河田 健司

Purpose A phase 1 study of pazopanib alone or in combination with lapatinib was conducted to assess the safety, tolerability, and pharmacokinetics of these oral tyrosine kinase inhibitors in Japanese patients with solid tumors. Methods In part A (monotherapy), 7 patients initially received pazopanib 800 mg/day, the recommended dose for non-Japanese patients. Then, 3 patients received pazopanib 400 mg/day on day 1 followed by 800 mg/day from day 2 onward. Three other patients received pazopanib 1,000 mg/day. In part B (combination therapy), 17 patients received pazopanib plus lapatinib (pazopanib/lapatinib) at once-daily doses of 400/1,000 mg (4 patients), 800/1,000 mg (3 patients), 400/1,500 mg (3 patients), and then 600/1,250 mg (7 patients). Results T here was no dose-limiting toxicity during the study. In part A, most drug-related adverse events were grade 2 or lower, including neutropenia/neutrophil count decreased, thrombocytopenia/platelet count decreased, diarrhea, hypertension, aspartate aminotransferase increased, and lipase increased. In part B, rash, decreased appetite, and serum thyroid-stimulating hormone increased also occurred. In all dose groups, the plasma concentrations after multiple doses of pazopanib exceeded the target trough concentration for inhibition of vascular endothelial growth factor receptor-2 activity (20 mu g/mL). Conclusions T he pharmacokinetic profiles of pazopanib and lapatinib in Japanese patients were not apparently different from those reported in non-Japanese patients. There were no consistent trends in pharmacokinetic drug interactions between pazopanib and lapatinib. Pazopanib monotherapy at 800 and 1,000 mg once daily and pazopanib plus lapatinib once daily at any doses studied were well tolerated in Japanese patients.

We report a case of primary small cell carcinoma (SCC) of the breast in a 59-year-old female. To the best of our knowledge, there are only 44 cases of this disease reported in the English literature. The patient also had regional nodal metastases, but no distant metastases. She underwent neoadjuvant chemotherapy according to a regimen of pulmonary SCC, and combination of cisplatin and etoposide (CDDP+VP16). The tumor partially responded to neoadjuvant chemotherapy. The treatment was followed by modified radical mastectomy and adjuvant chemotherapy, i.e., EC therapy (epirubicin and cyclophosphamide). She was also administered in total 50 Gy of radiation treatment to the chest wall. At this writing, the patient has evidenced no recurrence 36 months after her diagnosis.

Background: Corrected QT (QTc) interval prolongation can induce fatal arrhythmias such as torsade de pointes. Patients and methods: To assess the characteristics of QTc intervals and arrhythmias in women with early breast cancer who received FEC100 adjuvant chemotherapy, electrocardiograms (ECGs) were recorded before and after each chemotherapy. Associations between QTc interval prolongation and single nucleotide polymorphisms (SNPs) of potassium channel genes were also investigated. Results: A total of 131 ECG records were obtained in 34 patients who received 153 cycles of FEC100. QTc intervals could be measured in 127 records. There was a significant trend toward QTc interval prolongation after each treatment, persisting through four cycles of chemotherapy (P < 0.001). Median QTc interval prolongations were 13, 11, 18, and 14 ms in the first through fourth cycles of chemotherapy, respectively. QTc intervals differed significantly between cycles 1 and 4 before treatment as well as after treatment (P < 0.05). A single supraventricular premature contraction was noted in 3 (2.3%) of the 131 cycles in 2 (5.9%) of the 34 patients. There was no significant association between QTc interval prolongation and SNPs of potassium channel genes. Conclusion: This prospective study confirmed that FEC100 is associated with significant QTc interval prolongation in women with early breast cancer.

Objective: This pharmacokinetic study of S-1 was conducted in patients in whom glomerular filtration rate (GFR) was directly measured to explore the possibility of adjusting the S-1 dose on the basis of GFR in patients with normal or nearly normal renal function. Methods: S-1 was given to 12 patients twice daily for 28 consecutive days followed by 14 days of rest, repeated every 6 weeks. GFR was measured on the basis of inulin clearance (CLin) before the first day of treatment. Results: The area under the time-concentration curve (AUC) of 5-fluorouracil (5-FU) correlated with that of 5-chloro-2,4-dihydroxypyridine (CDHP, r = 0.750, p = 0.005). The AUC of CDHP correlated with the measured 24-hour creatinine clearance (CLcr) per subject (r = -0.620, p = 0.032), but not with the CLin (r = -0.356, p = 0.257). The AUC of 5-FU did not correlate with either the 24-hour CLcr per subject (r = -0.401, p = 0.187) or with the CLin (r = -0.300, p = 0.351). Conclusion: Dosage adjustment based on the GFR does not reduce individual variations in 5-FU concentrations among patients with normal or nearly normal renal function who receive S-1. Copyright (C) 2012 S. Karger AG, Basel

There is no established chemotherapy for anaplastic thyroid cancer. We conducted a prospective feasibility study at a single center to explore the antitumor activity of docetaxel against anaplastic thyroid cancer. Docetaxel was administered intravenously at a dose of 60 mg/m(2) over the course of 1 h every 3 weeks in patients with anaplastic thyroid cancer who had received no prior chemotherapy. A total of seven patients with anaplastic thyroid cancer were enrolled over the course of 30 months and received docetaxel. The treatment response was complete response in one patient, stable disease in two and progressive disease in four. The response rate was 14%, and the disease control rate (complete response plus stable disease) was 43%. The median time to progression was 6 weeks (range, 1-50). Toxicity was tolerable. Docetaxel could be an effective drug for the treatment of anaplastic thyroid cancer, with tolerable toxicity.

Background: To evaluate the role of FDG-PET in assessing anti-tumor efficacy of molecular targeted drugs, we prospectively performed FDG-PET and CT for response evaluation in patients treated with lapatinib, a dual inhibitor of ErbB1 and ErbB2 tyrosine kinases. Methods: Lapatinib was given orally once a day at doses ranging from 1200 to 1800 mg in a phase I study. CT and FDG-PET were performed before treatment, and at 1, 2 and 3 months after the initiation of the treatment and every 2 months thereafter. Results: A total of 29 FDG-PET examinations were performed in eight patients with various solid tumors and the metabolic activity in the tumor was evaluated as SUVmax. The best responses, as assessed by CT, were as follows; one partial response, four stable disease and three disease progression. The partial response was observed in a patient with trastuzumab-resistant breast cancer, whose SUVmax was decreased by 60% from baseline. In all of the four patients whose best response was stable disease, the SUVmax was decreased by 6-42% one month after the start of treatment. Prolonged stable disease (10 months) was observed in a patient with colon cancer, whose SUVmax was decreased by 42%. In the patient group with disease progression, SUVmax was increased in two out of three patients. Conclusions: FDG-PET detected decreases in the metabolic activity of the tumors in patients who experienced clinical benefits on treatment with lapatinib. Thus, FDG-PET may be useful for the evaluation of molecular targeted drugs, such as lapatinib.