Phase II study of amonafide: Results of treatment and lessons learned from the study of an investigational agent in previously untreated patients with extensive small-cell lung cancer

138 achieved an objective response (21%). 18 patients (75%) reported a complete disappearance or good improvement in at least one of their tumour-related symptoms. The overall symptomatic response rate was 67% with 16 patients feeling better or much better on treatment. The toxicity of treatment (primarily myelosuppression and nausea and vomiting) was mild and hair loss was minimal. The high incidence of symptomatic relief seen in this study, even in the absence of objective response, suggests that moderate dose chemotherapy may have arole in the palliation of NSCLC.

23% (95% confidence-limits S-53.8%). Toxicity was generaly very mild. Although the compliance of this regimen is excellent, its antitumor activity seems unsatisfactory even in this category of poor-risk small-cell lung cancer patients.

Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small-cell lung cancer: a study of the Eastern Cooperative Oncology Group Bonomi PD, Finkelstein DM, Ruckdeschel JC et al. Easrern Coopera-

Seventy-seven patients with small cell lung cancer were entered on comprising induction chemotherapy with cyclophosphamide 1 g m-*,adriamycin 40 mg m-2and vincristine 1.4 mg m-’ (CAV) every 21 days for four to six cycles. The overall response rate was 72.8%. Twenty-six patientsachievingcompleteremissionreceivedintensification with two further cycles of ifosfamide 5 g m.Z, mesna 8 g m-‘, methotrexate 30 mg m-2and etoposide 100 mg m-*per day for 3 days (IME). Six of the 15 patients in partial remission following CAV achieved a further remission on IME (response rate 40%). Median survival in the limited disease group was 11months compared with 7 months in the extensive disease patients and four patients are alive at more than 2 yr follow up. There was no significant prolongation of the median survival (1 I months) seen in those patients in complete remission who had negative second bronchoscopy examination.This sequential six drug regime produces high response rates in small cell lung cancer, and there is evidence of lack of cross-resistance between CAV and IME.

tive Oncology Group. Rush-PresbyWrian-St

Luke’s Medical Center.

Chicago, IL 60612. J Clin Oncol 1989;7:1602-13. During the last decade, the Eastern Cooperative Oncology Group (ECGG) has studied a series of combination chemotherapy regimens in metastatic (stage IV) non-small-cell lung cancer (NSCLC). In January 1984, the ECOG activated a randomized study, EST 1583, which concluded the evaluation of combination regimens in phase III trials and initiated the evaluation of single agents exclusively in previously untreated patients. The treatment regimens in EST 1583 consisted of: (1) mitomycin, vinblastine, and cisplatin (MVP); (2) vinblastine and cisplatin (VP); (3) MVP alternating with the regimen cyclophosphamide, doxombicin, methotrexate, and procarbazine (CAMP); (4) carboplatin followed by tbe MVP regimen at the time of progression; and (5) iproplatin followed by MVP at the time of progression. From January 1984 to July 1985, 743 patients were entered on this trial and 699 fulfilled the eligibility requirements. The following objective response rates (complete plus partial remissions) were observed: first-line MVP, 20%; VP, 13%; MVP/CAMP, 13%; carhoplatin, 9%; iproplatin, 6%; and second-line MVP, 6%. First-line MVP produced a significantly higher response rate than the other treatments (P = .03) adjusted for prognostic variables. Using analyses that were adjusted for prognostic covariates, survival for patients treated on a given regimen was compared with survival for all remaining patients. These analyses showed that treatment with carboplatin was associated with longer survival (median survival time, 3 1.7 weeks; P = ,008) while initial treatment with MVP was associated with a trend for shorter survival (median survival time, 22.7 weeks; P = .09). It should be noted that none of these regimens appear to have produced a clinically meaningful prolongation of survival. Similar analyses evaluating time to progression disclosed that carboplatin-treated patients had a significantly longer time to progression (median time to progression, 29 weeks) than all remaining patients (P = .Ol). Life-threatening and lethal toxicities (toxicity grades 4 and 5) were greater on the combination regimens than on the single agents (P < .OOOl).Based on these results, current group-wide ECOG trials in stage IV NSCLC consist of randomized phase II trials evahating single agents.

Oral chemotherapy for poor risk small-ceil lung cancer patients with combined idarubicin and etoposide Ardizzoni A, Pennucci C, Fusco V et al. Medical Oncology Dept., lssliruto Nazionale per lo Ricerca ml Concro, 16132 Geneva. Anticancer Res 1989;9:937-40. Sixteen patients with previously untreated small-cell lung cancer, unsuitable for standard aggressive intravenous chemotherapy due to advanced age or poor performance status or very advanced disease including brain metastases or either extensive liver or marrow involvement with impaired organ function, were treated with combined oral chemotherapy including 4-demethoxydaunorubicin (lM130, idarubitin) 30 mgfsm on day 1 and etoposide (VP16) 150 mg/sm on days 2,3,4 every 4 weeks. Out of 13 evaluable patients 1 had a complete response and 2 had a partial response with an overall objective response rate of

Treatment of small cell lung cancer with induction chemotherapy followed by late intensification Hardman PDJ, Green JA, Errington RD. Myint S, Warenius HM. CRC Deparrment ofRadiation Oncology, Clauerbridge t!ospital,Bebington L63 4JY. Med Oncol Tumor Pharmacother 1989;6:227-32. a protocol

Carboplatin in association with etoposide and either adriamycin or epirubicin for untreated small cell lung cancer: A dose escalation study of carboplatin Humhlet Y, Weynants P, Bosly A et al. Ludwig fnsliuue for Cancer Research (Brussels Branch), Brussels. Med Oncol Tumor Pharmacother 1989;6:207-12. A multi-center, open trial was conducted to determine the maximal tolerable dose of carboplatin in combination with conventional doses of both etoposide and an anthracycline for the treatment of previously untreated small cell lung cancer (SCLC) patients. Ninety-five patients [48 with limited disease (LD) and 47 with extensive disease (ED)] received a total of 376 courses of treatment. Carboplatin was given on day 1 at a dose of 250 mg m-2in 60 courses, 300 mg rn.*in 69,330 mg m2 in 236 and 350 mg m-2in 11, with 120 mg m-’ etoposide on days 1, 3 and 5 and either40 mg m-2adriamycin or 60 mg m-2epirubicin on day 1.Epirubicin was not administered before carboplatin reached the dose of 330 mg m-Z.Courses were repeated every 3 weeks. The main toxicity was hematological. The first course of therapy induced a dose-dependent decrease of leucocyte, neutrophil and platelet counts: all patients, except one, who received 350 mg m-2carboplatin had a neutmpenia below 200 pl-’ and a thromhopenia below ICQOGUPI-‘.Three patients died of septicemia. Other toxicities were well tolerated. After three courses, patients were re-staged by performing a mandatory fiberoptic bronchoscopy and a thoracic computed axial tomography (CAT). The overall objective response rate for 86 evaluable patients was 9 1% (98% forLD) with2l%completeremissions(3O%forLD). All23 hepaticand six brain sites, evaluable after chemotherapy alone, responded. This new combination, in which the recommended dose of carboplatin is 330 mg m-I, should be evaluated in a prospective study for SCLC.

Phase II study of amonafide: Results of treatment and lessons learned from the study of an investigational agent in previously untreated patients with extensive small-cell lung cancer Evans WK, Eisenhauer EA, Cormier Y et al. Ottawa Regional Cancer Cenfre, 190 Melrose Ave., Ormwa, Ont. KIY 4K7. J Clin Oncol 1990;8:390-5.

139 Thirteen previously untreated patients wirh extensive small-cell lung cancer (SCLC) were treated with the investigational agentamonafide in a dose of 300 mg/m’ intravenously (IV) over 1 hour daily for 5 consecutive days. No responses were seen in 12 eligible patients. Myelosuppression was only occasionally seen. Other toxicities included diaphoresis, chest pain, local irritation at the injection site, arthralgias,nausea and vomiting, and neuromuscular problems. There were two early deaths, both attributable to tumor progression with resultant obstruction of a vital structure, Ten patients crossed over to alternate active therapy (etoposide [VP-16]-cisplatin) and five responded. The median survival time (MST) of the whole group of treated patients was 31 weeks. In future trials of investigational new drugs in previously untreated SCLC, we recommend that patients with the following characteristics be excluded: Eastern Cooperative Oncology Group (ECGG) performance status 2, 3, and 4; superior vena cava (SVC) obstruction; any major paraneoplastic syndrome; serious comorbid illness; and extensive hepatic involvement by tumor. The trial design should include prompt crossover to active alternative therapy, such as VP-16 and cisplatin, for disease progression or for failure to respond after two treatment cycles. Also, the trial design should use an early slopping rule based on interest in identifying only very active agents with a minimum response rate of 30%.

Epirobicin in extensive small-cell lung cancer: A phase II study in previously untreated patients: A National Cancer Institute of Canada Clinical Trials Group Study Blackstein M, Eisenhauer EA. Wierzbicki R, Yoshida S. National Cancer Imiruk of Canada Clinical Trials Group, Queens University, 82-84 Barrie Street, Kingston, Ont. K7L 3N6. J Clin Oncol 1990;8:3859. The Clinical Trials Group of the National Cancer Institute. of Canada (NCIC) studied single-agent epirubicin in 40 previously untreated patients with extensive small-cell lung cancer (SCLC). The starting dose of epimhicin was 100 (eight patients) or 120 (32 patients) mplm’ administered intravenously every 3 weeks. Twenty patienrs (50%) achieved an objective response (95% confidence limits, 33% to 66%) and lhree of the 20 had complete responses (CRs). The median survival of all40patients was 8.3 months (35.4 weeks). Myelosuppression, mild or moderate nausea and vomiting, and hair loss were commonly seen. Therewasonechemotherapy-relateddeath. Thisdrugisactiveand well tolerated in SCLC and the use of it as first-line therapy did not appear to compromise survival in this group of patients. Treatment of small cell lung cancer by eight weeks chemotherapy Crawford SM, ParkerD, Glaser MG et al. Cancer Research Campaign Loborarories and Deparmw of Medical Oncology, Charing Cross Hospital, Fulham Palace Road, London W6 8RF. Mcd Chxol Tumor

Pharmacother 1989:6:279-83. Eighty-two patients with small cell lung cancer (SCLC), 32 with limited disease, were treated with alternating chemotherapy. Eight courses were administered at weekly intervals, and responding patients received radiotherapy to sites of bulk disease. Overall response rate was 76.8%. Overall median survival was 265 days, 408 days in patients with limited disease. The median symptom free period after chemotherapy was completed was 123 days. These results are comparable with those in reports of chemotherapy of longer duration and warrant the further investigation of short duration treatment in this disease. Comparison of etoposide and cisplatin with bis-chloro-ethylnitrosourea, thiotepa, vine&tine, and cyclophosphamide for salvage treatment in small cell long cancer. A southwest oncology group study G’Bryan RM, Crowley JJ, Kim PN et al. Sourhwesc Oncology Group, Operations O#ice.S430 Fredericksburg Road, San Antonio, TX 78229. Cancer 1990;65:856-60.

Small cell lung cancer patients who failed primary systemic therapy or who failed after response were randomly assigned to salvage treatment with etoposide (VP-16) and cisplatin (CDDP) or bis-chloroethylniuosourea,thiotepa,vincristine,andcyclophosphamide(BTOC). Good risk patients were those who had tolerated prior chemotherapy well, those who had not had priorradiation therapy, and those who were 65 years of age or younger. Patients with a history of poor tolerance, prior radiation therapy, or those who were older than 65 years of age were classified as poor risk. Forty-five patients were randomized to the BTOC regimen and 58 to the VP-16/CDDP regimen. The overall remission rate was 13% (13 of 103 patients). Goad risk patients treated with the BTGC regimen had a remission rate of 27% (three of 11 patients), which was the same rate as patients treated with the VP-161 CDDP regimen (three of 11 patients). Poor risk patients had remission rates of 9% (three of 34 patients) with the BTGC regimen and 9% (four of 47 patients) with the VP-16/CDDP regimen. ?he median survival time from the start of therapy was 16 weeks for all patients. BTOC good risk patients had a median survival time of 10 weeks, as compared with 14 weeks for poor risk patients. VP- 16/CDDP good risk patients had a median survival time of 35 weeks, as compared with 12 weeks for poor risk patients. Although based on small numbers, the advantage in survival time for good risk patients treated with VP-16/CDDP over these treated with BTGC is statistically significant. Prior exposure to VP-16 did not influence the outcome of patients treated with VP-16/ CDDP. Both regimens produced moderate toxicity, but were generally well tolerated. It was concluded that VP-16/CDDP may be a useful salvage treatment for good risk patients, despite its limited remission rate. Also, it was found that BTGC has no value for patients in this setting and that neither regimen helps patients who are poor risk.

Comparison of DNA cleavage induced by etoposide and doxorubitin in two human small-cell long cancer lines with different sensitivities to topoisomerase II inhibitors Binaschi M, Capranico G, De Isabella P et al. Division of&?erimenral Oncologytl, Istimto Nazionoleper lo Studio e la Cum dei Tumori, Via Venezian 1,20133 Milan. Int I Cancer 1990;45:347-52. In an atlempt to clarify the role of drug-induced protein-associated DNA breaks (i.e., DNA topoisomerase II-mediated DNA cleavage) in the cytotoxic aclivity of doxorubicin and etoposide, their cellular effects were compared in 2 human small-cell lung cancer (SCLC) lines, characterized by differential sensitivity toDNA topoisomeraseI1 inhibitars. These drugs were selected for comparative studies since they are among the most effective agents in the treatmentof SCLC. HI46 and N592 cell lines were obtained from pleural effusion and bone-marrow aspirate of pretreated patients, respectively. Both cell lines grew as floating aggregates with similar doubling times (30 and 33 hr for N592 and HI46 cells, respectively). Although, immediately after 1 hr exposure to equitoxic drug levels, the extent of DNA cleavage produced by doxorubicin was markedly lower than that produced by etoposide, DNA lesions produced by doxorubicin persisted and even increased following drug removal. In contrast, an almost complete disappearance of etoposide-induced DNA breaks was noted I hr after drug removal. Resealing of strand breaks was faster in N592 than in HI46 cells. These findings suggest that reversal of these leions plays a major role in cell survival rather than the occurrence of DNA breaks immediately following drug exposure. This observation is consistent with the view that inhibition of DNA re-ligation rathen than stimulation of DNA cleavage is thecritical step for drug action. The different response of these cell lines to cytotoxic action of the topoisomerase inhibitors is associated with a differential drug effect on DNA integrity (detected as DNA double-strand breaks and DNA-protein cross-links). However DNA lesions were comparable when cells were exposed IO equiloxic drug levels. The observation that etoposide-induced DNA breaks were similar in isolated nuclei from both cell lines suggests tiatdrug-target imcraction is modulaled in a different manner in the intact cells. As indicated by doxorubicin uptake and retention, cellular hg Pharma-