Clinical Investigation
RTOG 0417: Efficacy of Bevacizumab in Combination With Definitive Radiation Therapy and Cisplatin Chemotherapy in Untreated Patients With Locally Advanced Cervical Carcinoma

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Purpose

Radiation Therapy Oncology Group 0417 was a phase II study that explored the safety and efficacy of the addition of bevacizumab to chemoradiation therapy. The safety results have been previously reported. Herein we report the secondary efficacy endpoints of overall survival (OS), locoregional failure (LRF), para-aortic nodal failure (PAF), distant failure (DF), and disease-free survival (DFS).

Methods and Materials

Eligible patients with bulky Stage IB-IIIB disease were treated with once-weekly cisplatin (40 mg/m2) chemotherapy and standard pelvic radiation therapy and brachytherapy. Bevacizumab was administered at 10 mg/kg intravenously every 2 weeks for 3 cycles during chemoradiation. For OS, failure was defined as death of any cause and was measured from study entry to date of death. LRF was defined as any failure in the pelvis. PAF was defined as any para-aortic nodal failure. DF was analyzed both including and excluding PAF. DFS was measured from study entry to date of first LRF. DF was measured with or without PAF or death. OS and DFS were estimated by the Kaplan-Meier method, and LRF and DF rates were estimated by the cumulative incidence method.

Results

49 eligible patients from 28 institutions were enrolled between 2006 and 2009. The median follow-up time was 3.8 years (range, 0.8-6.0 years). The surviving patients had a median follow-up time of 3.9 years (range, 2.1-6.0 years). Most patients had tumors of International Federation of Gynecology and Obstetrics Stage IIB (63%), and 80% were squamous. The 3-year OS, DFS, and LRF were 81.3% (95% confidence interval [CI], 67.2%-89.8%), 68.7% (95% CI, 53.5%-79.8%), and 23.2% (95% CI, 11%-35.4%), respectively. The PAF, DF without PAF, and DF with PAF at 3 years were 8.4% (95% CI, 0.4%-16.3%), 14.7% (95% CI, 4.5%-24.9%), and 23.1% (95% CI 11.0%-35.2%), respectively.

Conclusion

In this study, bevacizumab in combination with standard pelvic chemoradiation therapy for locally advanced cervical cancer showed efficacy results that are promising and may warrant further investigation.

Introduction

In the management of locally advanced cervical carcinoma, concurrent chemoradiation has led to significant improvements over radiation therapy alone 1, 2, 3, 4, 5, 6. 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 7, 8, 9, 10, 11, 12. For this reason, VEGF inhibitors such as bevacizumab are increasingly being incorporated into standard therapeutic regimens in an effort to improve outcomes. The Gynecology Oncology Group (GOG) evaluated single-agent bevacizumab, at a dosage of 15 mg/kg every 21 days, in a phase II trial for patients with recurrent or metastatic cervical squamous or adenosquamous carcinoma who had experienced progression after 1 or 2 cytotoxic chemotherapy regimens (13). The majority of patients had undergone radiation therapy and at least 1 regimen of chemotherapy. The results were favorable in comparison with historical control individuals, with 24% of patients being without progression after 6 months. The authors recommended further evaluation in a phase III trial, the basis for GOG 240 14, 15, which evaluated the addition of bevacizumab to cisplatin and paclitaxel or cisplatin and topotecan as first-line therapy for chemotherapy-naive patients with Stage IVB or recurrent squamous or adenocarcinoma not amenable to surgery or radiation therapy. Cycles were repeated every 21 days until disease progression, unacceptable toxicity, or complete response occurred. Importantly, patients were eligible if they had just received sensitizing chemotherapy concurrent with radiation treatment but were otherwise chemotherapy naive. This trial was a 2 × 2 factorial randomization to 2 different chemotherapy doublets. The cisplatin and topetecan doublet was not found to be better than cisplatin and paclitaxel at the first interim analysis. The second interim analysis lumped all cytotoxic chemotherapy together and compared the group given chemotherapy alone with the group who received chemotherapy plus bevacizumab. The results showed a striking improvement in overall survival (OS) with the addition of bevacizumab compared with either chemotherapy doublet alone, and there was no decline in health-related quality of life with the addition of bevacizumab. The median OS for the 225 patients who received bevacizumab in addition to chemotherapy was 17 months, versus 14 months for the 227 patients who received the chemotherapy doublet alone. The results were published in abstract form after the second planned interim analysis crossed the threshold for efficacy that was predefined in the trial.

For this study, the selection of 10 mg/kg of bevacizumab every 2 weeks 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 16, 17.

Radiation Therapy Oncology Group (RTOG) 0417 was a phase II trial evaluating the addition of bevacizumab to weekly cisplatin concurrent with radiation treatment for patients with locally advanced cervical carcinoma. The study was powered for the primary endpoint of acute toxicity defined as treatment-related adverse events (AEs) and serious adverse events (SAEs). We previously reported that bevacizumab in addition to standard pelvic chemoradiation therapy for locally advanced cervical cancer was feasible and safe with respect to the protocol-specified treatment-related SAEs and AEs (18). This report focuses on the secondary efficacy endpoint results.

Section snippets

Patient eligibility

Patients were eligible if they had histologic proof of squamous carcinoma, adenocarcinoma or adenosquamous carcinoma of the uterine cervix, including International Federation of Gynecologists and Obstetricians (FIGO) Stage IIB to IIIB disease, or patients with FIGO Stage IB to IIA disease who had biopsy-proven pelvic node metastases, tumor size exceeding 5 cm, or both. The previous report contains a detailed account of other eligibility criteria (18).

Radiation, cisplatin chemotherapy, and bevacizumab treatment

The details of treatment have been

Patients

RTOG 0417 opened to accrual in August 2006 and completed accrual in August 2009. Sixty patients from 28 institutions were enrolled. Forty-nine patients were evaluable. Of the 11 patients excluded from analysis, 1 patient did not receive protocol treatment; 4 patients did not have blood work done, or it was done outside the allowable window; 1 patient had a biopsy performed <7 days before registration; 1 patient had FIGO Stage IVA disease; 1 patient had a hemoglobin level of 9.0 g/dL; 1 patient

Discussion

The addition of bevacizumab to weekly concurrent cisplatin and radiation treatment was well tolerated and was associated with encouraging OS and locoregional control in this phase II study. GOG 240 showed an OS improvement with the addition of maintenance bevacizumab to chemotherapy for chemotherapy-naive patients (those who had undergone sensitizing chemotherapy with radiation therapy but who were otherwise chemotherapy naive were eligible) with persistent, recurrent, or metastatic cervical

Conclusion

In this study, bevacizumab in combination with standard pelvic chemoradiation for locally advanced cervical cancer showed efficacy results that are promising and warrant further investigation.

References (19)

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    Considering this and our previous meta-analysis (Horeweg et al., 2021), we can only conclude that there is no benefit of adjuvant chemotherapy to chemoradiation and brachytherapy in unselected locally advanced cervical cancer patients. Now, the focus of research locally advanced cervical cancer has moved to targeted therapies such as anti-PD(L)1 (Mayadev et al., 2020; Merck Sharp & Dohme Corp. et al., 2020; Duska et al., 2020; Institute Curie and Bristol-Myers Squibb, 2017; Gustave Roussy, 2018; Grupo Español de Investigación en Cáncer de Ovario et al., 2019), anti-CTLA-4 (Mayadev et al., 2019; NCT, 2021), anti-VEGF (National Cancer Institute and Radiation Therapy Oncology Group, 2006; Air Force Military Medical University, China, 2019; Schefter et al., 2014; Lu et al., 2021) and anti-EGFR agents (Zhujiang Hospital, 2018; Chen et al., 2017; Qu et al., 2019; Rawat et al., 2020). Nonetheless, the cervical cancer research community should learn from the message hidden in the outcomes of all trials on adjuvant chemotherapy: non-selective allocation of adjuvant systemic treatment was not successful.

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Supported by RTOG grant U10 CA21661, CCOP grant U10 CA37422, and ATC grant U24 CA81647 from the National Cancer Institute (NCI).

This article's contents are the sole responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

Conflict of interest: none.

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