Seisuke Kumagai

Improvement of intraperitoneal chemotherapy for rat ovarian cancer using cisplatin-containing microspheres

Microspheres consisting of L‐lactic acid and glycolic acid copolymer containing cisplatin (CDDP‐PLGA) were developed to improve the delivery of cisplatin. We evaluated the effects of intraperitoneal administration of cisplatin prepared as CDDP‐PLGA in rats with ovarian cancer. The toxicity, platinum distribution, and therapeutic effects of CDDP‐PLGA were evaluated as compared with those in the case of cisplatin aqueous solution. The LD50 of CDDP‐PLGA was almost four‐fold higher than that of cisplatin aqueous solution. CDDP‐PLGA released cisplatin slowly and achieved a higher concentration in the peritoneal cavity and in peritoneal tumors for prolonged periods, while the tissue concentration of cisplatin was reduced elsewhere in the body, as compared with the case of cisplatin aqueous solution. The survival of rats with peritoneal carcinomatosis was increased by this delivery system relative to cisplatin aqueous solution. CDDP‐PLGA thus allows a higher dose to be given without increasing systemic toxicity, enhancing the therapeutic effect of cisplatin.

Phase II clinical study of the combination chemotherapy regimen of irinotecan plus oral etoposide for the treatment of recurrent ovarian cancer (Tohoku Gynecologic Cancer Unit 101 Group Study).

Objective: To evaluate the efficacy and safety of the combination chemotherapy regimen of irinotecan plus oral etoposide for the treatment of patients with recurrent ovarian cancer after previous treatment with platinum and taxane agents. Patients and Methods: A total of 42 patients with recurrent ovarian cancer who had an evaluable lesion and provided informed consent for participation in the present study were analyzed. Irinotecan was administered intravenously at a dose of 60 mg/m2 on days 1 and 15. Etoposide was administered orally at a daily dose of 50 mg/body weight from days 1 to 21. A 28-day period comprised one cycle. The tumor response, adverse events, progression-free survival, and overall survival were examined. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors and the serum CA125 levels (Gynecologic Cancer Intergroup criteria). Adverse events were assessed according to the NCI-CTCAE (version 3.0). Results: Partial response was observed in 21 patients, stable disease in 14 patients, and progressive disease in 7 patients. The response rate was 50.0%, and the clinical benefit (partial response + stable disease) rate was 83.3%. Hematological toxicities of at least grade 3 severity included leukopenia in 21 patients (50.0%), neutropenia in 22 patients (52.4%), thrombocytopenia in 1 patient (2.4%), anemia in 9 patients (21.4%), and febrile neutropenia in 3 patients (7.1%). Nonhematological toxicities of at least grade 3 severity included queasy feeling in 5 patients (11.9%), vomiting in 3 patients (7.1%), and diarrhea in 2 patients (4.8%). Acute myeloid leukemia occurred in one patient (2.4%). Conclusions: It is suggested that combination chemotherapy with irinotecan plus oral etoposide offers significant clinical benefit to patients with recurrent ovarian cancer previously treated with platinum and taxane agents.

Tako-Tsubo Cardiomyopathy Caused Immediately following Cesarean Section Delivery of Triplets: A Case Report

The name ‘tako-tsubo’ cardiomyopathy was initially used to describe a unique ‘short-neck round-flask’-shaped form of left ventricular apical ballooning, resembling a Japanese tako-tsubo, a jar (tsubo) used for capturing octopus (tako). Tako-tsubo cardiomyopathy exhibits acute onset, transient left ventricular apical wall motion abnormalities with chest symptoms and minimal myocardial enzymatic release, mimicking acute myocardial infarction in patients without angiographic stenosis on coronary angiography. There have been few case reports on tako-tsubo cardiomyopathy, and this disorder is especially rare in pregnant women. A 30-year-old woman who was pregnant with triplets, and had been treated with ritodrine hydrochloride for 12 weeks for threatened premature delivery, underwent cesarean section with spinal anesthesia at 30 weeks’ gestation. Three hours later, she complained of acute chest pain, dyspnea and episodes of unconsciousness. She was transferred to the intensive care unit and intubated for ventilatory support. We diagnosed heart failure due to tako-tsubo cardiomyopathy based on heart ultrasonography, blood tests, chest X-ray, electrocardiogram and myocardial scintigraphy. She was extubated from the ventilator after 3 days of catecholamine, furosemide and carperitide administration. She was discharged from the hospital on day 53 without symptoms.

Does severe anemia caused by dose-dense paclitaxel-carboplatin combination therapy have an effect on the survival of patients with epithelial ovarian cancer? Retrospective analysis of the Japanese gynecologic oncology group 3016 trial

Introduction To evaluate the incidence of anemia in patients with epithelial ovarian cancer receiving paclitaxel-carboplatin combination therapy (TC) using data from the Japanese Gynecologic Oncology Group (JGOG) 3016 trial, and to examine the effect of severe anemia on survival during dose-dense TC. Methods Retrospective analysis was conducted in patients enrolled in the JGOG 3016 trial who underwent at least one cycle of the protocol therapy (n = 622). Hemoglobin values at enrollment and during each cycle of TC were collected. One-to-one matching was performed between patients with and patients without grade 3/4 anemia during TC (anemia and nonanemia groups) to adjust the baseline characteristics of the patients. The cumulative survival curve and median progression-free survival were estimated using the Kaplan-Meier method. Results Grades 2 to 4 anemia was observed in 19.8% of patients before first-line TC. The incidence of grade 3/4 anemia rapidly increased to 56.1% after the fourth cycle of dose-dense TC. After matching, the median progression-free survival in the anemia (hemoglobin <8.0 g/dL) and nonanemia (hemoglobin >8.0 g/dL) groups was 777 and 1100 days, respectively (P = 0.3493) for patients receiving dose-dense TC. The median progression-free survival in patients receiving conventional TC was similar between the 2 groups. Conclusions The difference in progression-free survival between patients with epithelial ovarian cancer with and those without severe anemia during TC was not statistically significant, but for patients receiving dose-dense TC, severe anemia seems to have prognostic relevance. Prospective trials are needed to investigate whether the optimal management of chemotherapy-induced anemia, including appropriate use of erythropoiesis-stimulating agents, would further improve the survival of patients with ovarian cancer receiving dose-dense TC.

Weekly 1-h paclitaxel infusion in patients with recurrent endometrial cancer: a preliminary study

Abstract.Background: The aim of this study was to evaluate the toxicity and efficacy of weekly paclitaxel in patients with recurrent endometrial cancer. Methods: Nine patients with recurrent endometrial cancer who had previously received chemotherapy or radiotherapy participated in the study, between May 1999 and August 2001. Paclitaxel was given at a dose of 70 mg/m2 as a 1-h infusion every week for at least 20 consecutive weeks unless lesions became progressive. Intravenous dexamethasone and cimetidine and oral diphenhydramine were administered 30 min before paclitaxel infusion. Results: The nine patients received a total of 149 cycles of therapy. No hypersensitivity reactions were elicited. Grade 3 leukopenia, neutropenia, and anemia occurred in 22%, 33%, and 33% of the patients, respectively. Granulocyte colony-stimulating factor was required for two patients and no patients experienced febrile neutropenia. Neurotoxicity was commonly observed. Grade 1 peripheral neuropathy and myalgias were observed in 78% and 11% of the patients, respectively. No grade 3 or higher nonhematological toxicities were observed. Partial responses were seen in six of the nine patients (67%). The median progression-free interval was 8 months (range, 0–12 months) and the median overall survival was 10 months (range, 4–24 months). Conclusion: Weekly 1-h paclitaxel administration is considered safe and effective as a salvage therapy for recurrent endometrial cancer, with this schedule and delivery making its use more convenient and easier in the outpatient setting. The current results support further evaluation.

Neoadjuvant Chemotherapy Using Platinum-Based Regimens for Stage Ib2-II Squamous Cell Carcinoma and Non-Squamous Cell Carcinoma of the Cervix

The methods used for treating stage Ib2-IIb cervical cancers, with a bulky mass, differ between Japan and Western countries. In Western countries, concurrent chemoradiation (CCRT) has been recommended as a standard therapy for such tumors based on the results of multiple large-scale randomized trials and meta-analyses (Morris et al., 1999; Rose et al., 1999; Whitney et al., 1999; Pearcey et al., 2002; Eifel et al. 2004; Green et al. 2001; Lukka et al., 2002). In Japan, Korea, Italy and some other countries, the neoadjuvant chemotherapy (NAC) approach has been extensively introduced to clinical practice (Sugiyama et al., 1999). NAC is considered to be clinically significant in 2 respects: it is expected to improve the radicality and safety of surgery by reducing tumor size; and it is expected to exert systemic effects, i.e., effects on lymph node occult micrometastases, etc. A disadvantage of NAC is delayed initiation of the primary treatment, suggesting the necessity of completing NAC as an auxiliary therapy within a short period of time. Therefore, we may find that NAC is valuable if it can exert efficacy rapidly with high platinum dose intensity (DI), assuring that subsequent primary surgical therapy can be performed as soon as possible. At our facility, a platinum-based regimen has been used for NAC in patients with cervical cancer. Herein, we review the efficacy and safety data on NAC for squamous cell carcinoma of the uterine cervix. We previously reported our interim data and now present the results of an ongoing pilot study on the efficacy and safety of NAC for non-squamous cell carcinoma of the uterine cervix.

Are platinum agents, paclitaxel and irinotecan effective for clear cell carcinoma of the ovary? DNA damage detected with γH2AX induced by anticancer agents

ObjectivesDifferences in the incidences and types of DNA damage induced by antitumor agents for clear cell carcinoma (CCC) were determined in 2 ovarian CCC cell lines using γH2AX.Material and methodsThe antitumor activity of anticancer agents, CDDP, CBDCA, PTX and SN-38, was examined using ovarian clear cell carcinoma cultured cell lines (OVISE and RMG-I). After culture, each cell line was treated with each anticancer agent, the cells were collected, fixed, and then reacted with the anti-γH2AX antibody. γH2AX and nuclear DNA were then simultaneously detected by flow cytometry using FITC and propidium iodide, respectively, to determine γH2AX in each cell cycle phase.ResultsAfter administration of CDDP, DNA damage was frequent in S-phase cells, while cell-cycle arrest occurred in the G1 and G2/M phases and γH2AX did not increase in CDDP-resistant cells. Sensitivities to CDDP and CBDCA differed between the two cell lines. The antitumor effect of PTX is induced by G2/M arrest, and combination treatment with CBDCA, inducing DNA damage in G2/M-phase cells, might be effective.ConclusionsThis is the first study in Japan to evaluate the antitumor activity of anticancer agents by focusing on the relationship between the cell cycle and DNA damage using γH2AX as an indicator. The immunocytochemical method used in this study detects γH2AX, which indicates DNA damage even at very low concentrations and with high sensitivity. Therefore, a promising method of easily and rapidly identifying agents potentially effective against CCC.

Pegylated Liposomal Doxorubicin for Advanced Ovarian Cancer in Women who are Refractory to Both Platinum- and Paclitaxel-Based Chemotherapy Regimens

Pegylated liposomal doxorubicin (PLD) is doxorubicin HCl encapsulated in long-circulating STEALTH® liposomes (Doxil®). PLD achieves good response rates and many patients maintain long-lasting stable disease (SD), which is one of the advantages. In addition, the clinical benefit is high in platinum-resistant disease, and PLD is thus considered to be the first option. PLD is associated with a number of adverse events, but these events are mild to moderate. PLD is safer for heavily pretreated patients than topotecan and gemcitabine due to mild bone-marrow toxicity, but that nonhematotoxity, such as PPE, stomatitis, mucositis, and other cutaneous reactions were the most common side effects attributable to PLD. Based on a review of previous studies, there are no differences in efficacy between 50 and 40 mg/m2 of PLD, therefore, a dose of 40 mg/m2 is preferable in patients with platinum-resistant disease to reduce adverse events. The 1-hour infusion schedule every 4 weeks makes PLD easy to administer. A rational approach to combine PLD with other drugs should take the slow accumulation and delayed peak of PLD in tumors into consideration. When combined with other useful agents, the lower dose of PLD (30 to 35 mg/m2) with a 3-week schedule may reduce severe PPE and stomatitis with negligible effects on the level of DI and the therapeutic efficacy.

Emerging Pharmacotherapies in Ovarian Cancer: Focus on Pegylated Liposomal Doxorubicin

Pegylated liposomal doxorubicin (PLD) is doxorubicin encapsulated in MPEG-DSPE coated liposomes. PLD shows good response rates and maintains long-lasting stable disease (SD) in patients with recurrent ovarian cancer, and its clinical benefit is also high in platinum-resistant disease. PLD is considered the first option for platinum-resistant disease. A number of adverse events are associated with PLD. Hematotoxicity is generally milder than with topotecan or gemcitabine, especially in heavily pretreated patients, but PLD has characteristic nonhematotoxicities, such as palmar-plantar erythrodysesthesia (PPE), stomatitis, mucositis, and other cutaneous reactions. As for platinum-sensitive disease, non-inferiority of PLD-carboplatin combination in terms of progression-free survival (PFS) and tolerance, but with different toxicity, compared to paclitaxel-carboplatin was reported. However, it may be too early to judge the utility of PLD in combination with other agents because only few studies have been conducted and provided results to evaluate the efficacy of these. Further prospective studies are necessary.