Sunitinib and improved diabetes control.

There is increasing use of tyrosine kinase inhibitors as targeted therapy for several malignancies. Sunitinib is the first-line treatment for renal cancer and we report a case of a man receiving this medication who also had diabetes. When started on sunitinib he experienced improvement in his diabetes control with reduction in his insulin requirements, which later worsened when sunitinib was reduced or stopped. Several retrospective studies have been performed demonstrating this effect with sunitinib, but to date no prospective studies have been reported. Most tyrosine kinase inhibitors reduce blood glucose levels in diabetics, but some agents, such as nilotinib, may increase them. There is no consensus on the mechanism of action of sunitinib in reducing glucose levels. Several theories have been postulated, such as increased insulin secretion, increased insulin sensitivity, reduced loss of islet cells, the gastrointestinal side effects of sunitinib, or an interaction with other antihyperglycaemic agents.

Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) as neoadjuvant chemotherapy for patients with muscle-invasive transitional cell carcinoma of the bladder.

BACKGROUND: Meta-analysis data demonstrate a 5% absolute survival benefit for neoadjuvant chemotherapy (NAC) using cisplatin-based combination regimens in the radical treatment of muscle-invasive bladder cancer (MIBC). However, there are no randomized, controlled trial data on the optimum regimen. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) is a dose-intense regimen that has the potential to minimize delays to definitive, potentially curative therapy. A retrospective analysis is presented of the efficacy and toxicity of AMVAC as NAC in patients with MIBC and its impact on the patient pathway. METHODS: Eighty consecutive patients with MIBC were treated with AMVAC as NAC by 2 UK multidisciplinary uro-oncology teams. Three or 4 cycles of AMVAC (methotrexate 30 mg/m(2) , vinblastine 3 mg/m(2) , doxorubicin 30 mg/m(2) , and cisplatin 70 mg/m(2) ) were given at 2-week intervals, with granulocyte colony-stimulating factor support, prior to either radical surgery or radical radiotherapy. RESULTS: All planned cycles of chemotherapy were completed, without dose reduction or delay in 84% of patients. All 80 patients subsequently received their planned definitive therapy. Grade 3/4 toxicities were seen in 26% of the 42% of patients for whom toxicity data are available, including 12% grade 3/4 neutropenia. Pathological complete response to AMVAC was seen in 43% of 60 surgical patients. Objective radiological local response was seen in 83% of 57 evaluable patients. Two-year disease-free and overall survival were 65% and 77%, respectively. CONCLUSIONS: AMVAC is safe and appears to be a well-tolerated and effective NAC regimen for MIBC. It minimizes delays to definitive treatment and produces excellent pathological and radiological response rates. It is an appropriate comparator for future randomized trials.

A phase I, open-label, randomized crossover study to assess the effect of dosing of the MEK 1/2 inhibitor Selumetinib (AZD6244; ARRY-142866) in the presence and absence of food in patients with advanced solid tumors.

PURPOSE: This Phase I study assessed whether food influences the rate and extent of selumetinib absorption in patients with advanced solid malignancies and determined the safety, tolerability, and pharmacokinetic (PK) profile of selumetinib and its active metabolite N-desmethyl-selumetinib in fed and fasted states. METHODS: A single dose of 75 mg selumetinib was to be taken with food on Day 1 followed by a single dose of 75 mg after fasting for at least 10 h on Day 8, or vice versa, followed by twice daily dosing of 75 mg selumetinib from Day 10. Plasma concentrations and PK parameters were determined on Days 1 and 8. Patients could continue to receive selumetinib for as long as they benefitted from treatment. RESULTS: In total, 31 patients were randomized to receive selumetinib; 15 to fed/fasted sequence and 16 to fasted/fed sequence. Comprehensive PK sampling was performed on 11 and 10 patients, respectively. The geometric least-squares means of C(max) and AUC for selumetinib were reduced by 62% (ratio 0.38 90% CI 0.29, 0.50) and 19% (ratio 0.81 90% CI 0.74, 0.88), respectively, under fed compared with fasting conditions. The rate of absorption (t(max)) of selumetinib (fed) was delayed by approximately 2.5 h (median). The food effect was also observed for the active metabolite N-desmethyl-selumetinib. Selumetinib was well tolerated. CONCLUSIONS: The presence of food decreased the extent of absorption of selumetinib. It is recommended that for further clinical studies, selumetinib be taken on an empty stomach. Selumetinib demonstrated an acceptable safety profile in the advanced cancer population.

An adult Xp11.2 translocation renal carcinoma showing response to treatment with sunitinib.

A rare variant of renal cell carcinoma (RCC) with a translocation involving Xp11.2 has become increasingly recognized as a separate entity in the 2004 World Health Organization (WHO) kidney carcinoma classification. These tumors predominantly affect children and young adults and tend to present with advanced stage disease. Although reported to be indolent in children, adult cases run a more aggressive course. Little is known about their natural history, prognosis and response to therapy. We report a case of Xp11 translocation renal cancer in a 33-year-old male patient who presented with widespread rapidly progressive metastatic disease involving extensive intra-thoracic lymph nodes, supra-clavicular, retroperitoneal lymph nodes, lung nodules, and peritoneal mass. He had failed to respond to treatment with high dose interleukin 2, but showed a significant clinical response to treatment with the multikinase inhibitor sunitinib. CT scan performed after 3 cycles (18 weeks) of therapy revealed more than 65% reduction of measurable disease by response evaluation criteria in solid tumors (RECIST) criteria, resolution of other assessable lesions, and a clinical benefit that lasted for over 13 months. But unfortunately, this was subsequently followed by a rapidly progressive course. The well-recognized clinical efficacy of multikinase inhibitors such as sunitinib and sorafenib is based on the outcomes in patients with clear cell histology. There is limited data on efficacy in non-clear cell RCC, but activity in translocation RCC has not been reported. To our knowledge, this is the first documented case of Xp11 translocation carcinoma to have demonstrated an objective durable response to sunitinib. It remains unclear how resistance to sunitinib develops, but the results to date support further evaluation of sunitinib in cases of translocation RCC.

Regional hepatic chemotherapies in the treatment of colorectal cancer metastases to the liver.

The liver is the most common site of metastatic spread of colorectal cancer (CRC). Liver may be the only site of spread in as many as 30% to 40% of patients with advanced disease and can be treated with regional therapies directed toward their liver tumors. Surgery is currently the only potentially curative treatment, with a 5-year survival rate as high as 30% to 40% in selected patients. However, fewer than 25% of cases are candidates for curative resection. A number of other locoregional therapies, such as radiofrequency or microwave ablation, cryotherapy, and chemotherapy, may be offered to patients with unresectable but isolated liver metastases. However, for most patients with metastatic spread beyond the liver, systemic chemotherapy rather than regional therapy is a more appropriate option. We review the status of various regional hepatic chemotherapies in the treatment of colorectal metastases to the liver in the light of the available, published prospective, randomized trials; this discipline has not yet been properly applied to the burgeoning use of locally ablative techniques. The regional strategies reviewed include portal venous infusion (PVI) of 5-fluorouracil (5-FU), intra-arterial chemotherapy (hepatic arterial infusion [HAI]), chemoembolization, and selective internal radiation therapy (SIRT).