith chemoradiotherapy, possibly followedby surgery. When chemotherapyis combined with concurrentradiotherapy, usually only suboptimalsystemic doses of chemotherapy canbe delivered due to increased toxicity.It is possible that giving full-dosesystemic therapy treats micrometastaticdisease immediately before it hasthe opportunity to progress or becomeresistant to the lower doses of chemotherapythat are typically given withradiation.Ichinose et al attempted to identifyrisk factors for recurrence and survivalin 406 patients with resected N2NSCLC that might allow selection ofpatients who should have adjuvanttherapy.[6] In the multivariate analysis,survival was worse in patients withmultiple N2 stations, pathologic T2,T3, or N1 disease, and age older than65. Local recurrence was increasedwith multiple N2 lymph nodes andclinical N1 or N2 disease. Patientswith multiple involved mediastinallymph nodes had a 5-year survivalrate of 17% and a freedom from localrecurrence rate of 48%, compared with43% and 75%, respectively, for patientswith an isolated mediastinallymph node. Ichinose et al surmisedthat the number of mediastinal lymphnodes involved is an important prognosticfactor. It is necessary to betterselect patients who would benefit fromeach treatment approach, and it couldwell be that patients with bulkier diseasefare worse regardless of the additionof radiation to induction therapy.Similiarly, Andre et al evaluatedprognostic factors in 702 patients whounderwent surgical resection forstage IIIA disease.[14] Negative prognosticindicators were clinical N2disease, multiple lymph node involvementof the mediastinum, pathologicT3 or T4 disease, and no preoperativechemotherapy.The role of surgery in the multimodalitytherapy of resectable stage IIINSCLC has been questioned by someclinical studies. In fact, three smallphase III trials with nonsurgical armsfailed to show benefit for surgery overradiation.[77-79] More recently, asdiscussed previously, the results ofIntergroup trial 0139 seem to fuel thedebate. Many have questioned the roleof radiotherapy in the therapy regimen.It may be that the early noncancerdeaths may have been a functionof the radiation, not the chemotherapy.Emerging data on adjuvant therapyfor NSCLC has certainly changedthe practice of oncology. The InternationalAdjuvant Lung Cancer Trial(IALT) Collaborative Group concludedthat cisplatin-based adjuvant therapyimproved survival in patients withcompletely resected NSCLC.[9] Inthis study of 1,867 patients who wererandomly assigned to adjuvant therapyor to observation, overall survivalwas significantly higher in the adjuvantchemotherapy group (
P
< .03),with an absolute increase of 4% in the5-year survival rate. Similarly, both theNational Cancer Institute of Canadatrial JBR.10[10] and the Cancer andLeukemia Group B (CALGB)[11]study 9633 presented at the AmericanSociety of Clinical Oncology meetingin 2004 conducted in early-stage homogeneouspopulations demonstrateabsolute survival benefits of 15% at 5years (
P
= .0022) and 12% at 4 years(
P
= .028) respectively.No randomized study has yetreported results of a comparison betweeninduction and adjuvant chemotherapyfor resectable NSCLC, butmost believe that at least a comparablesurvival benefit will be demonstratedwith the use of inductiontherapy. The ongoing study enrollingpatients with stage IB to IIIA NSCLC,orchestrated by Rosell et al, iscomparing induction chemotherapy,adjuvant chemotherapy, and surgeryalone. Patients in both chemotherapyarms receive carboplatin andpaclitaxel.
Conclusions
Despite what appears to be completeresection of NSCLC, the majorityof patients with non-small-celllung cancer die from recurrent, metastaticdisease. Therapy aimed at eradicatingmicrometastatic disease hasbeen the goal of induction chemotherapy.It is hoped that improvementsin systemic chemotherapy with theadvent of targeted agents will translateinto a survival benefit for patientswith resectable NSCLC.Induction treatment represents animportant paradigm for clinical researchin NSCLC, allowing in vivochemosensitivity assessment and offeringa testing field for new, targetedagents. Furthermore, the delivery ofinduction chemotherapy seems moreeffective than the same therapy in theadjuvant setting.For patients with stage I and IINSCLC, the use of induction has beenshown to be feasible but is not recommendedoutside of a clinical trial. Forpatients with resectable stage III disease,induction chemotherapy-withor without radiotherapy-appears todefinitively answer lingering questionsis by the timely accrual of patientsto well designed clinical trials.be the best approach. The only way todefinitively answer lingering questionsis by the timely accrual of patientsto well designed clinical trials.
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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