Phase II Trial Results of Bevacizumab in Combination With Radiotherapy and Cisplatin in Locally-Advanced Cervical Cancer

The results warrant further investigation

An article published in the January issue of the International Journal of Radiation Oncology, Biology and Physics reports results of the Radiation Therapy Oncology Group (RTOG) phase II clinical trial of bevacizumab in addition to cisplatin and pelvic radiation for previously untreated patients with locally-advanced cervical cancer. The RTOG investigators report promising results for bevacizumab when added to the existing standard of care.

In the management of locally advanced cervical cancer, concurrent chemoradiation has led to significant improvements over radiation therapy alone. However, patients still experience unacceptably high rates of local and distant failure. Overexpression of vascular endothelial growth factor (VEGF) is common in both cervical squamous cell carcinoma and adenocarcinoma, and this overexpression is correlated with compromised outcome. For this reason, VEGF inhibitors such as bevacizumab are increasingly being incorporated into standard therapeutic regimens in an effort to improve outcomes. 

The study results

The current phase II clinical trial enrolled 49 eligible patients from 28 institutions in the years 2006-2009. The study previously reported that bevacizumab was safe and well-tolerated in combination with cisplatin and radiation therapy in this population. Now the group reports on the secondary efficacy endpoints at a median follow-up time of 3.9 years. The secondary efficacy endpoints included overall survival (OS), loco-regional failure (LRF), para-aortic nodal failure (PAF), distant failure (DF), and disease-free survival (DFS).

Specifically the group evaluated the addition of 10mg/kg bevacizumab every two weeks for 3 cycles during chemoradiation. The selection of bevacizumab dose and interval was based on the compilation of trials of bevacizumab with chemotherapy and chemoradiation therapy at the time. The dosage of 10 mg/kg was known to be safe when combined with both abdominal and pelvic radiation therapy.

Most patients had tumours of International Federation of Gynecology and Obstetrics stage IIB (63%), and 80% were squamous. The overall survival and loco-regional control results were favourable in comparison to historical controls of chemoradiation without bevacizumab. The 3-year OS, DFS, and LRF were 81.3%, 68.7%, and 23.2%, respectively. The PAF, DF without PAF, and DF with PAF at 3 years were 8.4%, 14.7%, and 23.1%, respectively.

The authors concluded that bevacizumab in combination with standard pelvic chemoradiation therapy for locally-advanced cervical cancer showed efficacy results that are promising and may warrant further investigation.

 “Cervical cancer is a huge problem worldwide, but isn’t as big a problem in the United States. So in many ways it tends to become a somewhat overlooked and under-studied disease,” according to Dr Tracey Schefter, investigator at the University of Colorado Cancer Center, director of the Stereotactic Body Radiation Therapy program at the University of Colorado School of Medicine, and the study’s lead author.

“Parenthetically, when we were designing this trial, one thing we discussed at length was whether to include a maintenance phase of bevacizumab after chemoradiation. Because of perceived issues with patient compliance at the time, we decided not to add to the overall duration of treatment by adding maintenance bevacizumab. Based on the recent results of GOG 240 which showed an overall survival benefit when bevacizumab was added to first line chemotherapy for patients with metastatic disease, a trial addressing the benefit of both concurrent and maintenance bevacizumab for locoregionally advanced cervical cancer will likely need to be done,” Schefter pointed out. 

The study was supported by RTOG grant U10 CA21661, CCOP grant U10 CA37422, and ATC grant U24 CA81647 from the USA National Cancer Institute (NCI).