Giuseppe Cartel, Francesco Cartel, Aldo Cantone, Domenico Causarano, Giuseppe Genco, Arnaldo Tobaldin, Gaetano Interlandi, Tullio Giraldi*

Transcription

1 CsplatnCyclophosphamdeMtomycn Combnaton Chemotherapy Wth Supportve Care Versus Supportve Care Alone for Treatment of Metastatc NonSmallCell Lung Cancer Guseppe Cartel, Francesco Cartel, Aldo Cantone, Domenco Causarano, Guseppe Genco, Arnaldo Tobaldn, Gaetano Interland, Tullo Grald* Background: Patents wth TNM stage IV nonsmallcell lung cancer have short survval tmes. Prevous controlled studes comparng chemotherapy and supportve care for the treatment of ths type of cancer have not gven consstent results, have ncluded patents wth dfferent dsease stages, and have rarely reported drug dose ntensty. Purpose: The present tral was desgned to assess the safety and the effect on survval of supportve care alone versus chemotherapy wth csplatn, cyclophosphamde, and mtomycn combned wth approprate supportve care n patents wth stage IV nonsmallcell lung cancer. Methods: Patents (n = 102) wth stage IV nonsmallcell lung cancer were randomly assgned to one of two treatment regmens. The combned modalty group (52 patents) receved supportve care along wth csplatn (75 mg/m 2 ), cyclophosphamde (400 mg/m 2 ), and mtomycn (10 mg/m 2 ) gven ntravenously at 3week ntervals. The supportve care group (50 patents) receved supportve care alone. Randomzaton was stratfed on the bass of hstology (squamous versus nonsquamous cell carcnoma), performance status (Karnofsky), and weght loss (durng the 6 months precedng randomzaton). The two groups were well matched for age and sex. Survval analyss was performed after the last patent ded. Results: The medan number of chemotherapy cycles was 3.5 per patent. Mean weekly delvered doses of drugs were as follows: csplatn, 22.1 mg/m 2 ; cyclophosphamde, 118 mg/m 2 ; and mtomycn, 2.9 mg/m 2. Toxc effects due to chemotherapy were generally mld, but perpheral neuropathy and hematologc and renal toxc effects were observed. In the supportve care group, mean survval was 6.1 months (medan, 4.0 months); sx patents lved at least 12 months and two lved at least 18 months. In the combned modalty group, mean survval was 11.3 months (medan, 8.5 months); 20 patents lved at least 12 months, 13 lved at least 18 months, and fve lved at least 24 months. Dfference n survval was statstcally sgnfcant (P<.0001). Survval was drectly related to ntal performance status n both groups (P<.01) and was sgnfcantly (/ > <.01) longer for patents wth squamous cell carcnoma than for those wth nonsquamous cell carcnoma. Conclusons: The combnaton of supportve care and csplatncyclophosphamdemtomycn therapy offers a survval advantage over supportve care alone n patents wth advanced nonsmallcell lung cancer. Implcatons: Metastatc nonsmallcell lung cancer, generally consdered to be unresponsve or margnally responsve to chemotherapy, can be treated wth chemotherapy, wth an expectaton of prolongng patent survval. Although the results of the present study are encouragng, clncal research should contnue to be drected toward developng more effectve treatments for ths dsease. [J Natl Cancer Inst 85: , 1993] Nonsmallcell lung cancer s a common malgnancy worldwde, and patents n whom ths dsease has metastaszed to dstant stes seem to receve lttle clncal beneft from current chemotherapy. Unselected patents wth TNM stage IV (dstant metastatc) nonsmallcell lung cancer have medan survval tmes of 4 months or less (7J). Recent data from Eastern Cooperatve Oncology Group (ECOG) studes ncludng 1272 ambulatory patents wth advanced nonsmallcell lung cancer treated wth combnaton chemotherapy ncludng csplatn show that medan survval n patents on these studes ranges from 18 to 26 weeks (47). Among 893 patents on two of these ECOG studes, only 19% survved more than 1 year, and only 4% survved more than 2 years (8). Because of results such as these, the effectveness of combnaton chemotherapy n patents wth ths dsease s frequently questoned, wth most oncologsts remanng dubous of any postve effect of chemotherapy on patent survval. Studes comparng chemotherapy and supportve care for the treatment of advanced nonsmallcell lung cancer have yelded equvocal results. Two early controlled trals (9,70) usng sngle agents or combnaton chemotherapy showed no *See "Notes" secton followng "References." 794 ARTICLES Journal of the Natonal Cancer Insttute, Vol. 85, No. 10, May 19, 1993

2 survval advantage for patents treated wth antneoplastcs. Subsequently, Cormer et al. (77) reported a survval advantage for patents gven chemotherapy compared wth those recevng only supportve care, but that tral ncluded very few patents. In 1984, we began the present study, a randomzed tral of combnaton chemotherapy and supportve care versus supportve care alone for the treatment of stage IV nonsmallcell lung cancer. The combnaton of csplatn, cyclophosphamde, and mtomycn was chosen after our earler phase II tral ndcated good patent tolerance of ths regmen (unpublshed data). Whle the present tral was under way, other researchers publshed reports on the effect of combnaton chemotherapy versus supportve care n patents wth ths dsease. Rapp et al. (72) randomly assgned 142 patents to receve supportve care, csplatnvndesne therapy, or csplatncyclophosphamdedoxorubcn therapy. Medan survval of patents on the supportve care arm was 3.97 months, versus 5.76 months for those gven csplatncyclophosphamdedoxorubcn and 7.61 months for those gven csplatnvndesne. Both chemotherapy combnatons yelded a statstcally sgnfcant (P =.05 to.01) survval advantage (72). Ganz et al. (75), who randomly assgned 48 patents wth advanced or metastatc nonsmallcell lung cancer to receve supportve care or supportve care plus csplatn and vnblastne, observed no statstcally sgnfcant dfference n patent survval. Cellerno et al. (74,75) randomly assgned 123 patents (115 fully evaluable) to receve chemotherapy wth cyclophosphamde, eprubcn, and csplatn alternatng every 4 weeks wth methotrexate, etoposde, and lomustne (58 patents) or supportve care (57 patents). No survval dfference was observed. Woods et al. (76) gave 188 assessable patents ether supportve care or vndesne and csplatn. Eleven percent of the patents n the supportve care arm and 28% of those n the chemotherapy arm had dstant metastases; medan survval was 17 and 27 weeks for patents recevng supportve care and chemotherapy, respectvely (7> =.33). The present tral was desgned to assess the safety and the effect on survval of supportve care versus a regmen of supportve care combned wth csplatn, cyclophosphamde, and mtomycn n patents wth stage IV nonsmallcell lung cancer. Cost of therapy and qualty of lfe were not assessed n the present study, although the supportve care wth an emphass on analgescs was chosen wth an eye toward optmum patent health and comfort. Patents and Methods Patents The planned number of patents for the study was 100, and recrutment was stopped at 102. Patent elgblty requrements ncluded age 75 years or less, geographc accessblty, hstologcally confrmed nonsmallcell lung cancer wthout possblty of curatve surgery or radotherapy, former TNM stage III Ml dsease (17) [equvalent to current TNM stage IV (2)], absence of bran metastass, no prevous chemotherapy, measurable or evaluable dsease, Karnofsky performance status of 50 or more, whte blood cell count greater than 4.0 X 10 9 /L (4000/u.L), platelet count greater than 100 X 10 9 /L (100000/ xl), creatnne clearance of 0.6 u.mol/mn (65 mg/ mn) or greater wth 24hour urne collecton, and serum blrubn level less than 35 u.mol/l (2.0 mg/dl). Excluson crtera ncluded uncontrolled hypertenson or angna pectors, central nervous system stroke wthn the prevous 3 months, arteral Burger dsease, and a second prmary tumor other than nonmelanoma cutaneous cancer. Informed consent was obtaned accordng to contemporaneous Italan regulatons. In addton to physcal examnaton, the stagng of dsease ncluded bronchoscopy (f possble, wth bopsy); totalabdomen examnaton wth ultrasound; totalbody 99mTc radonuclde bone scan; 99mTc radonuclde bran scan; and, begnnng n 1985, abdomnal, pelvc, and bran computed tomography. When necessary for dagnoss, lung or lver bopsy was performed; when bone scan ndcated suspcous pathology, xray tomography of bone segments was performed. Patents were then randomly assgned to receve combnaton chemotherapy wth supportve care or supportve care alone; dentcal supportve care was planned for both groups. Randomzaton was stratfed on the bass of hstology (squamous versus nonsquamous cell carcnoma), Karnofsky performance status (100%80%, 70%50%), and weght loss (none or 10% or more over the last 6 months). Patent characterstcs are lsted n Table 1. Randomzaton was performed mmedately before treatment, usng a randomnumber table. The randomzaton acheved a good balance among stratfed patent characterstcs (see Table 1). Brefly, the Karnofsky performance status was the same (both mean and medan) between the two groups. Patents wth squamous cell tumor were almost dentcally dstrbuted (25 of 50 n the supportve care group; 24 of 52 n the combned modalty group), and those wth adenocarcnoma and largecell types were also farly evenly dstrbuted. Weght loss of 10% or more durng the sx months pror to randomzaton was observed n 21 patents nne n the supportve care group and 12 n the combned modalty group. The study populaton was predomnantly (71.6%) male. Ages ranged from 39 to 73 years, wth a medan of 56. Supportve Care Brefly, supportve care conssted of analgescs, an anttussve, relef of ncreased ntracranal pressure, pallatve radotherapy, and treatment of nfectons and pleural effusons. For analgesa, patents were medcated on a regular cyclc schedule, nstead of on an "as needed" bass. Treatment ncluded the followng: dcoflenac sodum (50100 mg) every 24 hours, to be escalated up to every 18 or 12 or 6 hours, wth or wthout lorazepam (1 mg, up to 2.5 mg, every 24 hours), f requred. When the 24hour dose of dcoflenac sodum reached 150 mg, cmetdne ( mg), or begnnng n 1985, rantdne hydrochlorde ( mg), was gven at 9:00 PM on that and subsequent days. Further steps n analgesa were cyclc daly ntramuscular njectons of pentazocne lactate (30 mg) or morphne hydrochlorde (10 mg), or cyclc daly doses of buprenorphne hydrochlorde (0.3mg ntramuscular njecton or 0.2mg sublngual tablet). Neuronal anesthesa by means of an epdural catheter was avalable when clncally ndcated. Methylprednsolone (40125 mg/day, gven ntravenously) was used for analgesa at 9:00 AM and also gven by the epdural route (40 mg) f requred. To releve ncreased ntracranal pressure, dexamethasone sodum phosphate was gven, together wth manntol. Therapy for pleural effusons ncluded flud dranage and local nstllaton of tetracyclne ( mg). Oral codene salts were the anttussve of choce. For nfectons, ampcllncloxaclln or trmethoprmsulphamethoxazole was the prmary therapy. When requred, pallatve radotherapy was gven for panful osseous metastass or mpendng bone fractures, for bran metastass that developed after randomzaton, or for superor vena caval obstructon. Chemotherapeutc Regmen When the present tral was devsed, hghly toxc chemotherapeutc regmens were excluded because of concern that more than modest toxcty could exert a deleterous effect on the qualty of lfe of all patents and the length of survval of patents who dd not respond to chemotherapy. The chemotherapeutc drugs were to be gven on an outpatent bass, wth Journal of the Natonal Cancer Insttute, Vol. 85, No. 10, May 19, 1993 ARTICLES 795

3 Table 1. Characterstcs of 102 patents wth stage IV nonsmallcell lung cancer* Characterstc Patents Age, y (%) Range Medan Mean < >65 Males Females Maletofemale rato Kamofsky performance status 100%90% 80%70% 60%50% Medan, % Mean, % Weght loss 3=10% pror to randomzaton Hstologc type Squamous cell carcnoma Adenocarcnoma Largecell cancer 02 Total (13.7) 80 (78.4) 8 (7.8) Supportve care alone (12) 40 (80) 4 (8) Treatment regmen Csplatn, cyclophosphamde, and mtomycn plus supportve care (15.4) 40 (76.9) 4 (7.6) * Unless otherwse noted, values = No. of patents. Analyss of dfferences between the two groups dd not reveal sgnfcant varaton (Fsher's exact test, twotaled). csplatn (75 mg/m 2 ), mtomycn (10 mg/m 2 ), and cyclophosphamde (400 mg/m 2 ) admnstered at 3week ntervals; our ntal phase II tral had demonstrated ths treatment schedule to be well tolerated. Csplatn n 500 nl salne was gven by ntravenous nfuson over a 90mnute perod, preceded and followed by 500 ml of salne over a 60mnute perod. Prehydraton and posthydraton ncluded 40 meq of KC1; when urnary loss of magnesum was observed, magnesum sulfate was added durng hydraton. Furosemde (40 mg, gven ntravenously) preceded csplatn by 30 mnutes. Cyclophosphamde and mtomycn were gven as standard bolus ntravenous njectons at the end of posthydraton. To reduce emess, metoclopramde (1 mg/kg, gven ntravenously) preceded and followed csplatn. Because of some epsodes of extrapyramdal sde effects from metoclopramde, begnnng n 1985 alzaprde was preferred at a 100mg oral dose before csplatn nfuson and 175 mg/m 2 n 100 ml salne gven ntravenously 20 mnutes before and after csplatn admnstraton (18). Methylprednsolone (40 mg) was also gven ntravenously just before mtomycn. A maxmum of sx cycles of chemotherapy was planned; treatment was stopped earler f ntolerable toxc effects, patent refusal, or dsease progresson was encountered. Chemotherapy was delayed untl recovery from toxc effects n the event of the followng: whte blood cell count below 3900/u.L, granulocyte count below 2500/nL, platelet count below /u.L, or serum creatnne level above 1.4 mg/dl. No dose reductons were allowed. Patent Followup Patents were evaluated at least once every 3 weeks n both treatment arms for the frst 6 months from the begnnng of treatment, or up to the 6th cycle of chemotherapy, and every month thereafter. If a patent was unable to attend the outpatent clnc and dd not requre or refused hosptal admsson, a member of the medcal staff of the tral would seek out the patent's famly physcan, and together they would vst the patent. No patents were lost to followup, and all were ncluded n the survval analyss. Evaluaton of Toxc Effects Because frequent blood counts n the supportve care group were unnecessary and to avod excessve venpunctures n patents on chemotherapy, weekly hematologcal tests between cycles were not part of the protocol desgn. Tests were performed only before each chemotherapy cycle or once every 3 weeks n supportve care subjects. Testng conssted of complete blood counts; measurement of blood or serum levels of glucose, urea ntrogen, creatnne, urc acd, sodum, potassum, calcum, lactc dehydrogenase, gammaglutamyltranspeptdase, alanne and aspartate transamnase, alkalne phosphatase, total blrubn, total protens, albumn, blood osmolarty (Autoanalyzer SMAC 22, Techncon Corp., Tarrytown, N.Y.; or other autoanalyzers); and standard urnalyses. Creatnne clearance on 24hour urnary collecton was performed n selected cases. Evdence of hematologc, renal, lver, and gastrontestnal toxc effects, as well as har loss, perpheral neuropathy, and nfectons, was carefully recorded and graded accordng to the crtera of Mller et al. (19). Complete physcal examnatons were routnely performed; electrocardograms were done only when necessary. Response Crtera The patents' survval, rather than the response rate of the measurable dsease, was the prmary end pont of the present tral. However, classc crtera for measurng tumor response were followed (19). Treatment volumes rradated durng supportve care were excluded from consderaton n evaluaton of response to chemotherapy. Statstcal Methods Survval was calculated from the tme of randomzaton to the tme of death, usng the KaplanMeer method. Analyss was performed only after the last patent ded and ncluded Fsher's exact test (twotaled), analyss of varance, and KaplanMeer and logrank tests to analyze survval (Systat and Sygraph) (2022). No nterm analyss was performed ARTICLES Journal of the Natonal Cancer Insttute, Vol. 85, No. 10, May 19, 1993

4 Results Supportve Care Pallatve radotherapy was requred for sx patents n the supportve care group and for 10 patents n the combned modalty group. Chemotherapy A total of 200 chemotherapy cycles were gven, rangng from one to eght per patent, wth a mean of 3.85 and a medan of 3.5. Fve patents ded wthn the 1st month of treatment and receved only one cycle. These patents were consdered to have had dsease progresson. At response evaluaton before the thrd cycle, progresson was present n an addtonal 19 patents (36.5%), stable dsease n 15 (28.8%), and a partal response n 13 (25%). Calculaton of dose ntensty excluded the fve patents who ded before recevng the second cycle and the two patents who had more than sx (.e., eght) cycles. Consequently, 179 cycles were evaluated (from two to sx per patent) over 4193 patentdays versus an deal planned tme of 3759 patentdays. The delay was manly due to hematologc and/or renal toxc effects (see below). The ntended weekly dose ntenstes for the chemotherapeutc regmen were as follows: csplatn, 25.0 mg/m 2 ; cyclophosphamde, 133 mg/m 2 ; and mtomycn, 3.3 mg/m 2. The mean delvered dose ntenstes were 22.1, 117.9, and 2.9 mg/m 2 per week, respectvely. The relatve dose ntensty (delvered dose/ntended dose) was 0.88 for each drug. Toxc Effects The csplatncyclophosphamdemtomycn regmen was relatvely well tolerated. No deaths due to toxc effects were observed. Grade 2 nausea and vomtng was almost unversal (190/200 cycles), but grade 3 vomtng requrng further antemetc therapy was observed n only 18 cycles (9%). Three patents refused to contnue therapy after the fourth cycle because of vomtng; another patent refused the second cycle but subsequently accepted two further cycles. Perpheral neuropathy was observed n all patents who had at least three cycles of chemotherapy. After sx cycles, ths complcaton was grade 2 n sx patents and grade 3 n two patents. All patents who had more than two cycles of chemotherapy experenced almost complete har loss. Grade 2 stomatts was present n 11 cycles, and grade 3 n three cycles. There was one epsode of lfethreatenng sepss; although ths resolved wth antbotcs, t precluded further therapy after the fourth cycle. A grade 2 drop n hemoglobn levels was observed n 26 cycles (13%), and a grade 3 drop was observed n four cycles (2%). A grade 1 decrease n whte blood cell and platelet counts caused a 1week delay of chemotherapy n four patents. The overall delay due to hematologc toxc effects was 1 week n 32 cycles and 2 weeks n three cycles. Serum creatnne levels were above 1.5 mg/dl n four cycles and above 2.0 mg/dl n two cycles; n each case, normal levels were restored wth hydraton. In two patents, however, persstently elevated creatnne levels (grade 2) for at least 28 days followng the fourth cycle precluded further therapy. Survval Analyss Overall survval curves are shown n Fg. 1. Medan survval was 4.0 months n the supportve care group and 8.5 months n the combned modalty group (f<.0001). Survval longer than 12 months was observed n 20 patents (38.5%) n the combned modalty group and sx patents (12%) n the supportve care group (Table 2). Survval for both combned modalty and supportve care groups was drectly related to the ntal performance status (P<.01). Medan survval was 10.7 months for patents wth squamous cell carcnoma versus 7.0 months for those wth nonsquamous cell carcnoma (logrank test, P<.0l). Improvement n survval due to chemotherapy was sgnfcantly (P<.001) mantaned when patents were stratfed for performance status: for patents wth performance status less than 80, only 15% recevng supportve care and 56% recevng chemotherapy plus supportve care survved 6 months or longer; for patents wth performance status of 80 or more, 92% recevng supportve care and 100% recevng chemotherapy plus supportve care survved 6 months or longer (Fg. 2). Dscusson Twenty years ago, there was no general agreement on how patents wth noperable nonsmallcell lung cancer should racton survvng 1 n fn 1 L C) 10 In 1 «_ 1 X L 20 months Fg. 1. Survval of 102 patents wth stage IV nonsmallcell lung cancer randomly assgned to receve supportve care (trangles) or supportve care plus csplatn, cyclophosphamde, and mtomycn (squares). Dfference n survval s statstcally sgnfcant (KaplanMeer estmate, logrank test, / COOOl) Journal of the Natonal Cancer Insttute, Vol. 85, No. 10, May 19, 1993 ARTICLES 797

5 Table 2. Survval of patents wth nonsmallcell lung cancer recevng chemotherapy plus supportve care (n = 52) or supportve care alone (n = 50) Range Medan Meant Survval, No. of patents (%) s=6 mo 3=12 mo s=18 mo 5=24 mo *KapanMeer estmate. tlogrank test, /»< Supportve care group (34.0) 6 (12.0) 2 (4.0) 0 Survval, mo* Chemotherapy + supportve care group (67.3) 20 (38.5) 13 (25.0) 5 (9.61) be treated, or even f they should be treated at all f they were asymptomatc (9,70). Because survval was poor after treatment wth ether radotherapy or chemotherapy and because the treatments themselves caused varyng degrees of toxc effects, t was argued that these patents should only be treated pallatvely. Durrant et al. (9) desgned a tral n whch patents wth noperable nonsmallcell carcnoma of the bronchus confned to the thoracc cavty were randomly assgned to one of four treatment arms: supportve care only (wth rradaton as needed f symptoms developed), chest rradaton, chemotherapy wth mechlorethamne (ntrogen mustard), or rradaton and chemotherapy combned. The mean survval of the four groups ranged from 8.3 to 8.8 months, wth no sgnfcant dfference among groups. No pathologc dagnoss was avalable n 16%25% of the patents (9), and some cases of smallcell cancer mght have been ncluded n that tral. The study by Durrant et al. (9) opened the avenue for randomzed nvestgatons on the usefulness of therapes other than surgery n the treatment of advanced bronchal carcnoma. It also hghlghted the mportance of qualtyoflfe consderatons n addton to the assessment of dsease regresson rates. Subsequently, another randomzed study (70) was conducted where no mmedate treatment was compared wth sngle or multpleagent chemotherapy n patents wth noperable lung carcnoma. The drugs used were procarbazne and a combnaton of mechlorethamne, vnblastne, procarbazne, and prednsolone. Medan survval was as follows: wth no mmedate treatment, 220 days (P<.05); wth procarbazne, 190 days; and wth combnaton chemotherapy, 75 days. No dfference n survval was observed among groups at 1 year (70). Cormer et al. (7/) observed a statstcally better survval n patents treated wth methotrexate, doxorubcn, cyclophosphamde, and lomustne. However, ther study nvolved only 39 patents who had heterogeneous stages of dsease. Rapp et al. (72) observed that chemotherapy wth csplatnvndesne or csplatncyclophosphamdedoxorubcn produces a statstcally greater survval, compared wth supportve care alone. In the former regmen, csplatn was gven at 120 mg/m 2, and vndesne at 3 mg/m 2. In the latter regmen, doxorubcn and cyclophosphamde, at relatvely low doses (40 and 400 mg/m 2, respectvely), were added to csplatn (40 mg/m 2 ). Ths study also made an analyss of drug dose ntensty. The actual admnstered dose Fg. 2. KaplanMeer estmate of survval n patents wth stage IV nonsmallcell lung cancer grouped accordng to Kamofsky performance status. Patents wth performance status less than 80 (A). Patents wth performance status of 80 or more (B). Trangles = supportve care; squares = supportve care plus csplatn. cyclophosphamde, and mtomycn. Dfferences are sgnfcant for any stratfcaton (logrark test, P<.001). 798 ARTICLES Journal of the Natonal Cancer Insttute, Vol. 85, No. 10, May 19, 1993

6 of csplatn was substantally hgher n the csplatnvndesne arm (dose ntensty, 17.4 mg/m 2 per week) than n the other chemotherapy arm. Patents recevng csplatn and vndesne had a longer medan survval than those recevng csplatn, cyclophosphamde, and doxorubcn. Quox et al. {23) observed a statstcal mprovement n the survval of patents treated wth csplatn and vndesne, compared wth supportve care alone, although there were only 43 patents n the study. In a study nvolvng only 48 patents, Ganz et al. {13) compared supportve care to combnaton chemotherapy wth vnblastne (6 mg/m 2 ) and csplatn (120 mg/m 2 ) every 4 weeks for two cycles and every 6 weeks thereafter. Patents on chemotherapy had a slghtly longer medan survval (20.4 weeks versus 13.6 weeks), although the ncrease was not statstcally sgnfcant. Moreover, Kaasa et al. (24) observed no survval beneft wth csplatn and etoposde chemotherapy compared wth supportve care alone n 87 patents. In the largest of these randomzed trals (188 patents), Woods et al. {16) observed no statstcal mprovement n patents wth stage Illb or IV (2) nonsmallcell lung cancer when treated wth csplatn and vndesne compared wth supportve care alone. However, patents wthout dstant metastases (stage Illb) treated wth chemotherapy had longer survval {P.075). In contrast to the treatment polcy of Rapp et al. (72), these authors dscontnued chemotherapy n patents wth stable dsease. Cellerno et al. {14,15) evaluated 115 patents, 46 stage III and 69 stage IV patents, usng alternatng chemotherapy regmens of cyclophosphamdeeprubcncsplatn and methotrexateetoposdelomustne versus supportve care. Csplatn was planned at a dose of 10 mg/m 2 per week,.e., approxmately half the dose ntensty of csplatn used by Rapp et al. {12) or by us n the present study. Twelve (20.7%) of 58 patents experenced partal remsson and 31 (53.4%) acheved stable dsease n the chemotherapy group. No statstcally sgnfcant dfference n survval was observed n the study, although an advantage for chemotherapy was observed n some subsets of patents. Thus, only three randomzed studes, two prevously publshed n detal {11,12) and one prelmnary report {23), ndcate that chemotherapy s assocated wth a statstcally sgnfcant advantage n survval compared wth supportve care alone n patents wth advanced nonsmallcell lung cancer. Interpretaton of these data s complcated by varous factors, ncludng small sample sze, nadequate chemotherapeutc doses, unbalanced dstrbuton of patents, and loss of sgnfcant numbers of patents to followup. The present study, whch ncluded a balanced and adequate number of patents, ndcates that metastatc nonsmallcell lung cancer, generally consdered to be unresponsve or only margnally responsve to chemotherapy, can be treated wth csplatn, cyclophosphamde, and mtomycn chemotherapy, wth a statstcally sgnfcant though modest ncrease n patent survval compared wth supportve care alone. A specfc assessment of qualty of lfe or cost of therapy was not performed n ths study. However, chemotherapy was generally well tolerated by the patents, and only three of them refused contnued therapy because of vomtng. Supportve care was gven to allow an optmal qualty of lfe, and great attenton was pad to nutrton and analgesc therapy. Although our results are encouragng, the present combnaton chemotherapy should not be consdered standard snce all patents eventually ded. The search for more effectve chemotherapy for ths dsease should contnue. References (/) SELAWRY OS, HANSEN HH: Lung cancer. In Cancer Medcne, 2nd ed (Holland JF, Fre E III, eds). Phladelpha: Lea & Febger, 1982, pp (2) MOUNTAIN CF: A new nternatonal stagng system for lung cancer. Chest 89(Suppl 4):225233, 1986 (3) MINNA JD, PASS H, GLATSTEIN E, ET AL: Cancer of the lung. In Cancer: Prncples and Practce of Oncology, 3rd ed (DeVta VT Jr, Hellman S, Rosenberg SA, eds). Phladelpha: J B Lppncott, 1989, pp (4) RUCKDESCHEL JC, MEHTA CR, SALAZAR OM, ET AL: Chemotherapy for metastatc nonsmall cell bronchogenc carcnoma: EST 2575, generaton III, HAM versus CAMP. Cancer Treat Rep 65:959963, 1981 (5) RUCKDESCHEL JC, DAY R, WEISSMAN CH, ET AL: Chemotherapy for metastatc nonsmall cell bronchogenc carcnoma: Cyclophosphamde, doxorubcn, and etoposde versus mtomycn and vnblastne (EST 2575, generaton IV). Cancer Treat Rep 68: , 1984 (6) RUCKDESCHEL JC, FINKELSTEIN DM, MASON BA, ET AL: Chemotherapy for metastatc nonsmallcell bronchogenc carcnoma: EST 2575, generaton V a randomzed comparson of four csplatncontanng regmens. 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7 Inc, 1990 (23) Quox E, DIETEMAN A, CHARBONNEAU J: Dssemnated non small cell lung cancer (NSCLC): A randomzed tral of chemotherapy (CT) versus pallatve care (PC). Lung Cancer 1988 (Suppl 4), p 127 (24) KAASA S, LUND E, HOST H, ET AL: Combnaton chemotherapy n patents wth nonsmall cell lung cancer, extensve dsease. In Proceedngs of the Ffth European Conference on Clncal Oncology, London, 1989, abstr 00007, p 46 Notes Afflatons of authors: G. Carte, Dvson of Medcal Oncology and Cancer Center, Udne, Italy. F. Carte, Dvson and Insttute of Radology and Radotherapy, General Hosptal and Unversty of Psa, Italy. A. Cantone, Dvson of Internal Medcne, General Hosptal, Bassano del Grappa (VI), Italy. D. Causarano, Dvson of Internal Medcne, General Hosptal, Marostca (VI), Italy. G. Genco, Medcal Day Hosptal, Geratrc Hosptal, Padova, Italy. A. Tobaldn, Dvson of Internal Medcne, General Hosptal, Rovgo, Italy. G. Interland, Surgcal Dvson, General Hosptal, San Bonfaco (VR), Italy. T. Grald, Secton of Pharmacology, Department of Bomedcal Scences and Technologes, Unversty of Udne, Italy. Correspondence to: Prof. G. Carte, Dvsone d Oncologa Medca e Centro d Prevenzone de Tumor, USL7, Udne, Italy. Ths research was part of Assocazone Oncologca ItalanaUdne study programs. We gratefully acknowledge the skllful techncal assstance of Dr. V. Cescha (recpent of a postdoctoral fellowshp from Lega Italana per la Lotta contro Tumor, Sezone d Udne). We apprecate the assstance of Dr. P. Martn of Padua and many other famly doctors n helpng wth followup. We thank Dr. L. Lenaz (BrstolMyers, USA) for revewng ths artcle. Manuscrpt receved July 17, 1992; revsed February 23, 1993; accepted February 25, How n the world do you fnd out about the earth? The Earth Scence Data Drectory (ESDD) s compled and produced by the US Geologcal Survey, an agency of the Department of the Interor and the Federal Government's largest earthscence research agency. References n the ESDD nclude nformaton about Data bases concerned wth the geologc, hydrologc, cartographc, and bologc scences Data that supports the protecton and management of natural resources Geographc, socologc, economc, and demographc data sets To secure nformaton about becomng an ESDD user, wrte or call: ESDD Project Manager U.S. Geologcal Survey 801 Natonal Center Reston, Vrgna (703) or FTS ARTICLES Journal of the Natonal Cancer Insttute, Vol. 85, No. 10, May 19, 1993