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Adjuvant immunotherapy with interleukin 2 and lymphokine-activated killer cells after noncurative resection of primary lung cancer
344
Abstracts
/Lamg
Gmcer
t0 hunOr rtsponse and swivd. However, a significantIy greater rate of severe Or Life-threatening hematologic toxicity was noted on the 2 I-day Oral etoposide treatment schedule.
Ifosfamide plus high-dose cisplatin in patients with non-small cell lung cancer previously treated with chemotherapy Miller VA, Rigas JR, Pisten KMW, Ptister DG, He&n RT, Kris MG. Memorial Sloan-Kertering Cancer C&, 1275 York Avenue, New York, NY 10021. Am J Clin Oncol Cancer Clin Trials 1995;18:303-6. This study determined the maximum tolerated dose (MID) of ifosthmide that could be given with high-dose cisplatin to non-small cell lung cancer (NSCLC) patients previously treated with non-platincontaining chemotherapy and to assess the efficacy ofthis combination. Wenty-three patients with inoperable NSCLC treated with one prior chemotherapy regimen received continuous infusion ifosthmide 1.2 g/ ml per day with MESNA for 5 days every 35 days and cisplatin 120 mg/m’. After one patient who received cisplatin as a single dose developed grade 4 nephmtoxicity and myelosuppression, cisplatin was given in four divided doses (30 mp/m’ per day) and the ifosfamide dose was lowered to 1.0 g/m’ per day, infused over 4 days. Dose- limiting grades 3 and 4 leukopenia was seen in 43%. A major objective response rate of 9% was observed. The l-year survival was 30%. with a median sumival of 6.4 months. The MTD of ifosthmide administered with cisplatin (30 me/m’ per day for 4 consecutive days) to this population of patients is 1.0 g/m’ daily for 4 days. This combination produced limited anticancer activity and significant toxicity. Excessive toxicity was observed when cisplatin was given as a single dose with ifosfamide, and this schedule should not be used.
Phase I-11 and pharmacoldnetic study of a new fotemustine schedule in advanced non-small cell lung cancer Le Cesne A, Chabot G, Berille J, Lucas C, Baud M, Gouyette A et al. Service de Medecine 3. Institui Gustave-Roum 94805 VdlejuijTedex. Lung Cancer (Ireland) 199X13:69-78. Fotemustine, a new nitrosouma derivative has already demonstrated activity in non-small cell lung cancer (NSCLC). In order to improve its therapeutic index, we designed a protocol in which Fotemustine was delivered with dose escalation on 3 consecutive days as induction therapy followed by a S-week rest period. Maintenance therapy consisted of 100 mg/mz once every 3 weeks. Pharmacokinetic data were assessed during this Phase I-II study and reported here. Patients and methods: Nineteen patients with metastatic (17) or locally advanced (2) NSCLC were included in the present study. Ten of those with me&static disease had brain metastases and 15 had previously received chemotherapy. Fotemustine was given at 50 mg/m’ on day l-2-3 (group I: four patients), 75 mg/mr on day l-2-3 (group 2: 16 patients including two who had already received 50 mg/3) and LOO mg/m’ on day l-2-3 (group 3: one patient). Results: The maximal tolerated dose was 75 mglmr on day l2-3 (total cumulated dose 225 mp/m’. At this dose level, we observed 25%ofGrade3-4 neutropeniaand3l%ofGrade3-4thrombocytopenia. One patient died of pulmonary infection during aplasia. No other sign&ant toxicity occurred. Of the 17 evahusble patients, one obtained a PR lasting 6 months in group 2 and 1 PR lasting 3 months in group 3. No significant difference was noted in the AUC between days 1,2 or 3 in any of the seven patients in whom a pharrnacokinetic study of Fotemustine was performed. Conclusion: Administered on 3 consecutive days. Fotemustine seems to be less effective and more toxic than other schedules tested in NSCLC. Despite the quality of the two responses observed, this protocol has been discontinued and the standard administration on days 1 and 8 remains the schedule of choice in NSCLC.
13 (1995)
323-356
Adjuvant immunotherapy with interleuhin 2 and lymphohineactivauzd killer cells after noncurative reaction of primary lung cancer KimuraH, Yamaguchi Y. Division o/Thorn& Diseases, Chiba Cancer Cente,: Nitona-cho 666-2, Chuo-ku, Chiba 260. Lung Cancer (Ireland) 1995;13:31-44. A randomized controlled study of immunotherapy with interleukin 2 (IL-2) and lymphokine-activated killer (UK) cells was conducted in 105 patients after noncurative resection of primary lung cancer. Half the patients received only the standard postoperative radiation therapy or chemotherapy (control group). The other half received immunotherapy with IL-2 and LAK cells in addition to the standard therapy (immunotherapy group). The primary endpoint was survival. The 7-year survival rate was greater in the immunotherapy group than in the control group(39.1%vs. 12.7%. P < 0.01). Amongpatientswith squamous cell carcinoma, there was no statistical difference in outcome. In wntrast, the ‘l-year survival rate among patients with adenocarcinoma in the control group was only 5.2% but for those in the immunotherapy group it was 38.9% (P < 0.05). If resection was noncurative because of pulmonary metastasis, residual cancer or incomplete resection of lymph nodes, then immunotherapy was effective. If resection was noncurative because of residual cancer in the chest wag or diaphragm, or because of carcinomatous pleuritis or pleural dissemination, then there was no statistical difference in survival between the control group and the immunotherapy group. Singk-agent chemotherapy versus combination chemotherapy in advanced non-small cell lung cancer: A quality and metaanalysis study Marino P, Preatoni A, Cantoni A, Buccheri G. Department o/internal Medicine, University ofMilano, S. Paolo Hospital, Milan. Lung Cancer (Ireland) 1995;13:1-12. Study objective: To estimate the quality of the studies and to compare single-agent with combination chemotherapy in advanced non-small cell lung cancer. Design: Identification of published randomized trials and extraction of essential results directly from the published reports. Measutvments andmsults: Survival probability at 1 year, as estimated from the published survival curves, has been considered as the endpoint of interest. Quality scoring of the studies has also bsen performed. Arithmetical calculation, concerning the estimation of quantities necesmry for the meta-analysis of the literature, has been addressed. The estimated pooled Odds Ratio of death was 0.8, with 95% wniidence interval of 0.6-1.0, thus favoring combination chemotherapy. Conclusions: The results of our meta-analysis favor combination chemotherapy. They must, however, be considered in the light of their clinical relevance and of the balance between quality of life, toxicity and costs of chemotherapy. Characterisation of a human small-cell lung cancer cell line resistant to the DNA topoisomerase I-directed drug topotecan Sorensen M, Sehested M, Jensen PB. Department of Pathology Sundby Hospital, DK-2300 Copenhagen S. Br J Cancer 1995;72:399-404. Camptothecins are DNA topoisomerase I-directed anti-tumour drugs with a novel mechanism of action. Topotecan (ITT), a hydrophilic derivative of camptothecin, is currently undergoing phase II clinical trials in small-cell lung cancer (SCLC). Human SCLC GC-NYH cells were made more than 6-fold resistant to topotecan by stepwise drug exposure and resistance was stable for 70 passages without drug. NYIU TPT cells had half the topoisomeraae I level and activity of wild-type cells. However, no digerence in camptothecin or topotecan inhibition of topoisomerase I-mediated DNA relaxation was found, indicating that the enzyme itself was unchanged in the resistant cell. In NywrpT
Abstracts
/Lamg
Gmcer
t0 hunOr rtsponse and swivd. However, a significantIy greater rate of severe Or Life-threatening hematologic toxicity was noted on the 2 I-day Oral etoposide treatment schedule.
Ifosfamide plus high-dose cisplatin in patients with non-small cell lung cancer previously treated with chemotherapy Miller VA, Rigas JR, Pisten KMW, Ptister DG, He&n RT, Kris MG. Memorial Sloan-Kertering Cancer C&, 1275 York Avenue, New York, NY 10021. Am J Clin Oncol Cancer Clin Trials 1995;18:303-6. This study determined the maximum tolerated dose (MID) of ifosthmide that could be given with high-dose cisplatin to non-small cell lung cancer (NSCLC) patients previously treated with non-platincontaining chemotherapy and to assess the efficacy ofthis combination. Wenty-three patients with inoperable NSCLC treated with one prior chemotherapy regimen received continuous infusion ifosthmide 1.2 g/ ml per day with MESNA for 5 days every 35 days and cisplatin 120 mg/m’. After one patient who received cisplatin as a single dose developed grade 4 nephmtoxicity and myelosuppression, cisplatin was given in four divided doses (30 mp/m’ per day) and the ifosfamide dose was lowered to 1.0 g/m’ per day, infused over 4 days. Dose- limiting grades 3 and 4 leukopenia was seen in 43%. A major objective response rate of 9% was observed. The l-year survival was 30%. with a median sumival of 6.4 months. The MTD of ifosthmide administered with cisplatin (30 me/m’ per day for 4 consecutive days) to this population of patients is 1.0 g/m’ daily for 4 days. This combination produced limited anticancer activity and significant toxicity. Excessive toxicity was observed when cisplatin was given as a single dose with ifosfamide, and this schedule should not be used.
Phase I-11 and pharmacoldnetic study of a new fotemustine schedule in advanced non-small cell lung cancer Le Cesne A, Chabot G, Berille J, Lucas C, Baud M, Gouyette A et al. Service de Medecine 3. Institui Gustave-Roum 94805 VdlejuijTedex. Lung Cancer (Ireland) 199X13:69-78. Fotemustine, a new nitrosouma derivative has already demonstrated activity in non-small cell lung cancer (NSCLC). In order to improve its therapeutic index, we designed a protocol in which Fotemustine was delivered with dose escalation on 3 consecutive days as induction therapy followed by a S-week rest period. Maintenance therapy consisted of 100 mg/mz once every 3 weeks. Pharmacokinetic data were assessed during this Phase I-II study and reported here. Patients and methods: Nineteen patients with metastatic (17) or locally advanced (2) NSCLC were included in the present study. Ten of those with me&static disease had brain metastases and 15 had previously received chemotherapy. Fotemustine was given at 50 mg/m’ on day l-2-3 (group I: four patients), 75 mg/mr on day l-2-3 (group 2: 16 patients including two who had already received 50 mg/3) and LOO mg/m’ on day l-2-3 (group 3: one patient). Results: The maximal tolerated dose was 75 mglmr on day l2-3 (total cumulated dose 225 mp/m’. At this dose level, we observed 25%ofGrade3-4 neutropeniaand3l%ofGrade3-4thrombocytopenia. One patient died of pulmonary infection during aplasia. No other sign&ant toxicity occurred. Of the 17 evahusble patients, one obtained a PR lasting 6 months in group 2 and 1 PR lasting 3 months in group 3. No significant difference was noted in the AUC between days 1,2 or 3 in any of the seven patients in whom a pharrnacokinetic study of Fotemustine was performed. Conclusion: Administered on 3 consecutive days. Fotemustine seems to be less effective and more toxic than other schedules tested in NSCLC. Despite the quality of the two responses observed, this protocol has been discontinued and the standard administration on days 1 and 8 remains the schedule of choice in NSCLC.
13 (1995)
323-356
Adjuvant immunotherapy with interleuhin 2 and lymphohineactivauzd killer cells after noncurative reaction of primary lung cancer KimuraH, Yamaguchi Y. Division o/Thorn& Diseases, Chiba Cancer Cente,: Nitona-cho 666-2, Chuo-ku, Chiba 260. Lung Cancer (Ireland) 1995;13:31-44. A randomized controlled study of immunotherapy with interleukin 2 (IL-2) and lymphokine-activated killer (UK) cells was conducted in 105 patients after noncurative resection of primary lung cancer. Half the patients received only the standard postoperative radiation therapy or chemotherapy (control group). The other half received immunotherapy with IL-2 and LAK cells in addition to the standard therapy (immunotherapy group). The primary endpoint was survival. The 7-year survival rate was greater in the immunotherapy group than in the control group(39.1%vs. 12.7%. P < 0.01). Amongpatientswith squamous cell carcinoma, there was no statistical difference in outcome. In wntrast, the ‘l-year survival rate among patients with adenocarcinoma in the control group was only 5.2% but for those in the immunotherapy group it was 38.9% (P < 0.05). If resection was noncurative because of pulmonary metastasis, residual cancer or incomplete resection of lymph nodes, then immunotherapy was effective. If resection was noncurative because of residual cancer in the chest wag or diaphragm, or because of carcinomatous pleuritis or pleural dissemination, then there was no statistical difference in survival between the control group and the immunotherapy group. Singk-agent chemotherapy versus combination chemotherapy in advanced non-small cell lung cancer: A quality and metaanalysis study Marino P, Preatoni A, Cantoni A, Buccheri G. Department o/internal Medicine, University ofMilano, S. Paolo Hospital, Milan. Lung Cancer (Ireland) 1995;13:1-12. Study objective: To estimate the quality of the studies and to compare single-agent with combination chemotherapy in advanced non-small cell lung cancer. Design: Identification of published randomized trials and extraction of essential results directly from the published reports. Measutvments andmsults: Survival probability at 1 year, as estimated from the published survival curves, has been considered as the endpoint of interest. Quality scoring of the studies has also bsen performed. Arithmetical calculation, concerning the estimation of quantities necesmry for the meta-analysis of the literature, has been addressed. The estimated pooled Odds Ratio of death was 0.8, with 95% wniidence interval of 0.6-1.0, thus favoring combination chemotherapy. Conclusions: The results of our meta-analysis favor combination chemotherapy. They must, however, be considered in the light of their clinical relevance and of the balance between quality of life, toxicity and costs of chemotherapy. Characterisation of a human small-cell lung cancer cell line resistant to the DNA topoisomerase I-directed drug topotecan Sorensen M, Sehested M, Jensen PB. Department of Pathology Sundby Hospital, DK-2300 Copenhagen S. Br J Cancer 1995;72:399-404. Camptothecins are DNA topoisomerase I-directed anti-tumour drugs with a novel mechanism of action. Topotecan (ITT), a hydrophilic derivative of camptothecin, is currently undergoing phase II clinical trials in small-cell lung cancer (SCLC). Human SCLC GC-NYH cells were made more than 6-fold resistant to topotecan by stepwise drug exposure and resistance was stable for 70 passages without drug. NYIU TPT cells had half the topoisomeraae I level and activity of wild-type cells. However, no digerence in camptothecin or topotecan inhibition of topoisomerase I-mediated DNA relaxation was found, indicating that the enzyme itself was unchanged in the resistant cell. In NywrpT