Introduction Sunitinib is an approved treatment for metastatic renal cell carcinoma (RCC). A prospective clinical trial was conducted to evaluate the safety and clinical response to sunitinib administered prior to nephrectomy in patients with localized or metastatic clear cell RCC. Methods Patients with biopsy-proven clear cell RCC were enrolled and treated with sunitinib malate, 37.5 mg daily, for 3 months prior to nephrectomy. The primary endpoints was safety. Results Twenty patients were enrolled during an 18 month period. The most common toxicities were GI symptoms and hematologic. Grade 3 toxicities occurred in 6 patients (30%). No surgical complications were attributable to treatment with sunitinib. Seventeen of the 20 patients (85%) experienced a decrease in tumor diameter (mean change −11.8%, range −27% to 11%) and cross-sectional area (mean change −27.9%, range −43% to 23%). Enhancement on contrast-enhanced CT decreased in 15 patients, with a mean change in Hounsfield units of −22% (range −74% to 29%). Following a decrease in tumor size, 8 patients with cT1b tumors underwent laparoscopic partial nephrectomy. Surgical parameters such as blood loss, transfusion rate, operative time, and complications were similar to those who underwent surgery during the study period and were not enrolled on the trial. Conclusions Preoperative treatment with sunitinib is safe. Sunitinib decreased the size of primary RCC in 17 of 20 patients, and future trials can be considered to evaluate the use of neoadjuvant sunitinib to maximize nephron-sparing and decrease recurrence risk for high-risk, localized RCC.
OXP 85 mg/m(2) on days 1, 15, and 29 administered with PI 5-FU and XRT is safe, tolerable, and seems effective against primary EC. The role of OXP in multimodality regimens against EC deserves further evaluation.
Purpose We conducted a phase I study to determine the maximum tolerated dose (MTD) of vorinostat in combination with fixed doses of 5-Fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX). Experimental Design Vorinostat was given PO BID for 1 week every 2 weeks. FOLFOX was given on days 4 and 5 of vorinostat. The vorinostat starting dose was 100 mg BID. Escalation occurred in cohorts of 3–6 patients. Pharmacokinetics of vorinostat, 5-FU, and oxaliplatin were studied. Results Twenty-one patients were enrolled. Thrombocytopenia, neutropenia, gastrointestinal toxicities, and fatigue increased in frequency and severity at higher dose-levels (DL) of vorinostat. Two of 4 evaluable patients at DL 4 (vorinostat 400 mg PO BID) developed dose-limiting fatigue. One of 10 evaluable patients at DL3 (vorinostat 300 mg PO BID) had dose-limiting fatigue, anorexia, and dehydration. There were significant relationships between vorinostat dose and AUC on days 1 and 5 (Pearson, < 0.001). Vorinostat AUC increased (p = 0.005) and clearance decreased (p = 0.003) on day 5 compared to day 1. The median Cmax of 5-FU at each DL increased significantly with increasing doses of vorinostat, suggesting a pharmacokinetic interaction between 5-FU and vorinostat. Vorinostat-induced thymidylate synthase modulation was not consistent; only two of six patients had a decrease in intra-tumoral thymidylate synthase expression by RT-PCR. Conclusions The MTD of vorinostat in combination with FOLFOX is 300 mg PO BID x 1 week every two weeks. Alternative vorinostat dosing schedules may be needed for optimal down-regulation of thymidylate synthase expression.
Background: The impact of adjuvant chemotherapy on hepatic function and portal hypertension in patients with stages II–III colon cancer has not been previously described. We conducted a retrospective study to assess the effects of adjuvant FOLFOX chemotherapy on the splenic index (SI) as a surrogate marker for portal hypertension. Methods: Stage II–IIIcolorectal cancer patients treated with adjuvant FOLFOX or fluorouracil/leucovorin (5-FU/LV) at Roswell Park Cancer Institute between2002 and 2006were identified. Computerizedtomography (CT) scans obtained prior to and at completion of chemotherapy, and every 6 months thereafter were reviewed. Splenic size was evaluated using the SI (SI = length × width × height of the spleen). Results: 40 patientswere identified in the FOLFOX group and 23 in the 5-FU/LV group. After 6 months of adjuvant chemotherapy, the mean increase in SI was 45.7 and 16.3% in the FOLFOX and 5-FU/LV groups, respectively (p = 0.0069). SI increased by >100% in 6 patients (15%) in the FOLFOX group versus none in the 5-FU/LV group (p = 0.16). The mean SI at completion of adjuvant chemotherapy was significantly higher in the FOLFOX group than in the 5-FU/LV group (p = 0.007). The mean SI decreased steadily over a period of 2 years after discontinuation of FOLFOX, suggesting potential reversibility of oxaliplatin-induced hepatic injury in this setting. Conclusions: Adjuvant FOLFOX significantly increases the SI in patients with resected colorectal cancer in comparison to adjuvant 5-FU/LV. The increase in SI may be a marker of oxaliplatin-induced hepatic injury and should be investigated further in prospective longitudinal studies of oxaliplatin-based adjuvant chemotherapy.
Purpose: We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat × 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks.Experimental Design: Vorinostat doses were escalated in a standard 3 × 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m 2 i.v. over 2 hours followed by FU 400 mg/m 2 i.v. bolus and 2,400 mg/m 2 over 46 hours (sLV5FU2).Results: Forty-three patients were enrolled. Grade 3 fatigue, and hand and foot syndrome were the dose-limiting toxicities (DLT) at the 2,000 mg vorinostat once-daily dose level. Grade 3 fatigue and mucositis were DLTs at the 800 mg vorinostat twice-daily dose level. None of six patients at the 1,700 mg once daily or six patients at the 600 mg twice daily dose levels had a DLT; those dose levels represent the MTD. Twenty-one of 38 patients with FU-refractory colorectal cancer had stable disease, and one had a partial response. Vorinostat maximum serum concentrations at the MTD exceeded concentrations associated with thymidylate synthase downregulation in vitro. No pharmacokinetic interactions were noted between vorinostat and FU.
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