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Original research
Impact of vaginal brachytherapy on survival in stage I endometrioid endometrial carcinoma
  1. Mariam AlHilli1,
  2. Sudha Amarnath2,
  3. Paul Elson3,
  4. Lisa Rybicki3 and
  5. Sean Dowdy4
  1. 1 Subspeciality Care for Women's Health, Cleveland Clinic, Cleveland, Ohio, USA
  2. 2 Radiation Oncology, Cleveland Clinic, Cleveland, Ohio, USA
  3. 3 Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA
  4. 4 Gynecologic Surgery, Mayo Clinic, Rochester, New York, USA
  1. Correspondence to Dr Mariam AlHilli, Cleveland, Ohio, USA; alhillm{at}ccf.org

Abstract

Objective To evaluate trends in use of radiation therapy and its impact on overall survival in low- and high-grade stage I endometrioid endometrial carcinoma.

Methods Patients with stage I endometrial cancer who underwent hysterectomy from 2004 to 2013 were identified through the National Cancer Database and classified as: stage IA G1/2, stage IA G3, stage IB G1/2, and stage IB G3. Trends in use of vaginal brachytherapy and external beam radiation therapy were assessed. Overall survival was measured from surgery and estimated using the Kaplan-Meier method. The effect of radiation therapy on overall survival was assessed within each stage/grade group using Cox proportional hazards analysis in propensity-matched treatment groups.

Results A total of 132 393 patients met inclusion criteria, and 81% of patients had stage IA and 19% had stage IB endometrial cancer. Adjuvant therapy was administered in 18% of patients: 52% received vaginal brachytherapy, 30% external beam radiation therapy, and 18% chemotherapy ±radiation therapy. External beam radiation therapy use decreased from 9% in 2004 to 4% in 2012, while vaginal brachytherapy use increased from 8% to 14%. Stage IA G1/2 patients did not benefit from either external beam radiation therapy or vaginal brachytherapy, while administration of vaginal brachytherapy improved overall survival in stage IB G1/2 compared with no treatment (p<0.0001). In stage IB G1/2 and stage IA G3, vaginal brachytherapy was superior to external beam radiation therapy (p=0.0004 and p=0.004, respectively). Stage IB G3 patients had improved overall survival with either vaginal brachytherapy or external beam radiation therapy versus no treatment but no difference in overall survival was seen between vaginal brachytherapy and external beam radiation therapy (p=0.94).

Conclusions The delivery of adjuvant radiation therapy in patients with stage IA G1/2 endometrial carcinoma is not associated with improvement in overall survival. Patients with stage IB G1/2 and G3 as well as stage IA G3 are shown to benefit from improved overall survival when adjuvant radiation therapy is administered. These findings demonstrate potential opportunities to reduce both overtreatment and undertreatment in stage I endometrial cancer patients.

  • radiotherapy
  • endometrial neoplasms
  • uterine neoplasms

https://doi.org/10.1136/ijgc-2019-001182

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    Highlights

    • Use of vaginal brachytherapy has increased and external beam radiation therapy has decreased over time in the USA.

    • Patients with stage IA grade 1 and 2 do not benefit from adjuvant radiation.

    • Adjuvant radiation improves survival in stage IB grade 1 and 2 and stage IB grade 3.

    Introduction

    Endometrial cancer is the second most common gynecologic malignancy worldwide. Patients with uterine confined disease (stage I) represent approximately 75% of all patients with endometrial cancer.1 These patients have an excellent prognosis, and 5-year survival rates are generally well above 85%.2 3 However, stage I consists of a heterogeneous group of patients. Although less than 10% of women treated with surgery alone have a recurrence, certain subgroups are at substantial risk for locoregional recurrence and benefit from adjuvant therapy.

    Adjuvant therapy in patients with early-stage endometrioid endometrial cancer is generally administrated based on patient and tumor-specific risk factors such as age, deep myometrial invasion, tumor size, cervical stromal invasion, lymphovascular space invasion, and high-grade (grade 3) histology.1 4 Studies that explore adjuvant radiation therapy in stage I endometrial cancer have consistently shown an improvement in pelvic recurrence rate in high-risk subgroups.5 6 6–9 A recent randomized trial in high-risk and high-intermediate-risk patients with early-stage endometrial cancer (GOG 249) showed no difference in recurrence-free survival or overall survival with the use of vaginal brachytherapy (with chemotherapy) compared with external beam radiation therapy.10 Since patients with early-stage endometrial cancer generally have an excellent survival, randomized trials of adequate power to detect differences in overall survival are generally not feasible, and overall survival has not been used a primary outcome in most randomized trials to date. Therefore, there is a strong need to more clearly define the role of adjuvant radiation therapy in improving long-term overall survival in early-stage endometrial cancer using large population-based datasets in order to optimize treatment effectiveness while minimizing adverse effects. Few large population-based studies have been performed in patients with stage I endometrial cancer to determine if a survival benefit can be seen with larger sample size.11–14 Results of prior studies have shown conflicting results primarily due to the heterogeneity of patients within the substages of stage I endometrial cancer as well as variable definitions used to classify risk groups.11 12 The objective of this study was to evaluate trends in use of radiation therapy and assess its impact on overall survival in low-grade (G1/2) and high-grade (G3) stage I endometrioid endometrial cancer using a large population-based database.

    Methods

    The National Cancer Database (NCDB) was queried to identify patients with endometrial cancer diagnosed from 2004 to 2013. The analysis focused on patients with stage I, type I disease (endometrioid histology), including all grades. Patients were excluded if they met any of the following criteria: non-endometrioid histology, stage greater than IB, initial treatment non-surgical, missing post-operative treatment data or survival data, or if death occurred within 4 months of surgery and no adjuvant therapy was given. Survival was available for patients diagnosed from 2004 to 2012. NCDB data are de-identified to be compliant with the Health Insurance Portability and Accountability Act, thus institutional review board approval was not required to conduct the study.

    Patients with International Federation of Gynecology and Obstetrics (FIGO) stage 1 endometrioid endometrial cancer were divided into risk groups. The 2009 FIGO staging system was used. In order to account for changes in staging classification during the study period, patients defined as stage IA in this study included patients with stage IA or IB prior to 2009 and IA during or after 2009. Patients with stage IC prior to 2009 were grouped with stage IB during or after 2009 and referred to as stage IB. Patients were subsequently classified into four treatment groups: (1) stage IA grade 1 or grade 2, (2) stage IA grade 3, (3) stage IB grade 1 or 2, and (4) stage IB grade 3. Use of vaginal brachytherapy and external beam radiation therapy was determined, and trends in the use of radiation from 2004 until 2012 were evaluated.

    Demographic and clinical factors including age, race, stage, and co-morbidities (Charlson-Deyo Index) were reviewed. Other demographic and socioeconomic factors such as residence, income, education, insurance, treating facility, and distance to treating facility were included in the analysis. Adjuvant therapy was defined as radiation therapy, chemotherapy, or hormonal therapy given within 4 months of surgery. Treatment was considered multimodal if the patient was initially treated with radiation and then received chemotherapy or hormonal therapy within 90 days of the radiation; or if the patient received chemotherapy/hormonal therapy initially and then radiation within 6 months of the start of the systemic therapy. No attempt was made to determine if concurrent radiation therapy with systemic treatment was given beyond identifying those patients who were reported to have started radiation therapy and systemic therapy on the same day.

    Statistical Analysis

    Overall demographic and clinical data and trends in use of radiation therapy were based on data from 132 393 women. Patients with systemic therapy (with or without radiation therapy) were excluded from the remainder of the analysis. Therefore, treatment group comparisons of study factors were based on data from 128 004 women who had no treatment, vaginal brachytherapy only, or external beam radiation therapy only.

    Continuous study factors are described as median and IQR; and categorical factors are described as percentages. Factors were compared among treatment groups with Chi-square or Kruskal-Wallis test. Overall survival was measured from the date of surgery and estimated using the Kaplan-Meier method; 5-year estimates and SE are presented. Because most factors differed among treatment groups, propensity analysis was used to identify treatment groups that were well-matched on the basis of these factors separately for each stage/grade group. Propensity scores were calculated from a multinomial regression model that modeled treatment as a function of the following factors: year of diagnosis, age, race, income, education, residence, insurance, treating facility, distance from facility, cancer history, co-morbidities, days from diagnosis to hysterectomy, and lymphovascular space invasion. Propensity scores were used to identify treatment groups that were similar with respect to all factors included in the propensity model. After propensity matching, treatment group comparisons of overall survival were based on data from 17 112 women which reflect those of the original cohort of 128 004 patients.

    Cox proportional hazards analysis was then used to determine the effect of treatment on survival; results are summarized as HR and 95% CI. Analyses were done with SAS software, version 9.4 (SAS Institute, Inc., Cary, NC, USA). All statistical tests were two-sided. A p value <0.05 was used to indicate statistical significance.

    Results

    Among 349 404 women diagnosed with endometrial cancer from 2004 to 2013, 132 393 (38%) were eligible for analysis. The median age at diagnosis was 61 (IQR 54–69) years. Some 10% of patients had a prior cancer and 25% had at least one significant co-morbidity as characterized by the Charlson-Deyo Index (Table 1); 81% of patients had stage IA disease (48%, 25%, and 8% grade 1, 2, and 3, respectively) and 19% were stage 1B (8%, 7%, and 4% grade 1, 2, and 3, respectively). Adjuvant therapy was administered in 18% of patients overall: 11% vaginal brachytherapy with or without systemic therapy, 6% external beam radiation therapy with or without systemic therapy, and 1.7% systemic therapy alone. Vaginal brachytherapy use increased from 8% in 2004 to 14% in 2012, while external beam radiation therapy use decreased from 9% to 4% (Figure 1). Estimated 5-year overall survival was 90%±0.1% among all patients.

    View this table:
    Table 1

    Demographic and clinical characteristics of all 132 393 patients with stage I endometrial cancer including prevalence of use of adjuvant treatment modalities

    Figure 1
    Figure 1

    Trends in use of vaginal brachytherapy (VBT) and external beam radiation therapy (EBRT) over time during the period 2004–2012.

    Not surprisingly, among all patients, treatments differed by stage and grade. Of patients with stage IA grade 1–2 disease, 92% received no adjuvant treatment, 7% were treated with adjuvant external beam radiation therapy or vaginal brachytherapy with or without systemic therapy, and 1% were treated with systemic therapy alone. This compares to 54%, 45%, and 1% in stage IB grade 1–2; 59%, 36%, and 6% in stage IA grade 3; and 38%, 57%, 8% in stage IB grade 3, respectively. Figure 2 shows overall survival by each stage/grade group.

    Figure 2
    Figure 2

    Overall survival by stage/age group.

    Treatment group comparison of study factors based on data from 128 004 women who had no treatment, vaginal brachytherapy only, or external beam radiation therapy only is shown in Table 2. Most study factors differed among patients who received no treatment or who were treated with vaginal brachytherapy only or external beam radiation therapy only. However, due to the large study size, some of these differences are not clinically relevant.

    View this table:
    Table 2

    Comparison of demographic and clinical characteristics among patients with stage I endometrial cancer who were treated with vaginal brachytherapy alone, external beam radiation therapy alone, or no treatment

    Table 3 illustrates 5-year overall survival for each treatment group from the cohort of 17 112 propensity-matched patients. As shown, treatment had no effect on survival in patients with stage IA grade 1–2 disease (Table 3, Figure 3A). Five-year overall survival was 91% with vaginal brachytherapy, 89% with external beam radiation therapy, and 91% with no treatment. In stage 1B grade 1–2 disease, improved survival was seen with both vaginal brachytherapy (HR 0.64, 95% CI 0.56 to 0.73, p<0.0001) and external beam radiation therapy (HR 0.81, 95% CI 0.72 to 0.92, p=0.001) relative to no treatment. In addition, vaginal brachytherapy had superior survival to external beam radiation therapy (HR 0.78, 95% CI 0.68 to 0.90, p=0.0004). Five-year overall survival was 89% with vaginal brachytherapy, 87% with external beam radiation therapy, and 83% with no treatment (Table 3, Figure 3B).

    View this table:
    Table 3

    Propensity-matched survival analysis for patients who received no treatment, vaginal brachytherapy alone, or external beam radiation therapy alone

    Figure 3
    Figure 3

    (A) Propensity-matched survival for patients with stage IA grade 1 or 2. (B) Propensity-matched survival for patients with stage IB grade 1 or 2. (C) Propensity-matched survival for patients with stage IA grade 3. (D) Propensity-matched survival for patients with stage IB grade 3. EBRT, external beam radiation therapy; VBT vaginal brachytherapy

    With regard to patients with grade 3 disease, those with stage IA disease did not benefit from either external beam radiation therapy (HR 1.13, 95% CI 0.91 to 1.41, p=0.26) or vaginal brachytherapy (HR 0.81, 95% CI 0.64 to 1.02, p=0.07) relative to no treatment. However, vaginal brachytherapy had superior survival to external beam radiation therapy (HR 0.71, 95% CI 0.57 to 0.90, p=0.004). Five-year overall survival was 87% with vaginal brachytherapy, 79% with external beam radiation therapy, and 83% with no treatment (Table 3, Figure 3C). In patients with stage 1B grade 3, significant improvement in survival was seen with both vaginal brachytherapy (HR 0.82, 95% CI 0.68 to 1.00, p=0.04) and external beam radiation therapy (HR 0.83, 95% CI 0.69 to 1.00, p=0.05) compared with no treatment. No survival difference was seen between vaginal brachytherapy and external beam radiation therapy (p=0.94). Five-year overall survival was 71% with vaginal brachytherapy, 73% with external beam radiation therapy, and 66% with no treatment (Table 3, Figure 3D).

    Discussion

    Patients with early-stage endometrioid endometrial cancer, and particularly those with low-grade histology (defined as FIGO grade 1 or 2) are known to have excellent survival rates compared with many other cancers. This survival advantage is attributed to an inherently low risk of disease recurrence and high salvage rates of recurrent disease. The merits of adjuvant therapy in the population of patients with early-stage disease has been the subject of debate among gynecologic oncologists for decades. Large prospective clinical trials have been conducted to answer this question.5 7 8 15 16 Despite the selection of patients at highest risk of recurrence (high-intermediate-risk disease) based on pre-specified criteria, a survival benefit to the delivery of adjuvant radiation therapy has not been demonstrated in prospective clinical trials available to date.

    Our analysis of radiation therapy use in 17 112 propensity-matched patients with stage I endometrioid endometrial cancer showed that significant survival advantage for the delivery of radiation therapy use (either vaginal brachytherapy or external beam radiation therapy) compared with no further treatment in patients with stage IB grade 1 or 2 disease in addition to those with stage IB grade 3. Vaginal brachytherapy was associated with a HR of 0.64 of death and external beam radiation therapy HR of 0.81 in stage IB grade 1 or 2 patients. Herein, we reiterate the prognostic value of myometrial invasion in defining risk groups and triaging patients to adjuvant therapy in early-stage endometrial cancer. Among the two radiation therapy modalities, vaginal brachytherapy was found to be superior to external beam radiation therapy with regard to overall survival, which could be possibly explained by increased rate of toxicity and higher risk of secondary malignancy associated with external beam radiation therapy.3 As shown in our study as well as others, patients with stage IB grade 3 endometrial cancer represent the highest risk population of early-stage endometrial cancer. These patients have been consistently found to have a poor prognosis and a high rate of distant recurrence despite the use of contemporary therapies.17 18 In PORTEC 3, which included patients with high-risk stage I (deep myometrial invasion and grade 3 histology as well as stage 1 grade 3 with lymphovascular space invasion), there was no added benefit demonstrated to the addition of chemotherapy to external beam radiation therapy in early-stage patients.19 Therefore, the value of adjuvant therapy in this high-risk population likely lies in the use of external beam radiation therapy as a primary adjuvant therapeutic modality that provides the highest impact on survival.

    The increased trend in the use of vaginal brachytherapy and decrease in external beam radiation therapy reflects a prominent change in the treatment paradigm for patients with endometrial cancer even prior to publication of the results of PORTEC-2 in 2010.20 21 PORTEC-2, was a non-inferiority prospective randomized trial of vaginal brachytherapy compared with external beam radiation therapy that found that the rate of vaginal recurrence was not affected by either radiation therapy modality in high- intermediate-risk patients (defined as patients with two of three of the following: age >60 years, grade 3, or outer half myometrial invasion myometrial invasion).8 PORTEC-2 also demonstrated a higher rate of toxicity in patients receiving external beam radiation therapy without a significant impact of either vaginal brachytherapy or external beam radiation therapy on overall survival.20 Our results show improvements in overall survival when adjuvant radiation therapy is used in patients with grade 1 or 2, stage IB tumors in addition to stage IB grade 3 patients. Despite the trend of increasing use of vaginal brachytherapy shown, approximately 54% of patients with stage IB grade 1 or 2 endometrial cancer did not receive any form of adjuvant therapy. These results provide an opportunity for quality control, and the evaluation of disparities in receipt of adjuvant radiation in early-stage endometrial cancer. Conversely, nearly 8000 patients in our study cohort received vaginal brachytherapy with no suggestion of benefit. At a cost of over US$20 000 per patient, appropriate use of vaginal brachytherapy represents an important opportunity to reduce costs of endometrial cancer treatment.

    It is important to acknowledge prior publications that evaluated the role of radiation therapy in early-stage endometrial cancer through the NCDB similar to our study. Wong et at evaluated patients with stage IA and IB endometrial cancer and found that delivery of external beam radiation therapy (external beam radiation therapy ± vaginal brachytherapy was associated with improved survival in patients in stage IB grade 1, grade 2, and grade 3 endometrial cancer, whereas for patients with stage IA disease there was no benefit to the addition of radiation therapy across all three grades.22 Our study derived similar conclusions. However, we were able to demonstrate a differential effect of vaginal brachytherapy compared with external beam radiation therapy in patients with stage IB grade 1 and grade 2 as well as stage IA grade 3. In light of the increasing trend in the use of vaginal brachytherapy over time, our results are informative and support current national consensus guidelines.23–25 Rydzewski et al evaluated patients with stage IA and IB endometrial cancer diagnosed between 2007 and 2011. Their study noted a reduction in mortality associated with use of vaginal brachytherapy for both stage IA and IB endometrial cancer, which is contrary to our study. In the former study, patients were not stratified by histologic grade which implies that the benefit of vaginal brachytherapy seen in stage IA patients is likely due to the inclusion of patients with grade 3 histology. Additionally, propensity matching was not used.12 Furthermore, our study included a larger number of patients than the studies by Wong and Rydzeweski et al due to the addition of those treated in 2012 to the survival analysis. Harkenrider et al performed a similar evaluation of patients with early-stage endometrial cancer and found that the survival benefit of adjuvant radiation therapy was limited to patients with high-intermediate-risk or high-risk endometrial cancer.11 The effect of treatment modality (vaginal brachytherapy vs external beam radiation therapy) was not specifically assessed in their study and propensity matching was not used.

    Our study suffers from limitations which are inherent to the use of a large cancer registry. The difficulty in data scrutiny and possibility of misclassification of histologic diagnoses or treatment parameters are potential pitfalls of the database. We included patients with endometrial cancer regardless of the extent of surgical staging or information on lymphadenectomy as this variable is incompletely captured within the NCDB. In addition, information on cause of death, disease recurrence, and treatment after recurrence is not reported in the NCBD, which does not allow us to draw conclusions about disease-specific survival or recurrence-free survival. Although factors other than stage and grade may have contributed to survival outcomes and treatment decisions in our study, it is felt that these biases were diminished through propensity-matched analysis and the inclusion of a large number of patients. Furthermore, we opted for a simplified approach to categorization of early-stage endometrial cancer (using grade and stage), which does not include other variables that could potentially impact prognosis such as extent of lymphadenectomy, tumor diameter, and lymphovascular space invasion. As the reporting of these factors is inconsistent in the NCDB, a more granular risk stratification cannot be achieved. Since the impact of adjuvant radiation therapy on overall survival in early endometrial cancer cannot be demonstrated in a rigorous prospective trial due to insufficient power, the analysis of large population-based data such as the NCDB, is the most appropriate platform in which overall survival can be evaluated.

    Endometrial cancer is increasingly being recognized as a heterogeneous disease with unique molecular and biologic prognosticators outside of histology and stage. In the era of high-throughput genomic testing and emerging clinical trials that investigate novel therapeutic agents, it is anticipated that molecular predictive biomarkers will likely augment or replace traditional risk factors used in risk stratification and treatment decision-making in the future to provide an individualized approach to therapy.

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    Footnotes

    • Contributors Writing and editing: MMH, LR, SA, SCD. Concept development: MMH, SA, SCD. Statistical analysis: PE, LR. All authors gave final approval of the version published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

    • 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 may be obtained from a third party and are not publicly available. De-identified data were obtained from the National Cancer Database (American College of Surgeons) in compliance with the Health Insurance Portability and Accountability Act. These data are available upon request.