Clinical trialPhase 3Cervical cancer

Improved survival with bevacizumab in advanced cervical cancer

N Engl J Med · 2014452 patients

Tewari KS, Sill MW, Long HJ 3rd, Penson RT, Huang H, Ramondetta LM, et al. N Engl J Med. 2014. 370:734-43

A newer report of this study has been published: Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240) (2017)

Study type: Clinical trial
Study name: GOG 240
Phase: Phase 3
Design: Randomised trial with a 2×2 factorial design
Sample size: 452 patients
Source: N Engl J Med · 2014
Trial registration: NCT00803062

In plain words

This study showed that adding the drug bevacizumab (which blocks the tumour's blood supply) to chemotherapy in advanced or recurrent cervical cancer lengthens patients' lives by about 4 months on average. This drug may raise blood pressure and, rarely, cause blood clots or a fistula (an abnormal connection between the bowel and nearby organs); so its risks should be discussed with the doctor before starting.

Key results

17.0 vs 13.3 months

Median overall survival (with/without bevacizumab)

HR 0.71 (98% CI 0.54–0.95); P=0.004 (one-sided)

48% vs 36%

Response rate

P=0.008

HR for death 1.20

Topotecan–paclitaxel vs cisplatin–paclitaxel

Not superior

Drugs in this study:Bevacizumab (Avastin)Cisplatin (Platinol)Paclitaxel (Taxol)

Dose and schedule cards

Paclitaxel + cisplatin + bevacizumab (GOG 240)

First-line metastatic, persistent or recurrent disease; GOG performance status 0–1; no nonhealing wound or active bleeding; urine protein-to-creatinine ratio less than 1Cycle length: Every 21 daysOn the page “Cervical cancer” · Metastatic, persistent or recurrent disease: first line

First-line metastatic, persistent or recurrent disease; GOG performance status 0–1; no nonhealing wound or active bleeding; urine protein-to-creatinine ratio less than 1

Drug	Dose	Route	Schedule
Paclitaxel	175 mg/m² (3-hour infusion); or 135 mg/m² (24-hour infusion)	IV	Day 1
Cisplatin	50 mg/m²	IV	Day 1 or 2
Bevacizumab	15 mg/kg (30- to 90-minute infusion)	IV	Day 1

Cycle length: Every 21 days
Duration: Until disease progression, unacceptable toxicity or complete response

Platinum-free alternative: topotecan 0.75 mg/m² on days 1–3 + paclitaxel 175 mg/m² on day 1 (with or without bevacizumab), which was not superior to cisplatin–paclitaxel (HR for death 1.20). In KEYNOTE-826 and BEATcc, carboplatin AUC 5 on day 1 was also permitted instead of cisplatin. Source for doses and infusion durations:.

On the page “Cervical cancer” · Metastatic, persistent or recurrent disease: first line

GOG 240 (cervix)

Metastatic, persistent or recurrent cervical cancerCycle length: Every 21 daysOn the page “Paclitaxel (Taxol)” · Other regimens: key trials and nab-paclitaxel

Metastatic, persistent or recurrent cervical cancer

Drug	Dose	Route	Schedule
Paclitaxel	135 or 175 mg/m²	IV	Day 1
Cisplatin	50 mg/m²	IV	Day 1
Bevacizumab	15 mg/kg	IV	Day 1

Cycle length: Every 21 days
Duration: Until progression, unacceptable toxicity or complete response

The GOG 240 trial regimen.

On the page “Paclitaxel (Taxol)” · Other regimens: key trials and nab-paclitaxel

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

1Chemotherapy ± bevacizumab (factorial design)

IV chemotherapy regimens every 21 days: cisplatin 50 mg/m² (day 1 or 2) plus paclitaxel 135 mg/m² (over 24 hours) or 175 mg/m² (over 3 hours) on day 1; or topotecan 0.75 mg/m² (over 30 minutes) on days 1 to 3 plus paclitaxel 175 mg/m² on day 1. Each regimen with or without bevacizumab 15 mg/kg IV (over 30 to 90 minutes) on day 1. Cycles were repeated until disease progression, unacceptable toxicity or complete response.

The bevacizumab dose was adjusted only for a weight change of more than 10%; if chemotherapy was delayed because of low neutrophil or platelet counts, bevacizumab was also held; bevacizumab was delayed or discontinued for uncontrolled hypertension (systolic above 150 or diastolic above 100 mmHg), proteinuria (urine protein-to-creatinine ratio 3.5 or higher), arterial or venous thrombosis, coagulopathy and bowel obstruction or perforation.

Source of the regimen details: Abstract and methods section of the paper (NEJM 2014, PMC4010094), ClinicalTrials.gov NCT00803062 (infusion duration) and the full text of the final analysis (Lancet 2017; bevacizumab 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

Patients with recurrent, persistent or metastatic cervical cancer; most had previously received cisplatin with radiotherapy.

Endpoints

Primary endpoint: overall survival (a 30% reduction in the hazard of death was considered clinically important). Secondary: progression-free survival, response rate and safety.

Safety and side effects

Bevacizumab was associated with grade 2 or higher hypertension (25% versus 2%), grade 3 or higher thromboembolic events (8% versus 1%) and grade 3 or higher gastrointestinal fistula (3% versus 0%).

Clinical significance and place in guidelines

GOG 240 established the basis of first-line treatment for metastatic/recurrent disease (platinum–paclitaxel plus bevacizumab). The FDA approved bevacizumab for this indication in 2014. The later KEYNOTE-826 and BEATcc trials added immunotherapy to this backbone. The ESGO/ESTRO/ESP 2023 guideline recommends adding bevacizumab after careful assessment of the risk of gastrointestinal/urinary toxicity [I, A].

Limitations

Most patients had previously received cisplatin; there was no direct comparison with carboplatin regimens; the risk of fistula, especially in patients with prior pelvic radiotherapy, requires careful patient selection.

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.