Clinical trialCervical cancer

Concurrent Cisplatin-Based Radiotherapy and Chemotherapy for Locally Advanced Cervical Cancer

N Engl J Med · 1999526 women

Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. N Engl J Med. 1999. 340:1144-1153

Study type: Clinical trial
Study name: GOG
Design: Three-arm randomised trial of the Gynaecologic Oncology Group comparing radiotherapy with three concurrent chemotherapy regimens
Sample size: 526 women
Source: N Engl J Med · 1999

In plain words

In this study, women with advanced cervical cancer received one of three drug regimens alongside radiotherapy. Women who received the drug cisplatin (alone or with other drugs) lived longer and stayed free of disease progression for longer than those who received only hydroxyurea. So adding cisplatin-containing chemotherapy to radiotherapy can improve the result of treatment.

Key results

Relative risk of progression or death 0.57 (95% CI 0.42–0.78)

Progression-free survival: group 1 (cisplatin) vs group 3 (hydroxyurea)

P<0.001

Relative risk of progression or death 0.55 (95% CI 0.40–0.75)

Progression-free survival: group 2 (cisplatin, fluorouracil and hydroxyurea) vs group 3

P<0.001

Relative risk of death 0.61 (95% CI 0.44–0.85)

Overall survival: group 1 vs group 3

Overall survival in groups 1 and 2 was significantly higher than in group 3

Relative risk of death 0.58 (95% CI 0.41–0.81)

Overall survival: group 2 vs group 3

Median follow-up 35 months

Drugs in this study:Cisplatin (Platinol)Fluorouracil (5-FU)Hydroxyurea (Hydrea)Pembrolizumab (Keytruda)

Dose and schedule cards

Chemoradiotherapy with weekly cisplatin (standard)

Locally advanced cervical cancer (IB3 to IVA), and stages IB2 and IIA1 when surgery is not appropriateCycle length: WeeklyOn the page “Cervical cancer” · Locally advanced disease: chemoradiotherapy and its add-ons

Locally advanced cervical cancer (IB3 to IVA), and stages IB2 and IIA1 when surgery is not appropriate

Drug	Dose	Route	Schedule
Cisplatin	40 mg/m² (in INTERLACE, maximum 70 mg per dose)	IV	Once weekly concurrent with external beam radiotherapy, 5 to 6 doses
Pelvic external beam radiotherapy	45 to 50.4 Gy in 20 to 28 fractions	External beam radiotherapy	Concurrent with cisplatin
Brachytherapy	To a total equivalent dose in 2-Gy fractions (EQD2) of 78 to 86 Gy; in KEYNOTE-A18, at least 80 Gy (volume-based) or 75 Gy (point-based)	Intracavitary	After external beam radiotherapy

Cycle length: Weekly
Duration: Cisplatin for 5 to 6 weeks; total radiotherapy course up to 50 days (up to 56 days for unforeseen delays; KEYNOTE-A18 protocol)

In the landmark GOG trial, eligibility required serum creatinine ≤2 mg/dL, white blood cell count ≥3000/mm³ and platelets ≥100,000/mm³, and weekly cisplatin 40 mg/m² for 6 weeks improved survival compared with hydroxyurea. Source for dosing and radiotherapy: the INTERLACE and KEYNOTE-A18 protocols.

On the page “Cervical cancer” · Locally advanced disease: chemoradiotherapy and its add-ons

Weekly cisplatin

Locally advanced cervical cancer, with radiotherapyCycle length: WeeklyOn the page “Weekly cisplatin with radiotherapy (cervical cancer)”

Locally advanced cervical cancer, with radiotherapy

Drug	Dose	Route	Schedule
Cisplatin	40 mg/m²	IV	Weekly during radiotherapy

Cycle length: Weekly
Duration: 5 to 6 doses

As in GOG 120. Many centres cap each dose at 70 mg.

On the page “Weekly cisplatin with radiotherapy (cervical cancer)”

KEYNOTE-A18

High-risk locally advanced cervical cancerEach drug’s schedule in the tableOn the page “Pembrolizumab in cervical cancer: with chemoradiotherapy and in metastatic disease”

High-risk locally advanced cervical cancer

Drug	Dose	Route	Schedule
Phase 1
Pembrolizumab	200 mg	IV	Every 3 weeks, 5 doses
Cisplatin	40 mg/m²	IV	Weekly, 5 to 6 doses with radiotherapy
Phase 2
Pembrolizumab	400 mg	IV	Every 6 weeks, 15 doses

Cycle schedule: Every 3 weeks during chemoradiotherapy; then every 6 weeks
Duration: About 2 years

As in KEYNOTE-A18; weekly cisplatin as in GOG 120.

Dose source:.

On the page “Pembrolizumab in cervical cancer: with chemoradiotherapy and in metastatic disease”

Weekly chemoradiotherapy for cervical cancer (GOG)

Locally advanced cervical cancer (off-label use)Cycle length: WeeklyOn the page “Cisplatin (Platinol)” · Regimens and dosing

Locally advanced cervical cancer (off-label use)

Drug	Dose	Route	Schedule
Cisplatin	40 mg/m²	Slow IV infusion	Weekly with external beam radiotherapy

Cycle length: Weekly
Duration: 6 weeks

Doses from the GOG trial with 526 women.

On the page “Cisplatin (Platinol)” · Regimens and dosing

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

1Group 1: weekly cisplatin

External-beam radiotherapy according to a strict protocol, with cisplatin 40 mg/m² once weekly for 6 weeks.

2Group 2: cisplatin, fluorouracil and hydroxyurea

External-beam radiotherapy according to a strict protocol, with cisplatin 50 mg/m² on days 1 and 29, then fluorouracil 4 g/m² as a 96-hour infusion on days 1 and 29, and oral hydroxyurea 2 g/m² twice weekly for 6 weeks.

3Group 3: hydroxyurea alone

External-beam radiotherapy according to a strict protocol, with oral hydroxyurea 3 g/m² twice weekly for 6 weeks.

Source of the regimen details: Abstract of the paper

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 previously untreated invasive squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma of the cervix, stage IIB, III or IVA, without para-aortic lymph node involvement. Eligibility: leucocyte count at least 3000 per cubic millimetre, platelet count at least 100,000 per cubic millimetre, serum creatinine at most 2 mg/dL (177 µmol/L) and adequate liver function.

Endpoints

The abstract does not explicitly define the primary endpoint. Reported outcomes include progression-free survival and overall survival.

Safety and side effects

Adverse event data are not reported in the abstract; see the full text of the paper for grade 3 and higher adverse events.

Clinical significance and place in guidelines

This trial showed that adding cisplatin to radiotherapy improves progression-free and overall survival in locally advanced cervical cancer compared with radiotherapy plus hydroxyurea. The abstract does not examine the difference between the weekly cisplatin regimen and the three-drug regimen. The current status in clinical guidelines and drug approvals should be checked separately, as it is not given in the abstract.

Limitations

This summary is based on the abstract only. Information on adverse events, the primary endpoint and a direct comparison of groups 1 and 2 is not available in the abstract. The control group received hydroxyurea, not radiotherapy alone. Median follow-up was 35 months. An erratum has been published for this paper and should be checked in the full text.

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.