Adjuvant Chemoradiotherapy versus Radiotherapy Alone for Women with High-Risk Endometrial Cancer (PORTEC-3)

Final Results of an International, Open-Label, Multicentre, Randomised, Phase 3 Trial

de Boer SM, Powell ME, Mileshkin L, et al.
Lancet Oncology 2018; 19: 295-309

Background & Rationale

• Women with high-risk endometrial cancer (15% of cases) have increased risk of recurrence and cancer-related death
• Standard adjuvant treatment has been pelvic external beam radiotherapy (EBRT)
• Radiotherapy shown to delay pelvic recurrence but not improve overall survival
• Chemotherapy shown to delay distant metastases but also without survival benefit
• RTOG 9708 phase 2 trial explored combination of EBRT with concurrent and adjuvant chemotherapy with promising results
• PORTEC-3 trial initiated to determine whether addition of chemotherapy to radiotherapy improves outcomes in high-risk endometrial cancer

Study Design

686 patients with high-risk endometrial cancer randomized 1:1

↓

Radiotherapy Alone

↓

EBRT (48.6 Gy in 1.8 Gy fractions)

5 days/week

Chemoradiotherapy

↓

EBRT (48.6 Gy) + concurrent cisplatin

50 mg/m² in week 1 & 4

↓

Adjuvant chemotherapy

4 cycles carboplatin AUC5 + paclitaxel 175 mg/m²

• Open-label, international, randomized phase 3 trial
• 103 centers in 6 clinical trial groups collaborating in the Gynaecological Cancer Intergroup
• Randomization stratified by participating center, lymphadenectomy, stage, and histological type
• Co-primary endpoints: overall survival and failure-free survival
• Vaginal brachytherapy boost allowed if cervical involvement (46% in chemoRT vs 48% in RT)

Eligibility Criteria

• Endometrioid endometrial cancer:

• Serous or clear cell histology:

• Additional criteria:

Patient Characteristics

660 eligible patients analyzed (330 in each arm)
Baseline characteristics well balanced between groups

Patient Characteristics

Treatment Completion

• Chemotherapy was discontinued in 61 patients (18%):
• Due to toxicity: 31 (9%)
• Patient decision: 20 (6%)
• Disease progression: 7 (2%)
• Other reasons: 3 (1%)
• Dose reductions:
• Cisplatin (40 mg/m²): 5 patients (2%)
• Carboplatin (AUC5 to AUC4): 36 patients (11%)
• Paclitaxel (175 mg/m² to 135 mg/m²): 50 patients (15%)

Recurrence Patterns

• Most recurrences were distant metastases in both arms
• Isolated vaginal and pelvic recurrences were rare
• Significant reduction in total pelvic recurrences with chemoradiotherapy
• Trend toward reduction in distant metastases with chemoradiotherapy

Subgroup Analysis - Stage III

*Adjusted for stratification factors

Prognostic Factors 

Conclusions

• Addition of chemotherapy to radiotherapy improved 5-year failure-free survival (75.5% vs 68.6%, p=0.022) but not overall survival (81.8% vs 76.7%, p=0.109)
• Greatest benefit seen in patients with:
• Stage III disease
• Age ≥70 years
• No significant benefit observed for stage I-II disease
• Significantly higher rates of toxicity during treatment with chemoradiotherapy:
• Grade 3-4 adverse events: 60% vs 12%
• Grade 2+ sensory neuropathy persisted long-term
• Pelvic control was high with radiotherapy alone (vaginal recurrence ~2%, pelvic recurrence ~9%)
• Majority of recurrences were distant metastases in both arms

Strengths and Limitations

Clinical Implications

• Combined chemoradiotherapy cannot be recommended as new standard for all high-risk endometrial cancer patients
• For stage III disease, chemoradiotherapy should be considered to maximize failure-free survival
• For stage I-II disease, radiotherapy alone provides excellent pelvic control without the added toxicity of chemotherapy
• Benefits and risks of combined treatment should be individually discussed with each patient
• Age should not be a limiting factor - elderly patients derived substantial benefit
• Long-term risk of persistent neuropathy should be balanced against potential benefits
• Further follow-up needed to evaluate long-term survival outcomes

Discussion Points

1. How do the PORTEC-3 results compare with other trials in high-risk endometrial cancer (GOG-258, GOG-249, NSGO-EC-9501/EORTC-55991)?
2. Would a different chemotherapy regimen or sequence (e.g., sequential rather than concurrent) have resulted in different outcomes?
3. How should we approach treatment decisions for specific histological subtypes, particularly serous cancers?
4. What is the role of molecular classification (POLE, p53, MSI) in treatment decision-making for high-risk endometrial cancer?
5. How do we balance the improved failure-free survival in stage III disease against the increased toxicity of combined treatment?

Subsequent Publications from PORTEC-3

• de Boer et al. (Lancet Oncol 2019): Toxicity and quality-of-life results
• Significantly higher symptom burden during and 3 months after treatment
• Rapid recovery of HRQOL after treatment completion
• Persistent sensory neuropathy and tingling in extremities
• León-Castillo et al. (JCO 2020): Molecular risk classification
• Benefit of chemoradiotherapy limited to p53-abnormal cancers
• No significant benefit in NSMP, MMRd, or POLE-mutant tumors
• POLE-mutant tumors had excellent outcomes in both arms
• Wortman et al. (IJROBP 2021): Comparison of IMRT vs. 3DCRT
• Significantly less grade 2+ GI toxicity with IMRT (15% vs. 4%)
• Improved patient-reported bowel symptoms with IMRT