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Objective: Cisplatin is administered in combination with massive hydration to avoid renal toxicity, making its administration difficult in an outpatient setting. Although a short hydration protocol for cisplatin has been recently developed, its safety is not fully understood., Methods: Consecutive patients with lung or other cancer and an Eastern Cooperative Oncology Group performance status of 0-2 who were receiving chemotherapy containing cisplatin at a dose of ≥60 mg/m(2) in a single administration were evaluated. Seventy-four patients were treated with a short hydration protocol consisting of 1750-2250 ml of hydration with mannitol and magnesium supplementation over a period of 3.75-4.75 h on Day 1. Sixty-nine patients were treated with a conventional hydration protocol consisting of 2100-2600 ml of hydration over 6.5-7.5 h on Day 1 with pre- and post-hydration on Days 0, 2 and 3. Toxicity was then compared between the two groups., Results: An elevated serum creatinine level ≥grade 1 was significantly less frequent in the group receiving the short hydration protocol than in the group receiving conventional hydration. Other toxicities were similar between the two groups. Consequently, the completion rate for the planned treatment in the short hydration group (73.0%, 54/74) was significantly higher than that in the conventional hydration group (53.6%, 37/69)., Conclusions: Short hydration is safe, making cisplatin-containing chemotherapy easier to perform., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Interferons (IFNs) have been tested for the therapeutic effects in various types of malignancy, but mechanisms of the anti-tumors effects and the differential biological activities among IFN members are dependent on respective cell types. In this study, we examined growth inhibitory activities of type I and III IFNs on 5 kinds of human mesothelioma cells bearing wild-type p53 gene, and showed that type I IFNs but not type III IFNs decreased the cell viabilities. Moreover, growth inhibitory activities and up-regulated expression levels of the major histocompatibility complexes class I antigens were greater with IFN-β than with IFN-α treatments. Cell cycle analyses demonstrated that type I IFNs increased S- and G2/M-phase populations, and subsequently sub-G1-phase fractions. The cell cycle changes were also greater with IFN-β than IFN-α treatments, and these data collectively showed that IFN-β had stronger biological activities than IFN-α in mesothelioma. Type I IFNs-treated cells increased p53 expression and the phosphorylation levels, and activated apoptotic pathways. A combinatory use of IFN-β and cisplatin or pemetrexed, both of which are the current first-line chemotherapeutic agents for mesothelioma, produced synergistic anti-tumor effects, which were also evidenced by increased sub-G1-phase fractions. These data demonstrated firstly to our knowledge that IFN-β produced synergistic anti-tumor effects with cisplatin or pemetrexed on mesothelioma through up-regulated p53 expression.

Although cisplatin and pemetrexed are key drugs in the treatment of malignant pleural mesothelioma, their drug-drug interactions, cross-resistance and resistance mechanisms in malignant pleural mesothelioma are not well understood. In the present study, the interaction of these 2 agents was determined by clonogenic assays followed by isobologram analysis of 4 human malignant pleural mesothelioma cell lines. The cell lines were exposed to the agents using a stepwise dose-escalation method to establish drug-resistant sublines. Thymidylate synthase mRNA expression was evaluated in the drug-resistant sublines. As a consequence, cisplatin and pemetrexed had synergistic effects in 3 cell lines and an additive effect in the fourth cell line. The former 3 cell lines showed similar pemetrexed sensitivity in the parental cells and their cisplatin-resistant sublines, whereas the fourth cell line exhibited cross-resistance. In contrast, cisplatin had diverse effects on pemetrexed-resistant sublines. High thymidylate synthase expression did not correlate with natural pemetrexed resistance. Elevated thymidylate synthase expression correlated with acquired pemetrexed resistance in 2 sublines. In conclusion, cisplatin and pemetrexed showed synergistic activity and no cross-resistance in 3 of the 4 malignant pleural mesothelioma cell lines, suggesting the clinical relevance of their combination in chemotherapy. Thymidylate synthase expression did not necessarily correlate with pemetrexed resistance. The information together with the experimental model presented here would be useful for further investigating therapeutic targets of malignant mesothelioma.

To compare the incidence and degree of renal toxicity associated with innovator and generic cisplatin formulations, increase in the serum creatinine (CRN) levels (mg/dL) and incidence of grade 2-3 CRN elevation during the first and all cycles of chemotherapy were retrospectively evaluated in patients treated with innovator (group 1, n = 296) and generic (group 2, n = 321) cisplatin formulations. There were no differences in the sex, age, performance status or number of chemotherapy cycles between groups 1 and 2. The median increases in CRN levels during the first cycle were 0.20 mg/dL regardless of the sex or group. There was no difference in the incidence of grade 2-3 CRN elevation between groups 1 and 2 among female or male patients. The median increases in CRN levels during all cycles were 0.2 (0-1.0) and 0.3 (0-1.8) in the female patients of groups 1 and 2, respectively (P = 0.68), and 0.3 (0-2.1) and 0.5 (0-3.6) in the male patients of groups 1 and 2, respectively (P < 0.001). Grade 2-3 CRN elevation was observed in 18.1% and 24.7% of the female patients in groups 1 and 2, respectively (P = 0.33), and 9.4% and 20.9% of the male patients in groups 1 and 2, respectively (P < 0.001). Renal toxicity was slightly more severe in patients treated with the generic cisplatin formulation than in those treated with the innovator formulation, especially among the male patients., (© 2010 Japanese Cancer Association.)

To determine whether bodyweight (BW) loss, daily urine volume (UV) or furosemide use are associated with cisplatin nephrotoxicity, performance status, serum chemistries before treatment, average daily UV, maximum BW loss and use of furosemide on days 1-5 of chemotherapy were evaluated retrospectively in chemotherapy-naive patients with thoracic malignancies who had received 80 mg/m(2) cisplatin. Associations between these parameters and the worst serum creatinine levels (group 1, grade 0-1; and group 2, grade 2-3) during the first cycle were evaluated. Of the 417 patients (327 men and 90 women; median age, 59 years), 390 were categorized into group 1 and 27 were categorized into group 2. More women and older patients were observed in group 2 than in group 1 (11.1 vs 5.2%, P = 0.044, and 65 vs 59 years, P = 0.041, respectively). The median average daily UV was 3902 mL in group 1 and 3600 mL in group 2 (P = 0.021). A maximum BW loss > or 2.1 kg was noted in 4.4% of patients in group 1 and 18.5% of patients in group 2 (P = 0.006). Furosemide was used in 206 (49.4%) patients. The median total dose of furosemide in groups 1 and 2 were 0 mg and 26 mg, respectively (P = 0.024). A multivariate analysis showed that a maximum BW loss > or = 2.1 kg and the total furosemide dose were significantly associated with group category. In conclusion, BW loss and total furosemide dose were associated with cisplatin nephrotoxicity.

Background: The efficacy of chemotherapy in patients with large cell neuroendocrine carcinoma of the lung (LCNEC) remains unclear., Methods: Of 42 consecutive patients with LCNEC, 22 with measurable disease receiving chemotherapy were enrolled as the subjects of this study. The clinical characteristics and objective responses to chemotherapy in these patients were analysed retrospectively., Results: The distribution of the disease stage in the patients consisting of 21 males and one female (median age: 67 years; range: 47-78 years) was as follows: stage IIB (n = 1), stage IIIA (n = 1), stage IIIB (n = 5), stage IV (n = 8), and post-operative recurrence (n = 7). Chemotherapy consisted of cisplatin and irinotecan (n = 9), a platinum agent and paclitaxel (n = 6), paclitaxel alone (n = 1), cisplatin and vinorelbine (n = 1), cisplatin and docetaxel (n = 1), and a platinum and etoposide (n = 4). The objective response rate in the 22 patients was 59.1% (95% CI, 38.1-80.1). An objective response was obtained in five of the nine patients receiving irinotecan and five of the seven patients receiving paclitaxel. The progression-free survival, median overall survival and 1-year survival rates were 4.1 months (95% CI, 3.1-5.1), 10.3 months (95% CI, 5.8-14.8) and 43.0% (95% CI, 20.7-65.3), respectively. The median overall survival of the patients treated with irinotecan or paclitaxel was 10.3 months (95% CI, 0-21.8), and the 1-year survival rate of these patients was 47.6% (95% CI, 20.4-74.8)., Conclusion: Our results suggest that irinotecan and paclitaxel may be active against LCNEC.

Background: To evaluate the feasibility and efficacy of docetaxel consolidation therapy after concurrent chemoradiotherapy for unresectable stage III non-small cell lung cancer (NSCLC)., Patients and Methods: The eligibility criteria included unresectable stage III NSCLC, no previous treatment, age between 20 and 74 years, and performance status 0 or 1. Treatment consisted of cisplatin (80 mg/m2 on days 1, 29, and 57), vinorelbine (20 mg/m2 on days 1, 8, 29, 36, 57, and 64), and thoracic radiotherapy (TRT) (60 Gy/30 fractions over 6 weeks starting on day 2), followed by consolidation docetaxel (60 mg/m2 every 3 to 4 weeks for three cycles)., Results: Of 97 patients who were enrolled in this study between 2001 and 2003, 93 (76 males and 17 females with a median age of 60) could be evaluated. Chemoradiotherapy was well tolerated; three cycles of chemotherapy and 60 Gy of TRT were administered in 80 (86%) and 87 (94%) patients, respectively. Grade 3 or 4 neutropenia, esophagitis, and pneumonitis developed in 62, 11, and 3 patients, respectively. Docetaxel consolidation was administered in 59 (63%) patients, but three cycles were completed in only 34 (37%) patients. The most common reason for discontinuation was pneumonitis, which developed in 14 (24%) of the 59 patients. During consolidation therapy, grade 3 or 4 neutropenia, esophagitis, and pneumonitis developed in 51, 2, and 4 patients, respectively. A total of four patients died of pneumonitis. We calculated a V20 (the percent volume of the normal lung receiving 20 Gy or more) on a dose-volume histogram in 25 patients. Of these, five patients developed grade 3 or more severe radiation pneumonitis. A median V20 for these five patients was 35% (range, 26-40%), whereas the median V20 for the remaining 20 patients was 30% (range, 17-35%) (p = 0.035 by a Mann-Whitney test). The response rate was 81.7% (95% confidence interval [CI], 72.7-88.0%), with 5 complete and 71 partial responses. The median progression-free survival was 12.8 (CI, 10.2-15.4) months, and median survival was 30.4 (CI, 24.5-36.3) months. The 1-, 2-, and 3-year survival rates were 80.7, 60.2, and 42.6%, respectively., Conclusion: This regimen produced promising overall survival in patients with stage III NSCLC, but the vast majority of patients could not continue with the docetaxel consolidation because of toxicity.

Purpose: Following phase I studies of docetaxel and cisplatin in patients with non-small-cell lung cancer, the recommended doses of docetaxel were different for elderly (> or = 75 years) and non-elderly (< 75 years) patients. To elucidate the mechanism of the difference, the pharmacokinetics of docetaxel and cisplatin were investigated in two phase II studies separately conducted in elderly and non-elderly patients., Patients and Methods: Twenty-seven elderly and 25 non-elderly patients were treated with three weekly administrations of docetaxel and cisplatin every 4 weeks. Doses of docetaxel were 20 and 35 mg/m(2) for elderly and non-elderly patients, respectively. All patients received 25 mg/m(2) of cisplatin. The pharmacokinetics and pharmacodynamics of docetaxel and cisplatin were compared in elderly and non-elderly patients., Results: There were no differences in pharmacokinetics of docetaxel or cisplatin between elderly versus non-elderly patients with regard to clearance and volume of distribution. In the pharmacodynamic analysis, neutropenia was positively correlated with the area under the concentration-time curve for docetaxel but not for cisplatin. In evaluating the relationship between neutropenia and the area under the concentration-time curve of docetaxel, elderly patients experienced greater neutropenia than those predicted by a pharmacodynamic model developed in non-elderly patients; the residual for prediction of the percent change in neutrophil count was -11.2% (95% CI, -21.8 to -0.5%)., Conclusion: The pharmacokinetics of docetaxel and unchanged cisplatin were not different between elderly and non-elderly patients. The elderly patients were more sensitive to docetaxel exposure than the non-elderly patients, resulting in the different recommended doses for the phase II studies.

Purpose: To evaluate the efficacy and toxicity of high-dose thoracic radiotherapy (TRT) alternating with chemotherapy (CH) for unresectable stage III non--small-cell lung cancer (NSCLC)., Patients and Methods: Forty-one patients received TRT with 1.5 Gy twice daily, 5 days a week, on weeks 1, 2, 5, 6, and 9, up to a total dose of 66 to 72 Gy, alternating with cisplatin 80 mg/m(2) on day 1 and vindesine 3 mg/m(2) on days 1 and 8, repeated every 4 weeks, for two or three courses beginning on week 3., Results: The median (range) total dose of TRT and number of CH courses were 72 Gy (16.5 to 72 Gy) and three (zero to three), respectively. Delay in TRT > or = 5 days was observed in 24 (75%) of 32 patients who completed the projected treatment, due to leukopenia in 12, esophagitis in seven, infection in two, and other causes in three patients. Partial responses were obtained in 36 patients (88%). The median survival time and 3- and 5-year survival rates were 18.4 months, 24%, and 10%, respectively. Grade 3 or 4 leukopenia and esophagitis developed in 32 and seven patients, respectively. Grade 3 or 4 late esophageal toxicity developed in two patients., Conclusion: Alternating high-dose TRT and CH for stage III NSCLC produced a high response rate with median and long-term survival comparable to prior trials utilizing standard approaches in this population. Acute and late esophageal toxicity was observed and interruption of TRT was required in most of the patients.

Background: Thymic carcinoma is a rare mediastinal neoplasm with poor prognosis. Although the clinical benefit of chemotherapy for thymic carcinoma is controversial, cisplatin-based chemotherapy with or without radiation therapy is ordinarily adopted in advanced cases. We evaluated the clinical outcome of platinum-based chemotherapy with or without radiation therapy in unresectable thymic carcinoma patients., Methods: Ten patients with unresectable thymic carcinoma were treated with platinum-based chemotherapy with or without radiation therapy in the National Cancer Center Hospital between 1989 and 1998. We reviewed the histological type, treatment, response and survival of these patients., Results: Four of the 10 patients responded to chemotherapy and both the median progression-free survival period and the median response duration were 6.0 months. The median survival time was 11.0 months. There was no relationship between histological classification and prognosis., Conclusions: Platinum-based chemotherapy with or without thoracic radiation is, regardless of tumor histology, marginally effective in advanced thymic carcinoma patients, giving only a modest tumor response rate and short response duration and survival.

Thirty-three patients with lung cancer receiving 80 mg m(-2) cisplatin were treated with high-dose dexamethasone (32 mg m(-2) on days 1-3, 16 mg m(-2) on day 4 and 8 mg m(-2) on day 5) combined with granisetron on day 1 and metoclopramide on days 2-5. Twenty-eight (85%) patients had no nausea or vomiting on day 1, and 16 (48%) achieved total control on days 1-5 with acceptable toxicity. High-dose dexamethasone for cisplatin-induced delayed emesis should be further evaluated in a phase III trial.

We studied the role of dexamethasone (DEX) administered on day 1 in controlling cisplatin-induced delayed emesis. Forty patients were randomly allocated to receive either granisetron (GRN) and DEX on day 1, or the same dose of GRN alone. On days 2-5, all the patients received metoclopramide and DEX. They were crossed over to the other antiemetic regimen with their second course of chemotherapy. Thirty-one patients were evaluable for efficacy. The mean visual analogue scale scores for nausea on days 1 and 2 were 9.1 and 18.8 mm for GRN and DEX, and 16.3 and 28.5 mm for GRN alone, respectively (P<0.05 on day 2). The mean numbers of emetic episodes on days 1-3 were 0.036, 0.46 and 0.36 for GRN and DEX, and 0.39, 0.89 and 0.57 for GRN alone, respectively (P<0.01 on day 1). Hiccups and restlessness were noted in 38% and 33% of cycles, respectively. Addition of DEX to GRN on day 1 thus enhanced the control of delayed emesis.

Patients with previously untreated extensive-disease small-cell lung cancer were treated with irinotecan 60 mg m(-2) on days 1 and 8 and cisplatin 60 mg m(-2) on day 1 with (n=55) or without (n=54) etoposide 50 mg m(-2) on days 1-3 with granulocyte colony-stimulating factor support repeated every 3 weeks for four cycles. The triplet regimen was too toxic to be considered for further studies. [ABSTRACT FROM AUTHOR]

Irinotecan (CPT-11) has been shown to exhibit excellent antitumour activity against small-cell lung cancer (SCLC). A multi-institutional phase II study was therefore conducted to evaluate the efficacy and toxicity of CPT-11 combined with cisplatin (CDDP) and etoposide (ETOP) (PEI regimen) for the treatment of sensitive relapsed SCLC. Patients who responded to first-line chemotherapy but relapsed more than 8 weeks after the completion of first-line therapy (n=40) were treated using the PEI regimen, which consisted of CDDP (25 mg m(-2)) weekly for 9 weeks, ETOP (60 mg m(-2)) for 3 days on weeks 1, 3, 5, 7, and 9, and CPT-11 (90 mg m(-2)) on weeks 2, 4, 6, and 8 with granulocyte colony-stimulating factor support. Five complete responses and 26 partial responses were observed, and the overall response rate was 78% (95% confidence interval 61.5-89.2%). The median survival time was 11.8 months, and the estimated 1-year survival rate was 49%. Grade 3/4 leucocytopenia, neutropenia, and thrombocytopenia were observed in 55, 73, and 33% of the patients, respectively. Nonhaematological toxicities were mild and transient in all patients. In conclusion, the PEI regimen is considered to be highly active and well tolerated for the treatment of sensitive relapsed SCLC. [ABSTRACT FROM AUTHOR]

Combinations of cisplatin-irinotecan and cisplatin-etoposide are active and well tolerated in patients with both small-cell lung cancer (SCLC) and nonsmall-cell lung cancer (NSCLC). To define the recommended dose for phase II trials of irinotecan combined with cisplatin and etoposide in chemonaive patients with stage IV disease, 56 patients (11 having SCLC and 45 NSCLC) received cisplatin 25 mg m(-2) weekly for 9 weeks, etoposide 60 mg m(-2) for 3 days on weeks 1, 3, 5, 7 and 9, and irinotecan 20-100 mg m(-2) (levels 1-8) on weeks 2, 4, 6 and 8, together with a prophylactical granulocyte colony-stimulating factor support (50 microg m(-2) on days 4-7 on weeks 1, 3, 5, 7 and 9, and on days 2-7 on weeks 2, 4, 6 and 8). Grade 3-4 leukocytopenia, neutropenia and thrombocytopenia were noted in 20 (36%), 28 (50%) and nine (16%) patients, respectively. Grade 3 diarrhoea, grade 3 cardiac toxicity, and grade 4 transaminase elevation developed in one (1.8%) patient each. Totally, four of 56 patients were removed from the study because of toxicity and recovered, and two other patients died in situations where drug toxicity might contribute to their death. Dose-limiting toxicity was noted in less than one-third of patients at dose levels 1-7, but in all patients at dose level 8. Thus, the recommended dose was determined to be level 7 (irinotecan 90 mg m(-2)). The response rates for SCLC and NSCLC were 91% (10/11) and 38% (17/45), respectively. The median survival time and 1-year survival rate were 11.9 months and 46% for SCLC and 10.1 months and 40% for NSCLC, respectively. This regimen was considered to be feasible and promising for the treatment of stage IV SCLC and NSCLC. [ABSTRACT FROM AUTHOR]