Did the PORTEC-3 trial provide treatment-changing guidelines for high-risk early-stage endometrial cancer in postmenopausal women?

PORTEC-3 Did Provide Treatment-Changing Guidelines

The PORTEC-3 trial fundamentally changed treatment guidelines for high-risk endometrial cancer by demonstrating significant overall survival and failure-free survival benefits with combined chemoradiotherapy, leading major guideline organizations to recommend this approach—particularly for stage III disease and serous histology—and establishing molecular classification as essential for treatment decisions. 1

Impact on Treatment Guidelines

The PORTEC-3 trial's updated analysis with 72.6 months median follow-up demonstrated:

• 5-year overall survival improved from 76.1% with radiotherapy alone to 81.4% with chemoradiotherapy (HR 0.70,95% CI 0.51-0.97, p=0.034) 1, 2
• 5-year failure-free survival improved from 69.1% to 76.5% (HR 0.70,95% CI 0.52-0.94, p=0.016) 1, 2
• Distant metastases as first recurrence decreased from 29.1% to 21.4% (HR 0.74, p=0.047) 2

These results directly led the European Society for Medical Oncology to state that PORTEC-3, along with GOG-249 and GOG-258, is "leading to a shift in the treatment paradigm" for high-risk endometrial cancer. 1

Specific Guideline Changes

For Stage III and Serous Cancers

The National Comprehensive Cancer Network now recommends combined chemoradiotherapy as standard for patients with stage III disease or serous cancers, as these subgroups demonstrated the most substantial survival benefit. 3

• Stage III patients showed the greatest benefit from adding chemotherapy to radiotherapy 1
• Serous histology patients obtained marked benefit, though only 105 patients were enrolled 1
• The standard regimen is now EBRT 48.6 Gy with concurrent cisplatin 50 mg/m² for two cycles, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m² 3

For Stage I-II Non-Serous Cancers

For stage I-II non-serous cancers, the ESMO guidelines recommend case-by-case discussion, as the absolute benefit was modest (2% improvement in 5-year OS, 4% in FFS), balanced against significantly increased toxicity. 1

• Grade 3 or worse adverse events during treatment occurred in 60% with chemoradiotherapy versus 12% with radiotherapy alone (p<0.0001) 3, 4
• Most grade 3 events were hematological (45%) 3, 5
• Persistent grade 2 or worse sensory neuropathy at 5 years occurred in 6% versus 0% 3, 2

Molecular Classification Integration

PORTEC-3 molecular analysis fundamentally changed risk stratification by demonstrating that p53-abnormal tumors show a 23% absolute recurrence-free survival improvement with chemotherapy (59% vs 36%, p=0.019), while POLE-ultramutated tumors showed excellent prognosis without chemotherapy (98% 5-year RFS). 6

The four molecular subgroups showed dramatically different outcomes:

• p53-abnormal: 48% 5-year RFS overall, but 59% with chemoradiotherapy versus 36% with radiotherapy alone 6
• POLE-ultramutated: 98% 5-year RFS with no benefit from chemotherapy 6
• MMR-deficient: 72% 5-year RFS with no significant chemotherapy benefit (68% vs 76%, p=0.428) 6
• No specific molecular profile: 74% 5-year RFS with trend toward benefit (80% vs 68%, p=0.243) 6

The ESMO guidelines now recommend that molecular classification be incorporated into risk stratification and treatment decisions, with strong consideration for chemotherapy in p53-abnormal tumors and potential de-escalation in POLE-ultramutated tumors. 1, 3

Treatment Algorithm Changes

Based on PORTEC-3, current guidelines recommend:

1. All high-risk endometrial cancer patients should undergo molecular classification (p53, MMR, POLE testing) 1, 3

2. For p53-abnormal tumors at any stage: recommend combined chemoradiotherapy regardless of histologic type 3, 6

3. For stage III disease or serous histology: recommend combined chemoradiotherapy 1, 3

4. For POLE-ultramutated tumors: consider treatment de-escalation given excellent prognosis 3, 6

5. For stage I-II non-serous, non-p53-abnormal tumors: individualized discussion weighing modest benefit against toxicity 1

Critical Caveats

The GOG-258 trial showed that chemotherapy alone is inadequate, as it resulted in significantly more vaginal and pelvic/para-aortic recurrences compared to chemoradiotherapy, reinforcing that radiotherapy must be included in the treatment regimen. 3

Clear-cell carcinomas showed markedly lower recurrence rates than serous carcinomas in PORTEC-3, particularly when p53 wild-type, suggesting they should not automatically be grouped with serous cancers for treatment decisions. 1