ytoin, and metoprolol (8-14). We have documented previously that pretreatment with cimetidine but not ranitidine significantly enhances cyclophosphamide's antileukemic activity and bone marrow toxic effects by increasing plasma levels of its alkylating species (17,18). Since the same pharmacokinetic and toxicologic effects of cyclophosphamide may occur in cancer patients treated concomitantly with cimetidine, we have suggested caution with respect to the administration of this H2 blocking agent in the presence of cyclophosphamide. We would have preferred that the design for our pharmacokinetic and toxicologic trial involve a toxicologic and pharmacokinetic comparison of ranitidine versus cimetidine in combination with cyclophosphamide. Because of the unpredictable nature of a cimetidine-cyclophosphamide interaction, however, we decided that this risk was unwarranted in the setting of a clinical pharmacokinetic trial. Instead, we focused on a comparison of ranitidine with placebo in a controlled trial. The lack of a clinically important toxicologic or metabolic interaction between ranitidine and cyclophosphamide in cancer patients, documented by theresultsof this study, suggests that ranitidine can be safely administered to patients during therapy with cyclophosphamide.

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Vol. 83, No. 23, December 4, 1991

Noriyuki Masuda, Masahiro Fukuoka* Kaoru Matsui, Yoko Kusunoki, Shinzoh Kudoh, Shunichi Negoro, Nobuhide Takifuji, Mamoru Fujisue, Hideo Morino, Kazuhiko Nakagawa, Masayuki Nishioka, Minoru Takada

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(2/) JONES RH, RUDGE Cl, BEWICK M, ET AL: (/) BROCK N, GROSS R, HOHORST HJ, ETAL: Acti-

Establishment of Tumor Cell Lines as an Independent Prognostic Factor for Survival Time in Patients With Small-Cell Lung Cancer

We studied tumor samples from 39 patients, who entered our study from January 1989 to May 1990, to assess whether the ability to establish a continually growing tumor cell line from fresh tumor specimens can be associated with decreased survival times in patients with small-cell lung cancer. The tumor samples were used to establish cell lines in culture using a serum-free medium supplemented with hydrocortisone, insulin, transferrin, estrogen, and selenium (HITES). Thirty-three of these specimens were obtained by Fiberoptic bronchoscopy from primary sites during routine diagnostic procedures. A total of 11 (28%) cell lines were established: seven (21%) from 33 primary tumors and four (80%) from five peripheral lymph nodes. Survival times of the 11 patients whose tumor cell specimens continually grew in culture at any time during their clinical course were significantly shorter than those of the 28 patients whose tumor cell specimens did not grow in vitro (median survival time of 26 weeks versus 73 weeks; P = .0068). Cox's proportional hazards model, including sex, age, Eastern Cooperative Oncology Group performance status, stage, source of specimen, treatment, and in vitro tumor cell growth in the overall patient group, showed that cell line establishment (P = .0017) and no therapy (P = .0015) were the most important factors indicating poor survival time.

REPORTS 1743

For the subgroup of 23 primary tumor patients, the important factors (in decreasing order) that indicated decreased survival times were the establishment of a cell line (P = .0112) and treatment with cyelophosphamidedoxorubicin-vincristine alternating with cisplatin-etoposide, versus cisplatinvincristine-doxorubicin-etoposide therapy (P = .0463). Our study demonstrates that in vitro tumor cell growth is an adverse predominant prognostic factor in patients with small-cell lung cancer. [J Natl Cancer Inst 83:17431748,1991]

Compared with other types of lung cancer, small-cell lung cancer is sensitive to both chemotherapy and radiation therapy (7). Nonetheless, after apparently successful induction therapy, most patients with small-cell lung cancer relapse within 1 or 2 years, and cures are rare (28). The major prognostic factors most consistently identified to date are extent of disease and performance status (9,JO). Although there are currently several reports relating in vitro tumor cell growth to survival times in various types of human malignancies (/1-15), they are incomplete and conflicting as to whether the ability to establish a continuously growing cell line from tumor specimens, especially from primary tumor specimens, has been associated with shortened survival times in patients with small-cell lung cancer. We have attempted to establish small-cell lung cancer cell lines in culture, mainly from primary tumor biop-

Received May 28, 1991; revised August 9, 1991; accepted September 11, 1991. Supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare (62-S-l and 63-13). N. Masuda, M. Fukuoka, K. Matsui, Y. Kusunoki, S. Kudoh, S. Negoro, N. Takifuji, M. Fujisue, K. Nakagawa, M. Takada (Department of Internal Medicine), H. Morino (Department of Pathology), M. Nishioka (Department of Radiology), Osaka Prefecture] Habikino Hospital, Habikino Osaka, Japan. We thank Mrs. Saeko Nakanishi for her help in statistical analysis and Mrs. T. Wada for excellent technical assistance. *Correspondence to: Masahiro Fukuoka, M.D., Department of Internal Medicine, Osaka Prefecture] Habikino Hospital, 3-7-1 Habikino, Habikino Osaka 583, Japan.

1744

sy specimens obtained with fiberoptic bronchoscopy. In this report, we describe the relationship between in vitro tumor cell growth and survival times of patients with small-cell lung cancer.

Materials and Methods Patients and treatment regimens. Following informed consent, 39 patients with pathologically confirmed small-cell lung cancer were entered in this study between January 1989 and May 1990. All patients underwent diagnostic and staging procedures to determine the extent of disease as described previously (16). Staging procedures followed the tumor-nodemetastasis system (77). All patients received chemotherapy, except three patients who died before the beginning of the chemotherapy. Most of the patients received one of the following protocol regimens. Before May 1989, patients were usually treated with cyclophosphamide-doxorubicin-vincristine alternating with cisplatin-etoposide with or without chest irradiation (7

Establishment of tumor cell lines as an independent prognostic factor for survival time in patients with small-cell lung cancer.

We studied tumor samples from 39 patients, who entered our study from January 1989 to May 1990, to assess whether the ability to establish a continual...
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