Clinical trialPhase 3Endometrial (womb) cancer

Adjuvant Chemotherapy plus Radiation for Locally Advanced Endometrial Cancer

N Engl J Med · 2019813 patients enrolled; 736 eligible patients in the relapse-free survival analysis

Matei D, Filiaci V, Randall ME, et al. N Engl J Med. 2019. 380:2317-2326

Study type: Clinical trial
Study name: GOG-258
Phase: Phase 3
Design: Multicentre randomised phase 3 trial (GOG and NRG Oncology); 1:1 randomisation stratified by age and the presence or absence of gross residual disease
Sample size: 813 patients enrolled; 736 eligible patients in the relapse-free survival analysis
Source: N Engl J Med · 2019
Trial registration: NCT00942357

In plain words

Women whose womb cancer had spread beyond the womb (stage 3, or stage 4 limited to the pelvis) received, after surgery, either chemotherapy with radiotherapy or chemotherapy alone. Adding radiotherapy reduced recurrence in the vagina and pelvic lymph nodes, but overall it did not keep patients free of recurrence for longer. So chemotherapy alone is also an accepted choice.

Key results

59% vs 58%

Alive and relapse-free at 60 months

Chemoradiotherapy vs chemotherapy alone; HR 0.90 (90% CI 0.74–1.10); median follow-up 47 months

2% vs 7%

5-year vaginal recurrence

HR 0.36 (95% CI 0.16–0.82)

11% vs 20%

5-year pelvic and para-aortic nodal recurrence

HR 0.43 (0.28–0.66)

27% vs 21%

5-year distant recurrence

HR 1.36 (1.00–1.86)

58% vs 63%

Grade 3, 4 or 5 adverse events

202 vs 227 patients

14% vs 30%

Acute grade 4 or higher adverse events

48 vs 108 patients

Immature

Overall survival

165 deaths (86 vs 79) at the time of the report

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

Dose and schedule cards

Cisplatin and radiotherapy, then carboplatin–paclitaxel (GOG-258 chemoradiotherapy arm)

Stage III or IVA (FIGO 2009) with residual disease of at most 2 cm; or serous and clear cell stage I and II with positive peritoneal washingsOn the page “Endometrial (womb) cancer” · After surgery: adjuvant radiotherapy and chemoradiotherapy

Stage III or IVA (FIGO 2009) with residual disease of at most 2 cm; or serous and clear cell stage I and II with positive peritoneal washings

Drug	Dose	Route	Schedule
Concurrent with radiotherapy
Cisplatin	50 mg/m²	IV	Days 1 and 29
Volume-directed external beam radiotherapy	45 Gy in 25 fractions of 1.8 Gy	Pelvis with or without para-aortic fields	5 days a week
Then: 4 cycles
Carboplatin	AUC 5 to 6	IV	Day 1 every 21 days
Paclitaxel	175 mg/m²	IV	Day 1 every 21 days

Cycle length: Cisplatin on days 1 and 29 of radiotherapy; carboplatin–paclitaxel every 21 days
Duration: About 6 months (median 21 weeks)

With G-CSF support during carboplatin–paclitaxel; IMRT and vaginal cuff brachytherapy were allowed; 75% completed all 4 cycles. This arm was not superior to chemotherapy alone but had fewer vaginal and pelvic recurrences.

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

Adjuvant carboplatin–paclitaxel, 6 cycles (GOG-258 chemotherapy arm)

Stage III or IVA after surgery; ESGO: chemotherapy with or without brachytherapy is an alternative to chemoradiotherapy in high-risk disease [I, B]Cycle length: Every 21 daysOn the page “Endometrial (womb) cancer” · After surgery: adjuvant radiotherapy and chemoradiotherapy

Stage III or IVA after surgery; ESGO: chemotherapy with or without brachytherapy is an alternative to chemoradiotherapy in high-risk disease [I, B]

Drug	Dose	Route	Schedule
Carboplatin	AUC 6	IV	Day 1
Paclitaxel	175 mg/m²	IV	Day 1

Cycle length: Every 21 days
Duration: 6 cycles

85% of patients completed all 6 cycles in a median of 17 weeks; acute grade 4 or worse adverse events 30% vs 14% with chemoradiotherapy. Place in the guideline:.

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 (346 treated patients)

Cisplatin 50 mg/m² IV on days 1 and 29 with volume-directed external beam radiotherapy to the pelvis with or without para-aortic fields (planned dose 45 Gy in 25 fractions of 1.8 Gy; IMRT and vaginal brachytherapy were allowed only in this group); then carboplatin to an AUC of 5 to 6 and paclitaxel 175 mg/m² every 21 days for 4 cycles, with G-CSF support.

2Chemotherapy alone (361 treated patients)

Carboplatin to an AUC of 6 and paclitaxel 175 mg/m² every 21 days for 6 cycles.

Source of the regimen details: Full text of the paper (PMC6948006, Trial Treatments section)

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 surgical stage III or IVA endometrial carcinoma (FIGO 2009) of any histological type, or stage I or II clear cell or serous carcinoma with positive peritoneal washings; hysterectomy and bilateral salpingo-oophorectomy within 8 weeks before entry; no single residual mass larger than 2 cm; normal organ function and GOG performance status of 2 or lower. Pelvic and para-aortic node sampling or dissection was optional. Carcinosarcoma and recurrent disease were excluded.

Endpoints

Primary endpoint: relapse-free survival. Secondary endpoints: overall survival, acute and chronic toxic effects, and quality of life.

Safety and side effects

Grade 3, 4 or 5 adverse events in 58% of the chemoradiotherapy group and 63% of the chemotherapy-alone group; acute grade 4 or higher events 14% vs 30%. Constitutional symptoms, fatigue and gastrointestinal, renal/genitourinary and musculoskeletal events were more frequent with chemoradiotherapy, and haematological events were more frequent and more severe with chemotherapy alone. Both treatment-related deaths (sepsis and sudden death) occurred in the chemotherapy-alone group. Chronic effects (diarrhoea, lymphoedema and musculoskeletal problems) were more common with chemoradiotherapy.

Clinical significance and place in guidelines

GOG-258 showed that in stage III and IVA disease, adding radiotherapy to chemotherapy does not improve relapse-free survival, although pelvic and vaginal control is better. Six cycles of carboplatin–paclitaxel therefore became a standard adjuvant treatment for locally advanced disease, and the ESGO/ESTRO/ESP 2025 guideline lists chemotherapy with or without brachytherapy as an alternative to chemoradiotherapy in the high-risk group [I, B]. The trial was designed before molecular classification and immunotherapy.

Limitations

Overall survival data were immature at the time of the report. 77 patients were ineligible, and 24 of the 29 untreated eligible patients were in the chemoradiotherapy group; 51 major protocol violations (43 in the chemoradiotherapy group) were recorded. Only 75% of patients in the chemoradiotherapy group completed all 4 chemotherapy cycles. Molecular classification was not assessed.

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.