# Endometrial Cancer: Adjuvant Radiation Indications and Vaginal Cuff Brachytherapy

## Introduction

Endometrial cancer represents the most common gynecologic malignancy in developed countries. After patients undergo total hysterectomy and bilateral salpingo-oophorectomy, the decision to administer adjuvant radiation therapy is guided by surgical staging, histologic subtype, and the presence of adverse risk factors. This lecture focuses on evidence-based indications for adjuvant external beam radiation therapy (EBRT) and vaginal cuff brachytherapy (VCB), highlighting their roles in reducing recurrence and improving patient outcomes.

## Risk Stratification

Risk stratification in endometrial cancer is essential for tailoring adjuvant therapy. Low-risk disease is characterized by Stage IA tumors with grade 1-2 histology and no lymphovascular space invasion (LVSI). In these patients, observation alone is standard, as the risk of recurrence is less than 5%. Intermediate-risk disease includes Stage IA grade 3 tumors, Stage IB grade 1-2 tumors, or the presence of LVSI. Within this group, the high-intermediate risk (HIR) category is defined by the GOG-99 criteria, which incorporate an age-dependent combination of tumor grade, LVSI status, and depth of myometrial invasion. High-risk disease encompasses Stage IB grade 3, Stage II, and Stage IIIA-C tumors, as well as serous, clear cell, or carcinosarcoma histologies regardless of stage, all of which carry a higher likelihood of recurrence and poorer prognosis.

## Landmark Trials

Several landmark clinical trials have shaped current adjuvant radiation practices in endometrial cancer. The PORTEC-1 trial randomized patients with Stage I endometrial cancer to pelvic EBRT versus observation. While EBRT significantly reduced locoregional recurrence rates (5% versus 14%), it did not confer an overall survival benefit. This trial also identified the vaginal cuff as the most common site of recurrence. The GOG-99 trial compared pelvic EBRT to observation in patients with Stage IB-II disease (using 1988 staging) and defined the high-intermediate risk subgroup that derived the greatest benefit from EBRT. In this group, the 2-year recurrence rate was reduced from 12% with observation to 3% with EBRT. PORTEC-2 further refined treatment by comparing pelvic EBRT to vaginal cuff brachytherapy in HIR patients. It demonstrated equivalent vaginal recurrence rates of approximately 2%, but VCB was associated with fewer gastrointestinal side effects and better quality of life, establishing VCB as the standard adjuvant treatment for HIR endometrioid carcinoma.

![Diagram showing PORTEC risk stratification and treatment algorithm for adjuvant radiation in endometrial cancer](images/endometrial-adjuvant-algorithm.jpg)

## Vaginal Cuff Brachytherapy Technique

Vaginal cuff brachytherapy typically employs a single-channel vaginal cylinder applicator, with the diameter selected to ensure adequate mucosal contact, usually between 2.5 and 3.5 cm. Multi-channel cylinders are available and allow for dose optimization, but the single-channel device remains most common. The usual high-dose-rate (HDR) prescription consists of 7 Gy delivered in three fractions, prescribed to a depth of 0.5 cm from the applicator surface. An alternative regimen involves 6 Gy in five fractions prescribed to the surface. Treatment generally covers the proximal 3 to 5 cm of the vaginal cuff. CT-based treatment planning is preferred to optimize dose distribution, with careful documentation of doses to the bladder and rectum to minimize toxicity. The target volume includes the vaginal cuff plus a distal margin of 3 to 5 cm to encompass potential microscopic disease.

![Axial CT image showing vaginal cylinder applicator in situ with isodose lines for cuff brachytherapy planning](images/vaginal-cuff-brachy-ct.jpg)

## Indications for Pelvic EBRT

Pelvic EBRT is indicated in several higher-risk scenarios. Patients with Stage IIIA-C endometrioid carcinoma typically receive EBRT, often combined with a vaginal cuff brachytherapy boost. Those with serous or clear cell histology and any degree of myometrial invasion are treated with EBRT plus chemotherapy, following the PORTEC-3 protocol. Positive pelvic lymph nodes (Stage IIIC1) and cervical stromal invasion (Stage II) in select cases also warrant pelvic radiation. The PORTEC-3 trial evaluated women with Stage I-III high-risk endometrial cancer, comparing chemoradiation (cisplatin concurrent with radiation followed by carboplatin/paclitaxel) to pelvic EBRT alone. The combined chemoradiation approach improved 5-year overall survival (81.4% versus 76.1%) and failure-free survival, establishing it as the standard of care for high-risk disease.

| Risk Group | Definition | Adjuvant Treatment | Key Evidence |
|---|---|---|---|
| Low risk | Stage IA, grade 1–2, no LVSI | Observation | Recurrence risk < 5% |
| Intermediate risk | Stage IA G3, IB G1–2, or LVSI | VCB alone | PORTEC-2 |
| High-intermediate risk (HIR) | GOG-99 criteria (age + grade + LVSI + depth) | VCB alone | PORTEC-2 (non-inferior to EBRT) |
| High risk (Stage II–III, endometrioid) | Stage II cervical stromal, IIIA–C | Pelvic EBRT ± VCB boost ± chemo | PORTEC-3 |
| High risk (serous, clear cell, carcinosarcoma) | Any stage with adverse histology | Chemoradiation (PORTEC-3 regimen) | PORTEC-3 |

## EBRT Treatment Planning

External beam radiation therapy is typically delivered using either a four-field box technique or intensity-modulated radiation therapy (IMRT). The clinical target volume (CTV) includes the vaginal cuff, parametrial tissues, and pelvic lymph node regions. The superior border of the radiation field is generally set at the L4-L5 vertebral level but may be extended to cover para-aortic nodes if involved. The total dose ranges from 45 to 50.4 Gy, delivered in daily fractions of 1.8 Gy.

![Coronal view of IMRT plan for adjuvant pelvic radiation in endometrial cancer with dose-volume histogram](images/endometrial-ebrt-imrt.jpg)

## Key Clinical Pearls

In early-stage endometrial cancer, the vaginal cuff is the most common site of recurrence, and vaginal cuff brachytherapy alone provides sufficient local control for patients with high-intermediate risk endometrioid histology. The PORTEC-2 trial demonstrated that VCB offers equivalent vaginal control compared to pelvic EBRT but with fewer gastrointestinal toxicities, making it the preferred option in this group. For patients with high-risk disease, including Stage III tumors and unfavorable histologies such as serous or clear cell carcinoma, combined chemoradiation as per the PORTEC-3 protocol improves survival outcomes. Accurate assessment of lymphovascular space invasion, depth of myometrial invasion, tumor grade, and histologic subtype is critical in guiding adjuvant therapy decisions. Additionally, molecular classification, as discussed in Lecture 52, is becoming increasingly integrated into risk stratification and treatment planning.

## References

1. Nout RA, Smit VT, Putter H, et al. Vaginal cuff brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial. *Lancet*. 2010;375(9717):816-823.  
2. Keys HM, Roberts JA, Brunetto VL, et al. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. *Gynecol Oncol*. 2004;92(3):744-751.  
3. de Boer SM, Powell ME, Mileshkin L, et al. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis. *Lancet Oncol*. 2019;20(9):1273-1285.  
4. Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. *Lancet*. 2000;355(9213):1404-1411.