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HLA class I and neuroendocrine antigen expression in multidrug resistant small cell lung carcinoma cell lines
122
Abstracts
/ Lung
Cancer
HL.A class I and neuroendocrine antigen expression in multidrug resistant small cell lung carcinoma cell lines Goguel AF, Arvelo F, Jacrot M, Le Chevalier T, Poupon MF. Lab. Cytogenet. Molecul./Oncologie, UMR 147 CNRS 26 Rue d ‘Ulm, 75231 Paris. Int J Oncol 1996;8:983-90. Antigenic marker expression was studied in a series of eight small cell lung carcinoma (SCLC) cell lines, according to their histological subtype, classic or variant. Them lines were obtained from human tumors xenografted into nude mice, originally derived from heterotransplanted tumor biopsy samples, We looked at an altered expression of HLA class I antigens, a battery of neuroendocrine antigens and the P-glycoprotein (Pgp) responsible for MDRl encoded multidrug resistance, as markers of tumor malignancy. Three cell lines out of four of the classic subtype and two cell lines out of four of the variant subtype showed a lack or a low expression of HLA class I antigen. Recombinant interferon gamma (@N-gamma) treatment (100 U/ml, for 48 h) increased HLA class I expression of the cell lines differently, but did not induce an imbalance between HLA-A and HLA-B molecules as described in other tumor models. Neuroendocrine antigens were tested in six out of these eight lines, using a family of moncclonal antibodies developed against the cell membrane antigens of low passage cell lines derived from pleural etlitsions (de Leij et al, Cancer Res 45: 2192-2200, 1985). Globally, these antigens were more highly expressed inclassic subtypes of SCLC. Neuroendocrine antigens corresponding to MOC-21 and MOC-32 monoclonal antibodies were weakly expressed in variant forms, Pgp expression was detectable with the JSBI monoclonal antibody on the three variant SCLCs out of the six lines. Comparing two cell lines originated from the same patient before and after therapy, we showed that neuroendocrine reactivity to MOC-21 and MOC-32 was lost simuhaneously with a gain of Pgp expression, and with a classic to variant histological transition. With regard to the clinical evolution, HLA class I expression and stimulation by rIFN-gamma was not related to malignancy It appears that for variant forms, a low expression of neuroendocrine antigens detected by MOC-21 and MGC-32 monoclonal antibodies and a high level of Pgp predict for a poor prognosis.
Ifosfamide plus prclitasel in advanced non-small-cell lung cancer: A phase I study Hot&ran PC, Masters GA, Drinkard LC et al. Department of Clinical Medicine, Vniversi@ of Chicago, Medical Cente,: 5841 S. Maryland Avenue, MC2115, Chicago, IL60637. Ann Oncol 1996;7:314-6. Background: Ifosfamide and paclitaxel are active drugs in the management of non-small-cell lung cancer, We have-performed a phase I study using a fixed dose of ifosfamide with escalating doses of paclitaxel, with G-CSF support, in an effort to determine the maximum tolerated dose (MTD) of paclitaxel in this combination, and to describe the doselimiting toxicities of the combination at the recommended phase I1 dose. of paclitaxel. We also studied the feasibility of delivering the paclitaxel as a one-hour infusion at the recommended phase II dose. Patients and methods: Thirtyane patients were treated, 25 with stage IV disease, and 6 with stage IIIB disease. Ifosfamide was administered at a dose of 1.6 g/m’ iv. bolus daily x 3 days, with mesna uroprotection. Paclitaxel was administeredas a 24-hour infusion at dose levels of 135, 170,200, 250, and 300 mg/m’; six patients were treated with a one-hour infusion, at a dose of 250 mg/mr. G-CSF, 5 ug/kg, was administered subcutaneously on days 4 through IO, or until the absolute neutrophil count exceeded 4OOO/pl. Cycles were repeated every 21 days. Results: The dose-limiting toxicity was granulocytopenia, which increased with increasingdose levelsofpaclitaxel. TheMTDwas 300 mg/m20fpaclitaxel, and the recommended phase II dose 250 mg/m’ administered as a 24hour infusion. Other toxicities were generally mild, with only 5 patients demonstrating grade 3 neurotoxicity and 5 with grade 3 thrombocytopenia. Partial responses were seen in seven patients (23%) all in the 18 patients who received dose levels of 250 mg/m2 or higher. Con-
16 (1996)
105-127
elusions: Ifosfamide plus paclitaxel is an active treatment regimen in advanced non-small-cell lung cancer, and compares favorably with the results of cisplatin-based chemotherapy. A phase II study is in progress by the Cancer and Leukemia Group B, in an effort to better characterize the tolerance of the regimen, as well as its effect on tumor response and survivaI.
Phase I study of paclitaxel (Taxola) and ifosfamide in previously untreated patients with advanced non-small-cell lung cancer. A study of the National Cancer Institute of Canada Clinical Trials Group. Shepherd FA, Latreille J, Crmnp M et al. Division of Hematology/ Oncology, The Toronto Hospital, M/L W?ng, 200 Elizabeth Street, Tomnto, Ont. MSG 2C4. Ana Gncol 1996;7:311-13. Backgromd Paclitaxel (Taxolx) and ifosihmide are among the most active single agents for the treatment of non-small-cell lung cancer. We undertook this phase 1 dose escalation study to determine the maximum tolerated doses of these drugs which could be administered witbout growth factors to untreated patients with tumours of this type. Patients and methods: Forty patients with advanced non-smallcell lung cancer were treated with a 3-hour infusion of paclitaxel and a I-hour infusion of ifosfamide every 3 weeks. Groups of 3 patients were entered at escalating dose levels in traditional phase I designStarting doses were paclitaxel, 100 mg/mz, and ifosfamide 3 g/m*, and all patients received premedication with dexamethasone, diphenhydramine and a 5-HT3 blocker. Dose escalation occurred only after full toxicity assessment for 2 cycles for all patients in the dose level. Results: Dose escalation of paclitaxel continued to 225 mg/m* without dose-limiting toxicity, but further escalation was not attempted because of the known likelihood of neurotoxicity above this level. Instead, ifosfamide was increased to 4 g/m* for the final level. At these doses, dose-limiting myelosuppression was not seen, and there was only 1 episode of febrile neutropenia in 164 treatment cycles. Drug-related toxicities of ifosthmide included gross hematuria and confusion in I patient each, and paclitaxelrelated symptoms included flu-like syndrome in most patients, mild to moderate arthralgia and/or myalgia in 8 and 25 patients, respectively, parasthesiae in 15 patients and mild to moderate hypersensitivity reactions in 15 patients each. Partial response was seen in 20.5% of patients (CI 9.3%-36.50/o). Summary: Gut-patient paclitaxel given over 3 hours and single-dose ifosfamide over 1 hour may be combined safely without the need for hematopoietic growth factors for the treatment of patients with non-small-cell lung cancer. The recommended doses for phase II study are paclitaxel, 225 mg/m* and ifosmmide, 4 g/m’ every 3 weeks.
Combination chemotherapy for advanced lung cancer: Survival differences between histological types and implications for prevention in Thailand Limsila T, Mitacek EJ, Caplan L, Bnmnemann KD. Department of Preventive Medicine. School Medicine, State Vniversi& New York, Stony Btvok, NY 11794-8036. Oncol Rep 1996;3:579-82. Lung cancer is now a major public health problem in Thailand. This study was undertaken to gain some preliminary data regarding the potential effectiveness in treating advanced non-small cell lung carcinoma (NSCLC) using an ifosfamide combination therapy IA(E)P. A clinical study was made of all 50 patients (Thais) with histologically proven, advanced NSCLC admitted to the University of Siriraj Hospital between 1985 and 1987 and followed up until February 1992. Survival was calculated for responders and non-responders as distinct groups, and for the different histological tumors among the responders. There were 22 cases of adenocarcinoma, 13 large cell carcinoma, and 15 squamous cell carcinoma. ‘Bventy-seven out of 50 (54%) responded to treatment. The median survival of the response group was 17 months, compared with 5.5 months in tbe non-response group. The longest sur-
Abstracts
/ Lung
Cancer
HL.A class I and neuroendocrine antigen expression in multidrug resistant small cell lung carcinoma cell lines Goguel AF, Arvelo F, Jacrot M, Le Chevalier T, Poupon MF. Lab. Cytogenet. Molecul./Oncologie, UMR 147 CNRS 26 Rue d ‘Ulm, 75231 Paris. Int J Oncol 1996;8:983-90. Antigenic marker expression was studied in a series of eight small cell lung carcinoma (SCLC) cell lines, according to their histological subtype, classic or variant. Them lines were obtained from human tumors xenografted into nude mice, originally derived from heterotransplanted tumor biopsy samples, We looked at an altered expression of HLA class I antigens, a battery of neuroendocrine antigens and the P-glycoprotein (Pgp) responsible for MDRl encoded multidrug resistance, as markers of tumor malignancy. Three cell lines out of four of the classic subtype and two cell lines out of four of the variant subtype showed a lack or a low expression of HLA class I antigen. Recombinant interferon gamma (@N-gamma) treatment (100 U/ml, for 48 h) increased HLA class I expression of the cell lines differently, but did not induce an imbalance between HLA-A and HLA-B molecules as described in other tumor models. Neuroendocrine antigens were tested in six out of these eight lines, using a family of moncclonal antibodies developed against the cell membrane antigens of low passage cell lines derived from pleural etlitsions (de Leij et al, Cancer Res 45: 2192-2200, 1985). Globally, these antigens were more highly expressed inclassic subtypes of SCLC. Neuroendocrine antigens corresponding to MOC-21 and MOC-32 monoclonal antibodies were weakly expressed in variant forms, Pgp expression was detectable with the JSBI monoclonal antibody on the three variant SCLCs out of the six lines. Comparing two cell lines originated from the same patient before and after therapy, we showed that neuroendocrine reactivity to MOC-21 and MOC-32 was lost simuhaneously with a gain of Pgp expression, and with a classic to variant histological transition. With regard to the clinical evolution, HLA class I expression and stimulation by rIFN-gamma was not related to malignancy It appears that for variant forms, a low expression of neuroendocrine antigens detected by MOC-21 and MGC-32 monoclonal antibodies and a high level of Pgp predict for a poor prognosis.
Ifosfamide plus prclitasel in advanced non-small-cell lung cancer: A phase I study Hot&ran PC, Masters GA, Drinkard LC et al. Department of Clinical Medicine, Vniversi@ of Chicago, Medical Cente,: 5841 S. Maryland Avenue, MC2115, Chicago, IL60637. Ann Oncol 1996;7:314-6. Background: Ifosfamide and paclitaxel are active drugs in the management of non-small-cell lung cancer, We have-performed a phase I study using a fixed dose of ifosfamide with escalating doses of paclitaxel, with G-CSF support, in an effort to determine the maximum tolerated dose (MTD) of paclitaxel in this combination, and to describe the doselimiting toxicities of the combination at the recommended phase I1 dose. of paclitaxel. We also studied the feasibility of delivering the paclitaxel as a one-hour infusion at the recommended phase II dose. Patients and methods: Thirtyane patients were treated, 25 with stage IV disease, and 6 with stage IIIB disease. Ifosfamide was administered at a dose of 1.6 g/m’ iv. bolus daily x 3 days, with mesna uroprotection. Paclitaxel was administeredas a 24-hour infusion at dose levels of 135, 170,200, 250, and 300 mg/m’; six patients were treated with a one-hour infusion, at a dose of 250 mg/mr. G-CSF, 5 ug/kg, was administered subcutaneously on days 4 through IO, or until the absolute neutrophil count exceeded 4OOO/pl. Cycles were repeated every 21 days. Results: The dose-limiting toxicity was granulocytopenia, which increased with increasingdose levelsofpaclitaxel. TheMTDwas 300 mg/m20fpaclitaxel, and the recommended phase II dose 250 mg/m’ administered as a 24hour infusion. Other toxicities were generally mild, with only 5 patients demonstrating grade 3 neurotoxicity and 5 with grade 3 thrombocytopenia. Partial responses were seen in seven patients (23%) all in the 18 patients who received dose levels of 250 mg/m2 or higher. Con-
16 (1996)
105-127
elusions: Ifosfamide plus paclitaxel is an active treatment regimen in advanced non-small-cell lung cancer, and compares favorably with the results of cisplatin-based chemotherapy. A phase II study is in progress by the Cancer and Leukemia Group B, in an effort to better characterize the tolerance of the regimen, as well as its effect on tumor response and survivaI.
Phase I study of paclitaxel (Taxola) and ifosfamide in previously untreated patients with advanced non-small-cell lung cancer. A study of the National Cancer Institute of Canada Clinical Trials Group. Shepherd FA, Latreille J, Crmnp M et al. Division of Hematology/ Oncology, The Toronto Hospital, M/L W?ng, 200 Elizabeth Street, Tomnto, Ont. MSG 2C4. Ana Gncol 1996;7:311-13. Backgromd Paclitaxel (Taxolx) and ifosihmide are among the most active single agents for the treatment of non-small-cell lung cancer. We undertook this phase 1 dose escalation study to determine the maximum tolerated doses of these drugs which could be administered witbout growth factors to untreated patients with tumours of this type. Patients and methods: Forty patients with advanced non-smallcell lung cancer were treated with a 3-hour infusion of paclitaxel and a I-hour infusion of ifosfamide every 3 weeks. Groups of 3 patients were entered at escalating dose levels in traditional phase I designStarting doses were paclitaxel, 100 mg/mz, and ifosfamide 3 g/m*, and all patients received premedication with dexamethasone, diphenhydramine and a 5-HT3 blocker. Dose escalation occurred only after full toxicity assessment for 2 cycles for all patients in the dose level. Results: Dose escalation of paclitaxel continued to 225 mg/m* without dose-limiting toxicity, but further escalation was not attempted because of the known likelihood of neurotoxicity above this level. Instead, ifosfamide was increased to 4 g/m* for the final level. At these doses, dose-limiting myelosuppression was not seen, and there was only 1 episode of febrile neutropenia in 164 treatment cycles. Drug-related toxicities of ifosthmide included gross hematuria and confusion in I patient each, and paclitaxelrelated symptoms included flu-like syndrome in most patients, mild to moderate arthralgia and/or myalgia in 8 and 25 patients, respectively, parasthesiae in 15 patients and mild to moderate hypersensitivity reactions in 15 patients each. Partial response was seen in 20.5% of patients (CI 9.3%-36.50/o). Summary: Gut-patient paclitaxel given over 3 hours and single-dose ifosfamide over 1 hour may be combined safely without the need for hematopoietic growth factors for the treatment of patients with non-small-cell lung cancer. The recommended doses for phase II study are paclitaxel, 225 mg/m* and ifosmmide, 4 g/m’ every 3 weeks.
Combination chemotherapy for advanced lung cancer: Survival differences between histological types and implications for prevention in Thailand Limsila T, Mitacek EJ, Caplan L, Bnmnemann KD. Department of Preventive Medicine. School Medicine, State Vniversi& New York, Stony Btvok, NY 11794-8036. Oncol Rep 1996;3:579-82. Lung cancer is now a major public health problem in Thailand. This study was undertaken to gain some preliminary data regarding the potential effectiveness in treating advanced non-small cell lung carcinoma (NSCLC) using an ifosfamide combination therapy IA(E)P. A clinical study was made of all 50 patients (Thais) with histologically proven, advanced NSCLC admitted to the University of Siriraj Hospital between 1985 and 1987 and followed up until February 1992. Survival was calculated for responders and non-responders as distinct groups, and for the different histological tumors among the responders. There were 22 cases of adenocarcinoma, 13 large cell carcinoma, and 15 squamous cell carcinoma. ‘Bventy-seven out of 50 (54%) responded to treatment. The median survival of the response group was 17 months, compared with 5.5 months in tbe non-response group. The longest sur-