Clinical trialPhase 3Endometrial (womb) cancer

Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial

Lancet Oncol · 2019660 eligible and evaluable patients (686 enrolled)

de Boer SM, Powell ME, Mileshkin L, et al. Lancet Oncol. 2019. 20:1273-1285

Study type: Clinical trial
Study name: PORTEC-3
Phase: Phase 3
Design: International, multicentre, open-label randomised phase 3 trial in 103 centres (Gynaecological Cancer Intergroup); 1:1 randomisation by biased-coin minimisation
Sample size: 660 eligible and evaluable patients (686 enrolled)
Source: Lancet Oncol · 2019
Trial registration: NCT00411138

In plain words

Women with high-risk womb cancer received, after surgery, either pelvic radiotherapy alone or radiotherapy with chemotherapy. With longer follow-up, the group that also had chemotherapy lived longer and had fewer recurrences; the benefit was greater in stage 3 and in the serous type. On the other hand, side effects during treatment were more frequent, and numbness or tingling in the hands and feet persisted in some patients.

Key results

81.4% vs 76.1%

5-year overall survival

Adjusted HR 0.70 (95% CI 0.51–0.97); p=0.034; median follow-up 72.6 months

76.5% vs 69.1%

5-year failure-free survival

HR 0.70 (0.52–0.94); p=0.016

21.4% vs 29.1%

Distant metastasis as first site of recurrence (5-year)

HR 0.74 (0.55–0.99); p=0.047

0.3% in both groups

Isolated vaginal recurrence as first site of recurrence

One patient in each group

78.5% vs 68.5%

Stage III: 5-year overall survival

HR 0.63 (0.41–0.99); p=0.043; post-hoc analysis

70.9% vs 58.4%

Stage III: 5-year failure-free survival

HR 0.61 (0.42–0.89); p=0.011

71.4% vs 52.8%

Serous: 5-year overall survival

HR 0.48 (0.24–0.96); p=0.037

81.8% vs 76.7%

First final analysis (Lancet Oncol 2018): 5-year overall survival

HR 0.76 (0.54–1.06); p=0.11; failure-free survival 75.5% vs 68.6% (HR 0.71)

59% vs 36%

Molecular analysis: 5-year recurrence-free survival in p53abn

p=0.019; POLEmut 100% vs 97%; MMRd 68% vs 76%; NSMP 80% vs 68% (JCO 2020)

Drugs in this study:Carboplatin (Paraplatin)Cisplatin (Platinol)Paclitaxel (Taxol)

Dose and schedule cards

Pelvic external beam radiotherapy (PORTEC-2 and PORTEC-3)

High–intermediate risk (preferred); and the radiotherapy component of chemoradiotherapy in high-risk diseaseCycle length: Daily, 5 days a weekOn the page “Endometrial (womb) cancer” · After surgery: adjuvant radiotherapy and chemoradiotherapy

High–intermediate risk (preferred); and the radiotherapy component of chemoradiotherapy in high-risk disease

Drug	Dose	Route	Schedule
Pelvic external beam radiotherapy	46 Gy in 23 fractions of 2 Gy (PORTEC-2); or 48.6 Gy in 1.8 Gy fractions (PORTEC-3)	External beam, 3D-planned	5 days a week

Cycle length: Daily, 5 days a week
Duration: 23 to 27 fractions

Clinical target volume: proximal vagina, parametria, and internal, external and lower common iliac nodes. In PORTEC-3 up to L5–S1, extended to the para-aortic region if nodes were involved; with cervical involvement, a brachytherapy boost equivalent to 14 Gy in 2 Gy fractions (suggested: 10 Gy HDR in 2 fractions of 5 Gy, at 5 mm depth); IMRT was allowed with approval, and 11 UK centres used 45 Gy.

On the page “Endometrial (womb) cancer” · After surgery: adjuvant radiotherapy and chemoradiotherapy

Adjuvant chemoradiotherapy (PORTEC-3)

High risk (FIGO 2009): endometrioid IA grade 3 with LVSI, IB grade 3, II or III; or serous and clear cell stage I to III; WHO performance status 0 to 2On the page “Endometrial (womb) cancer” · After surgery: adjuvant radiotherapy and chemoradiotherapy

High risk (FIGO 2009): endometrioid IA grade 3 with LVSI, IB grade 3, II or III; or serous and clear cell stage I to III; WHO performance status 0 to 2

Drug	Dose	Route	Schedule
Concurrent with radiotherapy
Cisplatin	50 mg/m²	IV	Weeks 1 and 4 of radiotherapy
Pelvic external beam radiotherapy	48.6 Gy in 1.8 Gy fractions	External beam	5 days a week
Then: 4 cycles
Carboplatin	AUC 5	IV	Day 1 every 21 days
Paclitaxel	175 mg/m²	IV	Day 1 every 21 days

Cycle length: Cisplatin in weeks 1 and 4 of radiotherapy; carboplatin–paclitaxel every 21 days
Duration: 2 cycles of concurrent cisplatin, then 4 cycles of carboplatin–paclitaxel

Eligibility: white cells at least 3.0×10⁹/L, platelets at least 100×10⁹/L, bilirubin at most 1.5 times the upper limit, creatinine clearance above 60 mL/min; grade 2 or worse neuropathy was an exclusion criterion. For toxicity, cisplatin was postponed by one week and stopped for grade 2 or worse neuropathy; paclitaxel was postponed for grade 2 neuropathy and stopped for grade 3. Grade 3 or worse adverse events during treatment: 60%.

On the page “Endometrial (womb) cancer” · After surgery: adjuvant radiotherapy and chemoradiotherapy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Chemoradiotherapy (330 patients)

Concurrent: cisplatin 50 mg/m² IV in weeks 1 and 4 of pelvic external beam radiotherapy (48.6 Gy in 1.8 Gy fractions, 5 days a week). Then: 4 cycles of carboplatin AUC 5 and paclitaxel 175 mg/m² IV at 21-day intervals. For toxicity, cisplatin was postponed by one week and stopped for grade 2 or worse neuropathy; paclitaxel was postponed for grade 2 neuropathy and stopped for grade 3.

2Radiotherapy alone (330 patients)

Pelvic external beam radiotherapy 48.6 Gy in 1.8 Gy fractions, 5 days a week (45 Gy was allowed in 11 UK centres). In both arms, cervical involvement was treated with a vaginal vault brachytherapy boost equivalent to 14 Gy in 2 Gy fractions (suggested: 10 Gy HDR in 2 fractions of 5 Gy, at 5 mm depth).

Source of the regimen details: Abstract and methods of the Lancet Oncol 2018 and 2019 papers (cisplatin timing in weeks 1 and 4, brachytherapy boost and dose-modification rules)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Women aged 18 or older with WHO performance status 0 to 2 and high-risk endometrial carcinoma (FIGO 2009): endometrioid stage IA grade 3 with documented LVSI; stage IB grade 3; stage II; stage IIIA, IIIB (parametrial invasion) or IIIC; or serous or clear cell stage IA (with invasion) to III. Laboratory requirements: white cells 3.0×10⁹/L or more, platelets 100×10⁹/L or more, bilirubin at most 1.5 times the upper limit, AST and ALT at most 2.5 times the upper limit, and creatinine clearance above 60 mL/min. Exclusions: uterine sarcoma or carcinosarcoma, residual macroscopic tumour, previous pelvic radiotherapy, previous hormonal therapy or chemotherapy, grade 2 or worse neuropathy and grade 3 or worse hearing impairment.

Endpoints

Co-primary endpoints: overall survival and failure-free survival. Secondary endpoints: vaginal, pelvic and distant recurrence by first site of recurrence. Survival was analysed by intention to treat and adjusted for stratification factors; competing-risk methods for failure-free survival and recurrence. The analysis of recurrence patterns with 1 additional year of follow-up was post hoc.

Safety and side effects

In the first analysis, grade 3 or worse adverse events during treatment occurred in 60% of patients in the chemoradiotherapy group and 12% in the radiotherapy group (mostly haematological). At 5 years, grade 3 adverse events did not differ significantly (8% vs 5%; p=0.24), the most common being hypertension; grade 2 or worse adverse events were 38% vs 23% (p=0.002). Grade 2 or worse sensory neuropathy at 5 years was 6% vs 0%. No treatment-related deaths were reported.

Clinical significance and place in guidelines

Together with GOG-258, PORTEC-3 is the basis of adjuvant treatment for high-risk endometrial cancer and showed the largest benefit in stage III and serous cancers. The molecular analysis of the same trial showed that the benefit of chemotherapy lies mainly in p53abn tumours and that POLEmut tumours do excellently even without intensive treatment; these findings are built into the FIGO 2023 staging and the ESGO/ESTRO/ESP 2025 guideline (external beam radiotherapy with concurrent and adjuvant chemotherapy for the high-risk group [I, A]).

Limitations

The survival analyses by stage and histology were post hoc and exploratory. The comparator was radiotherapy alone, and chemotherapy alone was not tested (the question of GOG-258). In the first analysis with shorter follow-up, the overall survival difference was not significant. Persistent sensory neuropathy and reduced quality of life during treatment should be weighed in shared decision making. Molecular classification was done in only 410 patients.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.