PORTEC-4 in Endometrial Cancer
PORTEC-4 is an ongoing trial investigating molecular-integrated risk profiling to guide adjuvant treatment decisions in endometrial cancer, but it is not yet complete and has not established a standard role in clinical practice. 1
Understanding the PORTEC Trial Series
The PORTEC trials represent a progressive evolution in endometrial cancer management:
PORTEC-1 demonstrated that external beam radiation therapy (EBRT) improves locoregional control in intermediate-risk disease but does not improve overall survival. 2
PORTEC-2 established that vaginal brachytherapy alone provides equivalent vaginal and pelvic control compared to EBRT with significantly less toxicity in high-intermediate risk patients. 2
PORTEC-3 showed that combined chemoradiotherapy (EBRT with concurrent cisplatin followed by carboplatin/paclitaxel) improves failure-free survival and overall survival compared to radiotherapy alone in high-risk endometrial cancer, particularly benefiting patients with stage III disease and serous histology. 1
PORTEC-4a (the ongoing trial) is investigating whether molecular profiling can further refine treatment recommendations beyond traditional clinicopathologic risk factors. 1
Current Clinical Application Based on Completed PORTEC Trials
For Intermediate-Risk Disease
Vaginal brachytherapy alone is the standard recommendation based on PORTEC-2 results, which demonstrated equivalent local control with reduced toxicity compared to EBRT. 2, 3 This applies to patients with stage I disease, grade 1-2 histology, and ≥50% myometrial invasion without lymphovascular space invasion (LVSI). 3, 4
For High-Intermediate Risk Disease
Vaginal brachytherapy alone remains appropriate if surgical nodal staging is performed and nodes are negative, particularly for patients with stage I, grade 3 with <50% myometrial invasion, or grade 1-2 with positive LVSI. 3, 4 However, PORTEC-1 and PORTEC-2 specifically excluded patients with 1998 FIGO stage 1C grade 3 disease (2009 FIGO stage IB grade 3), making treatment recommendations for this highest-risk subset more controversial. 2, 1
For High-Risk Disease
Combined chemoradiotherapy is recommended based on PORTEC-3 results, using EBRT (48.6 Gy in 1.8 Gy fractions) with concurrent cisplatin (50 mg/m²) followed by 4 cycles of carboplatin/paclitaxel. 1 This applies to patients with:
- Stage I grade 3 with deep myometrial invasion and LVSI 1
- Stage II or III disease 1
- Serous or clear cell histology at any stage 1
High-Dose Rate Brachytherapy Technical Considerations
When high-dose rate (HDR) brachytherapy is indicated based on PORTEC trial risk stratification:
For Adjuvant Vaginal Brachytherapy
- The largest diameter applicator should be selected to ensure close mucosal apposition 5
- Doses should be reported both at the vaginal surface and at 0.5-cm depth regardless of prescription point 5
- The median HDR dose is approximately 23.9 Gy, typically delivered in 3 fractions on a weekly schedule 6
For Medically Inoperable Patients
HDR brachytherapy can serve as primary treatment with excellent outcomes. For stage I disease established by MRI and treated with a total HDR dose of 30 Gy, disease-specific survival reaches 100% at 10 years. 6 An appropriate applicator allowing adequate irradiation of the entire uterus should be selected. 5
For Salvage Treatment of Vaginal Recurrence
HDR brachytherapy achieves 5-year local control rates of 78% and overall survival of 84% for isolated vaginal recurrence. 7 Interstitial brachytherapy should be used for bulky recurrences (>0.5-cm thick), while intracavitary techniques are restricted to nonbulky disease (<0.5-cm thick). 5, 7
Critical Pitfalls to Avoid
Do not routinely add vaginal brachytherapy boost after EBRT, as it provides no clear benefit for vaginal control and increases toxicity, with vaginal recurrence rates of only approximately 2% at 5 years after either modality alone. 4 The only clear indication for vaginal brachytherapy boost after EBRT is positive vaginal surgical margins. 4
Do not use vaginal brachytherapy alone for deeply invasive grade 3 tumors without careful consideration, as most NCCN panel members recommend adjuvant treatment for these patients, though the optimal approach remains controversial. 2
Do not undertreat high-risk patients (stage III, serous histology) with radiation alone when combined chemoradiotherapy has demonstrated survival benefit in PORTEC-3. 1
Molecular Classification Impact
Recent molecular analysis of PORTEC-3 samples has identified four molecular subgroups with significant prognostic implications: p53 abnormal, POLE-ultramutated, MMR-deficient, and no specific molecular profile. 1 This forms the basis for the ongoing PORTEC-4a trial, which may further refine treatment recommendations, but these molecular classifications are not yet standard practice for treatment selection. 1