1
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 1smfcrior 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)

A phase I-II study of sequential infusion VP-16 and cisplatin therapy in advanced lung cancer

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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)