Discussion
ovarian cancer, neutropenia, toxicity, thrombocytopenia, cholestatic, platinum-resistant recurrent ovarian cancer, Leucopenia
OVARIAN CANCER, HEPATOCELLULAR DAMAGE, NEUTROPENIA, RECURRENT OVARIAN CANCER, ADVERSE EVENTS, THROMBOCYTOPENIA, LEUCOPENIA
This phase I/II study investigated the combination of topotecan with the oral multi-targeted tyrosine kinase inhibitor pazopanib for the treatment of patients with platinum-resistant recurrent ovarian cancer. Based on the safety dose-escalation assessment we determined 400 mg/day pazopanib, as maximum tolerated dose, to be feasible and safe in the simultaneous combination with weekly topotecan followed by maintenance treatment. We were able to demonstrate a high adherence to study treatment, with only two interruptions due to patients’ preference. But as expected for patients in a 2nd and 3rd-line treatment, only 25% received six cycles of chemotherapy (Hanker et al. The summarized analyses within both—dose-finding and safety cohorts demonstrated that most relevant treatment related AE’s of grade 3–4 resulted from the accumulation of bone-marrow and liver toxicities, which finally determined the DLT of pazopanib. Leucopenia (25%), neutropenia (22%) and thrombocytopenia (19%), but also cholestatic (20%) and hepatocellular damage (15%) were identified to be the most clinical important treatment related AE’s. It is reasonable to assume that pazopanib plays a substantial role behind the spectrum of evaluated toxicity, even if severity of some adverse events could also be explained with accumulation of topotecan side-effects (Chekerov et al. The question on the wright way to integrate targeted agents into current treatment of recurrent ovarian cancer remains one of the greatest challenges for gynaecologic oncologists (Colombo In this context our study combining simultaneously topotecan with pazopanib 400 mg/day demonstrated with 68% an encouraging clinical benefit rate, which could assume some gain in efficacy caused by pazopanib, when compared to the above reports, and was even superior to previously reported activity of established topotecan regiments (Sehouli et al. Beyond the studies mentioned above the AGO-OVAR16 trial, a phase 3 study, demonstrated a significant improvement in PFS (progression free survival) for patients with advanced ovarian cancer who have not progressed after first-line platinum therapy and received maintenance therapy with pazopanib versus placebo (5,6 months improvement; HR 0.77; 95% CI: 0.64–0.91; 