Neoadjuvant radiotherapy combined with capecitabine and sorafenib in patients with advanced KRAS-mutated rectal cancer: A phase I/II trial (SAKK 41/08).

BACKGROUND: KRAS mutation occurs in ∼40% of locally advanced rectal cancers (LARCs). The multitarget tyrosine kinase inhibitor sorafenib has radiosensitising effects and might improve outcomes for standard preoperative chemoradiotherapy in patients with KRAS-mutated LARC. METHODS: Adult patients with KRAS-mutated T3/4 and/or N1/2M0 LARC were included in this phase I/II study. The phase I dose-escalation study of capecitabine plus sorafenib and radiotherapy was followed by a phase II study assessing efficacy and safety. Primary end-points were to: establish the maximum tolerated dose of the regimen in phase I; determine the pathologic complete response (pCR) rate in phase II defined as Dworak regression grade 3 and 4. RESULTS: Fifty-four patients were treated at 18 centres in Switzerland and Hungary; 40 patients were included in the single-arm phase II study. Recommended doses from phase I comprised radiotherapy (45 Gy in 25 fractions over 5 weeks) with capecitabine 825 mg/m2 twice daily × 33 plus sorafenib 400 mg/d. Median daily dose intensity in phase II was radiotherapy 100%, capecitabine 98.6%, and sorafenib 100%. The pCR rate (Dworak 3/4) was 60% (95% CI, 43.3-75.1%) by central independent pathologic review. Sphincter preservation was achieved in 89.5%, R0 resection in 94.7%, and downstaging in 81.6%. The most common grade 3 toxicities during phase II included diarrhoea (15.0%), skin toxicity outside radiotherapy field (12.5%), pain (7.5%), skin toxicity in radiotherapy field, proctitis, fatigue and cardiac ischaemia (each 5%). CONCLUSIONS: Combining sorafenib and standard chemoradiotherapy with capecitabine is highly active in patients with KRAS-mutated LARC with acceptable toxicity and deserves further investigation. www.clinicaltrials.gov: NCT00869570.

Langerhans cell histiocytosis with central nervous system involvement--complete response to 2-chlorodeoxyadenosine after failure of tyrosine kinase inhibitor therapies with sorafenib and imatinib.

Langerhans cell histiocytosis (LCH) is rare in adults, and only a subset of these patients suffers from central nervous system (CNS) involvement. Hence, evidence-based treatment recommendations are lacking. A case of a 20-year-old student with multisystem LCH and extensive CNS involvement is described, who showed a durable response to 2-chlorodeoxyadenosine after prior therapies with the tyrosine kinase inhibitors sorafenib and imatinib. In accordance to the experiences provided by other case series, which are reviewed herein, 2-chlorodeoxyadenosine can be considered an effective and safe option for adult LCH with CNS involvement.

Guidelines for the adjuvant treatment of postmenopausal women with endocrine-responsive breast cancer: past, present and future recommendations.

Treatment guidelines are useful tools that enable physicians to integrate the latest clinical research into their practices. The large volume of rapidly evolving clinical data in breast cancer has been summarised and incorporated into treatment recommendations by well-known and reliable institutions, including the National Comprehensive Cancer Network, the American Society for Clinical Oncology, the European Society for Medical Oncology and the St. Gallen International Consensus Panel. Adjuvant therapy is a key component of breast cancer treatment, and many of the current consensus guidelines now recognise the important role of the aromatase inhibitors as an alternative to or in sequence after tamoxifen, hitherto the standard adjuvant treatment of choice for receptor-positive women. Data from ongoing trials such as the Breast International Group 1-98 trial and those still in the accrual phase will be forthcoming and will likely result in a further refinement of treatment recommendations over the course of the next few years. Despite the availability of such guidelines, however, there is evidence that adherence to and implementation of treatment recommendations is less than optimal. Further research is needed to determine more effective means of disseminating those clinical recommendations that can have a significant impact on treatment strategies and ultimately improve outcomes in breast cancer.