Long-term outcomes of concomitant cisplatin plus radiotherapy versus radiotherapy alone in patients with stage IIIB squamous cervical cancer: A randomized controlled trial

Highlights

• Chemoradiotherapy offers a significant benefit in disease free survival for stage IIIB squamous cervical cancer.

• Chemoradiotherapy offers a significant benefit in overall survival for stage IIIB squamous cervical cancer.

• Longer follow-up meant the study was sufficiently powered to demonstrate benefit in survival with chemoradiotherapy.

• This is one of two clinical trials in stage IIIB showing similar results.

Abstract

Objective

The present analysis determined the disease free survival (DFS) and overall survival (OS) at up to 14 years of follow-up in women who participated in our previous phase 3 randomized controlled clinical trial, in which women with stage IIIB squamous cervical cancer received either cisplatin plus RT or RT alone for treatment. The first study showed that the addition of cisplatin to RT offered a significant benefit in DFS, but not in OS.

Methods

The present analysis examined DFS and OS in 146 women from the original cohort (72 patients in the CRT arm and 74 patients in the RT-only arm) with follow-up of up to 14 years.

Results

Longer term follow-up showed that treatment with CRT offers a significant benefit in DFS and OS compared with treatment with RT only. Patients who received RT alone had significantly worse OS (HR, 1.88; 95% CI, 1.09–3.24) and DFS (HR, 1.82; 95% CI, 1.07–3.08) compared with patients who received CRT. The multivariate analyses also showed that the patients with baseline Karnofsky performance status (KPS) <90% showed significantly worse OS (HR, 3.11; 95% CI, 1.78–5.43), as did those with hemoglobin <10 mg/dL (HR, 4.32; 95% CI, 2.23–8.36). Patients with baseline KPS < 90% showed significantly worse DFS (HR, 2.83; 95% CI, 1.60–5.01), as did those with hemoglobin <10 mg/dL (HR, 4.16; 95% CI, 2.17–7.95).

Conclusions

For stage IIIB cervical cancer, treatment with CRT offers a significant benefit in DFS and OS compared with treatment with RT only.

Introduction

Cervical cancer is the fourth most prevalent cancer in women worldwide, and a large proportion of cases are diagnosed at stage IIIB (International Federation of Gynecology and Obstetrics- FIGO 2009) [1], i.e., extension of the tumor into the pelvic wall and/or the presence of hydronephrosis or a non-functioning kidney [2,3]. Radiation therapy with concomitant chemotherapy is used to treat patients with stage IIIB (FIGO 2009) disease [[4], [5], [6]]. Data from five previous phase III trials showed a 30%–50% reduction in risk of death in women receiving combined treatment for cervical cancer. However, these studies were conducted in countries where few patients present with advanced-stage, bulky disease, meaning that data may not be applicable to patients in stage IIIB (FIGO 2009) [[7], [8], [9], [10], [11]].

Until 2014, the evidence comparing disease-free survival (DFS) and overall survival (OS) for women receiving chemoradiotherapy (CRT) versus radiotherapy alone (RT) was summarized in a meta-analysis, which included data from 3452 women in 15 studies. This analysis showed that CRT may benefit women at all stages of cervical cancer, although the magnitude of the benefit may vary across staging strata, suggesting a trend in the relative effect of CRT by tumor stage (P = 0.017) and a decrease in OS with increasing stage. However, chemotherapy regimens were heterogeneous across the 15 included studies, and no DFS and OS benefit was observed for patients with stage III-IVA (FIGO 2009) disease [6].

In 2018, a randomized controlled trial of concurrent CRT and RT alone in 850 women (424 patients in the CRT group and 426 patients in the RT-only group) with FIGO 2009 stage IIIB squamous cell carcinoma of the uterine cervix was reported. The 5-year DFS and OS were significantly higher in the CRT arm compared with the RT-only arm. These findings provided evidence in favor of concurrent weekly cisplatin chemotherapy in this patient population [12].

We conducted a phase 3 randomized controlled clinical trial in 147 women with stage IIIB (FIGO 2009) squamous cervical cancer who received either cisplatin plus RT or RT alone (72 patients in the CRT group and 75 patients in the RT-only group). Accrual lasted from September 2003 through July 2010. Ours was the first published randomized controlled trial specifically designed to address the outcome of patients with stage IIIB cervical cancer receiving CRT with high-dose RT versus RT alone. After 42.3 months of median follow-up time, the CRT group had significantly better DFS than the RT-only group, but patients in the CRT group did not have significantly better OS [13]. Given the sample size in this study, it may have been insufficiently powered to demonstrate more conclusive findings in a relatively short follow-up time. Therefore, the aim of the present analysis was to determine the DFS and OS at up to 14 years of follow-up in women who participated in our previous phase 3 trial. This longer follow-up may provide sufficient data to support the endpoints of the original trial.