Clinical Investigation
Outcomes for Hyperthermia Combined with Concurrent Radiochemotherapy for Patients with Cervical Cancer

https://doi.org/10.1016/j.ijrobp.2020.03.006Get rights and content

Purpose

To evaluate the effect of hyperthermia combined with concurrent radiochemotherapy (RCT) and treatment-related toxicity in patients with cervical cancer (CC) stage IB-IV.

Methods and Materials

This study was conducted between 2009 and 2013 in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB-IV CC. The patients were randomly assigned into 2 treatment groups: RCT and RCT plus hyperthermia (RCHT). Five-year survival, treatment-related toxicity, and other prognostic factors were evaluated.

Results

Three hundred seventy-three patients completed treatment and were analyzed by per-protocol (PP) analysis. The 5-year overall survival (OS) in the RCHT group (81.9%) was better than that in RCT group (72.3%), and the log-rank test showed a statistically significant difference between the 2 groups (P = .040). Univariate and multivariate Cox regression analysis for 5-year OS showed a statistically significant difference (P = .043, P = .045, respectively). The 5-year local relapse-free survival in RCHT (86.8%) was also better than that in RCT (82.7%), but the difference was not significant. Acute or late toxicity was not significantly different between the 2 groups. Advanced clinical stage (FIGO) and larger tumor size showed higher risk of death and a relatively poor prognosis in univariate and multivariate analysis.

Conclusions

The study confirmed that hyperthermia combined with RCT yielded a better 5-year OS in CC. Acute and late toxicity was similar between the RCT and RCHT groups. Clinical stage (FIGO) and tumor size were independent prognostic factors in CC.

Introduction

Patients with locally advanced cervical cancer (LACC) were usually treated with radiation therapy alone before 1990s. The survival rate was relatively poor, in the 30% to 50% range.1,2 Since 1999, 5 randomized clinical trials from the Gynecologic Oncology Group, Radiation Therapy Oncology Group, and Southwestern Oncology Group have demonstrated a 30% to 50% lower risk of recurrence or death for cervical cancer (CC) treated with concurrent chemotherapy (CT) and radiation therapy (RT), compared with RT alone.3, 4, 5, 6, 7 Therefore, on the basis of these trials, the National Cancer Institute issued a clinical alert in 1999 that “women who need RT for CC should strongly consider the incorporation of concurrent RCT.” Since then, concurrent RCT has become the standard treatment for the LACC in most areas of the world.

Another clinical trial conducted by the Dutch Deep Hyperthermia Group was published in The Lancet in 2000.8 In this trial, the group reported that hyperthermia (HT) plus RT for LACC rendered better local control and 3-year survival compared with RT alone. Twelve-year long-term survival data subsequently confirmed the advantage of HT + RT for LACC.9 To date, several clinical trials have contributed to an understanding of the feasibility and effect of HT in LACC8, 9, 10, 11 and showed that the combination of HT and RT can increase local control and survival rates.

Because concurrent RCT is the recommended treatment for LACC, and HT + RT can also improve its efficacy, would the trimodality combination approach be better? No more reliable data from a prospective, randomized trial with a large sample have supported this. A prospective, randomized trial of 101 patients showed that the triple-modality treatment increased complete response but not survival for patients with LACC.12 Until the long-term survival data from the trimodality study become available, further study is necessary.

Based on the feasibility and safety of our previous clinical trial of HT combined with RCT for patients with CC, we conducted a randomized, controlled clinical trial to investigate the long-term survival and toxicity of 3 combination treatment modalities (RT, CT, and HT) for patients with CC.

Section snippets

Patients

A total of 449 patients with CC between 2009 and 2013 were recruited into this randomized clinical trial. The trial has been approved by the ethics committee, and informed consent was obtained from all patients.

The inclusion criteria included (1) age between 25 and 70 years; (2) Karnofsky performance status ≥70; (3) International Federation of Gynecology and Obstetrics (FIGO, 2009) stages IB-IV; (4) no prior RT, CT, or surgery; (5) histologically confirmed cervical squamous carcinoma; (6) no RT

Patient characteristics

A patient flow diagram is presented in Figure 1. In total, 449 patients with CC were recruited into this clinical trial, and 14 patients were excluded (2 patients for histologically confirmed cervical adenocarcinoma; 1 patient for double primary cancer; 10 patients for not tolerating the treatments; and 1 patient for low white blood cell count). Four hundred thirty-five patients were assigned to 2 treatment groups according to a computer-generated random number list: 218 RCT and 217 RCT + HT.

Discussion

For patients with LACC, RT alone was the main treatment about 2 decades ago.1 Since 1999, 5 randomized clinical studies have compared the effect of RT alone and that with concurrent RCT and reported a better treatment outcome and decreased risk of death in patients with CC treated with concurrent RCT.3, 4, 5, 6, 7 Cisplatin-based concurrent RCT has become the standard treatment in LACC. Subsequently, 2 meta-analyses confirmed the effect of RCT on CC; however, they also suggested a decreasing

Conclusions

Adding HT to standard RCT yielded a better survival in patients with CC based on PP analysis instead of ITT analysis. Although ITT analysis (survival analysis) was not significantly different (P = .053), there was a tendency toward improved survival (multivariate Cox regression analysis showed a significant difference: P = .043). Acute and late toxicity were similar between the 2 groups. Advanced clinical stage and larger tumor size were independent prognostic factors that predicted relatively

References (33)

Cited by (0)

This work was supported by the National Natural Science Foundation of China (no. 81172194), the Research and Development Program of Science and Technology in Shaanxi Province (no. 2011K13-01-12), and funding for clinical research projects and new medical technology at the First Affiliated Hospital of Xi’an Jiaotong University (2008).

Research data are stored in an institutional repository and will be shared upon request to the corresponding author.

Disclosures: none.

View full text