Mitsumasa Ogawara

Phase II study of weekly irinotecan and carboplatin for refractory or relapsed small-cell lung cancer

We designed a phase II study of weekly irinotecan (CPT-11) and carboplatin for refractory or relapsed small cell lung cancer (SCLC) and assessed the response rate, survival, and toxicity. Twenty-nine patients with refractory or relapsed SCLC were entered onto the trial. The median time off chemotherapy was 3.5 months (range: 0.8-12.9). Patients were treated at 4-week intervals using CPT-11 (50 mg/m(2) intravenously on days 1, 8 and 15) plus carboplatin (AUC = 2 mg/ml min, intravenously on days 1, 8, 15). All patients were assessable for toxicity and survival; 28 patients were assessable for response. There were nine partial responses (PRs). Overall response rate was 31.0% (95% CI: 15.3-50.8%). The median time to progression was 3.5 months. Median survival time was 6.1 months. Major toxicity was myelosuppression. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 52 and 21% of patients, respectively. Grade 3-4 diarrhea was observed in 7%. There was one treatment-related death due to febrile neutropenia and sepsis. This combination of CPT-11 and carboplatin seems to be active second-line regimen with acceptable toxicity against small cell lung cancer.

Cisplatin-based combination chemotherapy for elderly patients with non-small-cell lung cancer

Purpose: To compare the response rates, toxicities and survival durations of elderly patients (70 years of age or more) with those of younger patients ( less than 70 years of age) with non-small-cell lung cancer (NSCLC) treated with cisplatin-based chemotherapy. Patients and methods: We analyzed retrospectively the data of 203 assessable patients entered on a prospective randomized trial of cisplatin-based combination chemotherapy. Chemotherapy consisted of three dosage regimens: (1) vindesine and cisplatin (VP); (2) mitomycin, vindesine and cisplatin (MVP); or (3) etoposide and cisplatin alternating with vindesine and mitomycin (EP/VM). Results: A greater proportion of elderly patients had localized disease and more squamous cell carcinoma than non-elderly patients. The overall response rates were 44% in the elderly group and 28% in the non-elderly group. In the EP/VM arm, the response rate was significantly better in the elderly group than in the non-elderly group. The frequency of grade 4 leukocytopenia in the MVP and EP/VM arms in the elderly group was significantly greater than in the non-elderly group (Pu2009<u20090.05). No differences were found in nonhematological toxicities between the two groups. There was no difference in overall survival between the groups. Conclusion: Elderly patients treated with mitomycin-containing regimens have higher hematologic toxicities than younger patients. The results of this study are consistent with the previously reported pharmaco logic data on mitomycin suggesting altered pharmacokinetics in elderly patients. The improved response rate in the elderly patients was probably because more elderly patients had earlier disease, squamous cell carcinoma and better performance status. Cisplatin-based chemotherapy was tolerable for most elderly NSCLC patients with good performance status.

A dried preparation of liposomes containing muramyl tripeptide phosphatidylethanolamine as a potent activator of human blood monocytes to the antitumor state

SummaryStudies were performed on the activation of human blood monocytes to the antitumor state by a dried preparation of multilamellar vesicle (MLV) liposomes in which synthetic muramyl tripeptide phosphatidylethanolamine (MTP-PE) was inserted directly into the liposome membrane. Dried liposomes composed of synthetic phospholipids [phosphatidylcholine (PC) and phosphatidylserine (PS) in a molar ratio of 7:3] were prepared by lyophilization. Dried liposome-MTP-PE was found to be superior in several ways to free desmethyl muramyl dipeptide (norMDP) or conventional liposome-MTP-PE, prepared immediately before use. First, dried lipsome-MTP-PE was stable and strongly activated monocytes when stored for over 3 months in a freezer at −°C or even in suspension at 4°C. Second, human monocytes in suspension, as well as in the adherent form, were activated to the tumoricidal state by interaction for at least 4 h with the dried preparation of liposome-MTP-PE. Third, monocytes activated with the dried liposome-MTP-PE or conventionally prepared liposome-MTP-PE maintained their tumoricidal activity for a longer period (4 days) than those activated with free norMDP. These results indicate that the dried preparation of liposome-MTP-PE can be stored for a long time, has a reproducible effect that can be standardized and should be valuable for in situ activation of human monocytes to the tumoricidal state, which is associated with eradication of cancer metastases.

Activation by a new synthetic acyltripeptide and its analogs entrapped in liposomes of rat alveolar macrophages to the tumor cytotoxic state

SummaryFK-565 (heptanoyl-γ-d-Glu-(l-meso-a, ε-A2pm (l)-d-AlaOH) is a synthetic acyltripeptide closely resembling cell wall peptidoglycan peptides of Streptomyces in structure. Alveolar macrophages (AM) lavaged from lungs of F344 rats were activated by in vitro treatment with FK-565 and its derivatives at concentrations of 1–50 μg/ml medium, and the activated AM killed syngeneic mammary adenocarcinoma cells. When FK-565 and related compounds were encapsulated in multilamellar (MLV) liposomes composed of phosphatidyl-choline and phosphatidylserine, dose-response experiments showed that they were about 800 times more effective than the free compounds in activating AM. Liposome-encapsulated FK-565 and its analogs caused significant activation of AM within 4 h. These data indicated that acyltripeptide and its analogs encapsulated in liposomes are more efficient than the free compounds in rendering AM tumoricidal.

A phase II study of continuous concurrent thoracic radiotherapy in combination with mitomycin, vindesine and cisplatin in unresectable stage III non-small cell lung cancer.

The split-course concurrent thoracic radiation therapy (TRT) and full-dose chemotherapy for unresectable stage III non-small cell lung cancer (NSCLC) has produced promising results by comparison with the sequential approach. Instead of split-course radiation, we conducted a phase II study to investigate the feasibility of continuous concurrent TRT and chemotherapy. Twenty-two patients with unresectable NSCLC were enrolled onto a phase II study of continuous concurrent radiotherapy and chemotherapy. Treatment consisted of two courses of cisplatin (80 mg/m(2) on days 1 and 29), vindesine (3 mg/m(2) on days 1, 8, 29 and 36), and mitomycin (8 mg/m(2) on days 1 and 29). TRT began on day 2 at a dose of 60 Gy (2 Gy per fraction and 5 fractions per week for a total of 30 fractions). Of 22 patients assessable for response, none achieved a CR and 17 (77.3%) achieved a PR with an overall response rate of 77.3% (95% confidence interval, 54.6-92.2%). Grade 3 or 4 leukopenia was observed in 5/13 (81.8%) patients. Six patients (27.3%) experienced > or = grade 3 thrombocytopenia. Non-hematological toxicity was relatively mild. The overall median survival time was 19.0 months and the 1- and 2-year survival rates were 84.8 and 34.5%, respectively. It was possible to administer two courses of chemotherapy in 18 patients (81.8%) as planned. Nineteen (86.4%) of the 22 patients received the planned 60 Gy radiation. It seems to be difficult to administer the planned treatment without any interruption for the majority of patients. However, in the selected patients who completed the 60 Gy TRT, nearly half of the patients completed TRT without interruption. This combination regimen is considered to be feasible on condition that the stopping rule of the treatment is followed. We recommend administering radiotherapy continuously as far as possible.

Determinants of Myelosuppression in the Treatment of Non-small Cell Lung Cancer with Cisplatin-containing Chemotherapy

Data on 16 potential risk factors for myelosuppression were assessed in 134 patients who received either vindesine and cisplatin (VP) or mitomycin C, vindesine and cisplatin (MVP) for inoperable stage III or IV non‐small cell lung cancer in a randomized trial. Determinant factors for myelosuppression were evaluated by using univariate analysis and the logistic regression model. Recursive partitioning and amalgamation (RPA) was also used to define patient subgroups frequently suffering from severe bone marrow toxicity. Overall, 33 (25%) of 134 patients experienced at least one episode of grade 4 leukopenia. In univariate analysis, age, body surface area, serum creatinine, and pretreatment hemoglobin concentration were associated with severe leukopenia. A multivariate analysis using the logistic regression method showed that only raised creatinine level was an independent predictor for grade 4 leukopenia (P=0.049). The RPA model generated three distinct subgroups based on age, body surface area and regimen. The three subgroups were distinguished by the frequency of severe (grade 4) leukopenia (50%, 25%, and 2.4%, respectively) (P<0.001). Grade 4 leukopenia occurred more frequently in patients in class 3 (age ≥65 years and treatment with MVP). The RPA model was useful in identifying the risk factors for myelosuppression induced by cisplatin‐based chemotherapy, and in defining patient subgroups with elevated risk of toxicity.