weekly doxorubicin versus doxorubicin every 3 weeks in cyclophosphamide, doxorubicin, and cisplatin...

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137 The present staging methods for non-small-cell lung cancer provide little more than epidemiologic assessment of prognosis for grossly defined groups of patients. Except in extreme instances, physicians can tell patients very little about their prognosis or the need for supplemen- tal therapy. More effective and less toxic chemotherapeutic agents are needed to treat this disease. Although improved results have been attained with combination therapy in patients with good functional status and less advanced disease, little help is available for lung cancer patients with advanced disease. Treating this large group of patients remains a great challenge for the surgical and medical oncologist. Chemotherapy Weekly doxorubicin versus doxorubicin every 3 weeks in cyclo- phospbamide, doxorubicin, and cisplatin chemotherapy for non- small cell lung cancer Umsawasdi T, Valdivieso M, Booser DJ et al. Deparmrenl ofMedical Oncology. The University of Texas M.D. Anderson Cancer Center, Houston. TX 77030. Cancer 1989:64:1995-2ooO. A prospective randomize study was done to determine the effect of differentdoxorubicin (Adriamycin [ADR],AdriaLaboratoties,Colum- bus, OH) administration (schedules every week versus every 3 weeks) on the productivity of a cyclophosphamide, ADR, cisplatin (CAP) chemotherapy regimen for patients with non-small cell lung cancer (NSCLC). Electrocardiograms, multigated cardiac scans, echocardi- ograms, and endomyocardial biopsies were done serially for cardiac monitoring.Of 102patients,47 hadinoperablelimiteddisease (LD),47 had extensive disease (ED), and eight had no evidence of disease. In the last group chemotherapy was given adjuvantly. Fifty-one patients were entered into each treatment arm. The groups were formed according to extent of disease and were comparable in terms of patient characteris- tics. In these groups, the overall response rates using both schedules in LD patients were similar: in patients without chest irradiation previ- ously, there was a response of 35% with ADR weekly, and 31% with ADR triweekly; in LD patients with chest irradiation previously, the response was 20% with ADR weekly, and 25% with ADR triweekly: and in ED patients, 16% with ADR weekly, and 11% with ADR triweekly. There was no significant differrence in survival between the two treatment groups. However, results for all responders suggested a longer duration of response with weekly than with hiweekly ADR (completepluspartial response: 35.8 venns 11.4 weeks, P=O.O6; minor response: 34 vetsus 1I.5 weeks, P = 0.003, respectively). Results also suggested that weekly ADR was less cardiotoxic than triweekly ADR 29% of patients in the former group had no changes or only minor changes in endomyocardial biopsy results, whereas all patients in the latter group had at least grade 0.5 changes at a similar dosage. The median doses of weekly ADR were higher at the same endomyocardial biopsy-defined toxicity levels. No correlation was found between toxic effects defined by endomyocardial biopsy results and those defined by nonmwistye monitoring techniques, although the number of patients assessed was small. Weekly ADR produced less granulocytopenia and a lower incidence of fever (6% versus 16%, P < 0.001) than did hiweekly ADR. Alopecia, nausea, vomiting, and diarrhea were signifi- cantly less for weekly ADR than triweekly Adr (P < O.ooO5, < 0.0005, and < 0.005, respectively). These data suggest that weekly ADR can achieve the same therapeutic results as the standard triweekly regimen with less cardiotoxicity, myelotoxicity, alopecia, diarrhea, nausea, and vomiting in patients with NSCLC. Reduced variation in the clonogenic assay obtained by standardiza- tion of the cell culture conditions prior to drug testing on human small cell lung cancer cell lines Buhl Jensen P, Rocd H, Vindelov L, Christensen IJ, Hansen HH. Department of Oncology, The Finsen InstitutelRigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen. Invest New Drugs 1989:7:307- 15. An advange of established tumor cell lines compared to fresh human tumor specimens used in sensitivity assessments is the possibility of repeated experiments. Ultimately a database of sensitivity profiles on a panel of cell lines can be made and the sensitivity to new drugs compared with historical data. A prerequisite of this strategy is a minimal interexperimental variation. The sensitivity of eight human small cell lung cancer cell lines to adriamycin, daunomycin, aclacino- mycin A, and mitoxantrone was tested in the clonogenic assay. A covariation in the sensitivity to the drugs emphasized the importance of simultaneous drug testing on the same batch of cells. On one cell line (NClN592) the interexperimental variation was further evaluated and a significant correlation was found between preexposure culture condi- tions, size of S-phase, and sensitivity to adriamycin, daunomycin, and mitoxantrone. Rigorous standardization of the growth conditions prior to clonogenic assay reduced the variation in the sensitivity to adriamy- tin from a factor of five to only lo- 15%. It is concluded that simultane- ous experiments on the same batch of cells in drug comparisons shotdd be used if possible. Specification and standardization of culture condi- tions are necessary in the comparison of drugs tested in different experiments. Inclusion of the same reference drug in all experiments may further increase the validity of comparisons in different experi- ments. Randomized phase II-III trial of combination beta and gamma interferons and etoposide and cisplatin in inoperable non-small cell cancer of the lung Schiller JH, Storer B, Dreicer R, Rosenquist D, Fronteira M. Carbone PP. University of Wisconsin Clinical Cancer Center, Madison. WI. J Nat1 Cancer Inst 1989:81:1739-43. We observed major responses in two patients with adenocarcinoma of the lung who had received a combination of interferon (IFN)-6 and IFN-gamma, immediately followed by chemotherapy. To verify these observations, we initiated a prospective randomized phase II-III trial of etoposide and cisplatin, with or without IFN-6 and IFN-gamma, in patients with inoperable non-small cell lung cancer. Thirty-seven patients were randomized to receive either two cycles of chemotherapy or 6 weeks of IFN-8 plus IFN-gamma followed by two cycles of chemotherapy. Chemotherapy consisted of 60 mg of cisplatirs/m2 on day 1 and I20 mg of etoposide/m’ on days 4,6. and 8, repeated every 21 days. Patients who were randomized to the IFN plus chemotherapy arm received 200 pg of IFN-gamma and 30 x 1 (P U of IFN-6 three times per week for 6 weeks, followed by two cycles of chemotherapy. Three of 18 (17%) eligible patients in the chemotherapy arm and two of I8 (11%) patients in tbe combination arm had partial responses. All responses cccmred while patients were receiving chemotherapy. Median survival was 190 days for the chemotherapy arm and 246 days in tbe combined modality arm, as estimated from Kaplan-Meier curves (P = .35). We observed no significant difference in subjective toxic effects between the two arms. We observed more hematologic toxicity during chemotherapy on the combined modality arm (P = .02). We conclude that pretreatment with IFN-8 and IFN-gamma does not enchance the efficacy of etoposide and cisplatin in this disease. Although the com- bined modality arm is relatively well tolerated, it does result in more chemotherapy-associated toxic effects This study also exemplifies a hybrid phase II-III trial design, which is useful in allowing phase II results to be quickly incorporated into a phase III trial. Symptom relief with moderate dose chemotherapy (mitomycin-C, vinblastine and cisplatin) in advanced non-small cell lung cancer Hardy JR, Noble T, Smith IE. Lung Unit, Royal Mar&n Hospital, Surrey SM2 SPT. Br J Cancer 1989;60:764-6. Twenty-four symptomatic patients with advanced non-small cell lung cancer (NSCLC) were treated with cisplatin-based chemotherapy (mitomycin-C 8 mg m-*q 6 weeks, vinblastine 6 mg m-2 g 3 weeks, cisplatin 50 mg m-*q 3 weeks). Patients were assessed for symptom relief as well as for objective response. Although only live patients

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Page 1: Weekly doxorubicin versus doxorubicin every 3 weeks in cyclophosphamide, doxorubicin, and cisplatin chemotherapy for non-small cell lung cancer

137

The present staging methods for non-small-cell lung cancer provide little more than epidemiologic assessment of prognosis for grossly defined groups of patients. Except in extreme instances, physicians can tell patients very little about their prognosis or the need for supplemen- tal therapy. More effective and less toxic chemotherapeutic agents are needed to treat this disease. Although improved results have been attained with combination therapy in patients with good functional status and less advanced disease, little help is available for lung cancer patients with advanced disease. Treating this large group of patients remains a great challenge for the surgical and medical oncologist.

Chemotherapy

Weekly doxorubicin versus doxorubicin every 3 weeks in cyclo- phospbamide, doxorubicin, and cisplatin chemotherapy for non- small cell lung cancer Umsawasdi T, Valdivieso M, Booser DJ et al. Deparmrenl ofMedical Oncology. The University of Texas M.D. Anderson Cancer Center, Houston. TX 77030. Cancer 1989:64:1995-2ooO.

A prospective randomize study was done to determine the effect of differentdoxorubicin (Adriamycin [ADR],AdriaLaboratoties,Colum- bus, OH) administration (schedules every week versus every 3 weeks) on the productivity of a cyclophosphamide, ADR, cisplatin (CAP) chemotherapy regimen for patients with non-small cell lung cancer (NSCLC). Electrocardiograms, multigated cardiac scans, echocardi- ograms, and endomyocardial biopsies were done serially for cardiac monitoring.Of 102patients,47 hadinoperablelimiteddisease (LD),47 had extensive disease (ED), and eight had no evidence of disease. In the last group chemotherapy was given adjuvantly. Fifty-one patients were entered into each treatment arm. The groups were formed according to extent of disease and were comparable in terms of patient characteris- tics. In these groups, the overall response rates using both schedules in LD patients were similar: in patients without chest irradiation previ- ously, there was a response of 35% with ADR weekly, and 31% with ADR triweekly; in LD patients with chest irradiation previously, the response was 20% with ADR weekly, and 25% with ADR triweekly: and in ED patients, 16% with ADR weekly, and 11% with ADR triweekly. There was no significant differrence in survival between the two treatment groups. However, results for all responders suggested a longer duration of response with weekly than with hiweekly ADR (completepluspartial response: 35.8 venns 11.4 weeks, P=O.O6; minor response: 34 vetsus 1 I.5 weeks, P = 0.003, respectively). Results also suggested that weekly ADR was less cardiotoxic than triweekly ADR 29% of patients in the former group had no changes or only minor changes in endomyocardial biopsy results, whereas all patients in the latter group had at least grade 0.5 changes at a similar dosage. The median doses of weekly ADR were higher at the same endomyocardial biopsy-defined toxicity levels. No correlation was found between toxic effects defined by endomyocardial biopsy results and those defined by nonmwistye monitoring techniques, although the number of patients assessed was small. Weekly ADR produced less granulocytopenia and a lower incidence of fever (6% versus 16%, P < 0.001) than did hiweekly ADR. Alopecia, nausea, vomiting, and diarrhea were signifi- cantly less for weekly ADR than triweekly Adr (P < O.ooO5, < 0.0005, and < 0.005, respectively). These data suggest that weekly ADR can achieve the same therapeutic results as the standard triweekly regimen with less cardiotoxicity, myelotoxicity, alopecia, diarrhea, nausea, and vomiting in patients with NSCLC.

Reduced variation in the clonogenic assay obtained by standardiza- tion of the cell culture conditions prior to drug testing on human small cell lung cancer cell lines Buhl Jensen P, Rocd H, Vindelov L, Christensen IJ, Hansen HH. Department of Oncology, The Finsen InstitutelRigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen. Invest New Drugs 1989:7:307- 15.

An advange of established tumor cell lines compared to fresh human tumor specimens used in sensitivity assessments is the possibility of repeated experiments. Ultimately a database of sensitivity profiles on a panel of cell lines can be made and the sensitivity to new drugs compared with historical data. A prerequisite of this strategy is a minimal interexperimental variation. The sensitivity of eight human small cell lung cancer cell lines to adriamycin, daunomycin, aclacino- mycin A, and mitoxantrone was tested in the clonogenic assay. A covariation in the sensitivity to the drugs emphasized the importance of simultaneous drug testing on the same batch of cells. On one cell line (NClN592) the interexperimental variation was further evaluated and a significant correlation was found between preexposure culture condi- tions, size of S-phase, and sensitivity to adriamycin, daunomycin, and mitoxantrone. Rigorous standardization of the growth conditions prior to clonogenic assay reduced the variation in the sensitivity to adriamy- tin from a factor of five to only lo- 15%. It is concluded that simultane- ous experiments on the same batch of cells in drug comparisons shotdd be used if possible. Specification and standardization of culture condi- tions are necessary in the comparison of drugs tested in different experiments. Inclusion of the same reference drug in all experiments may further increase the validity of comparisons in different experi- ments.

Randomized phase II-III trial of combination beta and gamma interferons and etoposide and cisplatin in inoperable non-small cell cancer of the lung Schiller JH, Storer B, Dreicer R, Rosenquist D, Fronteira M. Carbone PP. University of Wisconsin Clinical Cancer Center, Madison. WI. J Nat1 Cancer Inst 1989:81:1739-43.

We observed major responses in two patients with adenocarcinoma of the lung who had received a combination of interferon (IFN)-6 and IFN-gamma, immediately followed by chemotherapy. To verify these observations, we initiated a prospective randomized phase II-III trial of etoposide and cisplatin, with or without IFN-6 and IFN-gamma, in patients with inoperable non-small cell lung cancer. Thirty-seven patients were randomized to receive either two cycles of chemotherapy or 6 weeks of IFN-8 plus IFN-gamma followed by two cycles of chemotherapy. Chemotherapy consisted of 60 mg of cisplatirs/m2 on day 1 and I20 mg of etoposide/m’ on days 4,6. and 8, repeated every 21 days. Patients who were randomized to the IFN plus chemotherapy arm received 200 pg of IFN-gamma and 30 x 1 (P U of IFN-6 three times per week for 6 weeks, followed by two cycles of chemotherapy. Three of 18 (17%) eligible patients in the chemotherapy arm and two of I8 (11%) patients in tbe combination arm had partial responses. All responses cccmred while patients were receiving chemotherapy. Median survival was 190 days for the chemotherapy arm and 246 days in tbe combined modality arm, as estimated from Kaplan-Meier curves (P = .35). We observed no significant difference in subjective toxic effects between the two arms. We observed more hematologic toxicity during chemotherapy on the combined modality arm (P = .02). We conclude that pretreatment with IFN-8 and IFN-gamma does not enchance the efficacy of etoposide and cisplatin in this disease. Although the com- bined modality arm is relatively well tolerated, it does result in more chemotherapy-associated toxic effects This study also exemplifies a hybrid phase II-III trial design, which is useful in allowing phase II results to be quickly incorporated into a phase III trial.

Symptom relief with moderate dose chemotherapy (mitomycin-C, vinblastine and cisplatin) in advanced non-small cell lung cancer Hardy JR, Noble T, Smith IE. Lung Unit, Royal Mar&n Hospital, Surrey SM2 SPT. Br J Cancer 1989;60:764-6.

Twenty-four symptomatic patients with advanced non-small cell lung cancer (NSCLC) were treated with cisplatin-based chemotherapy (mitomycin-C 8 mg m-* q 6 weeks, vinblastine 6 mg m-2 g 3 weeks, cisplatin 50 mg m-* q 3 weeks). Patients were assessed for symptom relief as well as for objective response. Although only live patients