Yasuhiro Yamanaka

Efficacy of weekly paclitaxel in patients with docetaxel-resistant metastatic breast cancer.

SummaryBackground. Partial cross-resistance to paclitaxel and docetaxel has been demonstrated in pre-clinical studies. Patients and methods. We retrospectively evaluated the efficacy of weekly paclitaxel 80 mg/m2 in 82 patients with docetaxel-resisitant metastatic breast cancer. Docetaxel resistance was classified into primary resistance, defined as progressive disease while receiving docetaxel, and secondary resistance, defined as progression after achievement of a documented clinical response to docetaxel. Secondary resistance was subclassified according to the interval between the final infusion of docetaxel and the start of weekly paclitaxel into: (1) short interval, ≦120 days, and (2) long interval, >120 days. Results. The response rate of the 82 patients was 19.5% (95% confidence interval, 10.8–27.9%). The response rate according to the docetaxel resistance category was: primary resistance (n=24), 8.3%; secondary resistance (n=58), 24.1% (short interval [n=39], 17.9%, and long interval, [n=19], 36.8%). The differences in response rates among the three categories were statistically significant (p=0.0247, Cochran–Mantel–Haenszel test). The interval between from the final docetaxel infusion and disease progression were predictors for response of weekly paclitaxel. Conclusion. Weekly paclitaxel is modestly effective and safe in docetaxel-resistant metastatic breast cancer patients. However, weekly paclitaxel should not be recommended for primary resistance patients with docetaxel.

A Microarray-Based Gene Expression Analysis to Identify Diagnostic Biomarkers for Unknown Primary Cancer

Background The biological basis for cancer of unknown primary (CUP) at the molecular level remains largely unknown, with no evidence of whether a common biological entity exists. Here, we assessed the possibility of identifying a common diagnostic biomarker for CUP using a microarray gene expression analysis. Methods Tumor mRNA samples from 60 patients with CUP were analyzed using the Affymetrix U133A Plus 2.0 GeneChip and were normalized by asinh (hyperbolic arc sine) transformation to construct a mean gene-expression profile specific to CUP. A gene-expression profile specific to non-CUP group was constructed using publicly available raw microarray datasets. The t-tests were performed to compare the CUP with non-CUP groups and the top 59 CUP specific genes with the highest fold change were selected (p-value<0.001). Results Among the 44 genes that were up-regulated in the CUP group, 6 genes for ribosomal proteins were identified. Two of these genes (RPS7 and RPL11) are known to be involved in the Mdm2–p53 pathway. We also identified several genes related to metastasis and apoptosis, suggesting a biological attribute of CUP. Conclusions The protein products of the up-regulated and down-regulated genes identified in this study may be clinically useful as unique biomarkers for CUP.

Pharmacokinetics, safety, and efficacy of FOLFIRI plus bevacizumab in Japanese colorectal cancer patients with UGT1A1 gene polymorphisms

Previous reports of the influence of UGT1A1 gene polymorphisms on the pharmacokinetics of irinotecan metabolism have not assessed Asian patients treated with FOLFIRI plus bevacizumab for advanced and recurrent colorectal cancer. Twenty‐one Japanese colorectal cancer patients received intravenous FOLFIRI (bolus irinotecan, folinic acid, and fluorouracil followed by 46‐hour fluorouracil infusion) followed by bevacizumab (5 mg/kg) in Cycle 1. In Cycle 2, patients received bevacizumab followed by FOLFIRI. The regimen was in 2‐week cycles. The area under‐the‐curves ratio (AUC0–last) (Cycle 2/Cycle 1) was determined from plasma concentrations of irinotecan and metabolites (SN‐38, SN‐38G). Safety, efficacy, and drug–drug interactions were analyzed. Median observation period was 7.8 months; median number of cycles 15. Drug–drug interactions were evaluated in eight patients without irinotecan dose reduction. Mean AUC0–last ratios (with/without bevacizumab) of irinotecan, SN‐38, and SN‐38G were 0.959, 0.927, and 0.931 respectively. Response rate was 65%; median progression‐free survival 16.4 months. Response occurred in four patients with, and nine without, UGT1A1 polymorphism. No significant differences occurred between efficacy, safety, or polymorphism status. This cohort showed no differences in safety or efficacy compared to previous reports. Bevacizumab did not affect the pharmacokinetics of irinotecan and its metabolites, irrespective of UGT1A1 polymorphism status.

Effectiveness of MAID Therapy against Metastatic Malignant Phyllodes Tumors and Stromal Sarcoma of the Breast

Malignant phyllodes tumors and stromal sarcoma are rare malignancies of the breast. The efficacy of systemic chemotherapy against metastatic malignant phyllodes tumors and metastatic stromal sarcoma remains unknown. Patients and Methods: We retrospectively analyzed 8 patients with metastatic malignant phyllodes tumors or stromal sarcoma, who were treated with MAID (mesna, doxorubicin, ifosfamide, dacarbazine) chemotherapy. The MAID therapy was administered intravenously every 4 weeks as follows: mesna 1,500 mg/m2/day, days 1-4; doxorubicin 20 mg/m2/day, days 1-3; dacarbazine 300 mg/m2/day, days 1-3; ifosfamide 2,500 mg/m2/day, days 1-3. Results: Although complete response was not achieved in any of the patients, 4 of the 8 patients showed partial response. The median time to disease progression was 74 days, and the overall median survival was 148 days. Grade 3 or more severe hematological toxicity was encountered in all patients. Conclusion: MAID therapy for metastatic malignant phyllodes tumors and stromal sarcoma was moderately effective in terms of tumor reduction. However, the treatment was associated with severe toxicity.

Weekly paclitaxel in patients with CAP-resistant advanced or recurrent endometrial carcinoma: a series of four patients

We evaluated the feasibility of weekly paclitaxel in patients with recurrent or advanced endometrial carcinoma who had failed treatment with cyclophosphamide, doxorubicin, and cisplatin (CAP). We treated four patients with CAP-resistant recurrent or advanced endometrialcarcinoma with paclitaxel. Paclitaxel (80 mg/m2; infused over 1 h) was administered weekly for a maximum of 18 weeks, unless disease progression or intractable toxicity developed. A complete response was observed in onepatient and a partial response in two patients. Disease progression was found in one patient. Two patients developed grade 3 leukopenia or neutropenia. Neurotoxicity for all patients was within grade 1. Outpatient treatment with weekly paclitaxel was well-tolerated and feasible for patients with CAP-resistant recurrent or advanced endometrial carcinoma. Further trials to confirm the efficacy and toxicity of weekly paclitaxel are warranted.