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Treatment of advanced non-small cell lung cancer: The Southwest Oncology Group experience
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tine, Baltimore, MD 21231. Cancer Res 1989;49:639-43. We have compared the effects of treatment with each of three .bis(ethyl)polyamine analogues on a human small cell lung carcinoma (SCLC) line, NC1 H82, and a non-small cell line, NCI H157, an undifferentiated large cell lung carcinoma. The bis(ethyl)polyamines have been shown to interfere with polyamine metabolism, presumably byregulationofthepolyaminebiosyntheticpathway~namannersimilar to the natural polyamines, in contrast to direct inhibition of specific enzymes, such as omithine decarboxylase. Each of these compounds was found to be relatively inactive in reducing growth rate, polyamine levels, or polyamine biosynthetic enzyme activity in the SCLC cells, a line which we have previously shown to be particular sensitive to inhibition of polyamine biosynthesis by the direct omithine decarboxylase inhibitor difluoromethylomithine. By contrast, each of the bis(ethyl)polyamines tested was found to be markedly cytotoxic (at M) to the non-SCLC line, NC1 H157. concentrations of only 10 ?? Interestingly, the non-SCLC line has previously been demonstrated to be resistant to polyamine depletion by difluoromethylomithine. For each bis(ethyl)polyamine, cytotoxicity was accompanied by nearly complete depletion of all intracellular polyamines and a decrease in omithine decarboxylase activity to undetectable levels. The current studyemphasizes thephenotypic variability which can exist in response to inhibitors of polyamine biosynthesis and suggests a class of agents which may have clinical utility against the treatment-resistant nonSCLC lung cancers.
Comparative pharmacokinetia and alkylating activity of fractionated intravenous and oral ifosfamide in patients with bronchogenic carcinoma. Lind MJ, Margison JM, Cemy T, Thatcher N, Wilkinson PM. CRC Department of Medical Oncology, Christie Hospital. Manchester M20 9BX. Cancer Res 1989;49:753-7. 20 patients with advanced non-small cell lung cancer were treated withifosfamideandmesna 1..5g/m2dailyfor5days; 1Oreceivedthedrug by mouth and 10 i.v. Both schedules resulted in a reduction in the elimination half-life with an increased total and nonrenal clearance of ifosfamide over the 5&y period. Oral administration resulted in an unacceptably high incidence of encephalopathy(5/10) which was not seen in the iv. group. In two patients this encephalopathy manifested itself as coma which lasted for 24 to 48 h but was fully reversible and in the other three cases as somnolence occurring for more than 50% of the patients’ waking hours. Nadir blood counts and response rates were similar in both aims. The encephalopatby suggests that there are metabolic differences between the iv. and oral routes and that a metabolite rather than the parent drug is responsible for this syndrome. Inadditionitwasshown that the totalandnonrenalclearanceofthedrug was significantly less when the drug was administered orally. None of the pharmacokinetic parameters either singly or in combination predicted for ifosfamide toxicity. No correlation between the creatinine clearance and ifosfatnide renal clearance was demonstrated suggesting tubular reabsorption of the drug. In conclusion, ifosfamide cannot be given orally at the conventionally employed iv. doses. Combination versus sequential single-agent chemotherapy in the treatment of patients with advanced non-small cell lung cancer. Niell HB, Griffin JP, Hunter RF, Meredith CA, Somes G. Medical Service of VA. Medical Cenfer, Memphis, TN. Med Pediatr OnCOl 1989;17:69-75. We have carried out a randomized phase III study in 105 patients with advanced non-small cell lung cancer, comparing a four-drug cisplatinmitomycin-based combination chemotherapy regimen to sequential single-agent therapy. The combination chemotherapy regimen consisted of mitomycin C (10 mg/m3, vinblastine (5 mg/mz), metbotrexate :40 mum*), and cisplatin (40 mg/mz) given every 28 days. Sequential single-agent chemotherapy consisted of mitomycin C (10 mg/mf) nonthly until progression followed by vinblastine (5 mg/mz) every 2 ueeks until progression followed by methouexate (40 mg!m’) weekly mtil relapse. Patients failing eitherregimen were followed with supperive care. The objective response rate for the sequential single-agent
therapy was 19% versus 25% for the combination chemotherapy group (P > .5). The median survival for the single-agent group was 166 days and 191 days for the combination chemotherapy group. Overall survival was not statistically different between the two groups (P > .5). Leucopenia, anemia, and prolonged anorexia with nausea and vomiting were more common in the combination chemotherapy group compared to the single-agent group. This study failed to demonstrate a sufficient therapeutic benefit in the face of the added toxicity for the combination chemotherapy regimen compared to sequential single-agent therapy. Treatment of advanced non-small cell lung cancer: The Southwest Oncology Group experience. Livingston RB. Division of Oncology, University of Washington School ofMedicine, Seattle, WA 98195. Semin Onco11988;15:SuppI. 7:3741. Approximately 2,500 patients with advanced non-small cell lung cancer (NSCLC) have been treated by the Southwest Oncology Group (SWOG). These data, based on various trials and regimens over a 14year experience, areevaluated, summarized, and compared with results reported by other cooperative groups. Response rates are higher and 1 year survivals are more frequent in patients with good perfotmance status. Presently available chemotherapy for NSCLC is much more effective in limited (stage III) disease than in extensive (stage IV) disease.InextensivediseasepatienrswhoarefulIyambulatory,cisplatin based combinations have been shown to produce responses to up to 30% and probably exert modest beneficial effects on survival. Nonetheless, current therapies are suboptimal; better ways to use cisplatin and other drugs are needed. Combination chemotherapy confers modest survival advantage in patients with advanced non-small cell lung cancer: Report of a Canadian Multicenter randomized trial. Evans WK, Rapp E, Pater JL et al. National Cancer Institute. Clinical Trials Group. Queen’s University, Kingston. Ont. Semin Oncol 1988:15:Supp1.7:42-5. Between February 1983 and January 1986, the National Cancer InstituteofCanadaconductedaprospectiverandomizedvialcomparing bestsupponivecare(BSC)withtwochemolherapyregimens:Vindesine and cisplatin (Platinol) (VP) and cyclophosphamide, doxorubicin, and cisplatin (CAP). Twenty-three centers across Canada entered 251 patients on the basis of measurable or evaluable disease, with either distant metastases or bulky limited disease considered inoperable and unsuitable for radical radiation therapy; 233 patients were eligible for evaluation. The overall response rates on the chemotherapy arms were: VP, 25.3%; CAP, 15.3%. The median survival rates were: VP, 32.6 weeks:CAP,24.7weeks;BSC, 17weeks.Toxicityonthechemotherapy artns was significant. Although bettertherapiesarerequired, thedatain this study clearly indicate that VP and CAP combination chemotherapy confers a modest survival advantage over BSC in advanced non-small cell lung cancer. The European Organization for Research and Treatment of Cancer (EORTC) trials of new agents for advanced non-small cell lung cancer. G&cone G. National Cancer Institute. Navy Oncology Branch, US Naval Hospital, Bethesda, MD 20814. Semin Oncol 1988;15:Suppl. 7~46-8. The Lung Cancer Cooperative Group of the European Organization forResearchandTreaunentofCancer@ORTC)hasrecentlycompleted the study of three new agents in phase II trials to detemine their efticacy in non-small lung cancer (NSCLC). Elliptinium (an ellipticine alkaloid), ametantrone (an anthracenedione derivative), and mitozolomide (an antitumor imidazotetrazine) were evaluated. Elliptinium, ameuan@one, and mitozolomide are not recommended for further trials in NSCLC. Apilotstudy performed within thegroup with teniposide (VM26),apodophyllotoxinderivative,atdosesrangingfrom 120 to 180mg/ m2given on days 1.3, and 5 every 3 weeks resulted in a 21% response rate in previously untreated patients. Based on these results, theEORTC has initiated a randomized study using teniposide (VM-26) with or without cisplatin.
tine, Baltimore, MD 21231. Cancer Res 1989;49:639-43. We have compared the effects of treatment with each of three .bis(ethyl)polyamine analogues on a human small cell lung carcinoma (SCLC) line, NC1 H82, and a non-small cell line, NCI H157, an undifferentiated large cell lung carcinoma. The bis(ethyl)polyamines have been shown to interfere with polyamine metabolism, presumably byregulationofthepolyaminebiosyntheticpathway~namannersimilar to the natural polyamines, in contrast to direct inhibition of specific enzymes, such as omithine decarboxylase. Each of these compounds was found to be relatively inactive in reducing growth rate, polyamine levels, or polyamine biosynthetic enzyme activity in the SCLC cells, a line which we have previously shown to be particular sensitive to inhibition of polyamine biosynthesis by the direct omithine decarboxylase inhibitor difluoromethylomithine. By contrast, each of the bis(ethyl)polyamines tested was found to be markedly cytotoxic (at M) to the non-SCLC line, NC1 H157. concentrations of only 10 ?? Interestingly, the non-SCLC line has previously been demonstrated to be resistant to polyamine depletion by difluoromethylomithine. For each bis(ethyl)polyamine, cytotoxicity was accompanied by nearly complete depletion of all intracellular polyamines and a decrease in omithine decarboxylase activity to undetectable levels. The current studyemphasizes thephenotypic variability which can exist in response to inhibitors of polyamine biosynthesis and suggests a class of agents which may have clinical utility against the treatment-resistant nonSCLC lung cancers.
Comparative pharmacokinetia and alkylating activity of fractionated intravenous and oral ifosfamide in patients with bronchogenic carcinoma. Lind MJ, Margison JM, Cemy T, Thatcher N, Wilkinson PM. CRC Department of Medical Oncology, Christie Hospital. Manchester M20 9BX. Cancer Res 1989;49:753-7. 20 patients with advanced non-small cell lung cancer were treated withifosfamideandmesna 1..5g/m2dailyfor5days; 1Oreceivedthedrug by mouth and 10 i.v. Both schedules resulted in a reduction in the elimination half-life with an increased total and nonrenal clearance of ifosfamide over the 5&y period. Oral administration resulted in an unacceptably high incidence of encephalopathy(5/10) which was not seen in the iv. group. In two patients this encephalopathy manifested itself as coma which lasted for 24 to 48 h but was fully reversible and in the other three cases as somnolence occurring for more than 50% of the patients’ waking hours. Nadir blood counts and response rates were similar in both aims. The encephalopatby suggests that there are metabolic differences between the iv. and oral routes and that a metabolite rather than the parent drug is responsible for this syndrome. Inadditionitwasshown that the totalandnonrenalclearanceofthedrug was significantly less when the drug was administered orally. None of the pharmacokinetic parameters either singly or in combination predicted for ifosfamide toxicity. No correlation between the creatinine clearance and ifosfatnide renal clearance was demonstrated suggesting tubular reabsorption of the drug. In conclusion, ifosfamide cannot be given orally at the conventionally employed iv. doses. Combination versus sequential single-agent chemotherapy in the treatment of patients with advanced non-small cell lung cancer. Niell HB, Griffin JP, Hunter RF, Meredith CA, Somes G. Medical Service of VA. Medical Cenfer, Memphis, TN. Med Pediatr OnCOl 1989;17:69-75. We have carried out a randomized phase III study in 105 patients with advanced non-small cell lung cancer, comparing a four-drug cisplatinmitomycin-based combination chemotherapy regimen to sequential single-agent therapy. The combination chemotherapy regimen consisted of mitomycin C (10 mg/m3, vinblastine (5 mg/mz), metbotrexate :40 mum*), and cisplatin (40 mg/mz) given every 28 days. Sequential single-agent chemotherapy consisted of mitomycin C (10 mg/mf) nonthly until progression followed by vinblastine (5 mg/mz) every 2 ueeks until progression followed by methouexate (40 mg!m’) weekly mtil relapse. Patients failing eitherregimen were followed with supperive care. The objective response rate for the sequential single-agent
therapy was 19% versus 25% for the combination chemotherapy group (P > .5). The median survival for the single-agent group was 166 days and 191 days for the combination chemotherapy group. Overall survival was not statistically different between the two groups (P > .5). Leucopenia, anemia, and prolonged anorexia with nausea and vomiting were more common in the combination chemotherapy group compared to the single-agent group. This study failed to demonstrate a sufficient therapeutic benefit in the face of the added toxicity for the combination chemotherapy regimen compared to sequential single-agent therapy. Treatment of advanced non-small cell lung cancer: The Southwest Oncology Group experience. Livingston RB. Division of Oncology, University of Washington School ofMedicine, Seattle, WA 98195. Semin Onco11988;15:SuppI. 7:3741. Approximately 2,500 patients with advanced non-small cell lung cancer (NSCLC) have been treated by the Southwest Oncology Group (SWOG). These data, based on various trials and regimens over a 14year experience, areevaluated, summarized, and compared with results reported by other cooperative groups. Response rates are higher and 1 year survivals are more frequent in patients with good perfotmance status. Presently available chemotherapy for NSCLC is much more effective in limited (stage III) disease than in extensive (stage IV) disease.InextensivediseasepatienrswhoarefulIyambulatory,cisplatin based combinations have been shown to produce responses to up to 30% and probably exert modest beneficial effects on survival. Nonetheless, current therapies are suboptimal; better ways to use cisplatin and other drugs are needed. Combination chemotherapy confers modest survival advantage in patients with advanced non-small cell lung cancer: Report of a Canadian Multicenter randomized trial. Evans WK, Rapp E, Pater JL et al. National Cancer Institute. Clinical Trials Group. Queen’s University, Kingston. Ont. Semin Oncol 1988:15:Supp1.7:42-5. Between February 1983 and January 1986, the National Cancer InstituteofCanadaconductedaprospectiverandomizedvialcomparing bestsupponivecare(BSC)withtwochemolherapyregimens:Vindesine and cisplatin (Platinol) (VP) and cyclophosphamide, doxorubicin, and cisplatin (CAP). Twenty-three centers across Canada entered 251 patients on the basis of measurable or evaluable disease, with either distant metastases or bulky limited disease considered inoperable and unsuitable for radical radiation therapy; 233 patients were eligible for evaluation. The overall response rates on the chemotherapy arms were: VP, 25.3%; CAP, 15.3%. The median survival rates were: VP, 32.6 weeks:CAP,24.7weeks;BSC, 17weeks.Toxicityonthechemotherapy artns was significant. Although bettertherapiesarerequired, thedatain this study clearly indicate that VP and CAP combination chemotherapy confers a modest survival advantage over BSC in advanced non-small cell lung cancer. The European Organization for Research and Treatment of Cancer (EORTC) trials of new agents for advanced non-small cell lung cancer. G&cone G. National Cancer Institute. Navy Oncology Branch, US Naval Hospital, Bethesda, MD 20814. Semin Oncol 1988;15:Suppl. 7~46-8. The Lung Cancer Cooperative Group of the European Organization forResearchandTreaunentofCancer@ORTC)hasrecentlycompleted the study of three new agents in phase II trials to detemine their efticacy in non-small lung cancer (NSCLC). Elliptinium (an ellipticine alkaloid), ametantrone (an anthracenedione derivative), and mitozolomide (an antitumor imidazotetrazine) were evaluated. Elliptinium, ameuan@one, and mitozolomide are not recommended for further trials in NSCLC. Apilotstudy performed within thegroup with teniposide (VM26),apodophyllotoxinderivative,atdosesrangingfrom 120 to 180mg/ m2given on days 1.3, and 5 every 3 weeks resulted in a 21% response rate in previously untreated patients. Based on these results, theEORTC has initiated a randomized study using teniposide (VM-26) with or without cisplatin.