PORTEC-3 NCT00411138
ForHigh-risk endometrial cancer, FIGO 2009 stage I-III, post-hysterectomy
HR 0.76
95% CI 0.54–1.06, p=0.11, OS not met; co-primary FFS HR 0.71, p=0.022
TL;DR5y FFS 75.5% vs 68.6% (HR 0.71, p=0.022) with CRT over pelvic RT alone; co-primary 5y OS 81.8% vs 76.7% not met (HR 0.76, p=0.11).
Pelvic control was 91% with RT alone, so chemotherapy is not buying locoregional control here; 48.6 Gy pelvic EBRT (plus brachy boost in 47%, balanced by arm) stays the backbone in both arms. The RT question left open is whether pelvic RT can be dropped once chemo is given, which GOG-258 tests and its abstract suggests costs vaginal and nodal control.
In stage III high-risk endometrial cancer, this supports discussing concurrent cisplatin plus adjuvant carboplatin/paclitaxel with pelvic RT for failure-free survival; in stage I-II disease the FFS estimate (HR 0.85, p=0.47) does not clearly justify the added toxicity.
Pelvic control was 91% with RT alone, so chemo adds nothing locoregionally and 48.6 Gy pelvic EBRT plus indicated brachy boost stays the backbone. The RT decision this trial leaves open is omission of pelvic RT once chemo is given, where GOG-249 and the GOG-258 abstract both show more pelvic and nodal failure without it.
The regimen is demanding: all 4 carboplatin and paclitaxel cycles were completed by 79% and 71%, G3+ AEs ran 60% vs 12%, and G2+ neuropathy persisted at 3y in 8%. The FFS gain concentrates in stage III, and the authors flag a larger benefit in women over 70 and at least as much benefit in serous or clear cell histology.
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Open-label, international, randomised phase 3 at 103 centres across six GCIG groups; 1:1 by biased-coin minimisation, stratified by centre, lymphadenectomy, stage and histology. 686 enrolled, 660 in the ITT analysis; median follow-up 60.2 mo.
High-risk endometrial cancer, FIGO 2009: stage IA EEC grade 3 with LVSI, IB EEC grade 3, EEC stage II or III, or serous / clear cell stage IA (with invasion) to III. WHO PS 0-2, no upper age limit; median age 62, stage III in 46% vs 43%.
Experimental arm added cisplatin 50 mg/m² x2 concurrent, then 4 cycles carboplatin AUC5 + paclitaxel 175 mg/m². Both cisplatin cycles completed by 92%; all 4 carboplatin and paclitaxel cycles by 79% and 71%.
Pelvic EBRT 48.6 Gy in 1.8 Gy fractions in both arms; 45.0-50.4 Gy delivered in 100% vs 98%. Vaginal brachy boost for cervical invasion, given in 46% vs 48%.
Co-primary: overall survival and failure-free survival, ITT, Cox-adjusted for stratification factors.
G3+ AEs during treatment 60% vs 12% (p<0.0001). G2+ neuropathy persisted at 3y in 8% vs 1%.
Direction matches the pooled NSGO-EC-9501/EORTC-55991 + ManGO Iliade analysis (PFS 78% vs 69%, OS trend 82% vs 75%), here in a larger trial with concurrent plus adjuvant chemo. GOG-249 found chemo + VBT no better than pelvic EBRT in stage I-II with more pelvic and para-aortic recurrence; the GOG-258 abstract reported no OS/RFS gain for CRT over chemo alone but more vaginal and nodal failures without RT.
Final analysis was time-based, with OS events at 69% of the number required, so a 5% OS difference was below what the trial could detect. RT plan QA outside ANZGOG was still pending, and the stage and age subgroup reads are exploratory.
CRT buys FFS, not OS, at 5y, at the price of a fivefold G3+ toxicity rate and persistent neuropathy. The authors read the stage I-II FFS gain as not outweighing toxicity, so the combined regimen fits individual counselling, mainly in stage III.
| Endpoint | CRT | RT alone | Effect |
|---|---|---|---|
| 5y OS | 81.8% (77.5–86.2) | 76.7% (72.1–81.6) | HR 0.76 (0.54–1.06), p=0.11 |
| 5y FFS | 75.5% (70.3–79.9) | 68.6% (63.1–73.4) | HR 0.71 (0.53–0.95), p=0.022 |
| Stage III 5y OS | 78.7% | 69.8% | HR 0.71 (0.45–1.11), adjusted p=0.074 |
| Stage III 5y FFS | 69.3% | 58.0% | HR 0.66 (0.45–0.97), adjusted p=0.014 |
| Stage I–II 5y FFS | 80.8% | 76.6% | HR 0.85 (0.54–1.33), p=0.47 |
| G3+ AEs during treatment | 198 (60%) | 41 (12%) | p<0.0001 |
| G2+ neuropathy at 3y | 20 (8%) | 1 (1%) | p<0.0001 |
CONSORT flow
Randomised phase 3 met co-primary FFS but missed OS with only 69% of required OS events; direction matches pooled NSGO-EC-9501/ManGO data. Toxicity cost tempers adoption.
- Does the OS difference emerge with longer follow-up?
- Is pelvic RT still needed in stage III when chemotherapy is given? not yet Chemotherapy vs Chemoradiotherapy for Post-operative Endometrial Cancer Patients With P53-mutation Phase 2/3n=294 · primary completion 2028-08 · randomizes chemo alone vs CRT, p53abn stage I-IVA
- Can stage I-II pts be spared chemotherapy toxicity safely? n=590 · primary completion 2026-12 · molecular profile assigns CRT vs RT, stage I-IIn=316 · primary completion 2030-01 · RT + durvalumab vs RT ± chemo in MMRd ECn=600 · primary completion 2030-12 · RT + progestin vs RT + chemo, high-risk NSMP
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The longer read
The trial asked what systemic therapy adds on top of a fixed pelvic RT backbone, and the answer at five years is a failure-free survival gain without a confirmed survival gain. That framing matters for an RT reader. Pelvic RT was given in both arms, pelvic control was already 91% with radiotherapy alone, and the brachytherapy boost was balanced between groups, so nothing in this trial suggests chemotherapy improves locoregional control. Whatever chemotherapy contributes, it contributes beyond the pelvis, and the high proportion of deaths from endometrial cancer in both arms points to systemic failure as the unresolved problem.
The OS result should be read as underpowered rather than as a clean negative. Event rates ran lower than planned, the final analysis was triggered by time rather than events, and only 69% of the required OS events had accrued. A hazard ratio of 0.76 with an upper bound of 1.06 is compatible with a real but modest survival benefit and also with none. The unadjusted and adjusted estimates differ (FFS HR 0.76 unadjusted, p=0.067, versus 0.71 adjusted, p=0.022), which is a reminder that the co-primary that did clear its bar did so narrowly and depended on the prespecified Cox adjustment. The authors themselves call for continued follow-up, and that is the honest read.
Against prior randomised data the result is consistent rather than surprising. The pooled NSGO-EC-9501/EORTC-55991 and ManGO Iliade analysis showed the same pattern, a progression-free gain and a survival trend, with sequential chemotherapy in a cohort carrying fewer stage III patients. PORTEC-3 reproduces that signal at larger scale with a concurrent-then-adjuvant schedule derived from RTOG 9708. What it does not do is settle the question GOG-258 asks: whether radiotherapy remains necessary once a platinum doublet is given. The GOG-249 experience in stage I-II, where replacing pelvic EBRT with chemotherapy plus vaginal brachytherapy increased pelvic and para-aortic recurrence, and the GOG-258 abstract reporting more vaginal and nodal failures with chemotherapy alone, both argue that the pelvic field is doing real work and that omission would trade locoregional control for convenience.
The stage split is where the decision sits. Stage III pts had the largest absolute FFS gain, which the authors note exceeded the 10% difference the trial was designed around, while the stage I-II FFS estimate had a confidence interval spanning one. Read with a G3+ toxicity rate of 60% versus 12% and neuropathy persisting at three years in 8%, the stage I-II benefit is hard to defend for routine use. The older-age and serous-histology signals are interesting, particularly given the authors' caution about selection of fitter older women, but they come from exploratory subgroups and should not drive treatment on their own.
For the trial to be wrong in its practical message, the FFS gain would have to be an artefact of the stratification adjustment or of imbalance in a subgroup, and the consistent direction across prior pooled data makes that less likely. The more plausible risk is overgeneralisation: applying a stage III-weighted benefit to every high-risk pt, including stage I-II disease where the toxicity cost clearly dominates.