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Concurrent carboplatin (CBDCA) and radiotherapy (RT) for unresectable stage III (Mo) non-small cell lung cancer (NSCLC)
Abskacls/Luy
Cancer 10 Suppl. 1
(1994)S331-S340
The median survivalof the first 100patients was 6.9 months (95% confidence interval : 5.9-7.9 months). There were no significantdifferencesbetween treatment armswith respectto time, to local progressionor survival.Six out of 51 (12%)of patients randomizedto RT alone had a complete or partial response, compared with 17/49 (35%)patients randomizedto RT t SFU (P = 0.009).Patients actuallyreceivingcombined treatment had significantlymore vomiting,oesophagitis and skin reactions. We concludethat since 5FU alone has lowactivityin NSCLCthe increasedresponserate to combinedtreatment maybe due to a synergisticradiosensitizingeffect of 5FU.
A phase III randomizedstudy of concurrentradical acceleratedradiotherapy(RT)and carboplatinin inoperablenon-smallcell lungcancer (NSCLC) J.F. Bishop”,D.L. Ball”, J. Smith”,A.M. Hayes”.E. Crennana, S. Davis”, I.N. Olve?, P. O’Brienb, D. Joseph@Peter MacCallum Cancer Institute, Melbourne, Australia,bRoyalAdelaideHospital,Adelaide, Australia, ‘Mater MisericordiaeHospital, Newcastle, Australia Inoperable, histologicallyproven NSCLC patients with good performance status (ECOG O-l), weight loss < lo%, diseaseconfinedto lung and mediastinum, no prior RT or chemotherapyand adequate pre-therapy blood counts were entered on this study. Patients were randomizedto arm I : conventionalRT 60 Gy/30 fractions/6 weeksor arm II : acceleratedRT 60 Gy/30 fractions/3 weeksor arm III : conventionalRT as in arm I plus carboplatin 70 mg/m2/day, days 1 to 5, weeks1 and 5 or arm IV : acceleratedRT as in arm II plus carboplatinon week1 only.Of 69 patients,median age was 65 (range 46-79) years, 81% were male, 19% female; 25% were ECOG performancestatus grade 0 and 75% grade 1, 72% were squamousand 28% nonsquamoushistology.The incidenceof acuteWHOgrade 2 to 4 toxicityoccurringin the first 4 months is : Nauseat vomitingNeutropeniaThrombocytopenia OesophagitisARMI 18060% 0% 29%ARMII 33% 0% 0% 67%ARMIII 31% 44% 25% 75%ARMIV 35% 13%0% 71% Patients in arm II had significantlymore severe oesophagitisthan arm 1 (P = O.Ol),those in arm III had significantlymore severe oesophagitisthan arm I (P = 0.01)but no significantdifferencewas seen comparing arm II and IV or III and IV. The median
SX
duration of oesophagitiswas significantlylonger in patients having accelerated RT. No patient with con-
ventional fractionation had oesophagitisat 4 months comparedwith 40% of patients on arm II and 29% on arm IV (P = 0.0001).Patients in arm III had aignificantlymore neutropenia(P = 0.00015)and thrombocytopenia (P=O.O17)than in arm I but there were no significantdifferencesin cytopeniaseen between the other arms.Three patients on arm III did not have the planned second course of carboplatin because of cytopenia. The median survival was 19.3 (s.e. +3.2) months.We concludethat acceleratedRT is associated with significantlymore severeoesophagitis.Concurrent carboplatinwas tolerable but was associatedwith significantlymore oesophagitis,neutropeniaand thrombocytopeniawhen addedto conventionalbut not to accelerated RT. The influence of this approachon tumor control requiresfurther accrual.
ConcurrentcarboplatinICBDCA)and radiotherapy (RT) for unresectablestage III (MO)non-smallcell lungcancer(NSCLC) C.P. Belani, R. Slawson,D. Hiponia and J. Aisner. University of Maryland Cancer Center. Baltimore, Maryland21201,USA. Thirty-sevenpreviouslyuntreated stage III (MO)unresectableNSCLChave been treated with concurrent RT and weeklyCBDCAadministeredas a single IV bolus of 7.5mg/m2/week to the first 6 patients: then 100 mg/m’/week to subsequentpatients. Radiotherapy, 1.8-2.0Gy/day in fivefractionsweeklyfor a total of M)Gy was given concurrently.Patients characteristics include : median ECOG PS 1 (range O-21,median age 61 years (range 42-73), 32 men and 5 women.The histologicsubtype was squamous cell carcinoma 14, adenocarcinoma12, adenosquamouscarcinoma5 and large cell carcinoma6. Among the first 35 evaluable patients, there was one completeresponse, I1 partial responsesand 15 had stable disease.The median survivalof all evaluablepatients is 13months.Overallthe treatment was well tolerated.Two patients developed acute hypersensitivityreactions : in the first this was manifested as hypotension,dyspnea,chest pain. rash and fever to 105Fwhile the second patient had only dyspnea,rash and hyperthermia(T,,,,,“’105F).Other toxicities included nausea/vomiting (2 grade III, 2 grade IV), mild pharyngitis(3 grade II), esophagitis(5 grade II, 1 grade III), leucopenia(5 grade III, 2 grade IV). thrombocytopenia(2 grade IV), anemia (I grade
S336
III, 1 grade IV) and radiationskin changes.The combination of carboplatin and RT is well tolerated and shows considerable promise in patients with unresectablelocallyadvancedNSCLC.
Acceleratedhyperfixctionatedthoracic radiation therapy (AIITRT) plus concomitant VPlWDDP chemotherapyfor unresectahlestage III non-small cell lung cancer (NSCLC) E. Shaw,W. McGinnis,J. Jett, J. Su, J. Mailliard,R. Engel,M. Wiesenfeld,K. RowlandNorth Central Cancer TreatmentGroup(NCCTG)and MayoClinic.55905 RochesterMN, Des Moines IA, Omaha NE, St Cloud MN, Cedar RapidsIA, and Urbana IL. The purpose of this study was to determine the incidenceof severeor greater acute treatment toxicity, and secondarily,response, local control, and survival utilizing AHTRT plus concomitant VPlbCDDP chemotherapyfor patientswithunresectablestagesIIIA and IIIB NSCLC. From 5/90 through l/91,23 evaluablepatientswere treated with AHTRT (6000cGy in 40 fractionsof 150 cGy BID, 6 h between fractions,2 weekbreak midway through treatment), plus two cycles of concomitant VP16 (100 mg/m2) and CDDP (30 mg/m2) chemotherapy(d 1,2,3,28,29,30). The 13 males and 10 females had a median age of 61 years (range 42-75). Twenty-onepatients had an ECOG performancestatus of 0 or 1, and 15 had weightloss > 5%. Nine patients had squamous cell carcinoma, 7 adenocarcinoma,5 large cell carcinoma,and 2 mixed NSCLChistologies. Nine patients (39%) had stage IIIA disease while 14 (61%)were stage IIIB. With follow-upof 12-18 months, 18 patients are alive, 11 without and 7 with disease progression, whereas 5 are dead, 4 of disease progression.Three patients (13%)had acute grade 3 radiation esophagitis requiring i.v. hydration. Three patients (13%) developed grade 3 (1 patient) or grade 4 (2 patients) acute radiation pneumonitis requiring oxygenand steroids. Four patients (17%) developed grade 4 leukopenia; there were no other severe or greater hematologic toxicities.Overall,8 patients (35%)experiencedeither an acute grade 3 or 4 radiation toxicityor a grade 4 hematologictoxicity.These resolved to < grade 2 exceptin 1 patient who developedARDSand died. Six patients (23%) achieveda completeresponsewhile 9 (39%)had a partial response or regression.Of the 11
Abstracts/Lung Cancer 10 Suppl.l(1994) S331-S340
patients who experiencedtreatment failure, 10 developed systemicmetastasesand only one a local failure, i.e., local control has been achievedin 22/23 patients (96%).Median survivalhas not been reached.The 18 month actuarialsurvivalis 72%. In conclusion,this regimenof AHTRTplus concomitant VPlbCDDP chemotherapycan be given with an acceptableincidenceof acute toxicity.Response,local control,and survivalrates in this unfavorablegroup of patients are encouraging.A North Central Cancer Treatment Group Phase II study of standard TRT (6000 cGy in 30 fractions of 200 cGy each) versus AHTRTversusAHTRTplusconcomitantVP16-CDDP chemotherapyis nowopen.
A phase II study of vindesineand cisplatin (VP)used concurrentlywith thoracic radiotherapy(TRT)for locallyadvancednon-small cell lung cancer (NSCLC) NagahiroSaijo, MasahiroFukuoka, KiyoyukiFuruse, Yutaka Ariyoshi, Harumichi Ikegami, Yuko Kurita, Yutaka NishiwakiJapaneseLung Cancer Chemotherapy Group (JLCCG)supportedby Grants-in-Aidfrom the Ministryof Health and Welfare,Japan. The JLCCGinitiated a phase II studyof concurrent VP chemotherapyand TRT in patientswith stage IIIA or IIIB NSCLCin October 1989.The treatment consistedof cisplatin100mg/m2 iv on day 1 and vindesine 3 mg/m2 iv on days 1 and 8 every 4 weeks, and concurrentTRT 2 Gy once dailyX 5/w for twoweeks in each chemotherapycycle (total 50-60 Gy). When grade 4 toxicity(WHO criteria) occurred,the dosesof VP were reducedby 75% As of May 1991,there were 34 patients enrolledin this study.The median age was 58 years (range : 40-71). Thirtywere male and 4 were female.Twenty-sevenhad a ECOG PS of 0 or 1, and 7 had a PS of 2. All patients had had no prior therapy. To date 21 patientshaveprovedto be evaluable.Twelve of 21 patients (570/o,95% CI : 34%~80%)achieveda PR, although no patients achieveda CR. The median duration of responsewas 22 t weeks.The median survival has not been reached yet. Grade 2 3 leukopenia wasobservedin 96%of the patients,thrombocytopenia in 4%, and anemia in 28%. Twelvepatients experienced mild esophagitis.These preliminaryresults suggest that concurrentVP regimenand TRT is activefor locallyadvancedNSCLCwith acceptabletoxicity,and warrants a randomizedphase III trial comparingwith TRT alone.
Cancer 10 Suppl. 1
(1994)S331-S340
The median survivalof the first 100patients was 6.9 months (95% confidence interval : 5.9-7.9 months). There were no significantdifferencesbetween treatment armswith respectto time, to local progressionor survival.Six out of 51 (12%)of patients randomizedto RT alone had a complete or partial response, compared with 17/49 (35%)patients randomizedto RT t SFU (P = 0.009).Patients actuallyreceivingcombined treatment had significantlymore vomiting,oesophagitis and skin reactions. We concludethat since 5FU alone has lowactivityin NSCLCthe increasedresponserate to combinedtreatment maybe due to a synergisticradiosensitizingeffect of 5FU.
A phase III randomizedstudy of concurrentradical acceleratedradiotherapy(RT)and carboplatinin inoperablenon-smallcell lungcancer (NSCLC) J.F. Bishop”,D.L. Ball”, J. Smith”,A.M. Hayes”.E. Crennana, S. Davis”, I.N. Olve?, P. O’Brienb, D. Joseph@Peter MacCallum Cancer Institute, Melbourne, Australia,bRoyalAdelaideHospital,Adelaide, Australia, ‘Mater MisericordiaeHospital, Newcastle, Australia Inoperable, histologicallyproven NSCLC patients with good performance status (ECOG O-l), weight loss < lo%, diseaseconfinedto lung and mediastinum, no prior RT or chemotherapyand adequate pre-therapy blood counts were entered on this study. Patients were randomizedto arm I : conventionalRT 60 Gy/30 fractions/6 weeksor arm II : acceleratedRT 60 Gy/30 fractions/3 weeksor arm III : conventionalRT as in arm I plus carboplatin 70 mg/m2/day, days 1 to 5, weeks1 and 5 or arm IV : acceleratedRT as in arm II plus carboplatinon week1 only.Of 69 patients,median age was 65 (range 46-79) years, 81% were male, 19% female; 25% were ECOG performancestatus grade 0 and 75% grade 1, 72% were squamousand 28% nonsquamoushistology.The incidenceof acuteWHOgrade 2 to 4 toxicityoccurringin the first 4 months is : Nauseat vomitingNeutropeniaThrombocytopenia OesophagitisARMI 18060% 0% 29%ARMII 33% 0% 0% 67%ARMIII 31% 44% 25% 75%ARMIV 35% 13%0% 71% Patients in arm II had significantlymore severe oesophagitisthan arm 1 (P = O.Ol),those in arm III had significantlymore severe oesophagitisthan arm I (P = 0.01)but no significantdifferencewas seen comparing arm II and IV or III and IV. The median
SX
duration of oesophagitiswas significantlylonger in patients having accelerated RT. No patient with con-
ventional fractionation had oesophagitisat 4 months comparedwith 40% of patients on arm II and 29% on arm IV (P = 0.0001).Patients in arm III had aignificantlymore neutropenia(P = 0.00015)and thrombocytopenia (P=O.O17)than in arm I but there were no significantdifferencesin cytopeniaseen between the other arms.Three patients on arm III did not have the planned second course of carboplatin because of cytopenia. The median survival was 19.3 (s.e. +3.2) months.We concludethat acceleratedRT is associated with significantlymore severeoesophagitis.Concurrent carboplatinwas tolerable but was associatedwith significantlymore oesophagitis,neutropeniaand thrombocytopeniawhen addedto conventionalbut not to accelerated RT. The influence of this approachon tumor control requiresfurther accrual.
ConcurrentcarboplatinICBDCA)and radiotherapy (RT) for unresectablestage III (MO)non-smallcell lungcancer(NSCLC) C.P. Belani, R. Slawson,D. Hiponia and J. Aisner. University of Maryland Cancer Center. Baltimore, Maryland21201,USA. Thirty-sevenpreviouslyuntreated stage III (MO)unresectableNSCLChave been treated with concurrent RT and weeklyCBDCAadministeredas a single IV bolus of 7.5mg/m2/week to the first 6 patients: then 100 mg/m’/week to subsequentpatients. Radiotherapy, 1.8-2.0Gy/day in fivefractionsweeklyfor a total of M)Gy was given concurrently.Patients characteristics include : median ECOG PS 1 (range O-21,median age 61 years (range 42-73), 32 men and 5 women.The histologicsubtype was squamous cell carcinoma 14, adenocarcinoma12, adenosquamouscarcinoma5 and large cell carcinoma6. Among the first 35 evaluable patients, there was one completeresponse, I1 partial responsesand 15 had stable disease.The median survivalof all evaluablepatients is 13months.Overallthe treatment was well tolerated.Two patients developed acute hypersensitivityreactions : in the first this was manifested as hypotension,dyspnea,chest pain. rash and fever to 105Fwhile the second patient had only dyspnea,rash and hyperthermia(T,,,,,“’105F).Other toxicities included nausea/vomiting (2 grade III, 2 grade IV), mild pharyngitis(3 grade II), esophagitis(5 grade II, 1 grade III), leucopenia(5 grade III, 2 grade IV). thrombocytopenia(2 grade IV), anemia (I grade
S336
III, 1 grade IV) and radiationskin changes.The combination of carboplatin and RT is well tolerated and shows considerable promise in patients with unresectablelocallyadvancedNSCLC.
Acceleratedhyperfixctionatedthoracic radiation therapy (AIITRT) plus concomitant VPlWDDP chemotherapyfor unresectahlestage III non-small cell lung cancer (NSCLC) E. Shaw,W. McGinnis,J. Jett, J. Su, J. Mailliard,R. Engel,M. Wiesenfeld,K. RowlandNorth Central Cancer TreatmentGroup(NCCTG)and MayoClinic.55905 RochesterMN, Des Moines IA, Omaha NE, St Cloud MN, Cedar RapidsIA, and Urbana IL. The purpose of this study was to determine the incidenceof severeor greater acute treatment toxicity, and secondarily,response, local control, and survival utilizing AHTRT plus concomitant VPlbCDDP chemotherapyfor patientswithunresectablestagesIIIA and IIIB NSCLC. From 5/90 through l/91,23 evaluablepatientswere treated with AHTRT (6000cGy in 40 fractionsof 150 cGy BID, 6 h between fractions,2 weekbreak midway through treatment), plus two cycles of concomitant VP16 (100 mg/m2) and CDDP (30 mg/m2) chemotherapy(d 1,2,3,28,29,30). The 13 males and 10 females had a median age of 61 years (range 42-75). Twenty-onepatients had an ECOG performancestatus of 0 or 1, and 15 had weightloss > 5%. Nine patients had squamous cell carcinoma, 7 adenocarcinoma,5 large cell carcinoma,and 2 mixed NSCLChistologies. Nine patients (39%) had stage IIIA disease while 14 (61%)were stage IIIB. With follow-upof 12-18 months, 18 patients are alive, 11 without and 7 with disease progression, whereas 5 are dead, 4 of disease progression.Three patients (13%)had acute grade 3 radiation esophagitis requiring i.v. hydration. Three patients (13%) developed grade 3 (1 patient) or grade 4 (2 patients) acute radiation pneumonitis requiring oxygenand steroids. Four patients (17%) developed grade 4 leukopenia; there were no other severe or greater hematologic toxicities.Overall,8 patients (35%)experiencedeither an acute grade 3 or 4 radiation toxicityor a grade 4 hematologictoxicity.These resolved to < grade 2 exceptin 1 patient who developedARDSand died. Six patients (23%) achieveda completeresponsewhile 9 (39%)had a partial response or regression.Of the 11
Abstracts/Lung Cancer 10 Suppl.l(1994) S331-S340
patients who experiencedtreatment failure, 10 developed systemicmetastasesand only one a local failure, i.e., local control has been achievedin 22/23 patients (96%).Median survivalhas not been reached.The 18 month actuarialsurvivalis 72%. In conclusion,this regimenof AHTRTplus concomitant VPlbCDDP chemotherapycan be given with an acceptableincidenceof acute toxicity.Response,local control,and survivalrates in this unfavorablegroup of patients are encouraging.A North Central Cancer Treatment Group Phase II study of standard TRT (6000 cGy in 30 fractions of 200 cGy each) versus AHTRTversusAHTRTplusconcomitantVP16-CDDP chemotherapyis nowopen.
A phase II study of vindesineand cisplatin (VP)used concurrentlywith thoracic radiotherapy(TRT)for locallyadvancednon-small cell lung cancer (NSCLC) NagahiroSaijo, MasahiroFukuoka, KiyoyukiFuruse, Yutaka Ariyoshi, Harumichi Ikegami, Yuko Kurita, Yutaka NishiwakiJapaneseLung Cancer Chemotherapy Group (JLCCG)supportedby Grants-in-Aidfrom the Ministryof Health and Welfare,Japan. The JLCCGinitiated a phase II studyof concurrent VP chemotherapyand TRT in patientswith stage IIIA or IIIB NSCLCin October 1989.The treatment consistedof cisplatin100mg/m2 iv on day 1 and vindesine 3 mg/m2 iv on days 1 and 8 every 4 weeks, and concurrentTRT 2 Gy once dailyX 5/w for twoweeks in each chemotherapycycle (total 50-60 Gy). When grade 4 toxicity(WHO criteria) occurred,the dosesof VP were reducedby 75% As of May 1991,there were 34 patients enrolledin this study.The median age was 58 years (range : 40-71). Thirtywere male and 4 were female.Twenty-sevenhad a ECOG PS of 0 or 1, and 7 had a PS of 2. All patients had had no prior therapy. To date 21 patientshaveprovedto be evaluable.Twelve of 21 patients (570/o,95% CI : 34%~80%)achieveda PR, although no patients achieveda CR. The median duration of responsewas 22 t weeks.The median survival has not been reached yet. Grade 2 3 leukopenia wasobservedin 96%of the patients,thrombocytopenia in 4%, and anemia in 28%. Twelvepatients experienced mild esophagitis.These preliminaryresults suggest that concurrentVP regimenand TRT is activefor locallyadvancedNSCLCwith acceptabletoxicity,and warrants a randomizedphase III trial comparingwith TRT alone.