In China, endometrial cancer (EC) is the second common gynecological malignancy in women, with about 63,400 cases diagnosed and 21,800 of related deaths in 2015. The Gynecologic Oncology Group (GOG)-99 trial and the post-operative radiation therapy in endometrial carcinoma (PORTEC)-1 trial demonstrated that radiation therapy (RT) reduced locoregional recurrences (LRs) but did not have an impact on overall survival (OS).[2–4] Recently, an analysis of the National Cancer Data Base (NCDB) showed that the improvement in local control with adjuvant RT leads to improved OS in stage I high-intermediate risk (HIR) EC, adjuvant RT was associated with a statistically significant 4.1% improvement in 5-year OS comparing to surgery alone.
Classification of the risk group is essential for choosing the specific radiotherapy strategy for each patient. Vaginal recurrence from EC with HIR after surgery constitutes more than 70% of all LRs, and vaginal cuff brachytherapy (VBT) is one of the suitable treatment options to reduce vaginal recurrence risk.[2,3] VBT alone or in combination with external beam radiotherapy (EBRT) have become an important component in the post-operative management of EC. Especially PORTEC-2 found that VBT was as effective as EBRT in locoregional control and was substantially less toxic for HIR cases. Multi-channel applicators (MCA) could significantly optimize target coverage and reduce dose to organs at risk (OARs) compared with single-channel applicators (SCA) through modulation of dwell time and positions in different channels.[7–9] However, there are only very few reports on clinical outcomes using MCA.
In Peking Union Medical College Hospital, we used in-house made multi-channel applicators (IH-MCA) for the post-operative VBT alone or as a boost after EBRT from 2003. The purpose of this study was to evaluate the clinical experience of treating IR to HR stage I EC using IH-MCA in a single institution.
The study was approved by the Institutional Research Ethics Committee of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (No. S-K139). After Institutional Review Board approval, we retrospectively reviewed the medical records of patients in our EC database. We identified 390 consecutive women with EC who underwent total abdominal hysterectomy, salpingo-oophorectomy, with or without pelvic and para-aortic lymph node dissection between January 2003 and December 2015. All patients had 2009 stage I, IR to HR disease, World Health Organization performance score 0 to 2, and had a minimum of 3 months of follow-up after hysterectomy. IR to HR features were defined according to the PORTEC criteria, and we defined stage IB grade 3, non-endometrioid type as the high-risk group.[2,10]
All patients received post-operative VBT which was delivered using an afterloading high dose rate (HDR) 192Ir source. The dose of VBT was prescribed to a depth of 0.5 cm to cover vaginal cuff and proximal one-half of the vagina. The prescriptions were 500 cGy per fraction for a total of 5 to 6 fractions for brachytherapy alone or 400 to 600 cGy per fraction for 2 to 3 fractions if it was combined with EBRT. The target volume of EBRT consisted of the previous site of the vaginal cuff, the parametria, the proximal two-thirds of the vagina, and the lymphatic drainage regions. The total dose of EBRT to be delivered to this volume was 45.0 to 50.4 Gy using 1.8 to 2.0 Gy daily fractions, 5 days a week. The radiation was delivered by a four-field box technique or intensity-modulated radiation therapy.
The majority of the patients were treated by in-house made rigid type MCA (Patent No. ZL201320564893.3) for VBT. The device includes an interchangeable MCA, applicator connecting pipe, pipe joint, telescopic stent, and bracket rod. While seven-channel applicator was the most used applicator. In the seven-channel applicator, one central channel and six peripheral channels formed a cylindrical seven-channel applicator with a diameter of 26 mm. From 2015, we began to use in-house made MCA with 3-dimension (3D) printing technology, especially for patients with special post-operative vaginal anatomy, such as “Dog-ear,” colpostenosis, and other irregular anatomy structure [Figures 1A and 1B].
Brachytherapy treatment planning
Brachytherapy prescription dose per fraction to 400 to 600 cGy and optimized plan to cover at least 90% of the clinical target volume (CTV) by the prescription dose. The CTV was defined as a 0.5-cm uniform expansion of the applicator surface from vaginal cuff and proximal one-half of the vagina excluding bladder, rectum, and applicator volume. Treatment plans using in-house made rigid type MCA and in-house made 3D printing MCA are shown in Figure 2.
Patients were assessed every 3 to 6 months for the first 2 years, every 6 to 12 months during the following 3 years, and then annually. Patterns of recurrence were recorded by the sites of treatment failure (TF): LR and distant metastasis (DM). LR was defined as vaginal or/and pelvic recurrences. DM included all recurrence outside the pelvis and distant metastatic disease. Progression-free survival (PFS) was defined as the time from radiotherapy to the occurrence of the first failure either locoregional or distant, and OS was defined as the time from radiotherapy to death due to EC or any other causes. Treatment complications were graded according to the Radiation Therapy Oncology Group criteria for side effects.[11,12]
PFS and OS rates were calculated using the Kaplan-Meier method, and possible prognostic factors were evaluated by log-rank test. Possible prognostic factors include age, anemia, diabetes mellitus, hypertension, stage (International Federation of Gynecology and Obstetrics [FIGO] 2009), grade, pathological types, risk stratification, lymphovascular space invasion (LVSI), lower uterine segment involvement (LUSI), surgery, radiotherapy, applicators, and chemotherapy.
Cox proportional hazards regression model was used for univariate and multivariate analysis. Statistical analyses were performed with SPSS, version 20.0 (International Business Machines Corporation, Armonk, NY, USA). And two-tailed P values lower than 0.05 were considered statistically significant.
The characteristics of patients are summarized in Table 1. And all patients were re-staged based on FIGO 2009 criteria. The median age was 58 years (range 28–85 years). Pelvic and para-aortic lymph node dissection were performed in 293 (75.1%) patients, and the median number of lymph nodes resected was 24 (range 6–65). One hundred and eighty-three patients were staged as Ia (FIGO 2009), and 207 patients were staged as Ib. According to our risk stratification criteria, the ratios of IR, HIR, and HR were respectively 65.6%, 24.4%, and 10.0%. Fifty-seven patients (14.6%) had presence of LVSI and 30.3% had LUSI. Of the entire cohort, 62.8% received adjuvant VBT alone (n = 245), 37.2% received a combination of EBRT and VBT (n = 145), and 10.0% received chemotherapy (n = 39).
Follow-up rate was 92.8%, and the median follow-up time, calculated from the date of radiotherapy, was 48 months (range 4–172 months). The 5-year OS and PFS were 96.3% and 92.1%, the 10-year OS and PFS were 89.7% and 87.9%, respectively. When age (<60 vs. ≥60 years), stage (Ia vs. Ib), grade (G1-2 vs. G3), risk stratification (IR vs. HR/HIR), LVSI (yes vs. no), LUSI (yes vs. no), and radiotherapy (VBT vs. EBRT + VBT) were analyzed for OS and PFS with univariate and multivariate analyses, only age and grade were found to be the significant prognostic factors for OS [Tables 2 and 3]. Patients aged <60 years had significantly higher OS than patients age ≥60 years. For patients younger than 60 years old, the 5- and 10-year OS rate was 96.0% and 96.0%, compared with 96.9% and 78.7% for those older than 60 years old (hazard ratio: 0.368, 95% confidence interval [CI]: 0.131–1.035, P = 0.048). Similarly, the OS rate of patients with G3 was lower than that of patients with G1-2 (hazard ratio: 0.576, 95% CI: 0.347–0.958, P = 0.026) [Figure 3]. None of the other prognostic factors were correlated with OS and PFS.
Patients’ age <60 years had significantly higher 10-year OS than patients’ age ≥60 years (96.0% vs. 78.7%, hazard ratio: 0.368, 95% CI: 0.131–1.035, P = 0.048). Patients with high-grade histology (G3) has significantly lower 10-year OS than patients with low-grade histology (G1-2) (83.4% vs. 92.1%, hazard ratio: 0.576, 95% CI: 0.347–0.958, P = 0.026).
Of the 390 patients, 22 (5.6%) developed recurrences. The median survival time after recurrences was 22 months (range 4–52 months). The rate of recurrence patterns was as follows: vagina 1.0% (four patients), pelvis 1.8% (seven patients), and distantly 4.9% (19 patients). Two patients had isolated relapse in vagina, and the site of vaginal relapse was lower vagina outside the irradiated volume. The sites of DM included retroperitoneal region, omentum, abdominal wall, lung, brain, inguinal lymph node, and bone. Eleven patients died of disease progression or disease-related complications. Two vaginal recurrences, one lung metastasis, and one brain metastasis were salvaged by RT and surgery. Furthermore, the retroperitoneal regional metastasis and other DM mainly underwent EBRT and chemotherapy. Factors predictive of TF included anemia, tumor grade, and LUSI (hazard ratio: 0.324, 95% CI: 0.126–0.835, P = 0.014; hazard ratio: 0.0.579, 95% CI: 0.351–0.963, P = 0.038; hazard ratio: 0.654, 95% CI: 0.430–0.993, P = 0.04).
In this study, 17.2% of patients experienced acute Grade 1 and 2 gastrointestinal (GI) toxic effects, and EBRT + VBT demonstrated higher acute GI toxicity of 25.5% (37/145) compared with VBT alone 12.2% (30/245). Forty-four patients (11.3%) experienced acute Grade 1 and 2 genitourinary toxic effects, no Grade 3 and greater. Late grade 3 GI toxic effects were reported in two (0.1%) patients receiving EBRT + VBT and no one receiving VBT. Those two patients received surgery for bowel obstruction due to adhesions. No treatment-related deaths occurred.
Although guideline recommendations have been published by the American Society for Radiation Oncology (ASTRO) and American Brachytherapy Society (ABS) to guide practitioners at delivering VBT for post-operative early-stage EC appropriately,[13,14] there is marked heterogeneity in terms of applicator selection, dose-fractionation schedules, prescription depth, and vaginal length treated. In most treatment centers, the proximal one-half to two-thirds of the vagina is treated with cylindrical applicators,[14–19] because the shape of the post-operative vagina is cylindrical. In recent years, MCA has received more attention due to its dosimetric advantages, including more homogeneous and conformal target dose coverage, reduced unnecessary dose to OARs.[7–9] There are rarely papers on clinical outcomes using MCA. Our study is the first report on long-term clinical results using MCA in China. Ten-year clinical results of using IH-MCA in our hospital showed that, for patients with IR to HR early-stage EC, adjuvant VBT alone and in combination with EBRT led to excellent survival and recurrence rates with low complication rates. The 5-year and 10-year OS were 96.3% and 89.7%, respectively. From our practical experience, self-made simply equipped MCA was the extremely convenient and economic applicator for post-operative VBT. Furthermore, custom-made 3D printing MCA provided more individualized choices to treat different and complicated anatomical variations.
Adjuvant RT has been controversial in the post-operative management of early-stage EC for a long time. PORTEC-1 and GOG-99 studies both showed that adjuvant RT decreased the local relapse rate from 12%–15% to 3%–6% for IR patients with EC, and decreased the risk of relapse from 18%–26% to 5%–6% for HIR disease.[2–4] Our data showed the similar results with the rate of recurrences at 5.6% and the rate of LR at 1.5%, which is in accordance with the literature by Solhjem et al, in which the total pelvic and vaginal recurrence rate has been reported as 1.7% in a total of 2042 patients treated with adjuvant VBT. The major pattern of recurrence remained DM, and the DM rate was 4.9%. Only two patients had isolated vaginal failure outside the irradiated volume. Both of them were salvaged successfully with RT and surgery. The other two patients developed vaginal apex failure and simultaneous multiple distant metastases. NCDB data analysis showed that the improvement in local control with adjuvant RT leads to a statistically significant 4.1% improvement in 5-year OS for HIR EC, even to patients who underwent lymph node dissection, adjuvant RT was still associated with improved OS. It is an exciting result that local control benefit for stage I HIR patients with EC could be converted into survival increases. In our cohort, the survival results were excellent with 5-year OS 96.3% and 5-year PFS 92.1%, probably because the proportion of IR group (65.6%) was slightly higher. The 10-year OS of the HR and HIR groups was lower than that of the IR group (77.7% vs. 95.4%), but it was not statistically significant.
Given the pattern of local-regional failure of EC and relatively poor outcomes with salvage therapy, VBT may be an important component of adjuvant RT for many patients. Usually, VBT involves the insertion of a rigid SCA into the vagina for treatment. Although the shape of the post-operative vagina is cylindrical, the vaginal cuff, which is the target of treatment, could have a “dog-ear” shape and therefore treatment delivered by using a SCA might be inadequate. Moreover, SCA offers limited possibilities to optimize the treatment plan because of its radial symmetry of dose distribution. In order to improve the capabilities of VBT, MCA has been developed and used extensively. Our previous results confirmed that MCA could be used to cover a larger volume of vaginal canal compared to SCA. MCA could provide more homogeneous dose coverage for the entire target and a better conformal plan for the vaginal cuff with reduced unnecessary dose to OARs. However, uniform and rigid MCA may be sub-optimal for patients with irregular vaginal vault configurations and colpostenosis. Nilsson et al offered a customizable applicator with mold material when traditional cylindrical or dome-type applicators could not be used or provided inadequate dose coverage of target. Our data of 10 years experience presented satisfactory clinical results with the practice of IH-MCA. The rigid type MCA was used for most patients owing to its convenience and simplicity for VBT. However, custom-made 3D printing MCA that adhered to the contours of the patients vaginal anatomy allowed flexibility of dose distribution and individualized usage for different anatomical variation which could further minimize the air gap between vaginal applicators and mucosal surface.
The risk factors regarded as prognostic impact on recurrence included older age, higher grade, deeper myometrial invasion, and LVSI in both PORTEC and GOG trials.[2–4,23] There were other adverse risk features for prognosis, such as stage, tumor histology, tumor size, and LUSI. Our analysis results showed that age and grade were significant prognostic factors for OS. Additionally, anemia, higher tumor grade, and LUSI were also adverse risk factors associated with TF. It is controversial that age was considered as an independent prognostic factor for patients with EC.[24–29] Actually, older women typically present with higher grade, deeper myometrial invasion, more advanced stage disease, and less favorable histology. So many guidelines defined older age as a risk factor for survival and relapse. The relatively young and low-grade patient group showed favorable outcome in our patients’ cohort. But the 5-year OS rates are similar, only 10-year OS rates are different, maybe indicating this is not treatment-related. In addition, stage and myometrial invasion depth were also prognostic factors for patients with EC. Even though our data did not find statistical difference, there was a trend in this regard. Over the last decades, risk stratification systems (RSS) are important and used worldwide to guide decision-making. Bendifallah compared discriminative performance of five major RSS in stratifying the risk of recurrence and nodal metastases, including the criteria that we used. They demonstrated that none of the five major RSS shows high accuracy to stratify recurrence risk and nodal metastases in women with early-stage EC. Therefore, we still need to improve existing RSS using additional tools such as biological markers.
Our study has several limitations to be considered, including its retrospective nature, more patients with IR in whole group, a relatively small number of custom-made 3D printing MCA usage, and no clinical comparative data between rigid type and custom-made 3D printing MCA. Individualized applicators are the most ideal method for different patients and thus different anatomical variations. However, it is difficult to apply custom-made 3D printing MCA for every case because of its requirement on production time and cost.
In conclusion, for patients with IR to HR stage I EC, adjuvant VBT alone or in combination with EBRT using IH-MCA led to excellent results. Traditional rigid type MCA was used for most patients with VBT owing to its convenience and simplicity. However, custom-made MCA with 3D printing technology offered additional flexibility of dose distribution and individualized usage for different anatomical variation when needed.
This study was supported by the grant from the Ministry of Science and Technology of China (No. 2016YFC0105207).
Conflicts of interest
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