Lung Cancer (2003) 42, S35—S40

CONFERENCE

Combined modality therapy for non-small celllung cancer, past, present, and future

KEYWORDSCombined modality;NSCLC;Lung cancer;Radiation therapy;Chemotherapy;Locally advanced;Unresectable

1. Introduction

Lung cancer is one of the most commonly oc-curring cancers, and is the leading cause ofcancer death in men and women in the UnitedStates far exceeding those of the acquired im-munodeficiency syndrome epidemic [1]. Similarlylarge incidence, and mortality are seen in othernations including Canada, Britain, France, Ger-many and Australia [2]. Global estimate of an-nual lung cancer incidence and and death rate in2000 was 1 in 240,000, and 1 in 100,000, respec-tively [3]. Roughly 80% of these malignancies arenon-small cell lung cancer (NSCLC) [1]. Further-more, a majority of these patients present withlocally advanced disease (35—40%), many beingunresectable. These patients are now typicallytreated with combined modality therapy, involv-ing chemotherapy and thoracic radiation therapy(TRT). Based on the most current data, concur-rent rather than sequential chemo/radiotherapyhas become the standard of care at most institu-tions for this disease. This paper will review themajor clinical data that forms the basis for thecurrent standard of care for unresectable, locallyadvanced NSCLC patients, and will also highlightsome of the upcoming novel targeted biologicagents being considered for combined modalityregimens.

2. Combined modality regimen,past and present

The evolution of the combined modality regimen–—the current standard of care for locally advancedNSCLC–—can be highlighted by several key studies.Furthermore, several important studies attemptingto delineate the optimal method of delivery of thecombined modality therapy have also been com-pleted.Pivotal trial by Dillman et al. demonstrated the

superiority of sequential TRT to TRT alone. Thistrial enrolled 155 eligible patients between May1984 and May 1987 [4,5]. These patients were ran-domized to receive either two cycles of cisplatin,vinblastine followed by 60Gy of thoracic radiationor 60Gy of thoracic radiation alone. Long-termfollow up has maintained the survival advantageseen with combined therapy with a 7-year survivalof 13% compared to 6% for the radiotherapy alonearm. A confirmatory intergroup phase III trial re-ported by Sause et al. [6] showed that not onlywas sequential chemoradiation (i.e. Dillman study)superior to thoracic radiation alone (median sur-vival of 13.2 months versus 11.4 months for TRTalone P = 0.04) but that it was also superior tohyperfractionated TRT with 1.2Gy delivered BIDto a total dose of 69.6Gy (median survival of 12months). Furthermore, Le Chevalier [7] reported a

0169-5002/$ – see front matterdoi:10.1016/j.lungcan.2003.08.009

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randomized study comparing 65Gy of thoracic radi-ation alone to three cycles of vindesine, lomustine,cisplatin and cyclophosphamide followed by thesame dose of thoracic radiation. Patients in the armthat received induction chemotherapy were eligi-ble for three additional cycles of treatment if theirdisease had not progressed. This trial confirmedthe benefit for the addition of chemotherapy witha 2-year survival rate of 14% for patients receiv-ing radiotherapy versus 21% for patients receivingthe combined treatment (P = 0.02). The distantmetastasis rate was significantly lower in the groupreceiving the combined treatment (P < 0.001). Lo-cal control at 1 year was poor in both groups (17and 15%, respectively) and remains a major prob-lem in the treatment of patients with this disease.With the demonstration of the benefit of sequen-

tial combined modality therapy from these earliertrials, a number of investigators sought to furtherdetermine the benefit of concurrent chemoTRTfor this group of patients. The rationale for ex-ploring concurrent delivery of chemoTRT includesenhancement of the local effect of radiation, im-mediate treatment of both local and potentialmicrometastatic disease, and avoidance of accel-erated repopulation from induction chemotherapy.The potential disadvantage was the concerns forincreased toxicity. The EORTC reported a random-ized phase II trial (later expanded to a phase IIItrial) in which patients were randomized to splitcourse TRT alone (30Gy/10 fractions followed bya 2 week break and then a further 25Gy/10 frac-tions) or the same radiation with either weeklycisplatin 30mg/m2 or daily 6mg/m2 [8]. 311 pa-tients were enrolled between June 1984 and May

Table 1 Phase II/III clinical trials involving sequential and concurrent chemoradiation therapy in locally advancedNSCLC

Study Phase N Treatment schema Mediansurvival(months)

P-value

Furuse [9] III 314 CMV → TRT 13.3 0.039CMV + TRT 16.5

RTOG 9410 [11] III 597 CVb → TRT 14.6 0.04CVb + TRT 17.0CE + BID TRT 15.6

GLOT-GFPC [12] III 207 CN → TRT 13.8 NSCE + TRT →CN 15.0

Czech [14] II 102 CN → CN + TRT → CN 619 days 0.02CN → TRT 396 days

Choy [13] II 276 PCb → TRT 13 NSPCb → PCb + TRT 12.8PCb+TRT→PCb 16.1

TRT: Thoracic radiation, C: cisplatin, Vb: vinblastine, V: vindesine, N: vinorelbine, M: mitomycin C, E: etoposide,P: paclitaxel, Cb: carboplatin, NS: Not significant.

1989. The study demonstrated that survival wasimproved when cisplatin was combined with TRT(P = 0.04) and substantially improved when it wasdelivered daily prior to TRT (P = 0.009). The majorcriticism of this trial was that TRT was deliveredin split course schedule. Despite this, the positiveresults serve as proof of principle that improvedlocal control leads to improved survival in locallyadvanced NSCLC.Further randomized trials have been completed,

investigating various chemotherapeutic regimenswith sequential and concurrent TRT (Table 1). Forpatients with good performance status and mini-mal weight loss, it was apparent that concurrentregimen provided a significant survival advantage.The Furuse trial with the longest follow-up [9]enrolled 320 patients, and randomized them toconcurrent versus sequential chemoradiation ther-apy. The radiation (56Gy) was delivered as a splitcourse in order to reduce the incidence of limit-ing esophagitis when given concurrently, and tosequential chemoradiation where 56Gy was deliv-ered without a planned break. Both arms receivedcisplatin (80mg/m2 D1), mitomycin C (8mg/m2

D1) and vindesine (3mg/m2 D1, 8) for two cycles.Despite the theoretical impact that split courseradiation may have on accelerated repopulation,the concurrent arm conferred a superior out-come with better median survivals (16.5 monthsversus 13.3 months, P = 0.03998) and better sur-vivals which were maintained out to five years(15.8% versus 8.9%). The 2-week break in the ra-diation treatment schedule in the concurrent armlead to a low incidence of grade 3/4 esophagitis(4/156) that was no different than that seen in the

Combined modality therapy for non-small celllung cancer, past, present, and future S37

sequential arm (3/158). On a subsequent analysis,these investigators reported that concurrent ther-apy was associated with a significant improvementin survival without local relapse with 5-year val-ues of 46% compared to 30% in the sequential arm(P = 0.0221) [10]. No difference was seen in thesurvival without distant metastases suggesting thatthe overall survival benefit seen in the trial was re-lated to the improvement in local control achievedthrough the concurrent delivery of chemoradiation.The RTOG reported on a phase III study in North

America comparing three different modes of com-bined modality delivery [11]. Total of 597 patientswere enrolled that were aimed at comparing out-comes when patients were treated with (a) sequen-tial chemoradiation,( b) concurrent chemoradiationor with (c) concurrent chemo-hyperfractionatedradiation. This study confirmed the Japanese expe-rience and has lead to the acceptance of concur-rent therapy as the standard of care for patientswith minimal weight loss and good performancestatus.Pierre et al. have presented early results of a

similar study comparing sequential and concurrentchemoTRT [12]. This study did not demonstratea statistically significant improvement in survival(Table 1) with concurrent chemoTRT. However,there was a trend in favor of the concurrent regi-men and local control was significantly improved inthe concurrent arm. With continued follow-up thismay reveal a statistically significant improvementin survival.Most recently, preliminary report of locally ad-

vanced multimodality protocol (LAMP trial), andthe Czech Lung Cancer Group trial have been re-ported in ASCO 2002 [13]. The LAMP trial wasa multi-institutional randomized phase II studyaimed at evaluating the optimal sequencing ofpaclitaxel and carboplatin with TRT for patientswith locally advanced NSCLC. The three arms ofthe study were: (a) neoadjuvant chemotherapyfollowed by TRT, (b) neoadjuvant chemotherapyfollowed by TRT/chemotherapy, of (c) imme-diate TRT/chemotherapy followed by adjuvantchemotherapy. 276 patients were enrolled in thistrial. Median overall survival of 13 months, 12.8months, and 16.1 months were noted in arms a—c,respectively. Grade 3 esophagitis were 4, 20, and28% in arms a—c, respectively. Despite the in-creased toxicity, 67% of the patients received all7 weeks of concurrent chemo/TRT, and 75% of pa-tients completed consolidation chemotherapy inarm c. Though not reaching statistical significance(P-value?), there was a trend toward improvedsurvival in the immediate concurrent followed byadjuvant arm.

The Czech trial was a phase II study investigatingthe role of concurrent versus sequential chemoRTusing vinorelbine plus cisplatin in locally advancedNSCLC [14]. Total of 102 patients were enrolled andfour cycles of chemotherapy were administered ina sequential or concurrent manner. At 2 years, thesurvival rate strongly favored the concurrent ther-apy (42% versus 18% survival), and as in the LAMPtrial, the toxicities were higher in the concurrentarm (esophagitis 17.6% versus 4.2%), and there wereno treatment related mortalities in either arm.

3. Combined modality regimen, lookingto the future

3.1. Targeted biological agents

Though concurrent chemoTRT has become thestandard of care in locally advanced NSCLC, theoptimal drug regimen has not been firmly estab-lished. Given the relative therapeutic equivalenceof many of the new combination chemotherapydrugs in stage IV disease [15], there is enthusiasmfor looking towards more targeted therapy for im-provement of the outcome in NSCLC. Novel targetswhich include epidermal growth factor receptor(EGFR), cyclo-oxygenase-2 (COX-2), vascular en-dothelial growth factor (VEGF), ras oncogene, far-nesyl transferases, amongst others are under activeinvestigation for treatment of advanced NSCLC.We will briefly discuss the roles of EGFR inhibitorsand COX-2 inhibitors as potential future targets forcombined modality therapy in NSCLC.

3.1.1. Cyclo-oxygenase 2COX-2 is a key inducible enzyme involved inprostaglandin metabolism, which is now felt toplay a significant role in carcinogenesis in additionto its well-known role in inflammatory processes.Furthermore, interestingly, there appears to bea role for COX-2 in the development, growth andspread of lung cancers. In invasive lung tumors,COX-2 upregulation has been reported in up to 90%of cases with COX-2 expression being more com-mon with adenocarcinomas. Its expression tendsto be more pronounced in well-differentiated le-sions compared to poorly differentiated tumors. Bycontrast, squamous cell carcinomas show substan-tial but less frequent expression of COX-2 whereassmall cell carcinomas have virtually no overexpres-sion of COX-2 [16,17]. It has also been reportedthat benzo[a]pyrene, a carcinogenic polycyclic aro-matic hydrocarbon, found in tobacco smoke, canupregulate COX-2 in oral epithelial cells [18].

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Prognostic significance of the presence and levelof COX-2 expression in patients with resected earlystage NSCLCs have been reported. Achiwa et al.evaluated a cohort of 130 adenocarcinoma patientswho had consecutively undergone potentially cu-rative resections [19]. Immunohistological exam-ination showed the presence of tumor cells withmarkedly increased COX-2 immunoreactivity in 93of 130 (72%) cases. No relationship was found be-tween the increase in COX-2 expression and clinicaloutcomes when the entire cohort was considered(P = 0.099). However, a significant relationship be-tween elevated COX-2 expression and shortenedpatient survival was observed only in the cohort ofpatients with stage I disease (n = 81) (P = 0.034).Similarly Khuri et al. used in situ hybridization withCOX-2 antisense riboprobe to assess the presenceof strong or intermediate versus weak or absentCOX-2 expression in specimens from 160 patientswith stage I NSCLC [20]. Increased COX-2 expres-sion was associated with a worse overall survivalrate (P = 0.001) and a worse disease-free sur-vival rate (P = 0.022). The median survival timesfor the strong, intermediate or weak, and nullCOX-2 expressers were 1.04, 5.50, and 8.54 years,respectively.Pyo et al. demonstrated in preclinical studies,

that COX-2 inhibition specifically enhances the ef-fect of RT in cells that express COX-2. Using NS-398,a COX-2 inhibitor, enhancement of the effect of ra-diation was demonstrated in NCI-H460 human lungcancer cells, which overexpress COX-2 (RER = 1.8),but not in HCT-116 cells, which lack COX-2 ex-pression [21]. NS-398 (36mg/kg per day for 7 daystreatment) also enhanced radiosensitivity of H460tumors grown in vivo but it did not enhance theradiosensitivity of HCT-116 tumors. Similar obser-vations of radiation enhancement with the additionof a COX-2 inhibitor has been reported by othersusing different experimental systems [22,23]. Kishiet al. have confirmed this effect and also foundthat SC-236 does not affect the radioresponse ofnormal tissues using preclinical models of acute(jejunal crypts) and late (murine leg contracture)[24]. Pyo et al. also reported that a COX-2 in-hibitor did not enhance the effect of radiation oncell survival in rat intestinal epithelial (RIE) cellstransfected with an antisense copy of the COX-2gene [21]. RIE cells transfected with COX-2 cDNA inthe sense direction demonstrated a concentrationdependent enhancement of the effect of radia-tion on cell survival. These data suggest that thecombination of a COX-2 inhibitor in combinationwith thoracic radiation may be able to realize atumor specific enhancement in patients withoutincreasing normal tissue toxicity.

Clinical trials looking at the addition of cele-coxib, a selective COX-2 inhibitor, have begun. Instage III, disease investigators from Vanderbilt Uni-versity have undertaken a phase II study of additionof celecoxib at a dose of 400mg PO BID with weeklypaclitaxel, carboplatin and thoracic radiation fol-lowed by consolidation paclitaxel and carboplatinfor two cycles. Accrual is ongoing. The RTOG isalso conducting a phase I/II effort in intermediateprognosis stage IIB and III patients who are notcandidates for chemotherapy. This study recentlyopened and requires 122 patients. As well, a groupof cancer centers in Canada and the USA, lead byVanderbilt University and The University of Ottawa,are conducting a phase II study of involved fieldradiation with concurrent and adjuvant celecoxibin patients with stage I or II medically inoperableNSCLC. In this study, patients will take celecoxib ata dose of 400mg PO BID for a total of 5 years. Allthree studies are looking at the prognostic value oflevels of circulating factors including VEGF.

3.1.2. EGFR inhibitorsThe rational for investigation of EGFR inhibitors asradiation sensitizers in cancer therapy are based onthe following observations: (1) positive correlationbetween EGFR expression and cellular resistanceto radiation [25—28]; (2) the degree of radiore-sistance correlates positively with the magnitudeof EGFR overexpression [27]; (3) cell survival andrepopulation during a course of radiotherapy areinfluenced by activation of EGFR/transforminggrowth factor-� (TGF-�) that is induced after ex-posure to radiation [29]; (4) inhibition of EGFRsignaling enhances radiation sensitivity [30,31].While several EGFR inhibitors have been devel-oped, the clinically furthest developed of theseare ZD1839 (‘Iressa’), OSI-774 (‘Tarceva’), andIMC-C225 (C225). Iressa and Tarceva are both smallmolecule receptor EGFR-specific tyrosine kinaseinhibitor (TKI). IMC-C225 (C225, IMCLONE Systemsincorporated, Sommerville, NJ) is a mouse-humanchimerized monoclonal antibody that specificallybinds to EGFR [32]. All three compounds workby inhibiting the downstream signal transductionpathways.A number of phase II and III studies have been

completed in patients with NSCLC using EGFR in-hibitors as a monotherapy, or in combination withother cytotoxic agents. The most advanced studiesin NSCLC have been with Iressa.Two monotherapy phase II studies, Iressa dose

evaluation in advanced lung cancer (IDEAL 1 andIDEAL 2) involving advanced NSCLC have been re-ported [33,34]. In IDEAL 1, 208 patients (from Eu-rope, Australia, South Africa, Japan) with locally

Combined modality therapy for non-small celllung cancer, past, present, and future S39

advanced/metastatic NSCLC were randomized toeither the 250mg or 500mg daily dose of ZD-1839.Response rates were 18.4% versus 19%, and overallsurvival was 7.6 months versus 8.1 months for the250 and 500mg, respectively and was not affectedby previous chemotherapy regimens. In IDEAL 2, 216patients (fromUSA) were randomized to 250mg ver-sus 500mg dose. Response rates for 250 and 500mgarms were at 11.8 and 8.8%, respectively. Mediansurvivals were 6.1 months, and 6 months for the250 and 500mg arms, respectively. Both studies in-dicated that 250mg is a well tolerated dose, withevidence of clinically significant anti-tumor activ-ity in patients who had previously failed one or twoprevious chemotherapy regimens. Many patients inboth IDEAL 1 and IDEAL 2 reported significant im-provement in disease related symptoms and qual-ity of life (40.3 and 43.1% for IDEAL 1 and IDEAL 2,respectively) [35,36].Two phase III studies–—the Iressa NSCLC Trial

Assessing Combination Treatment (INTACT) oneand two have been conducted enrolling about1000 patients in each trial. The three arms ofthis study include, chemotherapy+ 250mg/dayIressa, chemotherapy+ 500mg/day Iressa, andchemotherapy+ placebo, all of which are to befollowed by continuation of Iressa or placebo untildisease progression. Chemotherapeutic regimenin INTACT 1 was gemcitabine and cisplatin, and inINTACT 2, it was paclitaxel and carboplatin. Datafrom INTACT-2 have been presented at ESMO on10/21/2002. Median survival for the placebo armwas 9.92 months, and the Iressa 250mg arm was9.82 months, and 500mg arm was 8.74 months.Therefore the conclusion was that Iressa showed noadded benefit in survival for these patients beingtreated with standard chemotherapy regimen. Tox-icity profile was also as predicted from the previousstudies. INTACT-1 showed similar results as well.The optimal use of Iressa in NSCLC patients, there-fore, is an area that still needs to be researched.Most recently, a phase II study of C225 in combina-

tion with docetaxel in chemotherapy refractory pa-tients with advanced NSCLCwas reported [37]. C225was administered as 400mg/m2 IV during the firstweek followed by 250mg/m2 IV weekly. Docetaxelwas administered 75mg/m2 IV every 3 weeks. 25patients had been enrolled thus far, and 20 patientswere evaluable for response. Preliminary results sofar show that after two cycles of therapy, four pa-tients had partial response (PR), and six have stabledisease (SD). Toxicities to date included acneiformrash (grade 2—3) in five patients, and febrile neu-tropenia in two patients (grade 2—3).Three Phase II trials (Studies 248-1007, 248-101

and 248-1003) with OSI-774 have been conducted

in patients with advanced, refractory malignancies,including squamous cell carcinoma of the head andneck, ovarian carcinoma, and NSCLC [38—40]. Pa-tients in each of these studies received 150mg/dayof OSI-774. Available preliminary data based on in-vestigator assessments from all three phase II trialsdemonstrate objective response rates of 9—15%.Based on these and other clinical and preclinical

studies, the role of EGFR inhibitors in combinationwith RT for locally advanced NSCLC are being in-vestigated in a number of proposed and ongoingclinical trials. To date, there are no completedphase III study aimed at determining the role of RT+ EGFR inhibitor in NSCLC. In HN Cancer, one phaseIII study looking at the role of combination of C225and RT has been completed, and the results arestill pending.

4. Conclusion

The standard of care for locally advanced NSCLC hasnow evolved to concurrent delivery of chemother-apy and TRT in USA. Multiple studies have demon-strated an improvement in overall survival with thisapproach, largely due to an improvement in localcontrol. More recently completed studies show thatmany of the newer chemotherapies, i.e. paclitaxel,vinorelbine, irinotecan and docetaxel can be safelyand effectively integrated into concurrent therapy.The new therapies against molecular targets suchas EGFR or COX-2 are an active area of investiga-tion, and await the next generation of clinical trialsto verify whether or not this proves to be true.

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Dong Wook KimHak Choy∗

Department of Radiation OncologyVanderbilt-Ingram Cancer Center, B902 TVC

22nd Ave South, Nashville, TN 37232-5671, USA∗Corresponding author. Tel.: +1-615-322-2555

fax: +1-615-343-7218E-mail address:

hak.choy@mcmail.vanderblit.edu(H. Choy)