of 2 /2
60 Anronio Curie Hospital of Chest Diseases, Cuneo. Oncology 1989;46: 212-6. Ninety-two nonsmall cell lung cancer (NSCLC) patients were treated wilh a combination chemotherapy containing methotrexate, adriamy- tin, cyclophosphamide and CCNU (MACC). Theregimen wasadmini- stered in the dose and schedule originally reported. Median survival for all patients was 32 weeks. Only 6 patients demonstrated an objective response with a median survival rate of 5 1 weeks. The remaining 70 evaluable patients were nonrespondcrs. These latter patients had a survivalprobabililyreduced to29wecks. Mcdiantimetoprogressionfor the whole group was 17 weeks. Partial responses were seen in 3 squamous, 1 large cell carcinoma and 1 adenocarcinoma. One patient with bronchiole-alveolar carcinoma had complete disease regression and is still alive 136 weeks after starting treatment. Toxicity was significant with 2 treatment-related deaths. The major toxic effects consisted of myelosupprcssion, nausea, vomiting, and stomatitis. Alopecia was nearly universal; a mild cardiac, renal, or hepatic toxicity was relatively unfrequent. Polychcmotherapy with MACC regimen may benefit a few selected padents with NSCLC, but its overall antitumor efficacy appears to bc very limilcd. Mopidamol as adjuvant treatment of non-small cell bronchial carcinoma Blaha H, Dierkesmann R, Feuerer W et al. Zentrulkrunkenhuus. Gauring. Pneumologie 1989;43:299-304. Between January 1982 and April 1986 a double-blind randomized placeboconuolled study of mopidamol, employed as adjunct therapy to surgery in patients with non-small cell bronchial carcinoma, was performed at 7 hospitals. The main criteria were occurrence of melas- tases and survival. Mopidamol was given @operatively at a dose of 2 x 150 mg i.v. daily, and postoperatively orally at a dose of 3 x 500 mg daily. The treatment period was scheduled to at least 2 yearsand in some of the patients was prolonged to 3 years. The standard therapy of each individual center was given as basic therapy. A total of 270 patients were included in the study, 147 in the placebo and 123 in the mopidamol group. By the end of the study 52 deaths from metastases had occurred in the placebo group (35%) compared wilh only 32 (26%) in the mopidamol group. This dlffcrcncc is stadstically significant at p c 0.05 withtheone-sidedtest.Acomparisonoflife-tablesaccordingU,Kaplan- Mcier shows a statistically significant dlffcrencc in favour of the group treated with mopidamol (savage p < 0.05). Cox’s multivariate analysis confirmed the statistically sigmficant dlffcrence in favour of the group treated with mopidamol, Ihc inclusion of the risk factors tumour stage and histology in thceva1uaGon results in a p-valueof0.02. With respect to the incldcnce of mclastases thcrc wcrc no appreciable differences between thctreatmcntgroups.TheIncidenccofsideeffectsorundesired events was equal in both groups. The study shows that treatment with mopidamol given as adjunct lhcrapy to surgery leads to a statistically significant prolongation of survival in patients with non-small cell bronchial carcinoma. This prolongation of survival is not associated with any increased risk of adverse reactions. Chemotherapy plus RA223 in the treatment ofoat cell lung cancer Lipton A, Harvey HA, Walker B et al. Deparrment ofMedicine, The Milton S. Hershey Medical Center, Hershey, PA 17033. Am J Clin Oncol, Cancer Clin Trials 1989;12:259-63. One hundred and one patients with oat (small) cell lung cancer have been treated with CAVE [Cytoxan, Adriamycin, Vicristine, and eto- poside (VP-16)] chemotherapy + RA233 (a platelet-inhibiting agent). There was no difference in disease-free interval, pattern of relapse, or survival between groups. Correlation ofmultidrug resistance with decreased drug accumula- tion, altered subcellular drug distribution, and increased P- glycoprotein expression in cultured SW-1573 human lung tumor cells Keizer HG, Schuurhuis GJ, Broxterman HI et al. institute of Human Genetics, Free University, 1007 MC Amsterdam. Cancer Res 1989;49:2988-93. Four multidrug-resistant variants of the human squamous lung cancer cell line SW-1573 with levels of doxorubicin resistance ranging from IO- to 2000-fold were characterized with respect to drug accumulation and efflux, subcellular drug distribution pattern, antioxidant defenses, and P-glycoprotein expression. For all these parameters except the antioxidant defenses a correlation was observed with the level of doxorubicin resistance; with increasing drug resistance cellular drug accumulation capacity (as measured for doxorubicin) progressively decreased, initial drug efllux rates (as measured for daunorubicin) progressively increased, while Ihe subcellulardoxorubicm distribution (as mcacured by fluorcsccncc microscopy) gradually shifted from a ‘mainlynuclear’~oa‘main1ycy~oplasmic’pattem.Ourdatasuggestthat in the present set of cell lines the same mechanism of resistance is operating at all levels of doxorubicin resistance. Patients at risk of chemotherapy-associated toxicity in small cell lung cancer Morittu L, Earl HM, Souhami RL et al. Department of Oncology, University College. London W!P RBT. Br J Cancer 1989;59:801-4. During a climcal trial of duration of chemotherapy in small cell lung cancer (SCLC), 7 1 of 610 patients (11.6%) died in the fust 3 weeks. Chemotherapy consisted of cyclophosphamide 1 g m-2 i.v. day 1, etoposide 100 mg I.d.s. orally days l-3, vincristine 2 mg i.v. day 1. The time of dealh was found to be nonrandomly distributed within the first chemotherapy cycle, with a peak incidence between days 7 and 12 after chemotherapy. Patients were matched with controls who the next cases entered into the study who did not die in the first 3 weeks. Patients dying early were more likely to have clinical hepatomcgaly (PC O.OC@l), and ECOG score_ 1(P~0.00001).Asagroupthesepatientsa1sohadahigher alkalinephosphalase (PC O.OOOZ), an clcvated blood urea(P<O.OO@ll) and a lower serum albumin (P < 0.0001) than controls. It is probable that infection contributes 10 the death of these already ill patients at a time when the blood count is low. Early deaths have been noted in two other largeu~alsusingregimensincludingetoposide. ProphylacGcantibiotics or dosage modification may prcvcm the early death of these high risk patients. Etoposide combined with cyclophosphamide plus vincristine com- pared with doxorubicin plus cyclophosphamide plus vincristineand with high-dose cyclophosphamide plus vincristine in the treatment ofsmall-cell carcinoma of the lung: A randomized trial of the Bristol Lung Cancer Study Group Hong WK, Nicaise C, Lawson R et al. University of Texas MD. An- derson Cancer Center, Houston, 7X 77030 J Clin Oncol 1989;7:450-6. A total of 353 patients with previously untreated small-cell lung cancer (SCLC) were accrued in this multiccntcr trial. Patients were randomly ass&cd to receive one of the following three rcgimcns: cyclophosphamide 1,000 mg/m* intravenously (IV) day 1, vincrinstine I .4 mg/m2 IV day 1, and etoposidc 50 mg/m’ IV day 1, followed by etoposide 100 mg/m2/day orally days 2 through 5 (CEV); cyclo- phosphamide 1 ,000mg/m2 IVday 1, vincristine 1.4 mg/m’IV day 1, and doxorubicin50mg/m21Vday 1 (CAV);cyclophosphamide2,000mg/m2 day I and vincristine 1.4 mg/m” IV day 1 (CV). Cycles were repeated every 3 weeks. Treatment groups were comparable with rcspcct to

Etoposide combined with cyclophosphamide plus vincristine compared with doxorubicin plus cyclophosphamide plus vincristine and with high-dose cyclophosphamide plus vincristine in the

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Anronio Curie Hospital of Chest Diseases, Cuneo. Oncology 1989;46: 212-6.

Ninety-two nonsmall cell lung cancer (NSCLC) patients were treated wilh a combination chemotherapy containing methotrexate, adriamy- tin, cyclophosphamide and CCNU (MACC). Theregimen wasadmini- stered in the dose and schedule originally reported. Median survival for all patients was 32 weeks. Only 6 patients demonstrated an objective response with a median survival rate of 5 1 weeks. The remaining 70 evaluable patients were nonrespondcrs. These latter patients had a survivalprobabililyreduced to29wecks. Mcdiantimetoprogressionfor the whole group was 17 weeks. Partial responses were seen in 3 squamous, 1 large cell carcinoma and 1 adenocarcinoma. One patient with bronchiole-alveolar carcinoma had complete disease regression and is still alive 136 weeks after starting treatment. Toxicity was significant with 2 treatment-related deaths. The major toxic effects consisted of myelosupprcssion, nausea, vomiting, and stomatitis. Alopecia was nearly universal; a mild cardiac, renal, or hepatic toxicity was relatively unfrequent. Polychcmotherapy with MACC regimen may benefit a few selected padents with NSCLC, but its overall antitumor efficacy appears to bc very limilcd.

Mopidamol as adjuvant treatment of non-small cell bronchial carcinoma Blaha H, Dierkesmann R, Feuerer W et al. Zentrulkrunkenhuus. Gauring. Pneumologie 1989;43:299-304.

Between January 1982 and April 1986 a double-blind randomized placeboconuolled study of mopidamol, employed as adjunct therapy to surgery in patients with non-small cell bronchial carcinoma, was performed at 7 hospitals. The main criteria were occurrence of melas- tases and survival. Mopidamol was given @operatively at a dose of 2 x 150 mg i.v. daily, and postoperatively orally at a dose of 3 x 500 mg daily. The treatment period was scheduled to at least 2 yearsand in some of the patients was prolonged to 3 years. The standard therapy of each individual center was given as basic therapy. A total of 270 patients were included in the study, 147 in the placebo and 123 in the mopidamol group. By the end of the study 52 deaths from metastases had occurred in the placebo group (35%) compared wilh only 32 (26%) in the mopidamol group. This dlffcrcncc is stadstically significant at p c 0.05 withtheone-sidedtest.Acomparisonoflife-tablesaccordingU,Kaplan- Mcier shows a statistically significant dlffcrencc in favour of the group treated with mopidamol (savage p < 0.05). Cox’s multivariate analysis confirmed the statistically sigmficant dlffcrence in favour of the group treated with mopidamol, Ihc inclusion of the risk factors tumour stage and histology in thceva1uaGon results in a p-valueof0.02. With respect to the incldcnce of mclastases thcrc wcrc no appreciable differences between thctreatmcntgroups.TheIncidenccofsideeffectsorundesired events was equal in both groups. The study shows that treatment with mopidamol given as adjunct lhcrapy to surgery leads to a statistically significant prolongation of survival in patients with non-small cell bronchial carcinoma. This prolongation of survival is not associated with any increased risk of adverse reactions.

Chemotherapy plus RA223 in the treatment ofoat cell lung cancer Lipton A, Harvey HA, Walker B et al. Deparrment ofMedicine, The Milton S. Hershey Medical Center, Hershey, PA 17033. Am J Clin Oncol, Cancer Clin Trials 1989;12:259-63.

One hundred and one patients with oat (small) cell lung cancer have been treated with CAVE [Cytoxan, Adriamycin, Vicristine, and eto- poside (VP-16)] chemotherapy + RA233 (a platelet-inhibiting agent). There was no difference in disease-free interval, pattern of relapse, or survival between groups.

Correlation ofmultidrug resistance with decreased drug accumula- tion, altered subcellular drug distribution, and increased P- glycoprotein expression in cultured SW-1573 human lung tumor cells Keizer HG, Schuurhuis GJ, Broxterman HI et al. institute of Human Genetics, Free University, 1007 MC Amsterdam. Cancer Res 1989;49:2988-93.

Four multidrug-resistant variants of the human squamous lung cancer cell line SW-1573 with levels of doxorubicin resistance ranging from IO- to 2000-fold were characterized with respect to drug accumulation and efflux, subcellular drug distribution pattern, antioxidant defenses, and P-glycoprotein expression. For all these parameters except the antioxidant defenses a correlation was observed with the level of doxorubicin resistance; with increasing drug resistance cellular drug accumulation capacity (as measured for doxorubicin) progressively decreased, initial drug efllux rates (as measured for daunorubicin) progressively increased, while Ihe subcellulardoxorubicm distribution (as mcacured by fluorcsccncc microscopy) gradually shifted from a ‘mainlynuclear’~oa‘main1ycy~oplasmic’pattem.Ourdatasuggestthat in the present set of cell lines the same mechanism of resistance is operating at all levels of doxorubicin resistance.

Patients at risk of chemotherapy-associated toxicity in small cell lung cancer Morittu L, Earl HM, Souhami RL et al. Department of Oncology, University College. London W!P RBT. Br J Cancer 1989;59:801-4.

During a climcal trial of duration of chemotherapy in small cell lung cancer (SCLC), 7 1 of 610 patients (11.6%) died in the fust 3 weeks. Chemotherapy consisted of cyclophosphamide 1 g m-2 i.v. day 1, etoposide 100 mg I.d.s. orally days l-3, vincristine 2 mg i.v. day 1. The time of dealh was found to be nonrandomly distributed within the first chemotherapy cycle, with a peak incidence between days 7 and 12 after chemotherapy. Patients were matched with controls who the next cases entered into the study who did not die in the first 3 weeks. Patients dying early were more likely to have clinical hepatomcgaly (PC O.OC@l), and ECOG score_ 1 (P~0.00001).Asagroupthesepatientsa1sohadahigher alkalinephosphalase (PC O.OOOZ), an clcvated blood urea(P<O.OO@ll) and a lower serum albumin (P < 0.0001) than controls. It is probable that infection contributes 10 the death of these already ill patients at a time when the blood count is low. Early deaths have been noted in two other largeu~alsusingregimensincludingetoposide. ProphylacGcantibiotics or dosage modification may prcvcm the early death of these high risk patients.

Etoposide combined with cyclophosphamide plus vincristine com- pared with doxorubicin plus cyclophosphamide plus vincristineand with high-dose cyclophosphamide plus vincristine in the treatment ofsmall-cell carcinoma of the lung: A randomized trial of the Bristol Lung Cancer Study Group Hong WK, Nicaise C, Lawson R et al. University of Texas MD. An- derson Cancer Center, Houston, 7X 77030 J Clin Oncol 1989;7:450-6.

A total of 353 patients with previously untreated small-cell lung cancer (SCLC) were accrued in this multiccntcr trial. Patients were randomly ass&cd to receive one of the following three rcgimcns: cyclophosphamide 1,000 mg/m* intravenously (IV) day 1, vincrinstine I .4 mg/m2 IV day 1, and etoposidc 50 mg/m’ IV day 1, followed by etoposide 100 mg/m2/day orally days 2 through 5 (CEV); cyclo- phosphamide 1 ,000mg/m2 IVday 1, vincristine 1.4 mg/m’IV day 1, and doxorubicin50mg/m21Vday 1 (CAV);cyclophosphamide2,000mg/m2 day I and vincristine 1.4 mg/m” IV day 1 (CV). Cycles were repeated every 3 weeks. Treatment groups were comparable with rcspcct to

0 1

extent ofdiscasc, age, xx, perrormancc status, and mctastatic sites. No sigml’icanl differences m response rates, r4sponse duration, or survival could be detected in hmtted disease, although there appeared to be a trend favormg CEV. Among extensive-discasc paticn&, response dura- tionon thcCEVrcgimenwaslongerrhanon ~eCVre~inlcnor~heCAV program (P < .OOI). The superiority of the CEV regimen was also dcmonstratcd in the survival analysis in which diffcrcnccs attained statistical slgnificancc (P = .()I). In this group the median survival was mcrcascd from 79 weeks on CV to 31 weeks on CAV and 39 weeks on CEV. My~i~~sur)pr~ssion was the most frcqucnt toxicity. It was more severe with CV than CEV or CAV. Most nonhcmatologic sjdc effects wcrc comparable among the lhrcc trcatmcnt groups. However, the high dosch of oyclophosphamidc in the CV rcglmcn produccd a higher mcidcncc of hemorrhagic cystitis than in the CEV or CAV programs (P c .OOl 1. Cardtotoxtcity only occurred in the CAV group (P = .O5). The addition ol’ctoposide to the CV regimen rest&cd in significantly longer rcsponscduration andsurvIval without incrcascd toxicity. Similarly, the substitution of etoposldc for the doxorubicin in the CAV rcglmcn was assoctatcd with prolonged survival and reduced ca~d~otox~crly.

A phaseI-Ilstudyofsequentialinfusion VP-16andcisplatin therapy in advanced lung cancer Krook JE, JettJR,LittleC. Dulurhc~i~Jc,Du~~fh, M~VSS~YOS. Am JClin Oncol. Cancer Clin Trials 1989; 12: 114-7.

Although the etoposidc (VP- 16) and cisplatin combination has shown therapeutic activity in lung cancer, human results to date have not matched the expectation of synergism raised by animal model studies. Laboratory studies suggest that therapeutic synergism of etoposide and cisplatin may be related to factors of drug ConccnKatjou, time of exposure, and sequencing. To pursue this question, we developed regimens of ctoposide glvcn by 72 h infusion in conjunction with sequential bolus or mfusion cisplatin. Tbuty-two patlcnts wcreentcred. Fourteen of 15 small-cell lung cancer palicnts had a response (CR, PR, regression) with a median survival of 321 days. Nine of I7 patients with non-small-ceil lung~an~crachie\~cdaresponse,includin~two~Rs.The median survival is 201 days. The major toxicity was myclosupprcssion. At the highest etoposidc dosage tested, 42% of patients had leukopenia less than 2000/mm3. Thcrc wcrc no treatment-related deaths. This new approachof~ombin~ctoposidcand cisplatin therapy shows promising thcra~)cutt~ activity against hoth small ccl1 and non-small-cell lung cancer.

Duration of chemotherapy in small cell lung cancer: A cancer research campaign trial Spiro SG, Souhami RL, Geddes DM et al. Brompton Ihspitai. London SW.?. Br J Cancer 1989;59:578-83.

A total 01’610 patients with small ccl1 lung cancer were entered into a randomised trial designed to assess the effect of duration of initial chemotherapy on survival. Patients were randomised to receive either lour or eight courses OF cytotoxic chemotherapy wtth cycle- phosphamide, vincristineandetoposideandalsorandomised toreccivc, on disease progression, either second line chemotherapy (methotrexatc anddoxorubicm)orsymptomatictreatmentonly.In thewholestudy 196 (32.1%) had limited disease and 414 (67.9%) extensive disease. During initial ch~mo~crapy the rcsponsc rate (complete and partial responses) after ibur courses of treatment was 61% with no sigmficant increase in patients receiving eight courses (63%). In those rdndomlSed lo reccivc relapse chemotherapy the response rate was lmprovcd slightly for tbosc who hadcr~ginally received fourcourscsoTchcmotherapy (25.6W)over those rccclvmg eight (18.7%). The overall results show that of the f-our possible tre~~cntrandomisati(~ns, ~ourcourscsofchcrllothcrapyalonc 1s mfcrior m terms of overall survival (30 weeks median survival) to the other three treatment opttons (39 weeks median survival, P < 0.01). In palxnls responding to initial chemotherapy the disadvantage of [our courxs 01 chcmothcrapy alone was apparent (median sunrival of 40

weeks versus 40 weeks, P = 0.003) but not 11 drug trcalment was given on rclapsc. The study shows that limitmg treatment to four courses of chemotherapy alone is associated wtth inferior survlbal, but thiz is not the case if chemotherapy IS given at relapse.

Controlled trial of twelve versus six courses of chemotherapy in the treatment of small-cell lung cancer Bleehen N.M. Fayers P.M. Girling D.J. Stephen:; R.J. Cnrdiofhnracic Ep;d~~~oi~gy Group, ~r#~(~n ~i~.~pitui, Lon&xt SU’.+ rjHF Br J Cancer 1980;59:583-90.

A total of 497 patients with histologically or cyrologically confirmed small-cell lung cancerwercprescribed imtial treatmcntwith six courses of etoposidc, cyclophosphamide, methotrcxate and vincrtstme at 3- week intervals. Patients with limited disease (74% of the total) also received radiotherapy (40 Gy in 15 fractions in 3 weeks) to the primary site belwecn courses 2 and 3. At the end of this mltlal treatment, 265 patients still in complete or partial response were randomly allocated 10 six further courses of maintenance chemotherapy (M series: I3 I pa- tients) or lo no m~ntcnance chemo~erapy (NOM series. 134 patients). Response, as assessed 3 weeks after the second course of initial chemotherapy, was achieved in 85% of the 264 patients assessed, a complctc response tn 11 o/E, The median survival pcnod from the date of start of chemotherapy was 39 we&s; 154 (3 1% ) of the patients were alive at 1 year,29(6%)at 2 yearsand 17(3%)at3 years.The patients’ general condition and extent OF disease pretreatment correlated significantly with survival. Among the 131 M and I34 NOM pauents there was no overall survival advantage to either series (P = 0.27, log rank lcsl), although in 99 patlcnts who had a complete respun\e to imtial chemo- therapy as assessed at the time ofrandomisalion there was a suggestion that survival was longer in the M scnes (P < 0.O.S. log rank test), the median survival perrods from the date of randomisatlon b&g 4? weeks for the M and 30 weeks for the NOM patients. Maintenance chemother- apy was associated with additional toxicity and a poor quality of lift as asscsscd intermittently by clinicians and daily ply patients. In conclu- sion, no worthwhile clinical advantage was achkcved by the policy of continuing chemotherapy beyond six courses, cxccpt possibl) in pa- ticnts with a complctc response to the mttlal SIX CO~FSCS.

Cisplatin dose intensity in non-small cell lung cancer: Phase II results of a day I and day 8 high-dcrse regimen Ciandara DR, Weld H, Pcrcz A et al. Division ofllemu2olofiylOncoi~~~. Universily ofCa[$ornia, Davis. CA J Natl Cancer Ins1 1989;81:790-4.

Betwtxn October 1985 and March 1987,92 patients were registered on a phase II study of the Northern Califorma Oncology Group invcs- ttgating the importance of dose intensity in the trealmcnt of advanced non-small cell lung cancer (NSCLC). Trcatmcnt consisted of high-dose cisplatin in hypertonic saline (200 mg/m* on a ?:J-day cycle) given ma divided day 1 andday 8 schedule.The response rate among 76 assessable patients was3hB (27/76),wittrcomplctetrspons~(CR) 1118%(6/76)and partial rcsponsc (PR) in 28% (21176). If all ~tl~nts receiving any drug therapy wcrc considered, the overall response rate wa< 3 1 o/ i 27/X7), with CR in 7% (6/87) and PR in 24% (71/X7). Median survival times for all asscssablc patients and all patients rexx:clv~np any thcrap) were 37 and 35 wccks,rcspectivcIy. Withtheuscol aprottrcoldeslgn~pccifylngdosc delays rather than dose rcdu~tion for toxicicy. the mean do.sc mtensily delivered was 47.2 m&‘m’ per w-eck. or 04% of pn’jcttcd. Compared wuh other dose-mtcnsivc rcgimcns 01‘ claplatm, this day 1 and ddy 8 schcdulc wasrclat~vcly wclltolcratcd, wllhpcr~phcralnt,uropalllya\ the dose-limiting toxicity. The data on rcbponsc and mcdlan survival mncs among patients receiving this single-agent therap) arc encouraging. They support the potential importance ofcisplairn dose mtcnsny m ths treatment of NSCLC. Whsthcr thcsc results rcprcscnt a positive do=- rcsponsc cffcct in NSCLC will be lestcd in a randoml/cd comparallvc trial of tugh-dose versus standard-docc cl@arm thcrap)