What were the aims, outcomes, and practice-changing evidence of the Portec 3 trial for high-risk early-stage endometrial cancer in postmenopausal women?

PORTEC-3 Trial: Comprehensive Overview

Why the Trial Was Needed

The PORTEC-3 trial was designed to address a critical gap in treating high-risk endometrial cancer patients who faced substantial risk of distant metastases and death despite local radiotherapy alone. 1

Prior to PORTEC-3, the treatment landscape was uncertain:

• Retrospective data suggested chemotherapy alone was insufficient - patients receiving adjuvant chemotherapy alone had a 2.2-fold increased risk of recurrence and 4.0-fold increased risk of death compared to those receiving radiotherapy with or without chemotherapy 1
• Earlier trials (PORTEC-1 and PORTEC-2) established radiotherapy standards but only addressed intermediate-risk disease, leaving high-risk patients without clear evidence-based guidance 2
• About 15% of endometrial cancer patients have high-risk features with significantly elevated risk of distant metastases, creating an urgent need for systemic therapy evaluation 3
• The phase 2 RTOG 9708 trial showed promising results with combined cisplatin/paclitaxel and radiotherapy favoring combined modality treatment, warranting a definitive phase 3 trial 1

Trial Design and Patient Population

PORTEC-3 enrolled 686 women (660 eligible) with high-risk endometrial cancer between November 2006 and December 2013, randomizing them 1:1 to receive either radiotherapy alone versus chemoradiotherapy. 1, 4, 5

Eligibility Criteria:

• Stage I, grade 3 endometrioid cancer with deep myometrial invasion or lymphovascular space invasion (LVSI), or both 1
• Stage II or III disease of any grade 1
• Stage I-III serous or clear cell histology 1
• Age ≥18 years with WHO performance status 0-2 4

Treatment Arms:

• Radiotherapy alone: 48.6 Gy in 1.8 Gy fractions, 5 days per week 1, 4, 5
• Chemoradiotherapy: Two cycles of concurrent cisplatin 50 mg/m² during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m² 1, 4, 5

Primary Outcomes and Results

Overall Survival and Failure-Free Survival

At median follow-up of 72.6 months, chemoradiotherapy demonstrated significant survival benefits: 5-year overall survival was 81.4% versus 76.1% with radiotherapy alone (HR 0.70,95% CI 0.51-0.97, p=0.034), and 5-year failure-free survival was 76.5% versus 69.1% (HR 0.70,95% CI 0.52-0.94, p=0.016). 1, 4

Patterns of Recurrence

Distant metastases were the predominant site of first recurrence, occurring in 21.4% of chemoradiotherapy patients versus 29.1% of radiotherapy-alone patients at 5 years (HR 0.74,95% CI 0.55-0.99, p=0.047) 4

Isolated vaginal recurrence was remarkably rare - only 0.3% in both groups - demonstrating excellent local control with both treatment approaches 4

Isolated pelvic recurrence was similarly uncommon - 0.9% in both groups (HR 0.75,95% CI 0.17-3.33, p=0.71) 4

Subgroup Analysis: Who Benefits Most

Patients with serous cancers and stage III disease derived the greatest benefit from adding systemic therapy to radiotherapy. 1

For stage I-II non-serous cancers, the absolute improvement was modest - only 2% in 5-year overall survival and 4% in failure-free survival - requiring careful risk-benefit discussion 1

Toxicity Profile

Acute Toxicity

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, 5

Grade 2 or worse adverse events occurred in 94% of chemoradiotherapy patients versus 44% of radiotherapy-alone patients during treatment. 3

Long-Term Toxicity

At 24 months, grade 2 or worse sensory neuropathy persisted in 10% of chemoradiotherapy patients versus <1% of radiotherapy-alone patients (p<0.0001). 3

At 5 years, grade 2 or worse sensory neuropathy remained elevated at 6% in the chemoradiotherapy group versus 0% in radiotherapy alone. 4

At 5 years, grade 3 adverse events did not differ significantly between groups - 8% with chemoradiotherapy versus 5% with radiotherapy alone (p=0.24) 4

Most toxicity differences resolved by 12 months, with persisting differences primarily limited to grade 2 sensory neuropathy. 1

Practice-Changing Evidence: Molecular Classification Analysis

The Molecular Subgroup Breakthrough

A landmark follow-up molecular analysis of PORTEC-3 tissue samples fundamentally changed the treatment paradigm by demonstrating that molecular classification predicts both prognosis and benefit from chemotherapy. 1, 6

The tumors were classified into four molecular subgroups:

p53-abnormal tumors (23% of cases):

• 5-year recurrence-free survival with chemoradiotherapy was 59% versus 36% with radiotherapy alone (p=0.019) - the most dramatic benefit from systemic therapy 1, 6
• These patients had the worst prognosis overall with 5-year RFS of only 48% 6

POLE-ultramutated tumors (12% of cases):

• Excellent prognosis with 5-year RFS of 98% 6
• No benefit from chemotherapy: 100% versus 97% RFS (p=0.637) 1, 6

MMR-deficient tumors (33% of cases):

• 5-year RFS of 72% overall 6
• No clear benefit from chemotherapy: 68% versus 76% RFS (p=0.428) - potentially worse with chemotherapy 1, 6

No specific molecular profile (32% of cases):

• 5-year RFS of 74% overall 6
• Trend toward benefit with chemotherapy: 80% versus 68% RFS (p=0.243) 1, 6

Clinical Implementation

This molecular analysis suggests systemic therapy is most beneficial for p53-abnormal tumors, regardless of histologic type, fundamentally shifting treatment decisions from histology-based to molecular-based approaches. 1, 6

The ongoing PORTEC-4a trial is investigating molecular profile-based directed adjuvant treatment in high-risk endometrial cancer to prospectively validate these findings. 1

Current Clinical Practice Recommendations

For Stage III and Serous Histology

Combined chemoradiotherapy should be recommended and discussed as standard treatment for women with stage III disease or serous cancers, as these patients demonstrate the most substantial survival benefit. 1, 4

For High-Risk Early-Stage Disease (Stage I-II)

The decision for combined treatment in stage I-II non-serous cancers should be discussed on a case-by-case basis, considering the balance between increased adverse events and modest outcome benefit (2% OS improvement, 4% FFS improvement). 1

Molecular Classification Integration

Molecular classification should 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, 6

Treatment Schedule

When chemoradiotherapy is chosen, the standard regimen is 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. 1, 2

Common Pitfalls and Caveats

Do not apply PORTEC-3 results uniformly to all high-risk patients - the 5% absolute OS benefit masks substantial heterogeneity, with stage I-II patients deriving minimal benefit while stage III and serous histology patients derive substantial benefit 1, 4

Do not overlook the persistent sensory neuropathy - 25% of patients report severe tingling or numbness at 24 months, which persists in 6% at 5 years, requiring informed consent discussion 4, 3

Do not ignore molecular classification when available - p53-abnormal tumors show 23% absolute RFS improvement with chemotherapy, while POLE-ultramutated tumors show no benefit and excellent prognosis without chemotherapy 1, 6

Do not assume chemotherapy alone is adequate - the GOG-258 trial showed significantly more vaginal and pelvic/para-aortic recurrences with chemotherapy alone compared to chemoradiotherapy, despite similar overall survival 1

Recognize that quality of life recovers rapidly - despite increased toxicity during treatment, global health and quality of life scores were similar between groups by 12-24 months, with only sensory neuropathy persisting 3