Linnoila Ri

Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer

PURPOSE We performed a prospective randomized clinical trial to determine whether higher doses of etoposide and cisplatin (EP) yield more complete responses or longer survival in small-cell lung cancer (SCLC) patients. PATIENTS AND METHODS Ninety patients with previously untreated extensive-stage SCLC fulfilled criteria for randomization to standard-dose versus high-dose EP. Another 25 patients at risk of excessive toxicity from high-dose treatment were given standard-dose therapy. During cycles 1 and 2 of EP, patients on standard-dose treatment received intravenous etoposide 80 mg/m2 on days 1 to 3 and cisplatin 80 mg/m2 on day 1 every 3 weeks; high-dose treatment consisted of etoposide 80 mg/m2 on days 1 to 5 and cisplatin 27 mg/m2 on days 1 to 5 every 3 weeks. All patients received standard-dose EP in cycles 3 and 4. In cycles 5 through 8, completely responding patients continued standard-dose EP; all other patients received either cyclophosphamide, doxorubicin, and vincristine, or (if possible) a combination drug program based on in vitro drug sensitivity testing of tumor-cell lines established from individual patients. RESULTS Despite 68% higher doses and a 46% higher dose-rate intensity actually given to patients randomized to receive high-dose relative to those randomized to receive standard-dose EP, complete response rates (23% v 22%; P = .99) and median survival durations (10.7 and 11.4 months, respectively; P = .68) were virtually identical. Complete responses occurred in 4% of patients and the median survival duration was 5.8 months in nonrandomized patients. Leukopenia (P < .0001), thrombocytopenia (P < .0001), febrile neutropenia (P = .01), and weight loss (P = .02) were significantly more common in patients randomized to receive high-dose compared with standard-dose EP. CONCLUSION No therapeutic benefits resulted from increasing planned doses by 67% for the first two cycles of EP in patients with extensive-stage SCLC. Higher doses were associated with substantially worse toxicities.

Expression of early lung cancer detection marker p31 in neoplastic and non-neoplastic respiratory epithelium

In an immunocytochemical study of sputum, two antibodies, including a mouse monoclonal antibody (703D4) to a 31 kDa protein (p31) antigen, have been previously shown to detect lung cancer earlier than routine cytomorphology or chest X-ray. To understand the basis of p31 expression, the distribution of this antigen in the respiratory epithelium of individuals known to have lung cancer was mapped. These individuals are likely to demonstrate extensive changes throughout the epithelium due to field cancerization. p31 immunoreactivity was examined in primary tumors and surrounding non-neoplastic lungs containing both histologically normal and abnormal areas obtained from 28 Stage I non-small cell lung cancer (NSCLC) patients. Distribution and intensity of p31 expression was scored in three lung compartments (bronchi, bronchioli, alveoli). While p31 was present in histologically unremarkable bronchial and bronchiolar epithelium, no expression was detected in bronchi or bronchioli containing histologic abnormalities. Furthermore, in the peripheral lung p31 staining was frequently observed in alveolar type II cells and was most commonly detected in reactive, hyperplastic type II cells. When p31 immunoreactivity was correlated with clinicopathological features, a statistically significant increase in p31 expression was found both in bronchioli and alveoli of older individuals a well as in bronchioli of patients with most extensive smoking exposure. We conclude that p31 expression occurs in both non-neoplastic and neoplastic epithelium of the human respiratory tract. The increased expression of p31 in the peripheral lung may be potentially informative as to what critical cell populations are involved in the development of invasive cancers. Moreover, this study provides a model approach for analysis of the nature of early epithelial changes leading to the development of lung cancer.

Lack of relationship between in vitro tumor cell growth and prognosis in extensive-stage small-cell lung cancer.

The ability to establish a continuously growing tumor cell line from fresh tumor specimens has been associated with shortened survival in some human malignancies. Therefore, we assessed the relationship between survival and in vitro tumor cell growth from specimens obtained during routine staging procedures in 68 consecutive patients with untreated, extensive-stage small-cell lung cancer (SCLC) who received etoposide/cisplatin chemotherapy. Three groups of SCLC patients could be distinguished: (1) 23 patients in whom a tumor cell line was established in vitro; (2) 28 patients in whom tumor-containing specimens were cultured but in vitro growth did not occur; and (3) 17 patients in whom no tumor-containing specimen could be procured. No significant difference in response rates to chemotherapy of the three groups was noted. Poor performance status (P2 = .001), male gender (P2 = .0008), liver metastases (P2 = .0033), brain metastases (P2 = .0152), and the ability to obtain a tumor-containing specimen from the patient for laboratory culture (P2 = .0005) were all significant independent predictors of decreased survival in this patient population. While the ability to obtain a tumor cell specimen for cell culture using routine staging and diagnostic procedures identified patients with shortened survival, we found no significant survival differences between patients whose tumor cell specimens grew in cell culture v those that did not (median survival of 7 months v 11 months, P2 = .72). Our study indicates that the clinical outcome of extensive-stage SCLC patients from whom tumor cell lines can be established is not significantly different than in those cases from whom tumor-containing specimens could not be grown in vitro.