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Role of adjuvant therapy after radical hysterectomy in intermediate-risk, early-stage cervical cancer
  1. Lijie Cao1,2,
  2. Hao Wen1,2,
  3. Zheng Feng1,2,
  4. Xiaotian Han1,2,
  5. Jun Zhu1,2 and
  6. Xiaohua Wu1,2
  1. 1 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
  2. 2 Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
  1. Correspondence to Dr Xiaohua Wu, Fudan University Shanghai Cancer Center, Shanghai 200032, China; wu.xh{at}fudan.edu.cn

Abstract

Objective Adjuvant treatment remains a controversial issue for intermediate-risk cervical cancer. The aim of this study was to compare the prognosis of patients who underwent no adjuvant treatment, pelvic radiotherapy alone, or concurrent chemoradiotherapy after radical hysterectomy for intermediate-risk, early-stage cervical cancer.

Methods Patients with stage IB1–IIA2 (FIGO 2009) cervical squamous cell carcinoma treated with radical hysterectomy and pelvic lymph node dissection, with negative lymph nodes, surgical margins, or parametria, who had combined intermediate risk factors as defined in the Gynecologic Oncology Group trial (GOG-92; Sedlis criteria) were included in the study. Recurrence-free survival and disease-specific survival were compared.

Results Of 861 patients included in the analysis, 85 patients received no adjuvant treatment, 283 patients were treated with radiotherapy, and 493 patients with concurrent chemoradiotherapy. After a median follow-up of 63 months (IQR 45 to 84), adjuvant radiotherapy or concurrent chemoradiotherapy was not associated with a survival benefit compared with no adjuvant treatment. The 5-year recurrence-free survival and corresponding disease-specific survival were 87.1%, 84.2%, 89.6% (p=0.27) and 92.3%, 87.7%, 91.4% (p=0.20) in the no adjuvant treatment, radiotherapy alone, and concurrent chemoradiotherapy groups, respectively. Lymphovascular space invasion was the only independent prognostic factor for both recurrence-free survival and disease-specific survival. Additionally, significant heterogeneity exists in Sedlis criteria: higher risk of relapse (HR=1.88; 95% CI 1.19 to 2.97; p=0.007) and death (HR=2.36; 95% CI 1.41 to 3.95; p=0.001) occurred in patients with lymphovascular space invasion and deep 1/3 stromal invasion compared with no lymphovascular space invasion, middle or deep 1/3 stromal invasion, and tumor diameter ≥4 cm.

Conclusions Radical hysterectomy alone without adjuvant treatment may achieve a favorable survival for patients with intermediate-risk cervical cancer as defined by Sedlis criteria. Criteria for adjuvant treatment in patients without high risk factors need to be further evaluated.

  • cervical cancer

https://doi.org/10.1136/ijgc-2020-001974

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    HIGHLIGHTS

    • Radical surgery alone may achieve equal survival for patients with intermediate-risk, early-stage cervical cancer as compared with combined surgery and radiotherapy or chemoradiotherapy.

    • Adjuvant radiotherapy or chemoradiotherapy does not show significant prognostic benefit compared with no adjuvant treatment.

    • Among entities of Sedlis criteria, positive lymphovascular space invasion combined with deep 1/3 stromal invasion indicates poorer survival.

    INTRODUCTION

    In addition to positive pelvic lymph nodes,1 parametrial extension,2 and positive surgical margins,3 large tumor size, lymphovascular space invasion, and deep stromal infiltration have been identified as additional independent poor prognostic factors, irrespective of the nodal status.4 5 For women with any high risk factors, adjuvant pelvic radiation with concurrent chemotherapy is recommended over radiotherapy alone.6 For patients with negative lymph nodes, but a combination of intermediate risk factors, pelvic radiation was advocated as adjuvant treatment after radical hysterectomy and pelvic lymphadenectomy in a Gynecologic Oncology Group (GOG) trial (GOG-92).7 8 In this randomized controlled trial, after a prolonged follow-up period, the radiotherapy arm showed a statistically significant (46%) reduction in risk of recurrence compared with the observation arm. The role of adjuvant concurrent chemoradiotherapy in this sub-set of patients compared with radiation alone remains controversial and is currently being evaluated in an international phase III randomized trial (GOG-0263, NCT01101451).

    GOG-92 was conducted more than two decades ago, at which time diagnostic techniques and treatment protocol were different from those used today; and thus current application of the conclusion of GOG-92 is challenged by several recent studies showing that excellent local control can be achieved by surgery alone.9 10 Meanwhile, the results of GOG-0263 are still not available. Accordingly, the objective of this study was to evaluate the role of post-operative radiotherapy with or without concurrent chemotherapy in early-stage cervical cancer with intermediate risk factors compared with no adjuvant treatment.

    METHODS

    Patients

    Patients who underwent radical hysterectomy and pelvic lymph node dissection for International Federation of Gynecology and Obstetrics (FIGO 2009) stage IB1–IIA2 cervical squamous cell carcinoma between March 2006 and February 2014 at our institution and were pathologically confirmed to have negative lymph nodes, surgical margins, or parametrial involvement but did have intermediate risk factors as defined by the Sedlis criteria were included in our study. Patients who were treated with neoadjuvant chemotherapy, modified radical hysterectomy, or fertility-sparing surgery; had histological sub-type other than squamous cell carcinoma were excluded. All participants consented to the use of their medical records for research purposes.

    Intermediate risk was defined according to Sedlis criteria in GOG protocol 92: a tumor with positive lymphovascular space invasion with one of deep 1/3 stromal invasion, middle 1/3 stromal invasion and tumor diameter ≥2 cm, superficial 1/3 stromal invasion and tumor diameter ≥5 cm, or with no lymphovascular space invasion but with deep or middle 1/3 stromal invasion and tumor diameter ≥4 cm.

    For these intermediate-risk patients, adjuvant radiotherapy or concurrent chemoradiotherapy was recommended at our institution. The decision to recommend radiotherapy or concurrent chemoradiotherapy was at physician and patient discretion. However, a number of patients refused adjuvant treatment. Patients were classified into no adjuvant treatment, radiotherapy alone, or concurrent chemoradiotherapy groups. This study was approved by our institutional review board.

    Treatment

    Radical hysterectomy in this study was confined to type C1 surgery in the Querleu-Morrow classification system, or type III surgery in the Piver classification system. Pelvic lymphadenectomy was conducted in all cases. Pelvic radiation was given in 25 to 28 fractions for a total dose of 45 to 50.4 Gray. Patients who received radiotherapy with concurrent chemotherapy were given cisplatin in a single weekly dose of 40 mg/m2 for five to six doses concomitant with pelvic radiation.

    Statistical Analysis

    Continuous variables were described as median (IQR) and compared using Mann-Whitney U test; categorical variables were described as count (%) and compared using χ2 test or Fisher’s exact test, as appropriate. Survival curves were generated by the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariate analyses of the ability of prognostic factors to predict survival outcomes were performed using Cox proportional-hazards regression models. All statistical analyses were two-tailed, and p values of <0.05 were considered statistically significant. Statistical Software Package for Social Sciences version 23.0 (IBM corp., Chicago, Illinois, USA) was used for all analyses.

    RESULTS

    A total of 861 eligible patients were included in the study, of whom 85 underwent no adjuvant treatment, 283 underwent adjuvant pelvic radiotherapy, and 493 underwent concurrent chemoradiotherapy. Patient characteristics are shown in Table 1. The no adjuvant treatment group and the radiotherapy alone group were balanced in distribution of FIGO stage, tumor size, depth of stromal invasion, lymphovascular space invasion, Sedlis criteria, and duration of follow-up. Patients in the radiotherapy alone group were younger than those in the no adjuvant treatment group (47 vs 51 years, p=0.004). As compared with the no adjuvant treatment group, more patients in the concurrent chemoradiotherapy group had deep 1/3 stromal invasion (51.7% vs 36.5%, p=0.03) and lymphovascular space invasion (51.5% vs 35.3%, p=0.01); patients in the concurrent chemoradiotherapy group were younger (46 vs 51 years, p<0.001). When compared with the radiotherapy alone group, tumor size was smaller in the concurrent chemoradiotherapy group (p=0.005); there were, however, more cases with lymphovascular space invasion (51.5% vs 41.0%, p=0.003). Other parameters did not differ between the two groups.

    View this table:
    Table 1

    Characteristics of patients from different treatment groups

    The median follow-up period was 63 months (IQR 45 to 84). Only lymphovascular space invasion was found to be a significant prognostic factor for recurrence-free survival (p=0.04) and disease-specific survival (p=0.003) on univariate Cox regression analysis (Table 2). On multivariate analysis, lymphovascular space invasion was an independent negative prognostic factor for recurrence-free survival (HR=2.26; 95% CI 1.44 to 3.55; p<0.001) and disease-specific survival (HR=3.08; 95% CI 1.86 to 5.11; p<0.001). Another independent prognostic factor for recurrence-free survival was FIGO stage (HR=1.56; 95% CI 1.02 to 2.38; p=0.04). Adjuvant treatment was not a significant independent prognostic factor for recurrence-free survival (radiotherapy alone vs no adjuvant treatment, p=0.66; concurrent chemoradiotherapy vs no adjuvant treatment, p=0.51) and disease-specific survival (radiotherapy alone vs no adjuvant treatment, p=0.48; concurrent chemoradiotherapy vs no adjuvant treatment, p=0.63) after adjustment. Five-year recurrence-free survival and corresponding disease-specific survival were 87.1%, 84.2%, 89.6% (p=0.27) and 92.3%, 87.7%, 91.4% (p=0.20) in the no adjuvant treatment, radiotherapy alone, and concurrent chemoradiotherapy groups respectively (Figure 1). Although there were fewer pelvic recurrences in the radiotherapy alone (15/283, 5.3%) and concurrent chemoradiotherapy (13/493, 2.6%) groups compared with the no adjuvant treatment group (6/85, 7.1%), total recurrence rate (11.8% vs 14.5% vs 10.8% for no adjuvant treatment vs radiotherapy alone vs concurrent chemoradiotherapy, p=0.31) and death rate (8.2% vs 12.0% vs 8.5% for no adjuvant treatment vs radiotherapy alone vs concurrent chemoradiotherapy, p=0.26) were not different among the three groups (online supplemental table 1).

    Supplemental material

    View this table:
    Table 2

    Univariate and multivariate analyses of risk factors for recurrence-free survival and disease-specific survival in the whole cohort

    Figure 1
    Figure 1

    Kaplan-Meier curves of recurrence-free survival (A) and disease-specific survival (B) based on adjuvant treatment. Blue line: no adjuvant treatment (NAT) group, red line: radiotherapy (RT) group, green line: concurrent chemoradiotherapy (CCRT) group. Patients in the three adjuvant treatment groups had similar recurrence-free survival (RT vs NAT: p=0.54, CCRT vs NAT: p=0.76, RT vs CCRT: p=0.11) and disease-specific survival (RT vs NAT: p=0.30, CCRT vs NAT: p=0.92, RT vs CCRT: p=0.08).

    Tables 3 and 4 show the results of recurrence-free survival and disease-specific survival within sub-groups of Sedlis criteria, respectively. In all these sub-group analyses, adjuvant radiotherapy alone or concurrent chemoradiotherapy did not show a statistically significant advantage in reducing risk of recurrence or death compared with no adjuvant treatment. However, for patients with positive lymphovascular space invasion and deep 1/3 stromal invasion, risk of death was significantly lower in those treated with concurrent chemoradiotherapy than in those who underwent radiotherapy alone (HR=0.44; 95% CI 0.20 to 0.96; p=0.04). In the overall treatment effect analyses, after adjustment for the prognostic categories, patients receiving concurrent chemoradiotherapy had significant reduction in risk of relapse (HR=0.64; 95% CI 0.42 to 0.97; p=0.04) and death (HR=0.58; 95% CI 0.37 to 0.92; p=0.02) compared with those receiving radiotherapy alone. Survival of no adjuvant treatment patients and radiotherapy or concurrent chemoradiotherapy patients showed no significant difference.

    View this table:
    Table 3

    Estimated relative hazard for recurrence by prognostic sub-group, treatment effect, and 5-year recurrence-free survival by sub-group

    View this table:
    Table 4

    Estimated relative hazard for disease-specific death by prognostic sub-group, treatment effect, and 5-year disease-specific survival by sub-group

    Significant heterogeneity exists in Sedlis criteria. After adjustment for adjuvant treatment regimen, a significant increase in risk of recurrence (HR=1.88; 95% CI 1.19 to 2.97; p=0.007) and death (HR=2.36; 95% CI 1.41 to 3.95; p=0.001) occurred in patients with positive lymphovascular space invasion and deep 1/3 stromal invasion compared with those with negative lymphovascular space invasion, middle or deep 1/3 stromal invasion, and tumor diameter ≥4 cm (Tables 3 and 4). The increase in risk of death also occurred in patients with positive lymphovascular space invasion, middle 1/3 stromal invasion, and tumor diameter ≥2 cm (HR=2.07; 95% CI 1.18 to 3.64; p=0.01). Distant recurrence was more common in patients with positive lymphovascular space invasion and deep 1/3 stromal invasion than in other sub-groups (online supplemental table 2).

    DISCUSSION

    Our study showed that patients with intermediate-risk, early-stage cervical squamous cell carcinoma treated with no adjuvant treatment, radiotherapy alone, or concurrent chemoradiotherapy as adjuvant therapy after radical hysterectomy had similar recurrence-free survival and disease-specific survival. It also suggested that significant heterogeneity existed in Sedlis criteria: patients with positive lymphovascular space invasion and deep 1/3 stromal invasion had a higher risk of relapse and disease-specific death.

    The benefit of adjuvant radiotherapy in intermediate-risk cervical carcinoma was established through the seminal publication of the GOG-92 trial in 1999.7 Statistically significant reduction in risk of recurrence was observed in the radiotherapy arm (n=137) compared with the no further treatment arm (n=140), with recurrence-free rates at 2 years of 88% vs 79% for the two groups, respectively (p=0.008). After prolonged follow-up in the final report in 2005,8 increased recurrence-free survival for adjuvant radiotherapy was confirmed, although the improvement in overall survival with radiotherapy still did not reach statistical significance. Survival benefit of adjuvant radiotherapy for intermediate-risk patients was confirmed by other studies. A study reported improved recurrence-free survival but no significantly different overall survival after adjuvant radiotherapy, and reached a similar conclusion as the GOG trial.11 Benefits in both disease-free survival and cancer-specific survival from adjuvant radiotherapy were observed in the study by Pieterse et al.12 In another study, Schorge et al reported that patients with lymphovascular space invasion who received adjuvant radiotherapy were less likely to develop recurrence than those receiving surgery alone (p=0.04).13

    In contrast to the above-mentioned studies, our study showed similar disease control by surgery alone. Our study had an 87.1% of recurrence-free survival at 5 years for patients who underwent no adjuvant treatment, and evaluating the aforementioned studies, it was shown that there was a 79% recurrence-free survival at 2 years in the GOG trial,7 67.5% at 3 years in the study of Ryu et al,11 and 57% at 5 years in the study by Pieterse et al.12 This improved survival outcome in our study could be secondary to multiple factors, including a more accurate pre-operative staging system, a more precise pathological assessment of disease, and, above all, the improvement in surgical techniques, especially in parametrectomy and lymph node dissection.

    On the contrary, results of several recent studies have not been in favor of adjuvant radiotherapy for intermediate-risk patients. In a retrospective study published in 2016, none of 23 patients with two or more intermediate risk factors who underwent no further treatment experienced recurrence after an average follow-up of 82.6 months.14 One study published in 20189 compared two cohorts of intermediate-risk, lymph node-negative stage IB patients treated with radical surgery without adjuvant treatment (n=127) and with radical surgery followed by adjuvant radiotherapy (n=104), and reported 1.6% vs 0% pelvic recurrence rate for the two cohorts after a median follow-up of 6.1 years. That study illustrated a substantially excellent oncological outcome achieved by surgery alone, although the risk factors of the two cohorts were not equally balanced, with more prevalence of lymphovascular space invasion in the combined-treatment group (75.0%) than in the surgery-only group (52.8%), and no multivariate analysis was performed. Recently, a study reported only 2.5% (4/161) mortality from isolated loco-regional recurrence in intermediate-risk patients who were treated with radical hysterectomy type C2 alone.10 The differences between our study and these others might lie in our stricter inclusion criteria, more balanced prevalence of risk factors between the no adjuvant treatment and radiotherapy alone groups, and single-institutional research.

    After the illustration of benefit from addition of chemotherapy to adjuvant radiotherapy in patients with high risk factors,6 its application in intermediate-risk cervical cancer was examined. Significantly better progression-free survival (p=0.0026) and overall survival (p=0.0435) in the concurrent chemoradiotherapy group compared with the radiotherapy alone group was observed in the study of Mabuchi et al, although only a small number of patients were enrolled (22 patients in the concurrent chemoradiotherapy group and 35 patients in the radiotherapy group).15 Two studies from one institution showed significantly better recurrence-free survival yet more common hematologic toxicities with adjuvant chemoradiotherapy.16 17 Although longer progression-free survival (90.2% vs 77.5%, p=0.049) and overall survival were shown with concurrent chemoradiotherapy relative to radiotherapy in the study of Okazawa et al,18 the difference in progression-free survival was marginal on multivariate analysis (HR=2.82; 95% CI 0.99 to 8.02; p=0.053) and the advantage for overall survival was not significant (p=0.40) despite a larger sample size than the above-mentioned three studies (89 patients in the concurrent chemoradiotherapy group and 40 patients in the radiotherapy group). Similar findings were demonstrated in another study19: the 5-year overall survival was 87% and 81% (p=0.6) in the concurrent chemoradiotherapy and radiotherapy alone groups, respectively. That study, to our knowledge, was the largest study to examine the effect of adjuvant concurrent chemoradiotherapy in intermediate-risk cervical cancer, in which concurrent chemoradiotherapy or radiotherapy alone was delivered in 440 and 429 patients, respectively. In our study, although concurrent chemoradiotherapy was associated with improved recurrence-free survival and overall survival in comparison with radiotherapy alone on multivariate analysis, the difference in recurrence-free survival and overall survival was relatively small (5-year recurrence-free survival, 89.6% vs 84.2%; 5-year overall survival, 91.4% vs 87.7%), and there was no significant difference on univariate analysis. Moreover, no significant difference was observed between no adjuvant treatment and concurrent chemoradiotherapy on both univariate and multivariate analyses.

    Difference in prognosis among entities of Sedlis criteria also existed in the original GOG-92 trial. A marked increase was seen in risk of recurrence and death in patients with positive lymphovascular space invasion and deep 1/3 stromal invasion relative to those with negative lymph vascular space invasion, middle stromal invasion, and tumor diameter ≥4 cm (HR for recurrence=3.74, 90% CI 1.39 to 10.04; HR for death=2.99, 90% CI 1.26 to 7.11). The increase was also seen in a study published in 1999.20 However, recurrence rate did not vary significantly among sub-groups of Sedlis criteria in the study of Ryu et al.11 In our study, we also found that compared with other sub-groups of Sedlis criteria, distant recurrence was more common in patients with positive lymphovascular space invasion combined with deep 1/3 stromal invasion (10.9%, 21/193). In this sub-set of patients in GOG-92, those treated with adjuvant radiotherapy had better recurrence-free survival than those with no further treatment (HR=0.53; 95% CI 0.30 to 0.93), whereas in our study, those treated with adjuvant concurrent chemoradiotherapy had better disease-specific survival than those with adjuvant radiotherapy alone (HR=0.44; 95% CI 0.20 to 0.96); no significant difference in recurrence-specific survival and disease-specific survival existed between the no adjuvant treatment and concurrent chemoradiotherapy groups.

    Limitations of our study include the retrospective nature of the study, limited number of patients in the no adjuvant treatment group, lack of morbidity assessment, and lack of pathology review to validate risk factors. As a retrospective study, selection bias was not avoidable. The prevalence of risk factors among the three groups was not equally balanced, especially between the no adjuvant treatment and concurrent chemoradiotherapy groups, with lymphovascular space invasion and deep 1/3 stromal invasion being more frequent in the latter group. Nevertheless, the baseline characteristics were well balanced between the no adjuvant treatment and radiotherapy alone groups, except for patients being younger in the radiotherapy alone group. Furthermore, to reduce the impact of this imbalance, Cox proportional-hazards models and stratified analyses based on four sub-groups of Sedlis criteria were employed.

    In conclusion, our study showed that radical surgery alone may achieve equal survival for patients with intermediate-risk, early-stage cervical cancer in comparison with combined surgery and radiotherapy or chemoradiotherapy. Among entities of Sedlis criteria, positive lymphovascular space invasion combined with deep 1/3 stromal invasion indicated poorer survival. Intermediate-risk patients who would benefit from a combined treatment should be redefined in the present circumstances with modern imaging, accurate pathology assessment, and improved surgical standards.

    Acknowledgments

    We thank all the doctors, nurses, and women who participated for their generous support offered to the present study.

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    Supplementary materials

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    Footnotes

    • LC and HW contributed equally.

    • Contributors All authors contributed to study design, data interpretation and writing. Data analysis and manuscript writing was primarily performed by LC.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available upon reasonable request. The data are de-identified participant data.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.