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vincristine therapy in small cell lung cancer
142
Abstracts/Lung Cancer 10 (1993) 123-150
Chrom0Sonle 2, Whereas in the emergence of P-glycopmteio-mediated multidrug resistance P reammgement of the long arm of chromosome 7 is B critical event.
II has P better toxicity ~mfile than cisulatinl&~ide is very well tolerated by elderly patients. important
Multidmgresis~inasnallceUlungwith etoposide
and dtfferential
chemosensitization
he: Rapid sektior~ with cycIospmrin
when comoared
nonhenntologic
side effscts.
which has led to its assessment
iadoseesuwions~cswithcolony-stimulatingkctors~putologous hone marrow
tnnsplanlation.
A
Glisson BS, Alpeter MD. DepanmcntofMedical Oncology, Uniwrsity of Terar. MD Anderson Caner Center, Houston, 7X 77030. AntiCancer Drugs 1992;3:35946. We developed a multidrug resistant small cell lung cancer line, VPR2, by exposing H69 parent cells to etoposide (20 M) for 1 h daily for 8 days every 21-28 days, a schedule similar to that used in the clinic. Resistance. (20-fold) to the cytostatic and DNA cleavage activities of etoposide emerged after the third treatment, and this pheno?ype was stable in the absence of drug exposure for 2.5 years. VPR-2 cells exhibited cross resistanceto inlercalating agents and vincaalkaloids. but remained sensitive to X-radiation. cisplrdio and 5-tluorouracil. The human mdrl gene was overexpressed in the resistanl line, but steadystate concentrations of etoposide were reduced only 1.5-fold. Topoisomemse II catalytic and etoposide-stimulated DNA cleavage activity in nuclear extracts from both lines were identical despite retention of a 3-fold level of resistance to etoposide-induced strand breaLsinisolntednucleifromVPR-2ceUs. CyclospxinAaodverapnmil, both of which bind to P-glycoprotein, enhanced accumulation of etoposide in VPR-2 cells, and H69 cells to a lesser extent. Yet only cyclosporin A was effective in differentially enhancing etoposide cytostasis in VPR-2 relative lo H69. In VPR-2 whole celIs, cyclospotin A enhanced etoposide-induced DNA single-strand break frequency 9fold but had no effect in isolated nuclei. Rapid selection of this line with a clinically relevant drug exposure schema and stability of the resistant phenotype suggest these cells may have been a steady subpopulation of the parent line through years of serial passage in vitro. The data also indicatethat theability ofcyclosporin Atoenhanceetoposideseasitivity in VPR-2 cells is unlikely lo be mediated wholly through an interaction with P-glycopmtein. Sincecyclosporin A, but not vempamil, served to discriminate VP R-2 cells from the parent line, this effect may offer a clue to an additional mechanism of resistance in this cell line. phase
U feastbility
cispIatin
(HDEEC)
study
of bigh dose epirubiein
regimen
in small
plus etopaside
and
cell lung cancer
RosellR, CarlesJ,AbndA,Ji~oJM,M~re~oI,B~A.Ribelles N. Haboubi N. Medical OncoIogy Unit, Hosp. Uniwrsir. Germam i%as/Pujol, Box 72.08916 Bad&ma. Barc&na. Invest New Drugs 1992; lo: 123-8. Seventeen patients with small cell lung cancer entered P phase II hial testing the feasibility of adding high dose epimbicin (LOO-120mg13. day 1) in combination with dposide (60-80 mg/3! days l-5) and cisplatin (70 mg/&, day 1) courses repeated every three weeks. Complete responders received thoracic (40 Gy) and prophylactic cranial (30 Gy) irradiation. Sixteen @ieats were evaluable for response and toxicity. Myelosuppressionwssthedose-limitiagsiheffsct. NeutroPenic fever was observed in eight patients (53 %) and stomatitis in six (40%). No patient had a > 14% decline in the cardiac ejection fraction. Strict adherence to the doseschedule designed was impossible as doses were trimmed and delayed in 30% of instances. The overall objective response rate was 81%(95% confidence limits, 62% to 100%). in limited disease there were complete remissions in 57%. With a 16 months median follow-up. oven11 median survival was 13 months. This stiy was unable to prove the feasibility of epimbicin escalation when added to etoposidecisplatin combination, hampering the doseintensification Norton- Simon model test. t3rboplattn/etopostd
in mnaI1 &I
lung cancer
Bishop JF. Department of Hemoto~gy, Peter MacCallunt C~nfcr Inrritute, 281 Littk Lon.rdak St. Melbourne 3ooO Vk. OllCOlOgY (Switzerland) 1992;49:Suppl 1: 1 l-8. Cmbopladn/etoposide is an active combiition in small cell 1Ung qtivdat to cancer. In phase II studies, it produces results that qp cisplatin/etoposide, but it has notbeen compared in arandomi~ sdY.
CODEehwotherPpywithorwithoutroeombinrnth~gr~aul~ cyte
colony4imulating
factor
in extensivestage
smaIl
124 lung
cancer Masuda
N, Fukuoka M, Furuse K. Depanmenr of Internal Medicine. Osaka prejccrural Habikino Hospital. 3-7-I Habinkino. Habikino. OS& 5631. Oncology (Switzerland) 1992;49:Suppl I: 19-24. CODE therapy demonstrated high Pntihunor activity in extensivesinge small cell bmg cancer (SCLC). Toxicity was acceptable in P regimen with P nine-cycle schedule. 7be results obtaiied in this shady suggest that CODE tbempy impmves the outcome of patients with extensive-stage SCLC. The use. of recombii~ human gramdocyte colony-stimulating factor may well reduce the durption and degree of neutropeniaduringCODEchemother~pyandincre~sethedose~~etensi~y, leading lo further improvemenl of outcome.
CarbopIatin/ Gntzemeier
etoposide/
vbwistine
therapy
insmpll
cell lung eLneee
U, Van
Pave1 J. Laumeu R, Hossfsld DK, Neutwss R. Reck M et al. Depa~?men~of 7homcic Oneo@y, Grossha~~~~ Hospiral, Cenrer PneumocologyfZhoracic Surgery. D-W 2070 Grosshansdo$ Oncology (Switwxland) 1992;49:Suppl 1:25-33. Carboplatin is one of the most active agents in untreated small cell lung cancer (SCLC; 14% complete -rise. CR; and 61% CR + (CEV) (&se II t&l) led to M overall rem&ion r&f 84% in patients with limited disease, with 52 96CR. The me&i survival time with (his combination was 13 months in patients with limited disease and 9.5 months in those with extensive disease. The 4-year swvival rates are. 26 96 in limited disease and 8 % in exteasive disease, with a plateau of the survival curve. This regime is highly effective and exhibits low toxicity in SCLC. To evaluate the role of carboplntin in combination chemothenpy in p&ie.nts with extensive SCLC, D phase III trial was performed. In this ongoing trial comparing CEV and etoposidel vincristine in SCLC patienls with extensive disease, CR and overall response rates are higher in the.CEV arm (CR 32 vs. 17 I, CR - PR 80 vs. 60%). with statistically significant difference. In summary, chemotherapy regimens containing platinum wmpounds are among the most active in the treatment of SCLC. The use of the new compound carhoplatin instead ofcisplntin has led to similar or increased remission rates and is preferable because it has fewer side sffezts. Preliminary results from this ongoing, pmspextive, randomized phase III trial will be presented. PIatinum/etopaside Bonomi
P.
therapy
in non-smaIl
ceIl lung cancer
Section of Medical Oncology, Rush Clniwrsify Medical Cenrer, 1725 W. Harrison, Chicago, IL60612 Oncology (Switzerland) 1992;49:Suppl 1:43-50. Non-small cell lung cancer (NSCLC) is P major health problem in the United States and in many other parts of the world. Identification of systemic therapy that can maintainorimprove quIi?y of life and prolong survival iswealial becauselwallyadvanceddiseaeordistant metastasis is found in the majority of these patients. A variety of combination regimens have produced rssponse rates of 20% or grealer in stage IV NSCLC patients in coopertive group trials, including studies conducted within the Eastern Cooperative Chwology Group (ECOG). Although no regimenhasemergedPsclearlysuperior, thehighest I-yearsurvival rate (25 %) in ECOG trials was observed in EP(etoposidel cisplalin)-treated patients. Subsequently, P randomized trial in which EP was compared to etoposide/carbopIatin revealed no significant differences io survival orresponsente,andtoxicitywasslightlylesswithetoposidJurpI~~. Results fmm recent phase II trials in which stage III NSCLC patients received preoperative EP and concurrent thoracic irradiation have shown response rates of 65-85 96, aswell as acceptable toxicity and surgical morbidity and mortality. Future stage IV NSCLC trials should
Abstracts/Lung Cancer 10 (1993) 123-150
Chrom0Sonle 2, Whereas in the emergence of P-glycopmteio-mediated multidrug resistance P reammgement of the long arm of chromosome 7 is B critical event.
II has P better toxicity ~mfile than cisulatinl&~ide is very well tolerated by elderly patients. important
Multidmgresis~inasnallceUlungwith etoposide
and dtfferential
chemosensitization
he: Rapid sektior~ with cycIospmrin
when comoared
nonhenntologic
side effscts.
which has led to its assessment
iadoseesuwions~cswithcolony-stimulatingkctors~putologous hone marrow
tnnsplanlation.
A
Glisson BS, Alpeter MD. DepanmcntofMedical Oncology, Uniwrsity of Terar. MD Anderson Caner Center, Houston, 7X 77030. AntiCancer Drugs 1992;3:35946. We developed a multidrug resistant small cell lung cancer line, VPR2, by exposing H69 parent cells to etoposide (20 M) for 1 h daily for 8 days every 21-28 days, a schedule similar to that used in the clinic. Resistance. (20-fold) to the cytostatic and DNA cleavage activities of etoposide emerged after the third treatment, and this pheno?ype was stable in the absence of drug exposure for 2.5 years. VPR-2 cells exhibited cross resistanceto inlercalating agents and vincaalkaloids. but remained sensitive to X-radiation. cisplrdio and 5-tluorouracil. The human mdrl gene was overexpressed in the resistanl line, but steadystate concentrations of etoposide were reduced only 1.5-fold. Topoisomemse II catalytic and etoposide-stimulated DNA cleavage activity in nuclear extracts from both lines were identical despite retention of a 3-fold level of resistance to etoposide-induced strand breaLsinisolntednucleifromVPR-2ceUs. CyclospxinAaodverapnmil, both of which bind to P-glycoprotein, enhanced accumulation of etoposide in VPR-2 cells, and H69 cells to a lesser extent. Yet only cyclosporin A was effective in differentially enhancing etoposide cytostasis in VPR-2 relative lo H69. In VPR-2 whole celIs, cyclospotin A enhanced etoposide-induced DNA single-strand break frequency 9fold but had no effect in isolated nuclei. Rapid selection of this line with a clinically relevant drug exposure schema and stability of the resistant phenotype suggest these cells may have been a steady subpopulation of the parent line through years of serial passage in vitro. The data also indicatethat theability ofcyclosporin Atoenhanceetoposideseasitivity in VPR-2 cells is unlikely lo be mediated wholly through an interaction with P-glycopmtein. Sincecyclosporin A, but not vempamil, served to discriminate VP R-2 cells from the parent line, this effect may offer a clue to an additional mechanism of resistance in this cell line. phase
U feastbility
cispIatin
(HDEEC)
study
of bigh dose epirubiein
regimen
in small
plus etopaside
and
cell lung cancer
RosellR, CarlesJ,AbndA,Ji~oJM,M~re~oI,B~A.Ribelles N. Haboubi N. Medical OncoIogy Unit, Hosp. Uniwrsir. Germam i%as/Pujol, Box 72.08916 Bad&ma. Barc&na. Invest New Drugs 1992; lo: 123-8. Seventeen patients with small cell lung cancer entered P phase II hial testing the feasibility of adding high dose epimbicin (LOO-120mg13. day 1) in combination with dposide (60-80 mg/3! days l-5) and cisplatin (70 mg/&, day 1) courses repeated every three weeks. Complete responders received thoracic (40 Gy) and prophylactic cranial (30 Gy) irradiation. Sixteen @ieats were evaluable for response and toxicity. Myelosuppressionwssthedose-limitiagsiheffsct. NeutroPenic fever was observed in eight patients (53 %) and stomatitis in six (40%). No patient had a > 14% decline in the cardiac ejection fraction. Strict adherence to the doseschedule designed was impossible as doses were trimmed and delayed in 30% of instances. The overall objective response rate was 81%(95% confidence limits, 62% to 100%). in limited disease there were complete remissions in 57%. With a 16 months median follow-up. oven11 median survival was 13 months. This stiy was unable to prove the feasibility of epimbicin escalation when added to etoposidecisplatin combination, hampering the doseintensification Norton- Simon model test. t3rboplattn/etopostd
in mnaI1 &I
lung cancer
Bishop JF. Department of Hemoto~gy, Peter MacCallunt C~nfcr Inrritute, 281 Littk Lon.rdak St. Melbourne 3ooO Vk. OllCOlOgY (Switzerland) 1992;49:Suppl 1: 1 l-8. Cmbopladn/etoposide is an active combiition in small cell 1Ung qtivdat to cancer. In phase II studies, it produces results that qp cisplatin/etoposide, but it has notbeen compared in arandomi~ sdY.
CODEehwotherPpywithorwithoutroeombinrnth~gr~aul~ cyte
colony4imulating
factor
in extensivestage
smaIl
124 lung
cancer Masuda
N, Fukuoka M, Furuse K. Depanmenr of Internal Medicine. Osaka prejccrural Habikino Hospital. 3-7-I Habinkino. Habikino. OS& 5631. Oncology (Switzerland) 1992;49:Suppl I: 19-24. CODE therapy demonstrated high Pntihunor activity in extensivesinge small cell bmg cancer (SCLC). Toxicity was acceptable in P regimen with P nine-cycle schedule. 7be results obtaiied in this shady suggest that CODE tbempy impmves the outcome of patients with extensive-stage SCLC. The use. of recombii~ human gramdocyte colony-stimulating factor may well reduce the durption and degree of neutropeniaduringCODEchemother~pyandincre~sethedose~~etensi~y, leading lo further improvemenl of outcome.
CarbopIatin/ Gntzemeier
etoposide/
vbwistine
therapy
insmpll
cell lung eLneee
U, Van
Pave1 J. Laumeu R, Hossfsld DK, Neutwss R. Reck M et al. Depa~?men~of 7homcic Oneo@y, Grossha~~~~ Hospiral, Cenrer PneumocologyfZhoracic Surgery. D-W 2070 Grosshansdo$ Oncology (Switwxland) 1992;49:Suppl 1:25-33. Carboplatin is one of the most active agents in untreated small cell lung cancer (SCLC; 14% complete -rise. CR; and 61% CR + (CEV) (&se II t&l) led to M overall rem&ion r&f 84% in patients with limited disease, with 52 96CR. The me&i survival time with (his combination was 13 months in patients with limited disease and 9.5 months in those with extensive disease. The 4-year swvival rates are. 26 96 in limited disease and 8 % in exteasive disease, with a plateau of the survival curve. This regime is highly effective and exhibits low toxicity in SCLC. To evaluate the role of carboplntin in combination chemothenpy in p&ie.nts with extensive SCLC, D phase III trial was performed. In this ongoing trial comparing CEV and etoposidel vincristine in SCLC patienls with extensive disease, CR and overall response rates are higher in the.CEV arm (CR 32 vs. 17 I, CR - PR 80 vs. 60%). with statistically significant difference. In summary, chemotherapy regimens containing platinum wmpounds are among the most active in the treatment of SCLC. The use of the new compound carhoplatin instead ofcisplntin has led to similar or increased remission rates and is preferable because it has fewer side sffezts. Preliminary results from this ongoing, pmspextive, randomized phase III trial will be presented. PIatinum/etopaside Bonomi
P.
therapy
in non-smaIl
ceIl lung cancer
Section of Medical Oncology, Rush Clniwrsify Medical Cenrer, 1725 W. Harrison, Chicago, IL60612 Oncology (Switzerland) 1992;49:Suppl 1:43-50. Non-small cell lung cancer (NSCLC) is P major health problem in the United States and in many other parts of the world. Identification of systemic therapy that can maintainorimprove quIi?y of life and prolong survival iswealial becauselwallyadvanceddiseaeordistant metastasis is found in the majority of these patients. A variety of combination regimens have produced rssponse rates of 20% or grealer in stage IV NSCLC patients in coopertive group trials, including studies conducted within the Eastern Cooperative Chwology Group (ECOG). Although no regimenhasemergedPsclearlysuperior, thehighest I-yearsurvival rate (25 %) in ECOG trials was observed in EP(etoposidel cisplalin)-treated patients. Subsequently, P randomized trial in which EP was compared to etoposide/carbopIatin revealed no significant differences io survival orresponsente,andtoxicitywasslightlylesswithetoposidJurpI~~. Results fmm recent phase II trials in which stage III NSCLC patients received preoperative EP and concurrent thoracic irradiation have shown response rates of 65-85 96, aswell as acceptable toxicity and surgical morbidity and mortality. Future stage IV NSCLC trials should