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Evaluation of the optimal duration of chemotherapy in phase II trials for inoperable non-small-cell lung cancer (NSCLC)
Abstracts/Lung
CIancer I5 (19%) 139-157
Thomas P et al. NCIC Clinical Trials Group, Queen’s University, 8284 Barrie Srreer, Kingston, Ont. Anti-Cancer Drugs 1995;6:Suppl 6~33-7. CollaborativephaseIandlI studiesofthecombinationofgemcitabine and cisplatin in patients with advanced non-small cell lung cancer are ongoing at five centres in the UK and France. In the initial completed phase I study, 16 patients (15 evaluable) have been entered using a fixed dose of gemcitabine 1000 mglm’ given as a 30 min intravenous infusion weekly for 3 weeks. On the third week the gemcitabine was immediately followed by cisplatin with pre- and post-hydration. This regimen required only 1 night of hospitalization every 4 weeks. The study design was for sequential groups of patients to receive 3 dose levels of cisplatin (60mg/m2, 75mglm’and lOOmg/m’)butthesedoseswouldbemodif~ed and the number of patients at any dose level could be increased if significant toxicity was observed. Three patients were to be entered at the first two dose levels and 10 patients were to confirm the maximum tolerated dose (if reached) or expand the database on toxicity at the final predetermined dose level. The major haematological toxicities were neutropenia (grade 4 in 3 patients) and thrombocytopenia (grade 3 or 4 in 5 patients) but both were of short duration and uncomplicated. Grade 3 nausea and vomiting occurred in 12 patients but was no worse than would be expected from cisplatin alone. Alopecia was not a problem (no hair loss in 10 patients and grade 1 or 2 in 6 patients) and no significant renal orneurotoxicity wasseen. A phase II study using cisplatin 100 mg/ m’ in combination with gemcitabine 1000 mglm’ has been opened and to date 19 patients are evaluable for response. Eight (42%) have achieved partial remissions. The study is ongoing and will recruit 50 evaluable patients.
Gemcitabine: Clinical and economic impact in inoperable non-small cell lung cancer Koch P, Johnson N, Van Schaik J, Andersen S, Blatter J, Bosanquet N et al. Policy and Economics Group. Cambridge Pharma Consul~ancy. I Quayside, Bridge Street, Cambridge CBS &Is. Anti-Cancer Drugs 1995;6:Suppl 6:49-54. This study assesses retrospectively theclinical and economic impact of gemcitabine monotherapy on the management of inoperable stage III/ IV non-small cell lung cancer in Germany. Based on current methods of clinical practice and using the best outcome data available, the costs and benefits of gemcitabine were compared to a dual therapy (ifosfamide/ etoposide). While the two treatments showed broadly equivalent efficacy in terms of tumour response rate and survival, a cost analysis showed the potential for savings with gemcitabine. These largely related to hospital hotelling costs, due to the fact that gemcitabine may be given as an outpatient therapy. Further savings were found in investigative procedures and the management of treatment toxicity. Excluding the cost of the chemotherapy, gemcitabine was associated with potential savings of DM3,026 over two cycles of therapy, which included a 40% decrease in hospitalization costs and a 54% decrease in the cost of managing adverse events. We conclude that gemcitabine monotherapy could offer considerable cost savings while offering the potential for improved quality ofpalliative treatment compared to existing in-patient treatments, and it may have a place in shilling care from an in-patient to an outpatient setting in line with recent health care reforms.
Differential expression of DNA topoisomerases in non-small cell lung cancer and normal lung Giaccone G, Van Ark-O&J, Scagliotti G, Capranico G, Van der Valk P, Rubio G et al. Free University Hospilal. Deparzmennt of Oncolopv/ Pathology, 1081 HVAmsrerdam. B&him Bidphys ActaGene S&&t Expr 1995;1264:337-46. DNA topoisomerasesareubiquitousnuclearenxymea, and important
153
targ& of cancer chemotherapy. Expression of topoisomemse genes is oRea correlated with in vtro chemosensitivity. We investigated the expression of the topoisomerase genes in normal lung and non-small cell lung cancer. Expression of topoisomerase II-a topoisomerase II-D, and topoisomemse I genes has been assessed in tumor samples of 60 patients who underwent operation for a non-small cell lung carcinoma, by RNase protection assay, and by immunohistochemistry. The expression of topoisomerase 11-a gene was either undetectable or very low in normal lung, while most NSCLC expressed readily quantifiable levels of this gene. No alteration of the topoisomerase 11-a gene was found by Southern blotting in the NSCLC samples. In contrast to topoisomerase 11-a topoisomerase II-6 was expressed in most normal as well as in tumor tissue samples, at a similar level. The levels of expression of both topoisomII isoforms was lower than that ofhuman lung cancer cell lines. The results of the topoisomerase II mRNA expression were confirmed by immunohistochemistry. Whereas topoisomerase 11-a staining was mainly limited to the nucleus, staining with topoisomerase II-B antibody was exclusively observed in nucleoli. Topoisomerase I was localized in the nuclei and expression was mainly limited to tumor cells. By RNase protection, topoisomerase I expression in NSCLC samples was in the range of that of human lung cancer cell lines. The expression of the topoisomerase genes did not seem to be coordinated. In tumor cells, there was a positive association between expression of topoisomeraseIIasndKi-677amarkerofcell proliferation, asassessed by immunohistochemistry, but not with topoisomerase II-8 or topoisomerase I. Clinical characteristics of the patients, and their survival did not appear to be correlated to the level of expression of any of the topoisomerase genes, although a trend towards a shorter survival was observed in patieots whose tumors expressed relatively high topoisomerase 11-a mRNA levels. In conclusion, the two isoforms of topoisomerase II are differentially expressed in normal lung and NSCLC cells; (2) higher topoisomerase IIa expression is associated with higher cell proliferation in NSCLC; (3) the expression of topoisomerase IIa and topoisomerase 17 but not of topoisomerase 11-13,was higher in tumor cells compared to normal lung. Given the differential expression of topoisomerases in normal lung and tumors, research of more potent and specific topoisomerase inhibitors might prove beneficial in non-small cell lungcancer. Immunohistochemistrymaybeindicatedinprospectively ivestigating the correlation between expression of topoisomerases and results of chemotherapy treatment.
Evaluation of the optimal duration of chemotherapy in phase II trials for inoperable non-small-cell lung cancer (NSCLC) Larsen H, Sorensen JB, Nielsen AL, Dombemowsky P, Hansen HH. Ihe Finsen Center 5072, National Universiry Hospital, 9 Blegdamsvej. DK-2100 Copenhagen. Ann Gncol 1995;6:993-7. Purpose: To determine the optimal duration of chemotherapy in phase II trials for patients with non-small-cell lung cancer (NSCLC). Parienrsandmerhodx Thetimefromstartoftreatmentuntil achievement of response according to WHO criteria was determined retrospectively in 8 phase II trials. Results: Response to chemotherapy consisting of 4 complete and 39 partial remissions was registered in 43 of 333 patients. The median time from treatment start to response was 54 days. On day 84 on-study, 35 of the responding patients (81%) had achieved the response. Forty-three responses (98%) had occurred by day 168 and only one patient (2%) accomplished a response after 168 days of treatment. The responses had a median duration of 151 days (range 281559 days). Conclusions: The data indicate that patients with NSCLC included in phase II trials who have not yet achieved a response to chemotherapy after 168 days on study have a low likelihood (2 %) of a subsequent response. Hence, treatment cessation at this point should be considered fornon-responding patients. Continuation oftreatment from day 84 to day 168 resulted in response in only 7 patients out of the total
154
Abslracts/L.tmg
Cancer
of43 responsesnoted( 16%). Thus, tbetoxiceffectsofthechemotherapy in addition to the inconvenience of hospital visits renders it questionable whether it is worthwhile to continue treatment in patients with inoperable non-small-cell lung cancer beyond day 84 in the absence of response.
TWO schedules of teniposide with or without cisplatin in advanced non- small-cell lung cancer: A randomized Study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group Splinter TAW, Sahmoud T, F&en J, Van Zandwijk N, Sorenson S, Clerico M et al. Medical Oncology. Free Vtdversity Hospital, 1117De Boelelaan. HV 1081 Amsterdam. J Clin Oncol 1996; 14: 127-34. Purpose: We conducted a randomized trial to investigate the value of the addition of cisplatin to teniposide (VM26) and to investigate the schedule dependence of the topoisomerase II inhibitor VM26, in advanced non-small- cell lung cancer (NSCLC) patients. Patients and Methoak Two hundred twenty- five NSCLC patients were randomized to receive VM26 120 mg/m’ on days I, 3, and 5 or 360 mglm’ on day 1 only. either as a single drug or in combination with cisplatin 80 mgl m2 on day 1. Cycles were repeated every 3 weeks. Response rates, side effects, and survival were compared according to the 2 x 2 factorial design of this study. Results: The response rate of the two cisplatincontaining arms was superior to that of the hvo arms that contained VM26 only (22% v 646, P < ,001); progression-free survival and survival timeswerealso longerinthecisplatin-containingarms(median, 4.3 v 2.2 months, P = ,003; median 7.2 Y 5.9 months, P = .008. respectively). Toxicitywassignitictly higher in thecisplatin-containing arms; the most frequent side effects were leukopenia, nausea and vomiting, and alopecia. The schedule of VM26 did not significantly influence the response rate, progression-free suIvivaI interval, or survivalduration. However, theresponse rateofthe I-day administration was significantly lower than that of the 3day administration when given as single drugs. Conclusion: The addition of cisplatin to VM26 improves the response rate, progression-free survival interval, and survival duration over VM26 alone, although at the cost of a significant increase in toxicity. Cisplatin should be considered as the basis for combination chemotherapies in advanced NSCLC.
Randomized double-blind placebo-controlled trial of cisplatin and etoposide plus megestrol acetate/placebo in extensivestage small-cell lung cancer: A North Central Cancer Treatment Group Study Rowland KM Jr, Loprinzi CL, Shaw EG, Maksymiuk AW, Kuross SA, Jung S-H et al. Mayo Clinic, 2# First St SW, Rochester, MN 55905. J Clin Oncol 1996;14:135-41. Purpose: Megestrol acetate has been reported to Improve appetite and quality of life and to decrease nausea and vomiting in patients with cancer anorexialcachexia. The present trial was formulated to evaluate the impact of megestrol acetate onquality of life, toxicity, response, and survival in individuals with extensive-stage small-cell lung cancer who received concomitant chemotherapy. Patients and Methods: Patients were randomized to receive megestrol acetate 800 mg/d orally or placebo. In addition, all patients were scheduled to receive a maximum of four cycles of cisplatin and etoposide chemotherapy. Quality of life was self-assessed at entry onto study, with every cycle of chemotherapy, and 4 months thereafter with a linear visual analog scale. Toxicity was evaluated by patient questionnaire and investigator reports. Results: A total of 243 eligible patients were random&d. Those who received megestrol acetate had increased nonfluid weight gain (P = .004) and signiticantly less nausea (P = .0002) and vomiting (P = .OZ).
I5 (19%)
139-157
Significant thromboembolic phenomena occurred more often in patients who received megestrol acetate versus placebo (9% v 2%. P = .Ol). Patients who received megestrol acetate had more edema (30 96 v 20 96, P = ,002). an inferior response rate to chemotherapy (68 % v 80%. P = .03), and a trend for inferior survival duration (median, 8.2 v 10.0 months, P = .49). These findings may have been influenced by a poorer quality of life of the megestrol acetate group at study initiation. There were no significant changes in quality of life scores over time between either of the study arms. Conclusion: Megestrol acetate cannot be routinely recommended for all patients with small-cell lung cancer at the time of chemotherapy initiation. Rather, its therapeutic ratio may be more favorable for patients with problematic cancer anorexialcachexia.
Phase II trial of a J-hour infusion of paclitaxel in previously untreated patients with advanced non-small-cell lung cancer Millward MJ, Bishop JF, Friedlander M, Levi JA, Goldstein D, Olver IN et al. Div. of Hematology/Medical Oncology, Peter MacCallum Cancer Institute. A’Beckett St, Melbourne 3aK). J Clin Oncol 1996; 14: 142-8. Purpose: To determine the antitumor activity and toxicity of paclitaxel administered as a 3-hour infusion in patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods: Fifty-one patientswithadvancedmeasurableorassessableNSCLCandperfotmance status 0 to 2 who had not received prior chemotherapy were treated with paclitaxel 175 mglm* over 3 hours with premeditation. Cycles were repeated every 3 weeks for a maximum of nine cycles. Most patients had prior radiotherapy (57 %), extrathoracic me&static disease (65 W), and measurabledisease(754b). Twenty-two percent hadpreviouslyuntreated stage III disease. Results: The objective response rate was five of 51 (10%; 95% confidence interval, 3% to 21%). No subgroup with a higher response rate could be identified. There were no complete responses (CRs) and all responses lasted less than 5 months. Treatment was well tolerated with brief World Health Organiuction (WHO) grade IV neutropenia in only 16 96 of patients. Grade Ill/IV myalgialarthralgia occurred in 22% of patients. No significant hypersensitivity reactions occurred. Conclusion: The antitumor activity of this dose and schedule appears inferior to that reported in previously published phase 11 trials in NSCLC that used higher doses of paclitaxel infused over 24 hours, although confidence intervals for response overlap. Determining the optimal dose and schedule for using paclitaxel in NSCLC requires further investigation, and these results should caution against using shorter infusions outside appropriate clinical trials.
Clinical pharmacology of chronic oral etoposide in patients with small cell and non-small cell lung cancer Zucchetti M, Pagani 0, Torri V, Sew C, D’lncalci M, De Fusco M et al. Division of Oncology, Ospedale San Giovanni, CH45WBellinzona. Clin Cant Res 1995;1:1517-24. We aimed to evaluate the pharmacokinetics and pharmacodynamics of etoposide given chronically by the p.o. route to patients with small cell and non-small cell lung cancer. Single daily p.o. doses of 100 mg etoposide were given for 21 consecutive days every 4 weeks to 39 previously untreated patients with small cell lung cancer and 10 patients with non-small cell lung cancer. Bioavailability was studied after one i.v. and onep.o. doseof 100 mg etoposide given 48 h beforeand on day 1 of treatment, respectively. Etoposide plasma levels were measured using the HPLC method. Inter- and intrapatient variability of the area under the curve of the concentration versus time (AUC) during the first cycle were evaluated using a limited sampling model; the variability of etoposide plasma concentration (Ecs) during the first cycle was assessed by weekly blood samples taken 24 h after dosing. The overall
CIancer I5 (19%) 139-157
Thomas P et al. NCIC Clinical Trials Group, Queen’s University, 8284 Barrie Srreer, Kingston, Ont. Anti-Cancer Drugs 1995;6:Suppl 6~33-7. CollaborativephaseIandlI studiesofthecombinationofgemcitabine and cisplatin in patients with advanced non-small cell lung cancer are ongoing at five centres in the UK and France. In the initial completed phase I study, 16 patients (15 evaluable) have been entered using a fixed dose of gemcitabine 1000 mglm’ given as a 30 min intravenous infusion weekly for 3 weeks. On the third week the gemcitabine was immediately followed by cisplatin with pre- and post-hydration. This regimen required only 1 night of hospitalization every 4 weeks. The study design was for sequential groups of patients to receive 3 dose levels of cisplatin (60mg/m2, 75mglm’and lOOmg/m’)butthesedoseswouldbemodif~ed and the number of patients at any dose level could be increased if significant toxicity was observed. Three patients were to be entered at the first two dose levels and 10 patients were to confirm the maximum tolerated dose (if reached) or expand the database on toxicity at the final predetermined dose level. The major haematological toxicities were neutropenia (grade 4 in 3 patients) and thrombocytopenia (grade 3 or 4 in 5 patients) but both were of short duration and uncomplicated. Grade 3 nausea and vomiting occurred in 12 patients but was no worse than would be expected from cisplatin alone. Alopecia was not a problem (no hair loss in 10 patients and grade 1 or 2 in 6 patients) and no significant renal orneurotoxicity wasseen. A phase II study using cisplatin 100 mg/ m’ in combination with gemcitabine 1000 mglm’ has been opened and to date 19 patients are evaluable for response. Eight (42%) have achieved partial remissions. The study is ongoing and will recruit 50 evaluable patients.
Gemcitabine: Clinical and economic impact in inoperable non-small cell lung cancer Koch P, Johnson N, Van Schaik J, Andersen S, Blatter J, Bosanquet N et al. Policy and Economics Group. Cambridge Pharma Consul~ancy. I Quayside, Bridge Street, Cambridge CBS &Is. Anti-Cancer Drugs 1995;6:Suppl 6:49-54. This study assesses retrospectively theclinical and economic impact of gemcitabine monotherapy on the management of inoperable stage III/ IV non-small cell lung cancer in Germany. Based on current methods of clinical practice and using the best outcome data available, the costs and benefits of gemcitabine were compared to a dual therapy (ifosfamide/ etoposide). While the two treatments showed broadly equivalent efficacy in terms of tumour response rate and survival, a cost analysis showed the potential for savings with gemcitabine. These largely related to hospital hotelling costs, due to the fact that gemcitabine may be given as an outpatient therapy. Further savings were found in investigative procedures and the management of treatment toxicity. Excluding the cost of the chemotherapy, gemcitabine was associated with potential savings of DM3,026 over two cycles of therapy, which included a 40% decrease in hospitalization costs and a 54% decrease in the cost of managing adverse events. We conclude that gemcitabine monotherapy could offer considerable cost savings while offering the potential for improved quality ofpalliative treatment compared to existing in-patient treatments, and it may have a place in shilling care from an in-patient to an outpatient setting in line with recent health care reforms.
Differential expression of DNA topoisomerases in non-small cell lung cancer and normal lung Giaccone G, Van Ark-O&J, Scagliotti G, Capranico G, Van der Valk P, Rubio G et al. Free University Hospilal. Deparzmennt of Oncolopv/ Pathology, 1081 HVAmsrerdam. B&him Bidphys ActaGene S&&t Expr 1995;1264:337-46. DNA topoisomerasesareubiquitousnuclearenxymea, and important
153
targ& of cancer chemotherapy. Expression of topoisomemse genes is oRea correlated with in vtro chemosensitivity. We investigated the expression of the topoisomerase genes in normal lung and non-small cell lung cancer. Expression of topoisomerase II-a topoisomerase II-D, and topoisomemse I genes has been assessed in tumor samples of 60 patients who underwent operation for a non-small cell lung carcinoma, by RNase protection assay, and by immunohistochemistry. The expression of topoisomerase 11-a gene was either undetectable or very low in normal lung, while most NSCLC expressed readily quantifiable levels of this gene. No alteration of the topoisomerase 11-a gene was found by Southern blotting in the NSCLC samples. In contrast to topoisomerase 11-a topoisomerase II-6 was expressed in most normal as well as in tumor tissue samples, at a similar level. The levels of expression of both topoisomII isoforms was lower than that ofhuman lung cancer cell lines. The results of the topoisomerase II mRNA expression were confirmed by immunohistochemistry. Whereas topoisomerase 11-a staining was mainly limited to the nucleus, staining with topoisomerase II-B antibody was exclusively observed in nucleoli. Topoisomerase I was localized in the nuclei and expression was mainly limited to tumor cells. By RNase protection, topoisomerase I expression in NSCLC samples was in the range of that of human lung cancer cell lines. The expression of the topoisomerase genes did not seem to be coordinated. In tumor cells, there was a positive association between expression of topoisomeraseIIasndKi-677amarkerofcell proliferation, asassessed by immunohistochemistry, but not with topoisomerase II-8 or topoisomerase I. Clinical characteristics of the patients, and their survival did not appear to be correlated to the level of expression of any of the topoisomerase genes, although a trend towards a shorter survival was observed in patieots whose tumors expressed relatively high topoisomerase 11-a mRNA levels. In conclusion, the two isoforms of topoisomerase II are differentially expressed in normal lung and NSCLC cells; (2) higher topoisomerase IIa expression is associated with higher cell proliferation in NSCLC; (3) the expression of topoisomerase IIa and topoisomerase 17 but not of topoisomerase 11-13,was higher in tumor cells compared to normal lung. Given the differential expression of topoisomerases in normal lung and tumors, research of more potent and specific topoisomerase inhibitors might prove beneficial in non-small cell lungcancer. Immunohistochemistrymaybeindicatedinprospectively ivestigating the correlation between expression of topoisomerases and results of chemotherapy treatment.
Evaluation of the optimal duration of chemotherapy in phase II trials for inoperable non-small-cell lung cancer (NSCLC) Larsen H, Sorensen JB, Nielsen AL, Dombemowsky P, Hansen HH. Ihe Finsen Center 5072, National Universiry Hospital, 9 Blegdamsvej. DK-2100 Copenhagen. Ann Gncol 1995;6:993-7. Purpose: To determine the optimal duration of chemotherapy in phase II trials for patients with non-small-cell lung cancer (NSCLC). Parienrsandmerhodx Thetimefromstartoftreatmentuntil achievement of response according to WHO criteria was determined retrospectively in 8 phase II trials. Results: Response to chemotherapy consisting of 4 complete and 39 partial remissions was registered in 43 of 333 patients. The median time from treatment start to response was 54 days. On day 84 on-study, 35 of the responding patients (81%) had achieved the response. Forty-three responses (98%) had occurred by day 168 and only one patient (2%) accomplished a response after 168 days of treatment. The responses had a median duration of 151 days (range 281559 days). Conclusions: The data indicate that patients with NSCLC included in phase II trials who have not yet achieved a response to chemotherapy after 168 days on study have a low likelihood (2 %) of a subsequent response. Hence, treatment cessation at this point should be considered fornon-responding patients. Continuation oftreatment from day 84 to day 168 resulted in response in only 7 patients out of the total
154
Abslracts/L.tmg
Cancer
of43 responsesnoted( 16%). Thus, tbetoxiceffectsofthechemotherapy in addition to the inconvenience of hospital visits renders it questionable whether it is worthwhile to continue treatment in patients with inoperable non-small-cell lung cancer beyond day 84 in the absence of response.
TWO schedules of teniposide with or without cisplatin in advanced non- small-cell lung cancer: A randomized Study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group Splinter TAW, Sahmoud T, F&en J, Van Zandwijk N, Sorenson S, Clerico M et al. Medical Oncology. Free Vtdversity Hospital, 1117De Boelelaan. HV 1081 Amsterdam. J Clin Oncol 1996; 14: 127-34. Purpose: We conducted a randomized trial to investigate the value of the addition of cisplatin to teniposide (VM26) and to investigate the schedule dependence of the topoisomerase II inhibitor VM26, in advanced non-small- cell lung cancer (NSCLC) patients. Patients and Methoak Two hundred twenty- five NSCLC patients were randomized to receive VM26 120 mg/m’ on days I, 3, and 5 or 360 mglm’ on day 1 only. either as a single drug or in combination with cisplatin 80 mgl m2 on day 1. Cycles were repeated every 3 weeks. Response rates, side effects, and survival were compared according to the 2 x 2 factorial design of this study. Results: The response rate of the two cisplatincontaining arms was superior to that of the hvo arms that contained VM26 only (22% v 646, P < ,001); progression-free survival and survival timeswerealso longerinthecisplatin-containingarms(median, 4.3 v 2.2 months, P = ,003; median 7.2 Y 5.9 months, P = .008. respectively). Toxicitywassignitictly higher in thecisplatin-containing arms; the most frequent side effects were leukopenia, nausea and vomiting, and alopecia. The schedule of VM26 did not significantly influence the response rate, progression-free suIvivaI interval, or survivalduration. However, theresponse rateofthe I-day administration was significantly lower than that of the 3day administration when given as single drugs. Conclusion: The addition of cisplatin to VM26 improves the response rate, progression-free survival interval, and survival duration over VM26 alone, although at the cost of a significant increase in toxicity. Cisplatin should be considered as the basis for combination chemotherapies in advanced NSCLC.
Randomized double-blind placebo-controlled trial of cisplatin and etoposide plus megestrol acetate/placebo in extensivestage small-cell lung cancer: A North Central Cancer Treatment Group Study Rowland KM Jr, Loprinzi CL, Shaw EG, Maksymiuk AW, Kuross SA, Jung S-H et al. Mayo Clinic, 2# First St SW, Rochester, MN 55905. J Clin Oncol 1996;14:135-41. Purpose: Megestrol acetate has been reported to Improve appetite and quality of life and to decrease nausea and vomiting in patients with cancer anorexialcachexia. The present trial was formulated to evaluate the impact of megestrol acetate onquality of life, toxicity, response, and survival in individuals with extensive-stage small-cell lung cancer who received concomitant chemotherapy. Patients and Methods: Patients were randomized to receive megestrol acetate 800 mg/d orally or placebo. In addition, all patients were scheduled to receive a maximum of four cycles of cisplatin and etoposide chemotherapy. Quality of life was self-assessed at entry onto study, with every cycle of chemotherapy, and 4 months thereafter with a linear visual analog scale. Toxicity was evaluated by patient questionnaire and investigator reports. Results: A total of 243 eligible patients were random&d. Those who received megestrol acetate had increased nonfluid weight gain (P = .004) and signiticantly less nausea (P = .0002) and vomiting (P = .OZ).
I5 (19%)
139-157
Significant thromboembolic phenomena occurred more often in patients who received megestrol acetate versus placebo (9% v 2%. P = .Ol). Patients who received megestrol acetate had more edema (30 96 v 20 96, P = ,002). an inferior response rate to chemotherapy (68 % v 80%. P = .03), and a trend for inferior survival duration (median, 8.2 v 10.0 months, P = .49). These findings may have been influenced by a poorer quality of life of the megestrol acetate group at study initiation. There were no significant changes in quality of life scores over time between either of the study arms. Conclusion: Megestrol acetate cannot be routinely recommended for all patients with small-cell lung cancer at the time of chemotherapy initiation. Rather, its therapeutic ratio may be more favorable for patients with problematic cancer anorexialcachexia.
Phase II trial of a J-hour infusion of paclitaxel in previously untreated patients with advanced non-small-cell lung cancer Millward MJ, Bishop JF, Friedlander M, Levi JA, Goldstein D, Olver IN et al. Div. of Hematology/Medical Oncology, Peter MacCallum Cancer Institute. A’Beckett St, Melbourne 3aK). J Clin Oncol 1996; 14: 142-8. Purpose: To determine the antitumor activity and toxicity of paclitaxel administered as a 3-hour infusion in patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods: Fifty-one patientswithadvancedmeasurableorassessableNSCLCandperfotmance status 0 to 2 who had not received prior chemotherapy were treated with paclitaxel 175 mglm* over 3 hours with premeditation. Cycles were repeated every 3 weeks for a maximum of nine cycles. Most patients had prior radiotherapy (57 %), extrathoracic me&static disease (65 W), and measurabledisease(754b). Twenty-two percent hadpreviouslyuntreated stage III disease. Results: The objective response rate was five of 51 (10%; 95% confidence interval, 3% to 21%). No subgroup with a higher response rate could be identified. There were no complete responses (CRs) and all responses lasted less than 5 months. Treatment was well tolerated with brief World Health Organiuction (WHO) grade IV neutropenia in only 16 96 of patients. Grade Ill/IV myalgialarthralgia occurred in 22% of patients. No significant hypersensitivity reactions occurred. Conclusion: The antitumor activity of this dose and schedule appears inferior to that reported in previously published phase 11 trials in NSCLC that used higher doses of paclitaxel infused over 24 hours, although confidence intervals for response overlap. Determining the optimal dose and schedule for using paclitaxel in NSCLC requires further investigation, and these results should caution against using shorter infusions outside appropriate clinical trials.
Clinical pharmacology of chronic oral etoposide in patients with small cell and non-small cell lung cancer Zucchetti M, Pagani 0, Torri V, Sew C, D’lncalci M, De Fusco M et al. Division of Oncology, Ospedale San Giovanni, CH45WBellinzona. Clin Cant Res 1995;1:1517-24. We aimed to evaluate the pharmacokinetics and pharmacodynamics of etoposide given chronically by the p.o. route to patients with small cell and non-small cell lung cancer. Single daily p.o. doses of 100 mg etoposide were given for 21 consecutive days every 4 weeks to 39 previously untreated patients with small cell lung cancer and 10 patients with non-small cell lung cancer. Bioavailability was studied after one i.v. and onep.o. doseof 100 mg etoposide given 48 h beforeand on day 1 of treatment, respectively. Etoposide plasma levels were measured using the HPLC method. Inter- and intrapatient variability of the area under the curve of the concentration versus time (AUC) during the first cycle were evaluated using a limited sampling model; the variability of etoposide plasma concentration (Ecs) during the first cycle was assessed by weekly blood samples taken 24 h after dosing. The overall