154 Abstracts/Lung Cancer I2 (1995) 113-160

such as non-small cell lung cancer and colorectal cancer. Two combination phase I trials were undertaken to determine the maximum tolerated dose of CPT-II in combination with cisplatin and vindesine in patients with advanced non-small cell hmg cancer. All 46 patients (age 32-73 years) entered into these trials had a good performance status (Eastern Cooperative Oncology Group score, 0- I) and had received no prior chemotherapy or radiotherapy. In the first trial, 14 stage IV and 2 stage IIIb patients were studied, in the second trial 30 patients with stage IV disease were accrued. In the first trial, CPT-II was given as a 90-min i.v. infusion on days 1 and 8 in combination with a fixed dose of cisplatin (100 mg/m*, i.v., on day I) and vindeaine (3 mg/mz, iv., on days 1 and 8). every 4 weeks. The starting dose of CPT-11 was 25 mg/ mz, and the dose was increased in increments of 25 mg/m*. In the second trial, the doses of either CPT-11 (days 1 and 8) or cisplatin (day 1) were escalated with a fixed dose of vindesine (same dose as the first study) given in a 4-week cycle. The starting doses of CPT-I1 and cisplatin were 20 and 60 mg/m’, mapectively, and the dose of either CPT-11 or cisplatin was increased in increments of 20 mg/m’. At least 3 patients were entered at each dose level in both trials. Use of gramdocyte colony- stimulating factor or granulocyte-macrophage colony-stimulating factor was not permitted in this trial. In the first trial, grade 4 gramilocytopenia and grade 3 diarrhea were dose limiting at 50 mglm’ CPT-1 I, which represented the maximum tolerated dose. At the subsequent dose of CPT-I I,7 new patients were requited at the 50% reduced dose level of 37.5 mg/m2 on days I and 8. Nine patients were evahmble for response, and 4 of them achieved a partial response. In spite of a low dose of CPT-11 (25-37.5 mg/mt), the maximum concentration in plasma of CPT-II (XI.4 lg/ml) reached >lO-fold the in vitro concentration of CPT-11 required for 50% inhibition of growth. In the second trial, the dose-limiting toxicities were gmde 4 gramdocytopenia lasting for 7 days and grade 3 diarrhea. The maximum tolerated dose was 100 mg/ mz of CPT-11 and 60 mg/m’ of cisplatin in this regimen. The other severe toxicity was to the liver. Ten of 30 patients entered (10 of 22 patients assessable for response) achieved a partial response. intractable diarrhea induced by CPT-I 1 was associated with the dose of cisplatin used in our trials and occurmd coincidentally with gramdocytopenia of grade 4. For future phase II trials, we recommend doses of CPT-11 of 37.5 and 80 mg/m* on days 1 and 8 combined with vindesine and either highdose cisplatin (100 mg/m2) or low- dose cisplatin (60 mg/m*), respectively.

c-K-r= and p53 mutations occur very early in adeaocarciaoma of tbe lung Li Z-I-I, Zheng J, Weiss LM, Shibata D. Department ofPathologx USC School of Medicine, I200 N. State Shvet, No. 736, Las Angeles, CY 90033. Am J Path01 1994;144:303-9. The topographical distribution of a mutation provides insight into past patterns of tumor evolution. This approach was applied to two loci commonly mutated in adenocarcinoma of the lung-p53 and c-K-ras. In 41 primary adenocarcinomas, C-K-ras codon 12 point mutations were detected in 8 (19.5%) tumors and ~53 point mutations were detected in 10 (24.4%) tumors, with one tumor harboring both mutations. These mutations were only detected in maliguant cells and with a homogeneous topographical distribution throughout 16 tumors, including metastasis. Intratumor heterogeneity was detected in only one ttmror in which a small portion lacked the specific p53 mutation. Based on this topographical analysis, it is likely that when these mutations occur in adenocarcinoma of the lung, they are usually acquired during the very earliest phases of hmror formation before the bulk of clonal expansion, and in very small precurso r lesions.

Cisplatin-fotemusti combination in inoperable non-small cdl bmg cancer: Preliminary report of a French multicentrr pbase II trial Riviere A, Le Cesne A, Ekrille J, Baio S, Le Chevalier T. Centi Francois Bacfesse, Route de Lion-sur -me,: 14021 Caen Cedex. Eur J Cancer Part A Gen Top 1994;30:587-90. Fotemustine is a new nitrosourea derivative whose activity has been demonstrated on metastatic melanoma with specilic activity on brain memsmses and also on poor prognosis lung cancers. Results of in vitro studies ofa cisplatin-fotemustine combination seem promising In order to evahiate the efficacy and safety of this combination, we performed two trials. 6 patients entered a preliminary study whose schedule was cisplatin 120 mg/m2 on day 1 and fotemustine 100 mg/m’ on days I and 8. 22 patients were enrolled in a second study which added 120 m&m* cisplatin on day 22 followed by a 4-week rest period. In both trials, maintenance therapy consisted of cisplatin 100 mg/m2 and fotemustine 100 mg/m* every 3 weeks until progression. Despite the poor prognostic factors which chamcterised our population (metastatic disease 86%, brain metastases 59%, % 80% performance status 45%) the results remain attractive with a 23% partial response rate (29% in non-pretreated patients). Moreover, 3 out of 8 patients with evahrable cerebral metastases achieved a partial response (37.5%). Toxicity was mild and related to the cumulative dose of cisplatin (peripheral neuropathy and renal toxicity). We concluded that these results need to bc wnkmai in a randomised trial.

Pbase II study of nitrorourea fotemustiae as single-drug cbemotberapy in poor-pmosis non-smllleell lung cancer Pujol J-L, Molder A, Berille J, Cerrina M-L, Douilhud J-Y, Riviere A d al. Service des Maladies Respiratoiirs, Universite de Montpellier: Hopitai Arnmrd de Viiieneuve, 34295 Montpeliier Cedex. Br J Cancer 199469: 1136-40. A phase II study was designed to evaluate objective response rate and toxicity offotemustine as single-drug chemotherapy in non-small-cell lung cancer. Eightyaeven patients with unremctable non-smallcell lung cancer took part in the study. Seventy-seven were evahtable for response. Ofthese, 60% had received prior chemotherapy and 74% had me&static disease. Moreover, 22 patients had central nervous system memstases (of whom I2 were evahiable for this site). Treatment consisted of fotemustine 100 mg nrz administered on days 1 and 8 followed by a 5 week rest period. Aftewards, responding or stabilised patients received fotemustine 100 mg ma every 3 weeks as a maintenance therapy. Toxicity and quality of life were recorded during therapy. Thirteen patients (17%; 95% CI 9-25%) had an objective response (I 1% for pretreated, 26% for non-pretreated) with a median duration of 22 weeks (range 7-41 weeks). lbo objective responses were. observed among the I2 patients with evabmble brain metastases. No response was observed among the 14 patients with adenocarcinoma Haematological, gastrointestinal, hepatic and renal toxicities were mild to moderate and manageable. The most frequent biological adverse reactions were delayed thrombocympenia and neutropenia. Quality of life did not sigrrificantly decrease during the first 6 treatment weeks. Moreover, it remained stable during the study period in patients with response or stabilisation, whereas it significantly decreased in patients who experienced progression of the disease. Fotemustine is feasible for single-drug chemotherapy in non- small-cell lung cancer even though poor prognostic variables such as brain metastases are present. It can be administered on an outpatient basis and toxicity is moderate and manageable. Thus, fotemustine can he wnsidered as a putative drug in further combinations.