Phase II trial of combretastatin A4 phosphate, carboplatin, and paclitaxel in patients with platinum-resistant ovarian cancer.

BACKGROUND: A previous dose-escalation trial of the vascular disrupting agent combretastatin A4 phosphate (CA4P) given before carboplatin, paclitaxel, or both showed responses in 7 of 18 patients with relapsed ovarian cancer. PATIENTS AND METHODS: Patients with ovarian cancer that had relapsed and who could start trial therapy within 6 months of their last platinum chemotherapy were given CA4P 63 mg/m(2) minimum 18 h before paclitaxel 175 mg/m(2) and carboplatin AUC (area under the concentration curve) 5, repeated every 3 weeks. RESULTS: Five of the first 18 patients' disease responded, so the study was extended and closed after 44 patients were recruited. Grade ≥2 toxic effects were neutropenia in 75% and thrombocytopenia in 9% of patients (weekly blood counts), tumour pain, fatigue, and neuropathy, with one patient with rapidly reversible ataxia. Hypertension (23% of patients) was controlled by glyceryl trinitrate or prophylactic amlodipine. The response rate by RECIST was 13.5% and by Gynecologic Cancer InterGroup CA 125 criteria 34%. CONCLUSIONS: The addition of CA4P to paclitaxel and carboplatin is well tolerated and appears to produce a higher response rate in this patient population than if the chemotherapy was given without CA4P. A planned randomised trial will test this hypothesis.

A Phase Ib trial of CA4P (combretastatin A-4 phosphate), carboplatin, and paclitaxel in patients with advanced cancer.

BACKGROUND: The vascular disrupting agent combretastatin A4 phosphate (CA4P) causes major regression of animal tumours when given as combination therapy. METHODS: Patients with advanced cancer refractory to standard therapy were treated with CA4P as a 10-min infusion, 20 h before carboplatin, paclitaxel, or paclitaxel, followed by carboplatin. RESULTS: Combretastatin A4 phosphate was escalated from 36 to 54 mg m(-2) with the carboplatin area under the concentration curve (AUC) 4-5, from 27 to 54 mg m(-2) with paclitaxel 135-175 mg m(-2), and from 54 to 72 mg m(-2) with carboplatin AUC 5 and paclitaxel 175 mg m(-2). Grade 3 or 4 neutropenia was seen in 17%, and thrombocytopenia only in 4% of 46 patients. Grade 1-3 hypertension (26% of patients) and grade 1-3 tumour pain (65% of patients) were the most typical non-haematological toxicities. Dose-limiting toxicity of grade 3 hypertension or grade 3 ataxia was seen in two patients at 72 mg m(-2). Responses were seen in 10 of 46 (22%) patients with ovarian, oesophageal, small-cell lung cancer, and melanoma. CONCLUSION: The combination of CA4P with carboplatin and paclitaxel was well tolerated in the majority of patients with adequate premedication and had antitumour activity in patients who were heavily pretreated.

Insurance-based advantage to helpers in a tropical hover wasp.

The origin and maintenance of eusociality is a central problem in evolutionary biology. Eusocial groups contain individuals that forfeit their own reproduction in order to help others reproduce. In facultatively eusocial taxa, offspring can choose whether to found new nests or become helpers in their natal groups. In many facultatively eusocial insects, offspring need continuous care during development, but adult carers have life expectancies shorter than the developmental period. When a lone foundress dies, her partly reared brood are usually doomed. Here, we show that helpers in a tropical hover wasp (Liostenogaster flavolineata) have an insurance-based advantage over lone foundresses because after a helper dies, most of the brood that she has partly reared will be brought to maturity by surviving nest-mates. After some of the helpers are experimentally removed from a multi-female nest, the reduced group is left with more brood than it would normally rear. We found that larger, more valuable extra brood were reared through to maturity, but not smaller, less valuable brood. Smaller brood may be sacrificed to feed larger brood, and reduced groups probably benefited from increased short-term helper recruitment. Rearing extra brood did not increase adult mortality or brood development time.