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Tandem high dose chemotherapy (THDC) in patients (pts) with small cell lung cancer (SCLC)
Chemotherapy/Mix NSCLC and 1 of 2 patients with pleural mesothelioma. The recommended phase I1 dose is GEM 1250 rag/m2 dl, d8 with ALIMTA 500 mglm2 d8 given 90 min after GEM, q3wk. Transient, reversible neutropenia was the most common toxicity. The worst incidence of anemia was grade 3 (4%). The ALIMTNCDDP combination was likewise welltolerated, with neutropenia as the DLT. Grade 4 anemia occurred in 6 of 54 patients. Five out of 11 patients with pieural mesothelioma, and 1 of 7 patients with NSCLC obtained durable partial remissions. The recommended dose and schedule of this combination is 75 mg/m2 of CDDP and 500 rng/m2 of ALIMTA on day 1, q3wks. In the ongoing study with CBDCA, all 16 patients have pleurat mesothelioma. Drug doses have been escalated to the maximum single-agent doses of both drugs (ALIMTA 600 mg/m2; CBDCA AUC 5 q3wks) with no dose-limiting toxicity. Objective responses have been noted in 10 of the 16 patients. The remainder of the patients have stable disease. Similar to the other combination studies, the most common toxicity is neutropenia. Grades 3 and 4 thrombocytopenia are however more frequent (25%), compared to ALIMTA/CDDP (0%) and ALIMTNGEM (8% gr3, 0% gr4). The most common non-hematologic toxicities in all three studies were elevated hepatic transaminases and a maculopapular rash, which was ameliorated by steroid pre-treatment. ALIMTA combinations offer promise in the treatment of NSCLC and pleural mesothelioma. International multi-institutional studies are ongoing with ALIMTNGEM in NSCLC, and ALIMTNCDDP in pleural mesothelioma.
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Targeting the cell kill of etoposide to brain metastases. A method for prophylactic cranial chemotherapy (PCC) in small cell lung cancer P,B, Jensen, S.W. Langer, M, Sehested, Finsen Centre, Rigshospitalet, Copenhagen;Dept. of Pathology, Rigshospitalet, Copenhagen, Denmark
Targeting the cell kill of etoposide to brain metastases. A method for prophylactic cranial chemotherapy (PCC) in small cell lung cancer. Peter Buhl Jensen, Seppo W. Langer and Maxwell Sehested. Finsen and Laboratory Centers, Rigshospitalet 5073, DK-2100 Copenhagen, Denmark. In SCLC, prophylactic cranial irradiation (PCI) reduces the occurrence of brain metastases and improves survival. However, even after PCt, brain metastases are a major clinical problem with 2530% of SCLC patients experiencing this feared complication. We have demonstrated that the drug ICRF-187 blocks the cell kill of etoposide in vitro. This block is also seen in vivo and the use of a non-toxic dose of 1CRF-187 increased the maximum tolerated dose (MTD) of etoposide 320-340% in mice. Use of targeted high dose (HD) etoposide becomes possible as ICRF-187, in contrast to etoposide, does not enter the brain. Thus, ICRF-187 gives systemic protection against HD etoposide while allowing a higher etoposide exposure in the brain. This hypothesis was proved in vivo as HD etoposide + ICRF187 was significantly more effective than an equitoxic etoposide dose in mice with implanted brain tumours (Clin. Cancer Res. 4: 1367). We are now conducting a phase 1-11trial in patients relapsing from SCLC with brain metastases. MTD appears to be 1500 mg/m2 of ICRF-187 given over 30' and immediately followed by 500 mg/m2 of etopeside infused over 90~. This treatment is repeated every 2-3 wk depending on hematological recovery. Major toxicity is neutropenia CTG IV of maximum 3-4 days. Encouragingly, we have observed complete responses in three of eight evaluabte SCLC patients. Small metastases with intact blood brain barriers are probat~ specifically targeted by our approach and we are now planning a comparative clinical trial to study the efficacy of HD etoposide + ICRF-187 rescue given as prophylactic cranial chemotherapy (PCC) after PCI.
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Tandem high dose chemotherapy (THDC) in patients (pts) with small cell lung cancer (SCLC)
U. Seifart, M. SchrSder, K. Hans, D. Ukena, K.P. Thiele, A. Neubauer, M. Wolf. Philipps-Universit~tMarburg; Klinik Innere Medizin SP;
H~matologietOnkologieltmmunologie;Prof. Neubauer; 35033 Marburg, Germany Objective: SCLC is known as one of the most aggressive solid tumors. The median survival in pts with limited disease (LD) under therapy is 14-18 month and with extensive disease (ED) 6-10 month. This unsatisfactory situation should be improved by applying more aggressive therapy regimes. Therefore we start a randomised study to look for the effect of a THDC on SCLC-pts without distant metastasis. Material and Methods: We performed the following therapy on 20 pts. All pts received 2 cycles of PEI (Cisplatin 90 mg/m 2 dl, Etoposid 120 mg/m 2 dl-3, Ifosfomid 1500 mg/m 2 dl-4). After the second PEI a stern cell mobilisation with 10 l~g/kg G-CSF was conducted and peripheral stem cell collection (PBSC) were performed with minimal 5 × 106 CD 34 cells/kg. This was followed by a THDC CEC (Cyclofosfomid 2000 mg/m2 dl-2, Etoposid 700 mg/m2 dl-3, and Carboplatin 1200 mg/m2 dl). After each cycle of CEC 50% of the stemceUs were reinfused, Radiationtherapy with 45 Gy was conducted over the area of the primary tumor. Results: The two cycles PEI were given to all 20 pts. Results of 16 pts are available in the moment. 8 reached a complete remission, 8 a partial remission. PBSC were collected in all pts. The amount varied between 2, 8 and 40 x 106 CD 34/kg cells. The first CEC was done on 15 pts. One pt missed the therapy because of a bad performance status. The second CEC was done on 11 pts. Reasons for missing: local relaps 1 x, too few CD 34 cells 1 ×, bad performance status 2x. The recovery of the hematopoeses (Leucocytes > 1000, Platelets > 20 000) took 10.7 days after the first CEC and 11.4 days after the second CEC. The toxicity was as followed: Stomatitis: Stage IV WHO 2x, Stage III 3x. Infection: Stage III WHO 10x. There was no therapy related mortality The follow up is now 24 month. The median survival is 25 months and the 2-year survival rate is 54%. Conclusion: The THDC in SCLC-pts in LD or ED I with stem cell support is feasible. The toxicity is moderate. The median survival of 25 months and the 2-year survival rate of 54% indicates that THDC could be an attractive therapy for this subgroup of SCLC-pts.
carbobplatin be inferior to cisplatin in management •2-6• Could of small-cell lung cancer? S. Jezdi~, S. Jeli(~, Z. NikoliS-Toma~,eviS, I. Popov, D. RadosavljeviS.
Institute of Oncologyand Radiologyof Serbia, Departmentof Medical Oncology, Belgrade, Yugoslavia During the past decade there was a trend to substitute cisplatin with carboplatin in treatment of various solid tumors including smallcell lung cancer, mainly because carboptatin is easier to manage in everyday use and because the toxicities might be more tolerable. From 1995 to 1999 we have included 68 previously untreated patients with small-cell tung cancer in a prospective randomized study of etoposide-cisplatio versus etoposide-carboplatin. The present report shows our preliminary results. The arm A recruited 34 evaluable patients who received etoposide 120 mgtm2 i.v. day 1, 3 and 5 and cisplatin 100 mgtm 2 day 1. The arm B recruited 34 patients (29 evaluable for response) who received etoposide 120 mg/m 2 day 1, 3 and 5 and carboplatin 400 mg/m 2 day 1. The two arms were well balanced according to age, sex, performance status and presence of either limited or extensive disease. In arm A the median number of cycles was 5 and in arm B it was 4. There was no statistically significant difference in response rates, being 74% in arm A (95% CI 58-89%) and 62% in arm B (95% C144-80%). Grade tll and IV hematological toxicities were more frequent in the arm B, i.e. the carboplatin group (p < 0.05). The median survival time in the cisplatin group (arm A) was 15 months versus 10 months in the carboplatin group (arm B). This difference was statistically significant in favor of arm A, i. e. the cisplatin group (p < 0.05).
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Targeting the cell kill of etoposide to brain metastases. A method for prophylactic cranial chemotherapy (PCC) in small cell lung cancer P,B, Jensen, S.W. Langer, M, Sehested, Finsen Centre, Rigshospitalet, Copenhagen;Dept. of Pathology, Rigshospitalet, Copenhagen, Denmark
Targeting the cell kill of etoposide to brain metastases. A method for prophylactic cranial chemotherapy (PCC) in small cell lung cancer. Peter Buhl Jensen, Seppo W. Langer and Maxwell Sehested. Finsen and Laboratory Centers, Rigshospitalet 5073, DK-2100 Copenhagen, Denmark. In SCLC, prophylactic cranial irradiation (PCI) reduces the occurrence of brain metastases and improves survival. However, even after PCt, brain metastases are a major clinical problem with 2530% of SCLC patients experiencing this feared complication. We have demonstrated that the drug ICRF-187 blocks the cell kill of etoposide in vitro. This block is also seen in vivo and the use of a non-toxic dose of 1CRF-187 increased the maximum tolerated dose (MTD) of etoposide 320-340% in mice. Use of targeted high dose (HD) etoposide becomes possible as ICRF-187, in contrast to etoposide, does not enter the brain. Thus, ICRF-187 gives systemic protection against HD etoposide while allowing a higher etoposide exposure in the brain. This hypothesis was proved in vivo as HD etoposide + ICRF187 was significantly more effective than an equitoxic etoposide dose in mice with implanted brain tumours (Clin. Cancer Res. 4: 1367). We are now conducting a phase 1-11trial in patients relapsing from SCLC with brain metastases. MTD appears to be 1500 mg/m2 of ICRF-187 given over 30' and immediately followed by 500 mg/m2 of etopeside infused over 90~. This treatment is repeated every 2-3 wk depending on hematological recovery. Major toxicity is neutropenia CTG IV of maximum 3-4 days. Encouragingly, we have observed complete responses in three of eight evaluabte SCLC patients. Small metastases with intact blood brain barriers are probat~ specifically targeted by our approach and we are now planning a comparative clinical trial to study the efficacy of HD etoposide + ICRF-187 rescue given as prophylactic cranial chemotherapy (PCC) after PCI.
•5]
39
Tandem high dose chemotherapy (THDC) in patients (pts) with small cell lung cancer (SCLC)
U. Seifart, M. SchrSder, K. Hans, D. Ukena, K.P. Thiele, A. Neubauer, M. Wolf. Philipps-Universit~tMarburg; Klinik Innere Medizin SP;
H~matologietOnkologieltmmunologie;Prof. Neubauer; 35033 Marburg, Germany Objective: SCLC is known as one of the most aggressive solid tumors. The median survival in pts with limited disease (LD) under therapy is 14-18 month and with extensive disease (ED) 6-10 month. This unsatisfactory situation should be improved by applying more aggressive therapy regimes. Therefore we start a randomised study to look for the effect of a THDC on SCLC-pts without distant metastasis. Material and Methods: We performed the following therapy on 20 pts. All pts received 2 cycles of PEI (Cisplatin 90 mg/m 2 dl, Etoposid 120 mg/m 2 dl-3, Ifosfomid 1500 mg/m 2 dl-4). After the second PEI a stern cell mobilisation with 10 l~g/kg G-CSF was conducted and peripheral stem cell collection (PBSC) were performed with minimal 5 × 106 CD 34 cells/kg. This was followed by a THDC CEC (Cyclofosfomid 2000 mg/m2 dl-2, Etoposid 700 mg/m2 dl-3, and Carboplatin 1200 mg/m2 dl). After each cycle of CEC 50% of the stemceUs were reinfused, Radiationtherapy with 45 Gy was conducted over the area of the primary tumor. Results: The two cycles PEI were given to all 20 pts. Results of 16 pts are available in the moment. 8 reached a complete remission, 8 a partial remission. PBSC were collected in all pts. The amount varied between 2, 8 and 40 x 106 CD 34/kg cells. The first CEC was done on 15 pts. One pt missed the therapy because of a bad performance status. The second CEC was done on 11 pts. Reasons for missing: local relaps 1 x, too few CD 34 cells 1 ×, bad performance status 2x. The recovery of the hematopoeses (Leucocytes > 1000, Platelets > 20 000) took 10.7 days after the first CEC and 11.4 days after the second CEC. The toxicity was as followed: Stomatitis: Stage IV WHO 2x, Stage III 3x. Infection: Stage III WHO 10x. There was no therapy related mortality The follow up is now 24 month. The median survival is 25 months and the 2-year survival rate is 54%. Conclusion: The THDC in SCLC-pts in LD or ED I with stem cell support is feasible. The toxicity is moderate. The median survival of 25 months and the 2-year survival rate of 54% indicates that THDC could be an attractive therapy for this subgroup of SCLC-pts.
carbobplatin be inferior to cisplatin in management •2-6• Could of small-cell lung cancer? S. Jezdi~, S. Jeli(~, Z. NikoliS-Toma~,eviS, I. Popov, D. RadosavljeviS.
Institute of Oncologyand Radiologyof Serbia, Departmentof Medical Oncology, Belgrade, Yugoslavia During the past decade there was a trend to substitute cisplatin with carboplatin in treatment of various solid tumors including smallcell lung cancer, mainly because carboptatin is easier to manage in everyday use and because the toxicities might be more tolerable. From 1995 to 1999 we have included 68 previously untreated patients with small-cell tung cancer in a prospective randomized study of etoposide-cisplatio versus etoposide-carboplatin. The present report shows our preliminary results. The arm A recruited 34 evaluable patients who received etoposide 120 mgtm2 i.v. day 1, 3 and 5 and cisplatin 100 mgtm 2 day 1. The arm B recruited 34 patients (29 evaluable for response) who received etoposide 120 mg/m 2 day 1, 3 and 5 and carboplatin 400 mg/m 2 day 1. The two arms were well balanced according to age, sex, performance status and presence of either limited or extensive disease. In arm A the median number of cycles was 5 and in arm B it was 4. There was no statistically significant difference in response rates, being 74% in arm A (95% CI 58-89%) and 62% in arm B (95% C144-80%). Grade tll and IV hematological toxicities were more frequent in the arm B, i.e. the carboplatin group (p < 0.05). The median survival time in the cisplatin group (arm A) was 15 months versus 10 months in the carboplatin group (arm B). This difference was statistically significant in favor of arm A, i. e. the cisplatin group (p < 0.05).