ARTICLES Radotherapy Alone Versus Combned Chemotherapy and Radotherapy n Nonresectable Non-Small-Cell Lung Cancer: Frst Analyss of a Randomzed Tral n Patents Therry Le Chevaler* Rodrgo Arragada, Elzabeth Quox, Perre Ruffle, Mchel Martn, Mchele Tarayre, Mare-Jose Lacombe-Terrer, Jean-Yves Doullard, Agnes Laplanche We report the results observed n a large, randomzed study that compared the effects of radotherapy alone (the standard therapy) wth those of a combnaton of radotherapy and chemotherapy n nonresectable squamous cell and large-cell lung carcnoma. The radaton dose was Gy n each group, and chemotherapy ncluded vndesne, cyclophosphamde, csplatn, and lomustne. In ths study, patents receved radotherapy alone (group A), and patents receved the combned treatment (group B). The 2- year survval rate was 4% n group A and 2% n group B (P =.0). The dstant metastass rate was sgnfcantly lower n group B (P<.00). Local control was poor n both groups (% and %, respectvely) and remaned the major problem. [J Natl Cancer Inst :4-42,99] Non-small-cell lung cancer accounts for 0% of lung cancers, the prmary cause of mortalty from malgnant dsease n western countres (/). Squamous cell carcnoma and large-cell carcnoma represent approxmately % of non-small-cell lung cancer n France (2), and ther curatve treatment s surgery. In most cases, however, the dsease s noperable at the tme of presentaton because of ether metastass or locally advanced tumor that s nonresectable. Of patents wth locally advanced non-small-cell lung cancer, % to 0% wll de from ntrathoracc dsease, wth or wthout dstant metastases (,4). The medan survval of such patents s less than months wthout treatment (). Wth radcal radotherapy, a complete radologc response can be obtaned n % to 0% of these cases and an objectve radologc response n 40% to % of cases (,). Even n the case of apparent local control, however, long-term survval remans dsappontng because of the hgh rate of dstant metastases (). Ths stuaton led us n 90 to conduct a phase II study combnng radcal radotherapy and a four-drug chemotherapy regmen comprsng vndesne, csplatn, lomustne, and cyclophosphamde (VCPC). We observed a 42% objectve response rate after ntal chemotherapy and a 4.% complete remsson rate after combned-modalty treatment, wth a medan survval of.9 months (9). On the bass of these results, we desgned a phase III study comparng such a combned schedule wth radotherapy alone gven at the same doses. We report here the frst analyss of ths large multcenter randomzed tral that ncluded patents. Patents and Methods Patents entered n ths study were prevously untreated and had hstologcally proven squamous cell or large-cell carcnoma of the lung. Patents wth adenocarcnoma were excluded because of the dffculty of determnng the orgn of the prmary tumor n a large subset of patents (). Receved September,990; revsed December 4,990; accepted January,99. Supported n part by grant IGR CR 9 D9 from the Insttut Gustave-Roussy. T. Le Chevaler, R. Arragada, P. Ruffe, M. Tarayre, M.-J. Lacombe-Terrer, A. Laplanche, Insttut Gustave-Roussy, Vllejuf, France. E. Quox, Centre Hosptaler Regonal, Strasbourg, France. P. Ruffe, M. Martn, Centre Hosptaler Intercommunal, Crttel, France. J.-Y. Doullard, Centre Renf Gauducheau, Nantes, France. We thank Mrs Lorna Sant-Ange and Mrs Catherne Loge for ther help n preparng ths manuscrpt. *Corrcspondence to: Dr Therry Le Chevaler, Dfpartement de Mddecne, Insttut Gustave-Roussy, 9400 Vllejuf, France. Downloaded from http://jnc.oxfordjournals.org/ at Pennsylvana State Unversty on May, 20 Vol., No., March 20, 99 ARTICLES 4
All patents were judged to have nonresectable dsease but to be free of metastass after physcal examnaton and bronchoscopc, radologc, and nuclear dagnostc study. Elgblty crtera were as follows: age less than or equal to 0 years, Karnofsky performance status greater than 0%, measurable or evaluable dsease, no pror chemotherapy or radaton therapy, no hstory of malgnant dsease (except basal cell skn carcnoma), no hematologc, cardac, renal, or lver abnormaltes contrandcatng the combned modalty therapy, no esophageal or chest-wall nvolvement, no pleural effuson except for that n patents wth bopsy-proven negatve hstology, and no superor vena cava syndrome requrng urgent radaton therapy. All patents underwent the followng nvestgatons: chest x ray and fberoptc bronchoscopy; bone scan, bran scntgraphy, or computerzed axal tomographc (CAT) scan; and lver CAT scan or ultrasonography. Dsease had to be lmted to one hemthorax, the medastnum, and supraclavcular nodes, provded all nodes could be ncluded n the same radotherapy felds as the prmary tumor. Each patent who fulflled ncluson crtera was randomly allocated to one of two groups wthn 2 weeks of complete assessment. Study Desgn Patents were randomly allocated to one of two regmens (Fg ). Regmen A (group A patents) conssted of radotherapy alone gven to a volume ncludng prmary tumor, medastnum, and blateral supraclavcular nodes. A total radaton dose of Gy n 2 fractons gven durng a 4-day perod wth approprate spnal sheldng was prescrbed (). The sequental scheme of the technque was as follows: (a) Two large opposed anteroposteror/posteroanteror complex-shaped beams rradated the whole target volume, ncludng tumor volume and homolateral hlar, medastnal, and supraclavcular lymph nodes, wth a free margn of to. cm. The dose delvered wth ths frst-beam arrangement was lmted to 40 Gy n fractons gven durng a perod of 2 days. (b) Two opposed lateral beams rradated the target, ncludng the tumor and hlar and medastnal lymph nodes. The dose delvered wth ths second-beam arrangement was Gy n fractons gven durng a perod of days. (c) Two opposed oblque beams rradated the target, ncludng the tumor and homolateral hlar and medastnal lymph nodes. The dose delvered wth ths thrd-beam arrangement was Gy n 4 fractons gven durng a perod of days. Regmen B (group B patents) ncluded three monthly cycles of VCPC therapy: vndesne,. mg/m 2 on days and 2; lomustne, 0 mg/m 2 on day 2 and 2 mg/m 2 on day ; csplatn, 0 REGIMEN A: RADIOTHERAPY ALONE QY Fg. Desgn of the study. LOCALLY ADVANCED SQUAMOUSCELL OR LARGE CELL LUNQ CARCINOMA RANDOMIZATION REGIMEN B: VCPC + RADIOTHERAPY GY ±VCPC mg/m 2 on day 2; and cyclophosphamde, 200 mg/m 2 on days 2 through 4. Radographc, fberoptc, and hstologc examnatons were performed just before the thrd cycle to determne the response to ntal chemotherapy. All patents receved thoracc radotherapy dentcal to that of regmen A begnnng 2 to weeks after the thrd chemotherapy cycle. Three addtonal VCPC cycles were admnstered after completon of radotherapy to patents whose dsease had not progressed after ntal chemotherapy. Fnal assessments dentcal to those performed before randomzaton were performed months after completon of radotherapy to determne fnal response rates n both groups. Dose Adjustments n Regmen B If myelosuppresson was observed at the start of a new chemotherapy cycle, the course was delayed untl normal blood count recovery. If platelet count was less than 0 000/mm, lomustne was wthdrawn from the cycle. Response Crtera Complete remsson was ndcated by the complete dsappearance of all objectve tumor shown by chest x ray and no evdence of new dsease shown by optcal and hstologc examnaton durng fberoptc bronchoscopy. Partal remsson was ndcated by a decrease greater than or equal to 0% n the product of the two largest perpendcular dameters of radologcally measurable dsease, wth concurrent endoscopc verfcaton and no evdence of new dsease. Stable dsease was ndcated by no change shown by radologc and endoscopc examnaton and no evdence of new dsease. Progressve dsease was ndcated by radologc or endoscopc evdence of progresson or evdence of new dsease. Only patents n complete remsson were consdered as havng locally controlled dsease. Toxc Effects Toxc effects were evaluated accordng to World Health Organzaton crtera (2). Second-Lne Treatment Patents who faled after radotherapy alone were proposed for the VCPC regmen, any phase II study, or the best supportve care. Patents who dd not respond to the combned treatment could be ether ncluded n any phase II study or gven the best supportve care. Statstcal Methods The study was a multcenter controlled tral. Patents were randomly allocated to regmen groups at the Insttut Gustave- Roussy, and the treatment arm was allocated by means of a computer-generated lst balanced every four patents and stratfed by center. We estmated that a mnmum of patents per group would be needed to demonstrate a mnmum dfference of % n 2-year survval between the two groups, wth a type I error of % and a type II error of %. We compared the two groups of patents by usng the chsquare test, Student's / test, and Fsher's Exact Test. The Kaplan-Meer method () and the log-rank test (4) were used Downloaded from http://jnc.oxfordjournals.org/ at Pennsylvana State Unversty on May, 20 4 Journal of the Natonal Cancer Insttute
for the estmaton and comparson of survval curves for all patents and of local control curves for complete responders. Results Patent and Treatment Characterstcs From June 9 to February 99, patents were entered from the cooperatng centers lsted n the "Appendx" secton. Seven centers entered 9% of the patents. Patent characterstcs are lsted n Table. The Internatonal Unon Aganst Cancer (UICC) 99 TNM classfcaton was used (). Of the patents wth cancers classfed T-T2/N0-N at the tme of ntal workup, had exploratve thoracotomes, and the other 2 patents had functonal contrandcatons to surgery. The remanng 20 patents could not have surgery because of tumor or lymph node extenson. Two patents wth chest wall nvolvement were nelgble for study. Only dstrbuton of genders dffered sgnfcantly between groups A and B (P<.0). Performance status was slghtly better n the combned arm (P =.0). No patent was lost to follow-up, and all are avalable for survval rate estmatons. The sldes made from specmens of 0 patents (%) have been revewed. Among these, the hstologc subtype of the car- Characterstc Males, % Mean age, y Pathology, % Squamous cell carcnoma Well-dfferentated Moderately dfferentated Poorly dfferentated Large-cell carcnoma TNM classfcaton, % Tl T2 T NO Nl N2 N MO Ml* Chest wall nvolvement, % Ste, % Lung Upper lobe Mddle lobe Lower lobe Man bronchus Carna Trachea Kamofsky ndex 20, % Abnormal carcnoembryonc antgen, % Table. Patent characterstcs Radotherapy alone. tchemotherapy + radotherapy. t Apples only to supraclavcular nodes. A* 9 9 4 4 4 9 9 0 22 Group Bt 99 2 2 4 9 4 0 4 cnoma could not be determned for cases, and the lung was consdered a lkely metastatc ste n 4 cases. Complance Regmen A ( patents). Twenty-nne patents (%) receved an ncomplete course of radotherapy. Of these, 4 patents dd not receve rradaton; 20 patents receved only the frst seres; and patents receved two seres, but at a total dose rangng from 42 to Gy. Regmen B ( patents). Seven patents dd not receve ntal chemotherapy because of refusal (2 patents), early death (2 patents), or protocol volatons ( patents). Ffteen patents receved only one cycle of chemotherapy because of refusal ( patents), toxc effects ( patents), death (4 patents), dsease progresson ( patents), or protocol volatons (2 patents). Twenty patents receved only two cycles because of refusal (4 patents), toxc effects (2 patents), death ( patent), dsease progresson ( patents), or protocol volatons (2 patents). When chemotherapy was admnstered, the planned dose was delvered except n the case of lomustne (0% of the total dose). Ffty-seven patents (2%) receved an ncomplete course of radotherapy. Of these, patents dd not receve radotherapy because of death ( patents), dsease progresson ( patents), refusal ( patents), protocol volatons (4 patents), or surgcal resectons (2 patents); 22 receved a total dose of less than Gy each because of dsease progresson. Of 94 patents for whom ntal response to chemotherapy ndcated three addtonal VCPC cycles after radotherapy, 0 patents receved three cycles, 4 patents receved two cycles, and patents receved one cycle; the other patents dd not receve addtonal chemotherapy because of refusal ( patents), death ( patents), toxc effects (4 patents), or dsease progresson ( patents). Fnally, fve patents n regmen B underwent operatons after the thrd chemotherapy cycle. Tumor Response to Intal Chemotherapy Data are avalable for response n 4 of the 9 patents who receved at least one chemotherapy cycle. Forty-fve (2%) had objectve responses determned by radologc and endoscopc examnatons after two cycles of chemotherapy. Seventy-two patents (44%) had responses (<0%) or stable dsease, and 4 patents (29%) experenced progresson of dsease to local or dstant stes. Fnal Assessment The mean delay between randomzaton and the fnal assessment was. months for regmen A and. months for regmen B. Regmen A ( patents wth follow-up). Complete remssons were observed n patents (20%), and partal remssons were observed n 2 patents (objectve response rate, %). Stable dsease was observed n patents, and progressve dsease was observed n patents. Regmen B ( patents wth follow-up). Complete remssons were observed n 2 patents (%), and partal remssons were observed n 2 patents (objectve response rate, %). Stable dsease was observed n 2 patents, and progressve dsease was observed n patents. Downloaded from http://jnc.oxfordjournals.org/ at Pennsylvana State Unversty on May, 20 Vol., No., March 20, 99 ARTICLES 49
Survval Survval was calculated from the date of random allocaton of a patent to the date of death or last follow-up. The tme between randomzaton and the analyss ranged from to months; the mean follow-up tme for groups A and B was 40 months and 4 months, respectvely. Medan survval was months n group A and 2 months n group B. One hundred twenty-four patents n group A and 2 patents n group B ded of progressve dsease. Survval curves are shown n Fg 2. The survval rate was 4% at year, 4% at 2 years, and % at years for group A and 0%, 2%, and %, respectvely, for group B. A comparson of survval between the two arms by means of the logrank test yelded a P value of.0. The relatve rsk of death was.2 for the radotherapy arm compared wth that of the combned chemotherapy and radotherapy arm. Comparson of survval remaned statstcally nonsgnfcant when adjusted for center, performance status, and gender. Local Control Because local control was not the man goal of the study, the best local response was not determned. Local control at year was % for group A and % for group B. The local control curves of the complete responders n group A and the 2 complete responders n group B are shown n Fg ; there was no sgnfcant dfference between the two groups. Dstant Metastass Sxty-seven patents n group A and 4 patents n group B experenced metastass to dstant stes. The actuaral metastass rates are shown n Fg 4. The metastass rate was sgnfcantly lower n group B (f<.00). The relatve rsk of metastases was 2.0 n the radotherapy arm compared wth that of the combned chemotherapy and radotherapy arm. Ths dfference remans sgnfcant when adjusted for center, performance status, and gender. 0 0 Fg. Local control curves of complete responders n the two groups startng at the tme of fnal assessment. = radotherapy alone ( patents); = radotherapy + chemotherapy (2 patents). 0 0 40 20 b) 0 2 T I-"'" Fg 4. Actuaral metastass rate n the two groups. = radotherapy + chemotherapy. I 4 months - = radotherapy alone; As shown n Table 2, the stes of frst metastases, consdered at any tme of follow-up, are not sgnfcantly dfferent between the two groups. Long-Term Survval Only patent ded among the 2 patents for whom survval exceeded 0 months. Ten patents are stll n complete remsson, and the condton of patent s stable, wth persstent dsease observed by endoscopy and mcroscopy, for 4 months wth no specfc treatment. Table 2. Frst ste of metastass wth respect to type of therapy Downloaded from http://jnc.oxfordjournals.org/ at Pennsylvana State Unversty on May, 20 40 20 0 - - Yx 2 \ r 4 months No. recevng therapy Ste of metastass Group A* Group Bf Pleura/pulmonary tssue Lver Bone Subcutaneous tssue Bran Lymph nodes Multple stes Other stes 2 0 0 4 Fg 2. Overall survval curves n the two groups. = radotherapy + chemotherapy. - = radotherapy alone; Radotherapy alone. tchemotherapy + radotherapy. 420 Journal of the Natonal Cancer Insttute
Toxc Effects Toxc effects were prmarly hematologc abnormaltes and dgestve dsorders n the chemotherapy group. Grade III and IV toxc effects are lsted n Table. One patent experenced a grade IV neurologc toxc effect after the frst chemotherapy cycle, and chemotherapy was dscontnued. One patent experenced a grade V renal toxc effect after the second cycle of chemotherapy. Radaton-related toxc effects were observed n 2 of the patents who receved the frst course of radotherapy and n of the 20 patents who receved the second course of radotherapy. Toxc effects were mld to moderate n most cases, and the dscontnuaton of treatment was never necessary. Grade II through IV toxc effects are lsted n Table 4. Eght patents suffered treatment-related, ultmately fatal toxc effects. Of these, two patents developed pneumonts and one patent developed percardts n group A, and four patents developed aplasa and one patent experenced renal falure n group B. Dscusson Cycle Frst Second Thrd Fourth Ffth Sxth Table. Grade III or IV toxc effects after chemotherapy n 9 4 4 4 4 0 Abnormal hemoglobn level 4 The therapeutc approach for locally advanced non-small-cell lung cancer has been wdely dscussed. Extensve lterature has reported the possblty of mprovng survval wth thoracc rradaton, and ths treatment can be consdered as standard therapy for ths type of presentaton n spte of a poor medan survval not exceedng to 2 months {,). The hgh ncdence of local relapses and/or dstant metastases, however, calls for systemc treatment {); therefore, t was es- No. of patents wth Thrombocytopena Neutropena 2 9 Table 4. Grade II through IV toxc effects of radotherapy Dgestve tract dsorders No. of patents Toxc effect Group A* Group Bt Esophagts Cutaneous dsorder Pneumonts Hematologc dsorder Dgestve tract dsorder Weght loss Fever Radotherapy alone. tchemotherapy + radotherapy. 9 4 2 4 II 9 I sental that the combnaton of these two modaltes be clearly evaluated. The ratonale for combnng radotherapy and chemotherapy n nonresectable non-small-cell lung cancer n the present tral was ) to mprove the local control rate by delverng radaton at adequate doses, e, Gy n. weeks, 2) not to exceed ths dose as well as to avod toxc effects on normal tssues n the thorax, and ) to decrease the dstant-metastass rate by actng on mcrometastases exstng at the tme of presentaton n more than 0% of cases (/). The four drugs selected were among the most effectve avalable at the tme of the desgn, and the doses employed permtted delvery of adequate radaton doses n a prelmnary phase II tral (9). In the present study, the chemotherapy regmen allowed an objectve regresson of the prmary tumor n 2% of the cases. Ths response rate s modest when compared wth results of recent phase II studes {-20), but t s assocated wth patents wth bulky dsease who were ncluded n a multcentrc study and receved fberoptc control examnatons and systematc bopses after two chemotherapy cycles. Treatment response was evaluated at a fxed tme months after completon of radotherapy; therefore, t was possble for a patent to experence a complete local response but very soon after exhbt dstant metastases. Furthermore, our defnton of local control was delberately restrctve. These factors may explan the low complete remsson rate observed at the tme of fnal assessment. Nevertheless, the -year local control rate s partcularly poor n both groups. These fgures are obvously dfferent from the "best response rate per patent" reported n most studes n whch mpact on survval s not clearly defned (2,22). The most dramatc effect observed n the present tral s the sgnfcant mpact of chemotherapy on the rate of dstant metastases. Ths fact s of crtcal mportance because t demonstrates that chemotherapy can sgnfcantly decrease the metastass rate n locally advanced dsease. Nevertheless, the dfference n overall survval was margnal and remaned below sgnfcance; the lack of local control (% and % at year) s the most probable explanaton of the results observed here. We emphasze that 40% of complete responders are long-term survvors. Sx other randomzed studes {2-2) that compared results of radotherapy alone and those of combned chemotherapy and radotherapy that ncluded more than 0 patents each have been reported and are lsted n Table. Only one study has demonstrated a sgnfcant beneft for survval n the combned modalty arm {2). An advantage was demonstrated, however, for the combned arm n fve of sx studes, as n our tral the largest conducted to date a moderate, although nonsgnfcant, beneft of a strategy that employed moderately actve chemotherapy regmens. Our results wll have a clear mpact on the followng future protocol desgns accordng to the new UICC classfcaton {29) that takes nto account two dfferent subsets of patents wth locally advanced non-small-cell lung cancer: ) Use of newer drugs {0Jl) and combnaton regmen wll probably be able to ncrease the complete response rate and therefore mprove the control of mcrometastases. Downloaded from http://jnc.oxfordjournals.org/ at Pennsylvana State Unversty on May, 20 Vol., No., March 20, 99 ARTICLES 42
Table S. Randomzed studes comparng radotherapy (RT) alone wth combned radotherapy and chemotherapy (CT) n locally advanced non-small-cell lung cancer Reference No. (2) () (2) (2) (2) (2) Present study n 2 Dose RT, Gy 4 CT* Medan survval, mo: RT/RT+CT CAMP 2/ MACC / VDS 9/ VLB-CDDP 9/ ADM CAP VCPC (unresectable squamous cell lung carcnoma) 9/ / /2 -y survval, %: RT/RT+CT 4/4 / / 4/42 4/0 <.00 *CAMP = cyclophosphamde + doxorubcn + methotrexate + procarbazne; MACC = methotrexate + doxorubcn + lomustne + cyclophosphamde; VDS = vndesne; VLB-CDDP = vnblastne + csplatn; ADM = doxorubcn; CAP = cyclophosphamde + doxorubcn + csplatn; and VCPC = vndesne + cyclophosphamde + csplatn + lomustne. f = not sgnfcant. 2) Patents presentng wth margnally operable dsease (stage MA) can potentally beneft from preoperatve chemotherapy as suggested by many phase II studes (2-4). Randomzed trals able to defne adequately the subset of patents lkely to beneft from the effect of chemotherapy on both local and dstant dsease are urgently requred. ) Patents wth defntvely nonresectable tumor (most patents wth stage IIIB dsease) can be consdered for new combned-modalty strateges, ncludng multfractonated radotherapy () and concurrent chemotherapy and radotherapy (,), n an attempt to mprove local control. 4) Standard treatment of patents wth locally advanced, defntvely nonresectable non small-cell lung cancer remans manly pallatve, and radotherapy s probably the most cost-effectve and comfortable alternatve that can be proposed today. In concluson, treatment of locally advanced non-small-cell lung cancer remans controversal. The large mpact of chemotherapy on the metastass rate observed n the present study must be emphaszed, although the dsappontng local control rate does not afford a sgnfcant beneft for overall survval. The new stratfcaton of margnally operable or defntvely nonresectable tumors offers new therapeutc prospects, and recent strateges should therefore be adequately evaluated n each category. References (/) SILVERBERG E, LUBERA JA: Cancer statstcs, 9. CA :-22, 9 (2) Statstque des causes medcales de deces: 9-9. Pars: IEE and IERM () Cox JD, YESNER R, MIETLOWSKI W, ET AL: Influence of cell type on falure pattern after rradaton for locally advanced carcnoma of the lung. Cancer 44:94-9,99 (O MATTHEWS M, PICKREN J, KANHOUWA S: Who has occult metastass? Resdual tumor n patents undergong surgcal resectons for lung cancer. In Perspectves n Lung Cancer (Yohn DC, ed). Basel: Karger, 9, pp 9- () ZELEN M: Keynote address on bostatstcs and data retreval. Cancer Cbemother Rep 4:-42, 9 () Cox JD, KOMAKI R, BYHARDT RW: IS mmedate chest radotherapy oblgatory for any or all patents wth lmted-stage non-small cell carcnoma of the lung? Yes. Cancer Treat Rep :2-, 9 () PEREZ CA, STANLEY K, GRUNDAY G, ET AL: Impact of rradaton technque and tumor extent n tumor control and survval of patents wth unresectable non-oatcell carcnoma of the lung: Report by the Radaton Therapy Oncology Group. Cancer 0:9-99,92 () COHEN MH: IS mmedate radaton therapy ndcated for patents wth unresectable non-small-cell lung cancer? No. Cancer Treat Rep :-, 9 (9) LE CHEVALIER T, ARRIAGADA R. BALDEYROU P, ET AL: Combned chemotherapy (vndesne, lomustne, csplatn, and cyclophosphamde) and radcal radotherapy m noperable nonmetastatc squamous cell carcnoma of the lung. Cancer Treat Rep 9:49-42, 9 (0) LE CHEVAUER T, Cvrrxovc E, CAILLE P, ET AL: Early metastatc cancer of unknown prmary orgn at presentaton. A clncal study of 02 consecutve autopsed patents. Arch Intern Med 4:20-209, 9 (//) CHAVAUDRA J, ARRIAGADA R: Radotherapy plannng n lung cancer. The Gustave-Roussy Insttute approach. Cancer Treat Symp 2:-9, 9 (2) WORLD HEALTH ORGANIZATION: Handbook for reportng results of cancer treatment. WHO Publ No. 4, 99 () KAPLAN EL, MEIER P: Nonparametrc estmatons from ncomplete observatons. J Am StatAssoc :4-, 9 (4) PETO R, PIKE MC, ARMITAGE P, ET AL: Desgn and analyss of randomzed clncal trals requrng prolonged observatons of each patent. II. Analyss and examples. Br J Cancer : -9, 9 () HAEN HH, HIRSCH FR, RORTH M: Stagng and prognoss. In Lung Tumors (Hoogstraten B, Adds BJ, Hansen HH, et al, eds). Berln: Sprnger-Verlag, 9 () GRECO FA: Ratonale for chemotherapy for patents wth advanced nonsmall-cell lung cancer. Semn Oncol :92-9, 9 () GOLDSTRAW P: CT scannng n the preoperatve assessment of non-smallcell lung cancer. In Lung Cancer Basc and Clncal Aspects (Hansen HH, ed). Boston: Martnus-Njhoff, 9, pp -9 () BONOMI P: Bref overvew of combnaton chemotherapy n non-small-cell lung cancer. Semn Oncol :9-9,9 (9) BURKES R, GIBERG RF, SHEPHERD M, ET AL: Phase II plot program of neo-adjuvant chemotherapy for stage III (Tl-, N2, M0) unresectable nonsmall-cell lung cancer (CLC). Lung Cancer 4:A, 9 (20) GRALLA RJ, KRIS MG, POTANOVICH LM, ET AL: Enhancng the safety and effcacy of the MVP regmen (mtomycn + vnblastne + csplatn) n 0 patents wth noperable non-small-cell lung cancer. Proc ASCO :, 99 (2) CHOI NC, DOUCETTE JA: Improved survval of patents wth unresectable non-small-cell bronchogenc carcnoma by nnovated hgh-dose en-bloc radotherapeutc approach. Cancer 4:-9, 9 (22) SCHAAKE-KONING C, SCHUSTER-VlTTERHOEVE L, HART G, ET AL: PrOgnOStc factors of noperable localzed lung cancer treated by hgh dose radotherapy. Int J Radat Oncol Bol Phys 9:2-2, 9 (2) TROVO MG, VERONESI A, BORTOLUS R, ET AL: IS chemotherapy necessary n the management of unresectable non-metastatc non-small-cell lung cancer? In Treatment Modaltes n Lung Cancer (Arragada R, Le Chevaler T, eds). Basel: Karger, 9, pp 2- () MORTON RF, JETT JR, MAHER L, ET AL: Randomzed tral of thoracc radaton therapy wth or wthout chemotherapy for treatment of locally unresectable non-small-cell lung cancer. Proc ASCO abstract No. 2, 9 (2) JOHON DH, EINHORN LH, BIRCH R, ET AL: IS mmedate thoracc radotherapy ndcated for noperable, nonmetastatc non-small-cell lung cancer. Proc ASCO abstract No., 99 (2) DILLMAN RO, SEAGREN SL, PROPERT KJ, ET AL: A randomzed tral of nducton chemotherapy plus hgh-dose radaton versus radaton alone n stage III non-small-cell lung cancer. N Engl J Med 2: 940-94, 990 (2) WHITE JE, CHEN T, REED R, ET AL: Lmted squamous cell carcnoma of the lung: A Southwest Oncology Group randomzed study of radaton wth or wthout doxorubcn chemotherapy and wth or wthout levamsole mmunotherapy. Cancer Treat Rep :-20, 92 (2) MATTSON K, HOLSTI LR, HOLSTI P, ET AL: Inoperable non-small-cell lung cancer Radaton wth or wthout chemotherapy. Eur J Cancer Cln Oncol :4-42, 9 (29) MOUNTAIN CF: A new nternatonal stagng system for lung cancer. Chest 9:22-2, 9 (0) SHUM KY, KRIS MG, GRALLA RJ, ET AL: Phase II study of -ethyl-- deaza-amnoptern (-EDAM) n patents wth stage III and IV nonsmall-cell lung cancer. J Cln Oncol :44-^0,9 () DEPERRE A, LEMARIE E, DABOUIS G, ET AL: Effcacy of Navelbne (NVB) n non-small-cell lung cancer. Semn Oncol :2-29, 99 (2) GRALLA RJ: Preoperatve and adjuvant chemotherapy n non-small-cell lung cancer. Semn Oncol (Suppl ):-2, 9 () PUJOL JL, ROSSI JF, LE CHEVALIER T, ET AL: Neoadjuvant chemotherapy n stage IIIA non-small-cell lung cancer (CLC) wth csplatnum, fosfamde and etoposde. Proc ASCO 9:2, 990 Downloaded from http://jnc.oxfordjournals.org/ at Pennsylvana State Unversty on May, 20 422 Journal of the Natonal Cancer Insttute
(4) VOICES EE, BITRAN JD, HOFFMAN PC, ET AL: Neoadjuvant vndesne, etoposde and csplatn for locally advanced non-small-cell lung cancer. Chest 9:-, 99 () THAMES HD, HENDRY JM: Fractonaton n Radotherapy. London: Taylor and Francs, 9 () SCHAAXE-KONING C, BATERUNK H: Radotherapy and csdammne dchloroplatnum as a combned treatment modalty n patents wth noperable non-small-cell lung cancer A randomzed phase II study. Lung Cancer 4:A, 9 () SORESI E, CLERICI M, GRILU R, ET AL: A randomzed clncal tral comparng radaton therapy versus radaton therapy plus cs-dchjorodammne platnum (II) n the treatment of locally advanced non small-cell lung cancer. Semn Oncol :20-2, 9 Appendx The followng centers (prncpal nvestgators) partcpated n ths study: Insttut Gustave-Roussy, Vllejuf (R. Arragada, T. Le Chevaler, P. Ruffle); Centre Medtco-Chrurgcal de la Porte de Chosy, Pars (P. Baldeyrou); Centre Hosptaler Intercommunal, Cretel (H. de Cremoux, M. Martn, I. Monnet); Centre Hosptaler Regonal, Strasbourg (E. Quox); Centre Ren Gauducheau, Nantes (J.Y. Doullard); Fondaton Bergone, Bordeaux (P. Chomy); Hptal Antone Beclere, Clamart (M.L. Cerrna); Centre Hosptaler, Compegne (M.P. Challet); Centre Francos Baclesse, Caen (A. Rvere); Centre Paul Papn, Angers (C. Tuchas); Centre Hosptalo-Unverstare, Bchat (D. Belpomme); Centre Antone Lacassagne, Nce (J.L. Lagrange); Centre Hosptalo-Unverstare La Pt-Salptrere (B. Dautzenberg); Centre Hosptaler, Lorent (Y. Dumesnl); Cabnet de Pneumologe, Clermont-Ferrand (A. Tourreau); Centre Hosptaler, Troyes (P. Meekel); Centre Hosptaler, Corbel (J. Huet, J.C. Saltel); Centre Hosptaler, Beauvas (F. Ozanne); Centre Alexs Vautrn, Nancy (I. Krakowsk); Insttuto Portuguese de Oncologa Francsco Gentl, Lsbonne (M. Vlhena); Centre Hosptaler, Sant-Quentn (Tran Ngoc Quang); Centre de Physotherape du Rouget, Sarcelles (A. Kanou); Centre Hosptaler General Robert Ballanger, Aulnay-sous-Bos (M. Matheu); and Centre Hosptaler, La Roche-sur-Yon (J. Guevenoux). Alternatng Hepatc Intra-Arteral Floxurdne and Fluorouracl: A Less Toxc Regmen for Treatment of Lver Metastases From Colorectal Cancer Robert J. Stagg, Alan P. Venook* Judy L. Chase, Bran J. Lews, Robert S. Warren, Mark Roh, Sean J. Mulvhll, Barry J. Grobman, Anthony A. Rayner, Davd C. Hohn Hepatc ntra-arteral (HIA) nfuson of floxurdne (FUDR) va an mplanted pump has shown promse n the treatment of colorectal cancer metastaszed to the lver. However, the potental beneft of ths therapy may be offset by the hgh ncdence of treatment-lmtng blary toxcty. Although weekly HIA bolus of fluorouracl (-FU) s effectve aganst metastatc colorectal cancer to the lver wth no blary toxcty, t s lmted by systemc sde effects. In December 9, we began a phase II tral of alternatng HIA FUDR and -FU va the mplanted pump n an attempt to extend the duraton of treatment by obvatng the lmtng blary (FUDR) and systemc (-FU) drug toxc effects. Patents receved contnuous HIA FUDR at 0. mg/kg of body weght per day on days through followed by an HIA bolus of - FU at mg/kg gven va the pump sdeport on days, 22, and 29, wth the cycle repeated every days. Sxty-eght patents were enrolled n ths tral, and 4 were fully evaluable. Of the 4 patents, 0 (4%) prevously had receved chemotherapy. Major response (complete response plus partal response) was observed n 2 (0%) of 4 patents, and the medan survval from pump mplantaton n all patents was 22.4 months. In contrast to the experence wth the sngle-agent HIA FUDR regmen, no patent had treatment termnated because of drug toxcty. Alternatng HIA FUDR and -FU has effcacy smlar to that of HIA FUDR gven alone, but when closely montored and adjusted approprately, s not assocated wth toxc effects requrng treatment termnaton. [J Natl Cancer Inst :42-42, 99] Colorectal cancer s the thrd most common cancer n the Unted States, wth about 0 000 newly dagnosed cases per year (/). About one half of all these patents ultmately wll develop metastatc spread to the lver, and n one half of those, lver nvolvement wll be the domnant clncal problem (2J). Receved August, 990; revsed December, 990; accepted December, 990. R. J. Stagg, A. P. Venook, B. J. Grobman, Cancer Research Insttute, Unversty of Calforna, San Francsco, Calf. J. L. Chase, Department of Pharmacy, M. D. Anderson Cancer Center, Houston, Tex. B. J. Lews, Department of Oncology, Kaser Permanente Medcal Center, San Francsco, Calf. R. S. Warren, S. J. Mulvhll, Department of Surgery, Unversty of Calforna, San Francsco. M. Roh, D. C. Hohn, Department of Surgery, M. D. Anderson Cancer Center. A. A. Rayner, Department of Surgery, Kaser Permanente Medcal Center, San Francsco. *Correspondence to: Alan P. Venook, MD, Cancer Research Insttute, M- 22/02, Unversty of Calforna, San Francsco, CA 944. Downloaded from http://jnc.oxfordjournals.org/ at Pennsylvana State Unversty on May, 20 Vol., No., March 20,99 ARTICLES 42