PORTEC-3 Treatment Protocol Clarification
Not all patients in PORTEC-3 require concurrent chemoradiation followed by adjuvant chemotherapy—treatment should be stratified based on stage, histology, and increasingly, molecular classification, with the strongest benefit demonstrated in stage III disease and serous histology. 1, 2
PORTEC-3 Trial Design and Patient Population
The PORTEC-3 trial enrolled patients with high-risk endometrial cancer including:
- Stage I grade 3 endometrioid with deep myometrial invasion or LVSI 3
- Stage II-III endometrioid disease 3
- Stage I-III serous or clear cell histology 3
All patients in the experimental arm received the same regimen: concurrent cisplatin 50 mg/m² on days 1 and 28 with EBRT 48.6 Gy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m². 3, 4
Current Guideline-Based Treatment Recommendations
Stage III and Serous Histology (Strongest Indication)
Patients with stage III disease or serous cancers should receive combined chemoradiotherapy, as these subgroups demonstrated the most substantial survival benefit. 1 The updated analysis showed 5-year overall survival of 81.4% versus 76.1% with radiotherapy alone (HR 0.70, p=0.034). 4
Stage II Disease
Stage II endometrial cancer patients should receive combined chemoradiotherapy with concurrent cisplatin-based EBRT followed by adjuvant carboplatin/paclitaxel. 2 Stage II was specifically included in PORTEC-3 and demonstrated improved recurrence-free survival of 75.5% versus 68.6% for radiotherapy alone (HR 0.63). 2
Stage I Grade 3 Endometrioid (More Nuanced)
For stage I grade 3 endometrioid tumors, the decision should be individualized based on additional risk factors and molecular classification. 1, 5
- With deep myometrial invasion and negative nodal staging: Adjuvant EBRT with limited fields is recommended, with adjuvant systemic therapy under investigation. 1
- Without surgical nodal staging: Combined chemoradiotherapy provides greater evidence of benefit than either modality alone. 1, 5
- With substantial LVSI: Strong consideration for combined chemoradiotherapy, especially if lymph node staging was not performed. 5
Molecular Classification Integration (Critical Refinement)
Molecular profiling should guide treatment intensity, as it provides stronger prognostic information than traditional histopathology. 1, 6
p53-Abnormal Tumors
These patients show the greatest benefit from chemoradiotherapy with a 23% absolute recurrence-free survival improvement—chemotherapy should be strongly considered. 1, 5
POLE-Ultramutated Tumors
These patients have excellent prognosis without chemotherapy and may not require intensive chemoradiotherapy even with high-risk features. 1, 5
MMR-Deficient/NSMP Tumors
Follow standard risk-based algorithms as outlined above. 1
Toxicity Considerations
Grade 3 or worse adverse events during treatment occurred in 60% of chemoradiotherapy patients versus 12% of radiotherapy-alone patients (p<0.0001), with most grade 3 events being hematological (45%). 3, 7
Persistent sensory neuropathy (grade 2 or worse) occurs in 6-10% of patients at 5 years, which must be discussed during shared decision-making. 1, 4, 7
Common Pitfalls to Avoid
- Do not treat all PORTEC-3-eligible patients identically—stage I grade 3 with favorable molecular features may not require full chemoradiotherapy. 1
- Do not use chemotherapy alone—GOG-258 showed significantly more vaginal and pelvic/para-aortic recurrences with chemotherapy alone compared to chemoradiotherapy. 1
- Do not omit molecular testing when available—it provides critical prognostic information that can guide treatment de-escalation or intensification. 1, 6
Treatment Algorithm Summary
- Stage III or serous histology: Combined chemoradiotherapy (strongest indication) 1, 4
- Stage II: Combined chemoradiotherapy 2
- Stage I grade 3 with p53-abnormal: Combined chemoradiotherapy 1, 5
- Stage I grade 3 with POLE-ultramutated: Consider treatment de-escalation, potentially EBRT alone 1, 5
- Stage I grade 3 without molecular data and high-risk features (deep invasion, LVSI, no nodal staging): Combined chemoradiotherapy 1, 5
- Stage I grade 3 with negative nodes and favorable molecular features: EBRT with limited fields or brachytherapy 1