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Vindesine, cisplatin and bleomycin in non-small cell lung cancer (NSCLC): Survival and quality of survival
132
and previous treatment (response of disease previously untreated by radiation or chemotherapy greater than treated disease, p = O.0O6).
mstolo~ S~mous L a ~ e cell Adenoca All
EXtent
NO. C~+~+I/NO. Pmtlents (5) Untreated Treated Prevlously Prev1~Jsly Total
Any T,N2 11/21 (52) R/D 9/16 (56) R/D 6/7 (86) R/D I/7 (14)
-4/16 (25) 2/6 (33) 3/14 (21)
11/21 13/32 8/i] 4/21
Any TNM
9/36 (25)
36/87 (41)
27/51(53)
(52) (41) (62) (19)
Median survival for responders with R/D disease was 34 wk versus 16 wk for nonresponders. Performance status at initiation of BEP had no effect on either response rate or survival time. Comparative Study of Chemotherapy With Cisplatin (CDDP) Bleomycin (BLEO) and Vindesine (VDS) Versus CDDP, Bleo and VP 16 For The Treatment of Non Small Cell Lung Cancer (NSCLC). Gracia, J.M., Jimenez, A., Del Rio, A. Hospital General de Asturias, Oviedo, Spain. We have treated 90 patients (pts) with non operable NSCLC using 2 different s~hedules. Arm A consisted of CDDP 33 mg/m , 6 hours infusion for 3 days; BLEO 15 u.i. i~ hours infusion for 3 days and VDS 3 mg/ m i.v. weekly for 4 w, then every 2-4 weeks depending on neurotoxicity Arm B consisted of CDDP and BLEO at the s~me dosage of arm A, and VP 16 150 mg/m i.v. for 3 days. Both schedules were repeated every 4 weeks. Patient characteristics were: Arm A with 38 fully evaluable pts 24 males, median age 56 years (32-70). Median Karnofsky 80 (60-90). Metastatic disease 26. Histologic diagnoses were 18 epidermoid (E), i0 adenocarcinoma (A), 9 large cell (L), 1 undifferentiated (U). There were 3 complete responses (CR), 13 partial responses (PR), I0 stable disease (SD) and 12 progressive disease (PD). Arm B with 34 fully evaluable pts 34 males, median age 59 (46-70). Median Karnofsky 80 (50-90). Metastatic disease 14, histologic diagnosis were 20 E, 10A, 4L. There were 2 CR, 14 PR, 8 SD, i0 PD. Main toxicity using WHO code was: arm A neurotoxicity 17 (I), 16 (II) leucopenia 1 (I), i0 (II), thrombocytopenia 1 (I) Arm B neurotoxicity (i (I), leucopenia (I), 28 (II), ii (III), 2 (IV), thrombocytopenia ) (I), 6 (II), 2 (III), 2 (IV). Median survival duration is in arm A 27 w (14-137+) and in arm B 30 w (8-74). There are not significative differences. Chemotherapy With Cisplatin, Etoposide and Vindesine Prior Radiation Therapy For Non Small Cell Lung Cancer: A Randomized Study.
Van Houtte, P., Klastersky, J., Nguyen, H., Michel, J., Vendermoten, G., Renaud, A., Devriendt, J., Sculier, J.P., Mommen, P. and the EORTC Lung Cancer Working Party, Institut Jules Bordet, Bruxelles, Belgium. The encouraging results obtained with chemotherapy regimen (Ct) containing cisplatin in the treatment of non small cell lung cancer have led our Group to investigate its value as a combined approach with radiation therapy (Rt) for inoperable tumors. Since 1981, we conducted a randomized trial to compare the efficacy of 3 cycles of Ct 2 (cisplatin 60 mg/m dl, eto~oside 120 mg/m d2, 4, 8 and vindesine 1.5 mg/m dl, 8; repeated every 4 weeks) given prior to a course of Rt (55 Gy in 5.5 weeks). A total of 58 patients (pts) are evaluable: 32 in the Rt group and 26 in the Ct + Rt group; 8 pts did not receive Rt after Ct because of the progression of the disease or refusal. For the remaining patients, Rt could be completed without excessive in toxicity. The response rate were similar: 17/32 after Rt and 7/18 after Ct + Rt. Only 4 pts out of 26 presented a response after 3 cycles of CT including a one complete response. Patterns of failure were identical. Median survival is 9 months for Ct + Rt and 12 months for Rt alone. Toxicity related to Ct consisted mainly of nausea and vomiting which required to discontinue the treatment in one patient. Other side effects were moderated and consisted of alopecia and myelosuppression. We conclude that this Ct progr~n given before Rt does not appear to provide advantage for pts with a non small cell lung cancer compared to Rt alone. Vindesine, Cisplatin and Bleomycin in NonSmall Cell Lung Cancer (NSCLC): Survival and Quality of Survival. Bakker, W., van Breukelen, F., Bins, M.C., van Oosterom, A.T. Departments of Pulmonary and Clinical Oncology, University Hospital, Leiden, The Netherlands. Previous studies have shown the efficacy of vindesine and cisplatin with or without bleomycin in NSCLC (Cancer 1983; 51: 1050). Side effects were reported as acceptable, but quality of life measures during treatment were not as a rule reported. Twenty-eight patients (mean age 56.5, range 40-69 years) with advanced NSCLC with high performance status (Karnofsky mean288 , range 60190%) received vindesine 2 mg/m d~l, and 1 mg/ m d. 3, cisplati 9 (CDDP) i00 mg/m ~ d. 2 and bleomycin 15 mg/m- d. i, and every 3 weeks thereafter for 9 weeks. In case of a complete response (CR) or partial response (PR) after 3 courses another 2 courses were given. A PR was reached in 12 of 27 evaluable patients (44.4%), a CR in 1/27 (3.7%), with a median duration of response of 24 weeks. Responses did not vary significantly among histologic
133
subtypes. Median survival time was 33 weeks (47 for responders and 26 for non-responders, p = 0.08). Clinically important toxicity was mainly CDDP-related and included nephrotoxicity notwithstanding prehydration and mannitol-induced diuresis (a fall in creatinin clearance below 50 ml/min in 6 patients including 1 drug-related death), severe nausea and vomiting in 67% of patients. Performance status and body weight dropped significantly during chemotherapy both in responders and non-responders. Performance status tended to rise to pretreatment levels after discontinuation of chemotherapy in responders only. We confirmed the efficacy of this drug combination but conclude that an appreciable toxicity and deterioration of the patients' well-being as measured by body weight and performance status made a possibly added survival for the majority of patients futile. Correlation Between Dl~g Sensitivity Determined by the Clonogenic Cell Assay and the Clinical Effect of Chemotherapy in Patients with Primary Lung Cancer. Futami, H., Eguchi, K., Saijo, N., Sasaki, Y., Kanzawa, F., Hoshi, A., Shinkai, T., Tominaga, K., Fujita, J. National Cancer Center, Tokyo, Japan. Correlation between the drug sensitivity of tumor cells determined by the clonogenic cell assay and the clinical effect of chemotherapy was studied in patients with primary lung cancer. Sixty four patients were entered in this study from May 1982 to August 1984. Clonogenic cell assay were performed with the method of Hamburger and Salmon and specimens were freshly isolated tumor cells taken from lymph nodes, pleural effusion, subcutaneous metastasis and ascites. Anticancer agents tested were MMC, KW2083, CDDP, ACNU, VCR, PLM, ADM, VP-16 and I-PAM (instead of CPA). The criteria of in vitro chemosensitivity employed was greater than 50% reduction in colony numbers compared to control platd. Fourty five of 64 patients (70.3%) showed adequate colony formation (> 30 colonies/plate) to evaluate rate and the true negative rate of this assay were 50.0% and 85.3% respectively, compared to the clinical effect of chemotherapy in these patients retrospectively. The predictive accuracy was 78.0%. By Fisher's exact probability test, the over-all in vitro/in vivo correlation was statistically significant (p < 0.05) with the 50% cut-off point. In five cases clonogenic cell assays were done before and after chemotherapy. Three of these cases showed decreasing sensitivity of tumor cells to anticancer
agents with wide spectrum after chemotherapy. A Controlled Evaluation of Combined 5-Fluorouracil, Adriamycin and Mitomycin-S (FAM) for the Treatment of Advanced Non-Small Cell Lung Cancer (NSCLC). Jett, J., Krook, J., Fleming, T. for the North Central Cancer Treatment Group, Rochester, MN 55905, U.S.A. Patients with advanced NSCLC (N = 186) were randomly assigned to treatment with FAM or combined methotrexate, doxorubicin, cyclophosphamide and lomustine (MACC). Regression rates were comparable at 20% vs 16% respectively. Distribution of intervals to progression (overall median 2.8 months) and survival times (overall median 5.0 months) were eSsentially identical between the two regimens. The comparability of the therapeutic effect was also evident within the subset of 81 patients who had adenocarcinoma cell type. MACC showed a small advantage in survival after covariate analysis. In large cell carcinoma MACC showed a higher regression rate than FAM as well as a small survival advantage. In squamous cell carcinoma, however, FAM was superior to MACC in regression rates (32% vs 4%) and also resulted in somewhat longer survival. MACC produced a higher incidence of nausea and vomiting but FAM caused more frequent and severe thrombocytopenia. In summary, neither FAM nor MACC were particularly ~ t i v e against NSCLC. This study suggests that Mitomycin-C containing regimens may be selectively effective for squamous cell lung cancer. Improvement in Treatment Results in SCLC With the Addition of VP-16-213 To Cyclophosphamide, Adriamycin, and Vincristine (CAV). Zekan, P., Jackson, D., Muss, H., Richards, F., Cooper, M., White, D., Stuart, J., Hopkins, J., Spurr, C., Caldwell, R., Capizzi, R., Cruz, J. Biostaticians: Case, L., Wells, H., Morgan, T. Piedmont Oncology Association and the Oncology Research Center, Bowman Gray School of Medicine, Winston-Salem, NC 27103. A series of 259 patients who presented with SCLC between 12/79 and 8/84 were prospectively randomized to receive CAV + VP-16 in addition to local chest and prophylactic cranial RT. Therapy was with C-igm/m~, A-50 mg/m-, V-I.5 mg/m ~ ~ VP-16 60 mg mg/m-/dx5 days q 3 wkx3 cycles, followed by RT to the c~est and bra~n (3000r), fgllowed by C-750 m~/m ~, A-50 m g / m , V-I.5 mg/m ~ ~ VP-16 250 mg/m- i.v. d 1 q 3 wk for a total of 2 years of treatment. Pretreatment characteristics were well balanced. Median follow-up is now 26 months (mo). Of 195 patients evaluable for response, CR + PR was observed in 37 + 23/94 (64%) CAV-treated patients and 47 + 38/101 (84%) VCAV-treated patients, p=.0012. Patients with extensive disease (ED) had CR+PR in 5+9/35 (40%) in CAV-treated patients, and 15+22/44 (84%) in VCAV-treated patients, p=.00005. The estimated median time to progression overall is 8.2 mo on CAV and 10.4
and previous treatment (response of disease previously untreated by radiation or chemotherapy greater than treated disease, p = O.0O6).
mstolo~ S~mous L a ~ e cell Adenoca All
EXtent
NO. C~+~+I/NO. Pmtlents (5) Untreated Treated Prevlously Prev1~Jsly Total
Any T,N2 11/21 (52) R/D 9/16 (56) R/D 6/7 (86) R/D I/7 (14)
-4/16 (25) 2/6 (33) 3/14 (21)
11/21 13/32 8/i] 4/21
Any TNM
9/36 (25)
36/87 (41)
27/51(53)
(52) (41) (62) (19)
Median survival for responders with R/D disease was 34 wk versus 16 wk for nonresponders. Performance status at initiation of BEP had no effect on either response rate or survival time. Comparative Study of Chemotherapy With Cisplatin (CDDP) Bleomycin (BLEO) and Vindesine (VDS) Versus CDDP, Bleo and VP 16 For The Treatment of Non Small Cell Lung Cancer (NSCLC). Gracia, J.M., Jimenez, A., Del Rio, A. Hospital General de Asturias, Oviedo, Spain. We have treated 90 patients (pts) with non operable NSCLC using 2 different s~hedules. Arm A consisted of CDDP 33 mg/m , 6 hours infusion for 3 days; BLEO 15 u.i. i~ hours infusion for 3 days and VDS 3 mg/ m i.v. weekly for 4 w, then every 2-4 weeks depending on neurotoxicity Arm B consisted of CDDP and BLEO at the s~me dosage of arm A, and VP 16 150 mg/m i.v. for 3 days. Both schedules were repeated every 4 weeks. Patient characteristics were: Arm A with 38 fully evaluable pts 24 males, median age 56 years (32-70). Median Karnofsky 80 (60-90). Metastatic disease 26. Histologic diagnoses were 18 epidermoid (E), i0 adenocarcinoma (A), 9 large cell (L), 1 undifferentiated (U). There were 3 complete responses (CR), 13 partial responses (PR), I0 stable disease (SD) and 12 progressive disease (PD). Arm B with 34 fully evaluable pts 34 males, median age 59 (46-70). Median Karnofsky 80 (50-90). Metastatic disease 14, histologic diagnosis were 20 E, 10A, 4L. There were 2 CR, 14 PR, 8 SD, i0 PD. Main toxicity using WHO code was: arm A neurotoxicity 17 (I), 16 (II) leucopenia 1 (I), i0 (II), thrombocytopenia 1 (I) Arm B neurotoxicity (i (I), leucopenia (I), 28 (II), ii (III), 2 (IV), thrombocytopenia ) (I), 6 (II), 2 (III), 2 (IV). Median survival duration is in arm A 27 w (14-137+) and in arm B 30 w (8-74). There are not significative differences. Chemotherapy With Cisplatin, Etoposide and Vindesine Prior Radiation Therapy For Non Small Cell Lung Cancer: A Randomized Study.
Van Houtte, P., Klastersky, J., Nguyen, H., Michel, J., Vendermoten, G., Renaud, A., Devriendt, J., Sculier, J.P., Mommen, P. and the EORTC Lung Cancer Working Party, Institut Jules Bordet, Bruxelles, Belgium. The encouraging results obtained with chemotherapy regimen (Ct) containing cisplatin in the treatment of non small cell lung cancer have led our Group to investigate its value as a combined approach with radiation therapy (Rt) for inoperable tumors. Since 1981, we conducted a randomized trial to compare the efficacy of 3 cycles of Ct 2 (cisplatin 60 mg/m dl, eto~oside 120 mg/m d2, 4, 8 and vindesine 1.5 mg/m dl, 8; repeated every 4 weeks) given prior to a course of Rt (55 Gy in 5.5 weeks). A total of 58 patients (pts) are evaluable: 32 in the Rt group and 26 in the Ct + Rt group; 8 pts did not receive Rt after Ct because of the progression of the disease or refusal. For the remaining patients, Rt could be completed without excessive in toxicity. The response rate were similar: 17/32 after Rt and 7/18 after Ct + Rt. Only 4 pts out of 26 presented a response after 3 cycles of CT including a one complete response. Patterns of failure were identical. Median survival is 9 months for Ct + Rt and 12 months for Rt alone. Toxicity related to Ct consisted mainly of nausea and vomiting which required to discontinue the treatment in one patient. Other side effects were moderated and consisted of alopecia and myelosuppression. We conclude that this Ct progr~n given before Rt does not appear to provide advantage for pts with a non small cell lung cancer compared to Rt alone. Vindesine, Cisplatin and Bleomycin in NonSmall Cell Lung Cancer (NSCLC): Survival and Quality of Survival. Bakker, W., van Breukelen, F., Bins, M.C., van Oosterom, A.T. Departments of Pulmonary and Clinical Oncology, University Hospital, Leiden, The Netherlands. Previous studies have shown the efficacy of vindesine and cisplatin with or without bleomycin in NSCLC (Cancer 1983; 51: 1050). Side effects were reported as acceptable, but quality of life measures during treatment were not as a rule reported. Twenty-eight patients (mean age 56.5, range 40-69 years) with advanced NSCLC with high performance status (Karnofsky mean288 , range 60190%) received vindesine 2 mg/m d~l, and 1 mg/ m d. 3, cisplati 9 (CDDP) i00 mg/m ~ d. 2 and bleomycin 15 mg/m- d. i, and every 3 weeks thereafter for 9 weeks. In case of a complete response (CR) or partial response (PR) after 3 courses another 2 courses were given. A PR was reached in 12 of 27 evaluable patients (44.4%), a CR in 1/27 (3.7%), with a median duration of response of 24 weeks. Responses did not vary significantly among histologic
133
subtypes. Median survival time was 33 weeks (47 for responders and 26 for non-responders, p = 0.08). Clinically important toxicity was mainly CDDP-related and included nephrotoxicity notwithstanding prehydration and mannitol-induced diuresis (a fall in creatinin clearance below 50 ml/min in 6 patients including 1 drug-related death), severe nausea and vomiting in 67% of patients. Performance status and body weight dropped significantly during chemotherapy both in responders and non-responders. Performance status tended to rise to pretreatment levels after discontinuation of chemotherapy in responders only. We confirmed the efficacy of this drug combination but conclude that an appreciable toxicity and deterioration of the patients' well-being as measured by body weight and performance status made a possibly added survival for the majority of patients futile. Correlation Between Dl~g Sensitivity Determined by the Clonogenic Cell Assay and the Clinical Effect of Chemotherapy in Patients with Primary Lung Cancer. Futami, H., Eguchi, K., Saijo, N., Sasaki, Y., Kanzawa, F., Hoshi, A., Shinkai, T., Tominaga, K., Fujita, J. National Cancer Center, Tokyo, Japan. Correlation between the drug sensitivity of tumor cells determined by the clonogenic cell assay and the clinical effect of chemotherapy was studied in patients with primary lung cancer. Sixty four patients were entered in this study from May 1982 to August 1984. Clonogenic cell assay were performed with the method of Hamburger and Salmon and specimens were freshly isolated tumor cells taken from lymph nodes, pleural effusion, subcutaneous metastasis and ascites. Anticancer agents tested were MMC, KW2083, CDDP, ACNU, VCR, PLM, ADM, VP-16 and I-PAM (instead of CPA). The criteria of in vitro chemosensitivity employed was greater than 50% reduction in colony numbers compared to control platd. Fourty five of 64 patients (70.3%) showed adequate colony formation (> 30 colonies/plate) to evaluate rate and the true negative rate of this assay were 50.0% and 85.3% respectively, compared to the clinical effect of chemotherapy in these patients retrospectively. The predictive accuracy was 78.0%. By Fisher's exact probability test, the over-all in vitro/in vivo correlation was statistically significant (p < 0.05) with the 50% cut-off point. In five cases clonogenic cell assays were done before and after chemotherapy. Three of these cases showed decreasing sensitivity of tumor cells to anticancer
agents with wide spectrum after chemotherapy. A Controlled Evaluation of Combined 5-Fluorouracil, Adriamycin and Mitomycin-S (FAM) for the Treatment of Advanced Non-Small Cell Lung Cancer (NSCLC). Jett, J., Krook, J., Fleming, T. for the North Central Cancer Treatment Group, Rochester, MN 55905, U.S.A. Patients with advanced NSCLC (N = 186) were randomly assigned to treatment with FAM or combined methotrexate, doxorubicin, cyclophosphamide and lomustine (MACC). Regression rates were comparable at 20% vs 16% respectively. Distribution of intervals to progression (overall median 2.8 months) and survival times (overall median 5.0 months) were eSsentially identical between the two regimens. The comparability of the therapeutic effect was also evident within the subset of 81 patients who had adenocarcinoma cell type. MACC showed a small advantage in survival after covariate analysis. In large cell carcinoma MACC showed a higher regression rate than FAM as well as a small survival advantage. In squamous cell carcinoma, however, FAM was superior to MACC in regression rates (32% vs 4%) and also resulted in somewhat longer survival. MACC produced a higher incidence of nausea and vomiting but FAM caused more frequent and severe thrombocytopenia. In summary, neither FAM nor MACC were particularly ~ t i v e against NSCLC. This study suggests that Mitomycin-C containing regimens may be selectively effective for squamous cell lung cancer. Improvement in Treatment Results in SCLC With the Addition of VP-16-213 To Cyclophosphamide, Adriamycin, and Vincristine (CAV). Zekan, P., Jackson, D., Muss, H., Richards, F., Cooper, M., White, D., Stuart, J., Hopkins, J., Spurr, C., Caldwell, R., Capizzi, R., Cruz, J. Biostaticians: Case, L., Wells, H., Morgan, T. Piedmont Oncology Association and the Oncology Research Center, Bowman Gray School of Medicine, Winston-Salem, NC 27103. A series of 259 patients who presented with SCLC between 12/79 and 8/84 were prospectively randomized to receive CAV + VP-16 in addition to local chest and prophylactic cranial RT. Therapy was with C-igm/m~, A-50 mg/m-, V-I.5 mg/m ~ ~ VP-16 60 mg mg/m-/dx5 days q 3 wkx3 cycles, followed by RT to the c~est and bra~n (3000r), fgllowed by C-750 m~/m ~, A-50 m g / m , V-I.5 mg/m ~ ~ VP-16 250 mg/m- i.v. d 1 q 3 wk for a total of 2 years of treatment. Pretreatment characteristics were well balanced. Median follow-up is now 26 months (mo). Of 195 patients evaluable for response, CR + PR was observed in 37 + 23/94 (64%) CAV-treated patients and 47 + 38/101 (84%) VCAV-treated patients, p=.0012. Patients with extensive disease (ED) had CR+PR in 5+9/35 (40%) in CAV-treated patients, and 15+22/44 (84%) in VCAV-treated patients, p=.00005. The estimated median time to progression overall is 8.2 mo on CAV and 10.4