Efficacy
Adjuvant vaginal brachytherapy (VBT) is recommended by the ESGO/ESTRO/ESP guidelines for patients with intermediate and high-intermediate risk endometrial cancer to decrease the risk of vaginal recurrence. EBRT can be considered in the setting of substantial LVSI or pNx as an alternative for intermediate and high-intermediate risk groups.r
The 2015 ASTRO-ASCO consensus guidelines recommend that adjuvant VBT alone is given for FIGO stage IA grade 3, and IB grade 1-2, and considered for FIGO grade 1-2 with high risk features (LVSI or > 60 years of age).r
PORTEC-2
The randomised PORTEC-2 trial for FIGO 1988 stage I-IIA endometrial cancer patients with HIR factors confirmed external beam radiation therapy (EBRT) could safely be substituted by VBT, with less toxicity and better quality of life.r The trial included 427 women and had a median follow-up of 116 months. Patients were randomised to receive adjuvant VBT or EBRT. The 10-year vaginal recurrence rate was similar in the VBT group (3.4% vs 2.4%, p = 0.55). Ten-year pelvic recurrence was more often seen in the VBT group (6.3% vs 0.9%, p = 0.004), which most often occurred with distant metastases. The 10-year isolated pelvic recurrence was 2.5% vs 0.5% (p = 0.10). There was a non-significant difference in the rate of overall distant metastases (10.4% vs 8.9%, p = 0.45), and overall survival was similar in the VBT group (69.5% vs 67.6%, p = 0.72).
In the 10-year update of PORTEC-2, central pathology review and molecular analysis was performed on 416 patients with endometrial cancer.r L1CAM and p53-mutant expression and substantial LVSI were shown to be risk factors for pelvic recurrence and distant metastases, and EBRT was found to reduce pelvic recurrence in cases where these risk factors were found. There is an increasing role of molecular subtyping and risk stratification.
The 5-year quality of life review for PORTEC-2 demonstrated that patients tolerated VBT significantly better than EBRT, with better social functioning and lower symptoms scores for gastro-intestinal symptoms (p <0.001). Sexual functioning in both groups was lower, and sexual symptoms more frequent, in both treatment groups compared to the normal population.r
Post-operative VBT for low risk disease
There does not appear to be a benefit of post-operative VBT for low risk disease. Sorbe et al. 2009 reported on their randomised controlled trial of post-operative vaginal vault brachytherapy versus surgery alone for FIGO stage I low risk endometrial cancer (FIGO stage IA-IB, endometrioid histology, and FIGO grade 1-2).r The rate of loco-regional recurrence overall was low (2.6%) as was the rate of distant metastatic disease (1.4%). There was no significant difference in the rate of vaginal recurrence in the vaginal brachytherapy group (1.2%) vs the control group (3.1%) (p = 0.114), and survival was similar between the 2 groups.
Dose fractionation
The most frequently used schedule is 21 Gy/3# prescribed to 5 mm from the cylinder surface as per the PORTEC 2 trial.r There are a wide range of recognised dose fraction schedules in the literature, mostly from institutional series. These schedules are confounded by differing prescription points, typically to either the vaginal surface or 5 mm depth. When utilised in combination with EBRT, again there are a range of schedule reported. The most commonly used is 10-11 Gy/2# prescribed to 5 mm from the cylinder, equivalent to 14 Gy in 2 Gy/fraction boost, as per PORTEC 3.
GOG 249 trial
The GOG 249 trial used EBRT vs 3 cycles of carbo/taxol chemotherapy followed by VBT in Stage 1B GR 2/3 with LVSI, Stage 1 serous/clear cell histology and stage 2 and patients.r This non-inferiority design showed no difference in 5-year recurrence free or overall survival between the two arms. Pelvic and PA nodal recurrences were less common with pelvic EBRT.
Role of molecular subtyping
The predictive value and clinical benefit of the molecular profiles is yet to be prospectively determined. Determining adjuvant treatment for endometrial cancer is based on clinicopathological factors supported by several randomised trials. Recently the comprehensive genomic analysis of endometrial cancer by The Cancer Genome Atlas (TCGA) has led to the discovery of four key molecular subtypes:
- POLE-mutated/ultra-mutated (POLEmt),
- microsatellite-instable/hypermutated (MSI),
- copy-number-low/p53-wild-type (p53wt),
- copy-number-high/p53-mutated (p53mt).r
The prognostic value has been since determined retrospectively in the PORTEC biospecimens.r The TransPORTEC and PROMISE molecular classifiers were subsequently established using a combination of immunohistochemistry and targeted genomic sequencing for translational research.rr The PORTEC 4a (international randomised trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer) and the Refining Adjuvant Treatment IN Endometrial Cancer Based On Molecular Features (RAINBO) trials aim to address this issue.rr