- Email: [email protected]
Phase II trial of trimetrexate for unresectable or metastatic non-small cell bronchogenic carcinoma
280
Abstracts/Lung Cancer 10 (1993) 266-286
therapyiouseswithCRorpa&l response. However, severeleokopmia (< 2.ooO1”mt’) occurred more oRen after PEI (73 %) tha” after PE (44 I) therapy @ < 0.05). These results suggest that PEI is not superior to PE chemotherapy in SCLC. The use of ifosfamide in multimodality treatment regimens needs to be studied further.
Pbese n triad of trimetrexate for tmrsectable or metastatic nonsmall eelI bronchogenic carcinoma Fossella FV, Wii RJ, Holoye PY. Hallinao B, Raber MN, Hoelzer K et al. Taas Univ. M.D. Anderson Can. Ctr., Box 80, 1515 Holcombe BouLmwd, Houston, TX 77030. Invest New Drugs 1992;10:331-5. We trepted34chemotherspy-“~ive~tientswithstPgeIIIborIVno”small cell lung cancer with trimetrexate 150-200 mgld iotravenously over 30 mioutes every hue weeks. Six of 31 evnlwble patients (19%) achieved *partial reepolrse. The. major toxic effects from this regimen were myelosuppressioa, aawealvomiting. Pnd ski” rash. We conclude that this well- toI& schedule of trimetrexate has significant activity as P si”gle agent agaiast non-small cell hug cpocer.
Contpariso” between hvo dosages of cisplatinum and etoposide in relapsing s”aIl cell lung carci”o”la Trillet-Lenoir V, Lasset C, Arpia D, Bohas C, Riou R, Perol M et al. Hopital
Lmds-Pradel,
28 Avenue du Doyen-L@%
69394 Lyon Ceder
Bull Caacer 1992;79: 1173-81. Thesy”ergisticcombinntio”ofcispl~tiaumandetoposideappearsas the best second line. treatment in patients relapsing from small cell lung carcinoma (SCLC). I” order to test the dose-effect relationship of cisplatiaum pnd etoposide in this situation, we have performed a random&d phase II trial comparing 2 five-day regimens: Cisplatioum 20 mglm’lday + etopostde 60 mglm’lday (arm A) versw cisplatinum 40 mg/d/day + etoposide 100 mg/m’/day (art” B) every 4 weeks. Thir?y-seve”patientswereincluded(armA: 18,-B: 19),and32were consideredtobeeligible(armA: lS,am~B: 17). Eightpatientswerenoo evaluable, five of them because of toxic death occurring prior to the second course (arm A: one from neutropenia; arm 8: three from “eutropenia and o”e from tbrombopeoia). The hvo groups were well balancedwithregardtochemainpmgnosticfactors(age,sex, perfomwce status. LDH level, response to induction chemotherapy). A” objective respoose was observed in IO/24 evaluable patients (arm A: 4, ano B: 6) and was considered as complete in one pattent in arm A and in 2 pts in arm B; these two patients presented with cerebral metastases and their response lasted 9 Pnd I5 weeks respectively. The mean duration of respoose was 1 I weeks in arm A and 10.5 weeks in an” B. The median actuarial survival of the overall population of eligible patients was 15 weeks: 13 we&s in arot A and 16.5 weeks in an” B. The study was discontinued bec~useof the23.5 W toxicdeath rate in the highdosesarm in this heavily pre-treated population of patients. However, the high response rate (54 96overall, 35 W considering toxic death as a failure) is impressive sod presents evidence for the dose/effect relationship in SCLC. 03.
Effect of novobiocin on cisalatin cvtotoxicitv and DNA interstrand cell line De Jong S, Timmer-Bosscha H, De Vries EGE, Molder NH. Division of Medical Hospital,
Oncology,
Department
of Internal
Oosrersingef59,9713EZGrot~ir1ge~1,
Medicine,
University
IntJ Cancer 1993;53: I IO-
7.
Studies were performed to determine whether novobioci” cao be used to eohance cisplatin (CDDP) cytotoxicity in a human small-cell lungcarcinomncell line, GLC,/CDDP, resistant toCDDP. Continuous incuhtionwith”ovobiocinenhancedthecyto(oxicityofCDDPtreatment 1.9-fold in the parental cell line GLC,, but had no effect on ILS cytotoxtcity in the resistant cell line GLC,/CDDP. Short incubation with novobioci” enhanced the cytotoxicity of CDDP treatment in GLC, and GLC,/CDDP by B factor of 4. I and 2.8, respectively. Using the latter schedule. the amount of CDDP-induced DNA interstrand crosslinks (DNA ISC) at 4 hr as well as at 24 hr after “ovobiocin and CDDP tre&nent was higher in GLC, than in GLC,/CDDP. In this case, the amount of DNA 1SC bad increased 1.6-fold in GLC, and 1.3-fold in
GLC,/CDDP at 4 hr. and 2.7-fold and l.Cfold, respectively, in these cell lines at 24 hr after treatment compared to CDDP treatment alone. Our results suggest an effect of novobiocin on the fomtation of DNA ISC. The decreased efficacy of novobiocin, an inhibitor of DNA topoisomerase (Topo) II catalytic activity, in GLC,/CDDP may be due to the increased Topo II activity previously found in the resistant cells. In the present study, we showed that increased Topo 11activity was not due to changes m amounts of Topo II in nuclei or nuclear extracts of GLC,/CDDP. Further analysis of the chromatin, that includes Topo II, showed that the chromatin in nuclei of GLC,/CDDP was more sensitive to micrococcal nuclease digestion than GLC,. In addition, the amouot of a 56-kDa protein was increased 2-fold in nuclei and nuclear matrices from GLC,/CDDP. The reduced efficacy of novobiocin to increase. the CDDP cytotoxicity as well as the formation of DNA ISC m GLC,I CDDP compared to GLC, may be due to changes in the chromatin structure of the resistant cells.
Pharmacokinetics of IO-ethyl-lo-deam-antinopteri”, edatrexate, given weekly for non-small-cell lung cancer Hartley JM, Nicholson PW, Allen R, Lamond P, Harlaod SJ, Souhami RL. Depanment of Oncology, Univ. College London Medical School. 91 RidingHoureStreet. London WIPBBT. CaocerChemotherPharmacol 1993;31:328-32. We studied the phamwcokinetics of IO-ethyl-lo-deaza-atiinopterin (IO-EdAM), edatrexate and its ‘I-hydroxy metabolite during a phase II trial of treatment in advanced non-small-cell lung cancer. A dose of 80 mg/m’ was gtven weekly, with dose reduction being undertake” for mucositis or haematological toxicity. A triphasic pattern of plasma elimination was see”, the mean half-lives being 0.10 f 0.07.0.8 f 0.3 and 7 f 7 h, respectively. The mean plasma clearance was 25 f 14 I/ h, with I8 W * I1 % of the dose appeanng unchanged m the urine. The serum concentration at 1 h accurately predicted the area under the curve (AUC) with ti = 0.976. There was considerable variation of the clearance both within and behvee” patients but there was no evidence of a dependence on time or dose. The I-h concentration of the drug was shown to be related to the incidence of toxicity requiring dose reduction. The change in WBC due to the initial dose was show” to be related to both the AUC of the drug and that of its 7-OH metabolite.
Final evaluation of a phase II study on the effect of edelfosine (a” ether lipid) in advanced non-small-cell bmnchogenic carcinoma Drings P, Gunther I, Gntzemeier U, Ulbrich F. Khanavkar B. Schreml Zhoraklinik, LVA Baden, W. Abt. fur Innere Medizin-Onknlogie, Amalienstrasse 5, D-69a0 Heidelberg. Onkologie 1992;15:375-82. Background: Ether lipids could provide new prospects in cancer therapy after successfol preclinical investigations. Edelfosine has bee” the most thoroughly investigated substaoce in the ether lipid group. So far, no standard therapy has bee” set up for advanced non-small-zell broochogenic carcinoma. Therefore, in P phase II study 1 I6 patients with advanced inoperable “on-smallsell bmochogenic carcinoma were treated with the alkyl-lysopbospholipid edelfosine (EF). Material and Methods: The phenotype modifier EF was initially applied in a daily oral dosage of 300 mg (dissolved in milk) over a period of 4 weeks, then increased to a daily dosage of 900 mg if tolerated well, and continued with the highest tolerable dosage. Therapy was continued until either turt~orprogressionornegatives~deeffectsweredocumented. 35 patients could not be treated for the intended therapy period of at least 8 weeks doe toearly tumor progression (18patients). uaacceptablegastrointestinal side effects (14 patients), lack of compliance (1 patient), refusal of therapy(l patie”t)andcbaageoftherapy (I patient). Results: 81 patients could be evaluted for remission status; of these, 2 showed partial remission, 68 showed ‘no change’, nnd 11 had ormItered progression of the tumor. Median survival time for these 81 patients was 244 days, for all I16 patients it was 199 days. Retrospectively, in these 81 patients the spontaneous tumor development during the 2 months before EF therapy could be analyzed. Tumor progression during this period could be documented in I patient with partial remission, in 46 patients with diagnosis ‘no change’. and in I1 patients with unaltered tumor progression. Thesurvival timesofthesethreegroupsofpatieatsdidnot differ significantly. All 116 patients were evaluable for toxicity. Manifestations of gastrointestinal problems were. anorexia, “a_,
Abstracts/Lung Cancer 10 (1993) 266-286
therapyiouseswithCRorpa&l response. However, severeleokopmia (< 2.ooO1”mt’) occurred more oRen after PEI (73 %) tha” after PE (44 I) therapy @ < 0.05). These results suggest that PEI is not superior to PE chemotherapy in SCLC. The use of ifosfamide in multimodality treatment regimens needs to be studied further.
Pbese n triad of trimetrexate for tmrsectable or metastatic nonsmall eelI bronchogenic carcinoma Fossella FV, Wii RJ, Holoye PY. Hallinao B, Raber MN, Hoelzer K et al. Taas Univ. M.D. Anderson Can. Ctr., Box 80, 1515 Holcombe BouLmwd, Houston, TX 77030. Invest New Drugs 1992;10:331-5. We trepted34chemotherspy-“~ive~tientswithstPgeIIIborIVno”small cell lung cancer with trimetrexate 150-200 mgld iotravenously over 30 mioutes every hue weeks. Six of 31 evnlwble patients (19%) achieved *partial reepolrse. The. major toxic effects from this regimen were myelosuppressioa, aawealvomiting. Pnd ski” rash. We conclude that this well- toI& schedule of trimetrexate has significant activity as P si”gle agent agaiast non-small cell hug cpocer.
Contpariso” between hvo dosages of cisplatinum and etoposide in relapsing s”aIl cell lung carci”o”la Trillet-Lenoir V, Lasset C, Arpia D, Bohas C, Riou R, Perol M et al. Hopital
Lmds-Pradel,
28 Avenue du Doyen-L@%
69394 Lyon Ceder
Bull Caacer 1992;79: 1173-81. Thesy”ergisticcombinntio”ofcispl~tiaumandetoposideappearsas the best second line. treatment in patients relapsing from small cell lung carcinoma (SCLC). I” order to test the dose-effect relationship of cisplatiaum pnd etoposide in this situation, we have performed a random&d phase II trial comparing 2 five-day regimens: Cisplatioum 20 mglm’lday + etopostde 60 mglm’lday (arm A) versw cisplatinum 40 mg/d/day + etoposide 100 mg/m’/day (art” B) every 4 weeks. Thir?y-seve”patientswereincluded(armA: 18,-B: 19),and32were consideredtobeeligible(armA: lS,am~B: 17). Eightpatientswerenoo evaluable, five of them because of toxic death occurring prior to the second course (arm A: one from neutropenia; arm 8: three from “eutropenia and o”e from tbrombopeoia). The hvo groups were well balancedwithregardtochemainpmgnosticfactors(age,sex, perfomwce status. LDH level, response to induction chemotherapy). A” objective respoose was observed in IO/24 evaluable patients (arm A: 4, ano B: 6) and was considered as complete in one pattent in arm A and in 2 pts in arm B; these two patients presented with cerebral metastases and their response lasted 9 Pnd I5 weeks respectively. The mean duration of respoose was 1 I weeks in arm A and 10.5 weeks in an” B. The median actuarial survival of the overall population of eligible patients was 15 weeks: 13 we&s in arot A and 16.5 weeks in an” B. The study was discontinued bec~useof the23.5 W toxicdeath rate in the highdosesarm in this heavily pre-treated population of patients. However, the high response rate (54 96overall, 35 W considering toxic death as a failure) is impressive sod presents evidence for the dose/effect relationship in SCLC. 03.
Effect of novobiocin on cisalatin cvtotoxicitv and DNA interstrand cell line De Jong S, Timmer-Bosscha H, De Vries EGE, Molder NH. Division of Medical Hospital,
Oncology,
Department
of Internal
Oosrersingef59,9713EZGrot~ir1ge~1,
Medicine,
University
IntJ Cancer 1993;53: I IO-
7.
Studies were performed to determine whether novobioci” cao be used to eohance cisplatin (CDDP) cytotoxicity in a human small-cell lungcarcinomncell line, GLC,/CDDP, resistant toCDDP. Continuous incuhtionwith”ovobiocinenhancedthecyto(oxicityofCDDPtreatment 1.9-fold in the parental cell line GLC,, but had no effect on ILS cytotoxtcity in the resistant cell line GLC,/CDDP. Short incubation with novobioci” enhanced the cytotoxicity of CDDP treatment in GLC, and GLC,/CDDP by B factor of 4. I and 2.8, respectively. Using the latter schedule. the amount of CDDP-induced DNA interstrand crosslinks (DNA ISC) at 4 hr as well as at 24 hr after “ovobiocin and CDDP tre&nent was higher in GLC, than in GLC,/CDDP. In this case, the amount of DNA 1SC bad increased 1.6-fold in GLC, and 1.3-fold in
GLC,/CDDP at 4 hr. and 2.7-fold and l.Cfold, respectively, in these cell lines at 24 hr after treatment compared to CDDP treatment alone. Our results suggest an effect of novobiocin on the fomtation of DNA ISC. The decreased efficacy of novobiocin, an inhibitor of DNA topoisomerase (Topo) II catalytic activity, in GLC,/CDDP may be due to the increased Topo II activity previously found in the resistant cells. In the present study, we showed that increased Topo 11activity was not due to changes m amounts of Topo II in nuclei or nuclear extracts of GLC,/CDDP. Further analysis of the chromatin, that includes Topo II, showed that the chromatin in nuclei of GLC,/CDDP was more sensitive to micrococcal nuclease digestion than GLC,. In addition, the amouot of a 56-kDa protein was increased 2-fold in nuclei and nuclear matrices from GLC,/CDDP. The reduced efficacy of novobiocin to increase. the CDDP cytotoxicity as well as the formation of DNA ISC m GLC,I CDDP compared to GLC, may be due to changes in the chromatin structure of the resistant cells.
Pharmacokinetics of IO-ethyl-lo-deam-antinopteri”, edatrexate, given weekly for non-small-cell lung cancer Hartley JM, Nicholson PW, Allen R, Lamond P, Harlaod SJ, Souhami RL. Depanment of Oncology, Univ. College London Medical School. 91 RidingHoureStreet. London WIPBBT. CaocerChemotherPharmacol 1993;31:328-32. We studied the phamwcokinetics of IO-ethyl-lo-deaza-atiinopterin (IO-EdAM), edatrexate and its ‘I-hydroxy metabolite during a phase II trial of treatment in advanced non-small-cell lung cancer. A dose of 80 mg/m’ was gtven weekly, with dose reduction being undertake” for mucositis or haematological toxicity. A triphasic pattern of plasma elimination was see”, the mean half-lives being 0.10 f 0.07.0.8 f 0.3 and 7 f 7 h, respectively. The mean plasma clearance was 25 f 14 I/ h, with I8 W * I1 % of the dose appeanng unchanged m the urine. The serum concentration at 1 h accurately predicted the area under the curve (AUC) with ti = 0.976. There was considerable variation of the clearance both within and behvee” patients but there was no evidence of a dependence on time or dose. The I-h concentration of the drug was shown to be related to the incidence of toxicity requiring dose reduction. The change in WBC due to the initial dose was show” to be related to both the AUC of the drug and that of its 7-OH metabolite.
Final evaluation of a phase II study on the effect of edelfosine (a” ether lipid) in advanced non-small-cell bmnchogenic carcinoma Drings P, Gunther I, Gntzemeier U, Ulbrich F. Khanavkar B. Schreml Zhoraklinik, LVA Baden, W. Abt. fur Innere Medizin-Onknlogie, Amalienstrasse 5, D-69a0 Heidelberg. Onkologie 1992;15:375-82. Background: Ether lipids could provide new prospects in cancer therapy after successfol preclinical investigations. Edelfosine has bee” the most thoroughly investigated substaoce in the ether lipid group. So far, no standard therapy has bee” set up for advanced non-small-zell broochogenic carcinoma. Therefore, in P phase II study 1 I6 patients with advanced inoperable “on-smallsell bmochogenic carcinoma were treated with the alkyl-lysopbospholipid edelfosine (EF). Material and Methods: The phenotype modifier EF was initially applied in a daily oral dosage of 300 mg (dissolved in milk) over a period of 4 weeks, then increased to a daily dosage of 900 mg if tolerated well, and continued with the highest tolerable dosage. Therapy was continued until either turt~orprogressionornegatives~deeffectsweredocumented. 35 patients could not be treated for the intended therapy period of at least 8 weeks doe toearly tumor progression (18patients). uaacceptablegastrointestinal side effects (14 patients), lack of compliance (1 patient), refusal of therapy(l patie”t)andcbaageoftherapy (I patient). Results: 81 patients could be evaluted for remission status; of these, 2 showed partial remission, 68 showed ‘no change’, nnd 11 had ormItered progression of the tumor. Median survival time for these 81 patients was 244 days, for all I16 patients it was 199 days. Retrospectively, in these 81 patients the spontaneous tumor development during the 2 months before EF therapy could be analyzed. Tumor progression during this period could be documented in I patient with partial remission, in 46 patients with diagnosis ‘no change’. and in I1 patients with unaltered tumor progression. Thesurvival timesofthesethreegroupsofpatieatsdidnot differ significantly. All 116 patients were evaluable for toxicity. Manifestations of gastrointestinal problems were. anorexia, “a_,