Multicenter phase II trial of topotecan, cisplatin and bevacizumab for recurrent or persistent cervical cancer

Abstract

Objective We evaluated the activity and safety of the combination of topotecan, cisplatin and bevacizumab in patients with recurrent or persistent carcinoma of the cervix. Methods Eligible patients had persistent or recurrent cervical cancer not amenable to curative intent treatment. No prior chemotherapy for recurrence was allowed. Treatment consisted of cisplatin 50 mg/m2 day 1, topotecan 0.75 mg/m2 days 1,2 and 3 and bevacizumab 15 mg/kg day 1 every 21 days until disease progression or limiting toxicity. The primary endpoint was progression free survival at 6 months. We explored PET/CT as a potential early indicator of response to therapy. Results Twenty-seven eligible patients received a median of 3 treatment cycles (range, 1–19). Median fallow-up was 10 months (range, 1.7–33.4). The 6-month PFS was 59% (80% CI: 46-70%). in 26 evaluable patients, we observed 1 CR (4%; 80% CI: 0.4–14%) and 8 PR (31%; 80% CI: 19–45%) lasting a median of 4.4 months. Ten patients had SD (39%; 80% CI: 25–53%) with median duration of 2.2 months. Median PFS was 7.1 months (80%; CI: 4.7–10.1) and median OS was 13.2 months (80% CI: 8.0–15.4). All patients were evaluated for toxicity. Grade 3–4 hematologic toxicity was common (thrombocytopenia 82% leukopenia 74%, anemia 63%, neutropenia 56%). Most patients (78%) required unanticipated hospital admissions for supportive care and/or management of toxicities. Conclusion The addition of bevacizumab to topotecan and cisplatin results in an active but highly toxic regimen. Future efforts should focus on identification of predictive biomarkers of prolonged response and regimen modifications to minimize toxicity.

Bevacizumab in advanced cervical cancer

“…Finally, all data from trials using bevacizumab, including GOG 240 [2], RTOG 0417 [4], and the study of Zighelboim et al [5] are consistent with significant toxicities, particularly grade 3-4 bleeding, thromboembolic events, and GI fistulas as well as unanticipated hospital admissions for supportive care. This raises concerns about the anticipated goals of care, also given the absence of change in quality of life [2] particularly in heavily pretreated patients with residual toxicities.…”

Improving vascular maturation using noncoding RNAs increases antitumor effect of chemotherapy

“…The induction of hypoxia is not surprising given the pronounced reduction in the number of blood vessels with prolonged treatment (4). Targeting hypoxia pathways such as HIF1α (e.g., topotecan, temsirolimus) has resulted in improved efficacy of antiangiogenic drugs (5,6). However, novel approaches to target the tumor vasculature are needed to maintain antitumor efficacy without increasing hypoxia and other deleterious effects.…”

Chapter 8. Polymeric Nanoparticles and Cancer: Lessons Learnt from CRLX101

“…Although the study significantly improved mPFS (7.1 months) and mOS (13.2 months), grade 3/4 toxicity was common (thrombocytopaenia 82%, leukopaenia 74%, and anaemia 63%) and most patients (78%) required unanticipated hospital admission. 126 The SN38-bearing nanoparticle EZN-2208 (described in Section 8.2.4) has been shown to inhibit HIF-1a and its downstream targets such as VEGF1 in a U251 glioma xenograft model. 127 The nanoparticle is currently evaluated for potential HIF-1 inhibition and anti-tumour effects in combination with bevacizumab in patients with refractory tumours (ClinicalTrials.org identifier NCT01251926).…”