Can the PORTEC‑3 adjuvant protocol be used for a 61‑year‑old woman with mixed endometrial carcinoma (30 % endometrioid grade 2, 70 % serous with p53 mutation), 4.5 cm tumor, 86 % myometrial invasion, lymph‑vascular space invasion, and FIGO 2023 stage IICm (pT1bN0)?

PORTEC-3 Protocol for Mixed Endometrial Carcinoma with Serous Component and p53 Mutation

Yes, you should use the PORTEC-3 protocol for this patient—combined chemoradiotherapy (EBRT 48.6 Gy with concurrent cisplatin followed by carboplatin/paclitaxel) is the recommended treatment given her high-risk features: predominantly serous histology (70%), p53 mutation, deep myometrial invasion (86%), and LVSI. 1, 2

Why This Patient Qualifies for PORTEC-3

Meeting PORTEC-3 Eligibility Criteria

• The PORTEC-3 trial specifically enrolled patients with stage I-III serous or clear cell endometrial cancer, making this patient's 70% serous component with p53 mutation a direct indication for the protocol. 1

• Stage IICm (pT1bN0) with 86% myometrial invasion, LVSI, and high-grade histology places her squarely in the high-risk category that PORTEC-3 was designed to treat. 1

• Mixed carcinomas with a serous component behave according to their most aggressive histologic element—the 70% serous component with p53 mutation dominates the prognosis and treatment approach. 3, 4

Evidence Supporting Combined Chemoradiotherapy

Survival Benefit in High-Risk Disease

• The PORTEC-3 trial demonstrated 5-year overall survival of 81.4% with chemoradiotherapy versus 76.1% with radiotherapy alone (HR 0.70, p=0.034), with the greatest benefit seen in patients with serous cancers and stage III disease. 1, 2

• Molecular analysis of PORTEC-3 showed that p53-abnormal tumors (which includes serous carcinomas) had 5-year recurrence-free survival of 59% with chemoradiotherapy versus only 36% with radiotherapy alone—a 23% absolute improvement. 5, 2

• The updated PORTEC-3 analysis with 72.6 months median follow-up confirmed significant improvement in both overall survival and failure-free survival with combined treatment. 1

Why Radiotherapy Alone Is Insufficient

• Serous carcinomas with p53 abnormality have high rates of distant metastasis that cannot be controlled by pelvic radiotherapy alone, necessitating systemic chemotherapy. 1, 4

• The GOG-258 trial showed that chemotherapy alone resulted in significantly more vaginal and pelvic/para-aortic recurrences compared to chemoradiotherapy, establishing that both modalities are needed. 2

The PORTEC-3 Treatment Protocol

Standard Regimen Components

• External beam radiotherapy: 48.6 Gy in 1.8 Gy fractions to the pelvis. 1, 2

• Concurrent chemotherapy: Cisplatin 50 mg/m² on days 1 and 28 of radiotherapy. 1, 2

• Adjuvant chemotherapy: Four cycles of carboplatin AUC5 plus paclitaxel 175 mg/m² following completion of radiotherapy. 1, 2

• Timing: Adjuvant therapy should be initiated as soon as the vaginal cuff has healed, but no later than 12 weeks after surgery. 1

Risk Stratification Based on Molecular Features

P53 Mutation as High-Risk Marker

• P53 mutations occur in 91.66% of serous carcinomas and define them as high-risk regardless of stage, with significantly worse prognosis than endometrioid tumors. 6, 4

• All stages and all histologies with p53-abnormal status and myometrial invasion are classified as high-risk endometrial cancer requiring combined modality therapy. 1

• Mixed carcinomas with serous component show TP53 mutations in 22% overall, but when the serous component predominates (as in this case with 70%), the tumor behaves like pure serous carcinoma. 3

Deep Myometrial Invasion and LVSI

• The combination of 86% myometrial invasion (deep invasion) plus LVSI substantially increases both locoregional and distant recurrence risk, reinforcing the need for combined chemoradiotherapy. 2

• LVSI-positive disease markedly increases distant recurrence risk and is a strong indication for systemic chemotherapy in addition to radiotherapy. 2

Critical Pitfalls to Avoid

Do Not Undertreat Based on Stage Alone

• Stage IICm (pT1bN0) might appear "early" but the combination of serous histology, p53 mutation, deep invasion, and LVSI creates high-risk biology that requires aggressive treatment regardless of node-negative status. 1

• Observation or vaginal brachytherapy alone would be grossly inadequate for this patient and is contraindicated in high-risk disease with unstaged or negative nodes. 2

Do Not Use Radiotherapy Alone

• Pelvic radiotherapy alone fails to address the high risk of distant metastasis in p53-abnormal serous carcinomas, as demonstrated by the 36% 5-year RFS in the radiotherapy-only arm of PORTEC-3. 5

Do Not Use Chemotherapy Alone

• The GOG-249 trial showed that substituting chemotherapy plus vaginal brachytherapy for pelvic radiotherapy resulted in no improvement in recurrence-free survival and significantly worse acute toxicity. 1

Expected Toxicity Profile

Acute Toxicity During Treatment

• Grade 3 or worse adverse events during treatment occur in 60% of chemoradiotherapy patients versus 12% with radiotherapy alone, with most grade 3 events being hematological (45%). 2

• Acute grade 2 adverse events occur in 94% of patients receiving chemotherapy/brachytherapy versus 44% with radiotherapy alone. 1

Long-Term Toxicity

• Persistent sensory neuropathy occurs in 6% of patients at 5 years, with grade 2 sensory neuropathy at 24 months in 10% versus <1% with radiotherapy alone. 1, 2

Alternative Considerations (Not Recommended for This Patient)

When PORTEC-3 Might Not Apply

• POLE-ultramutated tumors show excellent prognosis (98% 5-year RFS) without chemotherapy benefit, but this patient has p53 mutation indicating serous carcinoma, not POLE mutation. 5, 4

• Pure endometrioid grade 1-2 tumors with <50% invasion and no LVSI can be observed or treated with vaginal brachytherapy alone, but this patient's 70% serous component excludes this approach. 1