Clinical trialEndometrial (womb) cancer

Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial

Lancet · 2010427 patients

Nout RA, Smit VT, Putter H, et al. Lancet. 2010. 375:816-823

Study type: Clinical trial
Study name: PORTEC-2
Design: Open-label, non-inferiority randomised trial in 19 Dutch radiation oncology centres (ISRCTN16228756)
Sample size: 427 patients
Source: Lancet · 2010

In plain words

Women with early-stage womb cancer at high–intermediate risk received, after surgery, either internal radiotherapy to the vagina (brachytherapy) or external radiotherapy to the pelvis. Internal radiotherapy prevented the cancer from coming back in the vagina just as well, but caused far fewer bowel side effects. That is why internal vaginal radiotherapy is now the preferred approach for many of these patients.

Key results

1.8% vs 1.6%

5-year vaginal recurrence

Brachytherapy vs external beam radiotherapy; HR 0.78 (95% CI 0.17–3.49); p=0.74

5.1% vs 2.1%

5-year locoregional recurrence (vaginal or pelvic)

HR 2.08 (0.71–6.09); p=0.17

1.5% vs 0.5%

Isolated pelvic recurrence

HR 3.10 (0.32–29.9); p=0.30

8.3% vs 5.7%

Distant metastases

HR 1.32 (0.63–2.74); p=0.46

84.8% vs 79.6%

5-year overall survival

HR 1.17 (0.69–1.98); p=0.57

82.7% vs 78.1%

5-year disease-free survival

HR 1.09 (0.66–1.78); p=0.74

12.6% vs 53.8%

Acute grade 1–2 gastrointestinal toxicity at the end of radiotherapy

27 of 215 vs 112 of 208

3.4% vs 2.4%

10-year follow-up: vaginal recurrence

p=0.55; median follow-up 116 months (Br J Cancer 2018)

6.3% vs 0.9%

10-year follow-up: pelvic recurrence

p=0.004; mostly together with distant metastases; isolated pelvic recurrence 2.5% vs 0.5%

69.5% vs 67.6%

10-year follow-up: overall survival

p=0.72

Dose and schedule cards

Vaginal brachytherapy (PORTEC-2)

Intermediate risk (preferred) or high–intermediate risk (alternative to external beam radiotherapy, especially pN0) after hysterectomyCycle length: WeeklyOn the page “Endometrial (womb) cancer” · After surgery: adjuvant radiotherapy and chemoradiotherapy

Intermediate risk (preferred) or high–intermediate risk (alternative to external beam radiotherapy, especially pN0) after hysterectomy

Drug	Dose	Route	Schedule
High-dose-rate (HDR) vaginal brachytherapy	21 Gy in 3 fractions of 7 Gy, prescribed at 5 mm from the cylinder surface	Vaginal cylinder; upper half of the vagina	One fraction per week

Cycle length: Weekly
Duration: 3 fractions

In PORTEC-2, HDR was used in 85% of patients and 15% received an equivalent dose with LDR (0.5 to 0.7 Gy per hour) or MDR; radiotherapy started within 8 weeks of surgery. LDR option in the original paper: 30 Gy. ESGO: intermediate risk [I, A]; high–intermediate risk as an alternative to external beam radiotherapy [II, B].

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

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

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

1Vaginal brachytherapy (213 patients)

Brachytherapy with a vaginal cylinder to the upper half of the vagina, dose prescribed at 5 mm from the cylinder surface: high-dose rate (HDR) 21 Gy in 3 fractions of 7 Gy one week apart (85% of patients), or an equivalent dose with low-dose rate (LDR; 30 Gy in the original paper) or medium-dose rate (MDR). Radiotherapy started within 8 weeks of surgery.

2Pelvic external beam radiotherapy (214 patients)

46 Gy in 23 daily fractions of 2 Gy, 5 times a week; the clinical target volume included the proximal vagina, parametria, and internal, external and lower common iliac nodes up to the promontory; CT-based 3D planning, usually with a four-field technique.

Source of the regimen details: Abstract of the Lancet 2010 paper and the methods of the 10-year report (Wortman et al, Br J Cancer 2018)

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 with stage I or IIA endometrial carcinoma with high–intermediate-risk features after total abdominal hysterectomy and bilateral salpingo-oophorectomy (lymphadenectomy was not routinely performed). High–intermediate risk by FIGO 1988: (1) stage IC (myometrial invasion of 50% or more) with age over 60 and grade 1 or 2; (2) stage IB (invasion of less than 50%) with age over 60 and grade 3; or (3) stage IIA (endocervical glandular involvement) at any age, except grade 3 with deep invasion. Exclusions: serous or clear cell carcinoma, staging lymphadenectomy, more than 8 weeks between surgery and radiotherapy, previous malignancy, previous radiotherapy, hormonal therapy or chemotherapy, and Crohn's disease or ulcerative colitis.

Endpoints

Primary endpoint: vaginal recurrence; the prespecified non-inferiority margin was an absolute difference of 6% in vaginal recurrence. Secondary endpoints: pelvic recurrence, distant metastasis, overall survival, cancer-specific survival, disease-free survival, toxicity and quality of life. Analysis was by intention to treat with competing-risk methods.

Safety and side effects

At the end of radiotherapy, acute grade 1 and 2 gastrointestinal toxicity was significantly lower with vaginal brachytherapy (12.6% [27 of 215] vs 53.8% [112 of 208]). According to the earlier reports reviewed in the 10-year paper, health-related quality of life was better with brachytherapy, and symptom scores in this group did not differ from an age-matched norm population.

Clinical significance and place in guidelines

PORTEC-2 made vaginal brachytherapy the standard adjuvant treatment for high–intermediate-risk endometrial cancer. 10-year follow-up confirmed vaginal control above 96% in both arms, but pelvic recurrence was more frequent with brachytherapy; substantial LVSI, p53-mutant expression and L1CAM expression identified a group in whom external beam radiotherapy reduced pelvic recurrence. The ESGO/ESTRO/ESP 2025 guideline recommends vaginal brachytherapy for intermediate risk [I, A] and as an alternative to external beam radiotherapy for high–intermediate risk, especially pN0 [II, B].

Limitations

Risk criteria were defined by FIGO 1988 and before molecular classification; on central pathology review, high–intermediate risk was confirmed in only 82.7% of patients. Lymphadenectomy was not routinely performed, and serous and clear cell carcinomas were excluded. The trial was not designed to compare survival.

Original article (DOI)PubMed

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.