European Society of Gynaecological Oncology (ESGO) Guidelines for Ovarian Cancer Surgery.

METHODS: The European Society of Gynaecological Oncology council nominated an international multidisciplinary development group made of practicing clinicians who have demonstrated leadership and interest in the care of ovarian cancer (20 experts across Europe). To ensure that the statements are evidence based, the current literature identified from a systematic search has been reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group (expert agreement). The guidelines are thus based on the best available evidence and expert agreement. Before publication, the guidelines were reviewed by 66 international reviewers independent from the development group including patients representatives. RESULTS: The guidelines cover preoperative workup, specialized multidisciplinary decision making, and surgical management of diagnosed epithelial ovarian, fallopian tube, and peritoneal cancers. The guidelines are also illustrated by algorithms.

Treatment with the HIV protease inhibitor nelfinavir triggers the unfolded protein response and may overcome proteasome inhibitor resistance of multiple myeloma in combination with bortezomib: a phase I trial (SAKK 65/08).

Downregulation of the unfolded protein response mediates proteasome inhibitor resistance in multiple myeloma. The Human Immunodeficieny Virus protease inhibitor nelfinavir activates the unfolded protein response in vitro. We determined dose-limiting toxicity and recommended dose for phase II of nelfinavir in combination with the proteasome inhibitor bortezomib. Twelve patients with advanced hematologic malignancies were treated with nelfinavir (2500-5000 mg/day p.o., days 1-14, 3+3 dose escalation) and bortezomib (1.3 mg/m(2), days 1, 4, 8, 11; 21-day cycles). A run in phase with nelfinavir monotherapy allowed pharmakokinetic/pharmakodynamic assessment of nelfinavir in the presence or absence of concomittant bortezomib. End points included dose-limiting toxicity, activation of the unfolded protein response, proteasome activity, toxicity and response to trial treatment. Nelfinavir 2×2500 mg was the recommended phase II dose identified. Nelfinavir alone significantly up-regulated expression of proteins related to the unfolded protein response in peripheral blood mononuclear cells and inhibited proteasome activity. Of 10 evaluable patients in the dose escalation cohort, 3 achieved a partial response, 4 stable disease for 2 cycles or more, while 3 had progressive disease as best response. In an exploratory extension cohort with 6 relapsed, bortezomib-refractory, lenalidomide-resistant myeloma patients treated at the recommended phase II dose, 3 reached a partial response, 2 a minor response, and one progressive disease. The combination of nelfinavir with bortezomib is safe and shows promising activity in advanced, bortezomib-refractory multiple myeloma. Induction of the unfolded protein response by nelfinavir may overcome the biological features of proteasome inhibitor resistance. (clinicaltrials.gov identifier: 01164709).

Randomized multicenter phase II study of larotaxel (XRP9881) in combination with cisplatin or gemcitabine as first-line chemotherapy in nonirradiable stage IIIB or stage IV non-small cell lung cancer.

INTRODUCTION: This randomized phase II study investigated the efficacy and safety of a new taxane, larotaxel (XRP9881), in combination with either cisplatin or gemcitabine in the first-line treatment of patients with nonirradiable stage IIIB or stage IV non-small cell lung cancer to select the combination having the most promising antitumor activity. METHODS: Patients received either larotaxel (50 mg/m) as a 1-hour infusion, followed by a 1-hour infusion of cisplatin (75 mg/m), every 3 weeks (arm A), or gemcitabine (800 mg/m) as a 30 minute infusion, on days 1 and 8, and larotaxel (60 mg/m) as a 1-hour infusion, on day 8 (following gemcitabine), every 3 weeks (arm B). The primary end point was the objective response rate (per-protocol population). RESULTS: Thirty-two patients were randomized to arm A and 30 to arm B. The response rate was higher in arm A compared with arm B in both the per-protocol (26.7% versus 18.2%) and intention-to-treat (28.1% versus 13.3%) populations. In the intention-to-treat population, median progression-free survival for arm A versus arm B was 4.7 versus 3.3 months and median overall survival was 8.6 versus 7.3 months, respectively. Fifty percent of patients in arm A and 66.7% in arm B experienced at least one National Cancer Institute common toxicity criteria grade 3/4 adverse event and grade 3/4 neutropenia was observed in 46.9% and 41.4% of patients, respectively. CONCLUSIONS: Both larotaxel combinations were effective and manageable, however all measured efficacy parameters (response rate, progression free survival, and survival) seemed to favor the combination with cisplatin.