Chemotherapy Followed By Surgery Vs Radiotherapy Plus Chemotherapy in Patients With Stage IB or II Cervical Cancer

Randomized Phase III Study Of Neoadjuvant Chemotherapy Followed By Surgery Vs. Concomitant Radiotherapy And Chemotherapy In FIGO Ib2, IIa>4 cm or IIb Cervical Cancer

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Giving chemotherapy drugs before surgery may shrink the tumor so that it can be removed during surgery. Radiation therapy uses high-energy x-rays to kill tumor cells. Combining radiation therapy with chemotherapy may kill more tumor cells. It is not yet known whether chemotherapy is more effective followed by surgery or combined with radiation therapy in treating cervical cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of chemotherapy followed by radical hysterectomy with that of chemotherapy plus radiation therapy in treating patients who have stage IB or stage II cervical cancer.

Study Overview

• Status: Unknown
• Conditions: Cervical Cancer
• Intervention / Treatment: Procedure: conventional surgery; Procedure: neoadjuvant chemotherapy; Drug: cisplatin; Radiation: brachytherapy; Radiation: radiation therapy

Detailed Description

OBJECTIVES:

• Compare the overall and progression-free survival of patients with stage IB2, IIA, or IIB cervical cancer treated with neoadjuvant cisplatin-based chemotherapy followed by radical hysterectomy vs standard therapy comprising concurrent radiotherapy and cisplatin-based chemotherapy.
• Compare the toxicity of these regimens in these patients.
• Compare the quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, FIGO stage, age (18 to 50 vs 51 to 75), and histological subtype (adenomatous vs non-adenomatous component). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive neoadjuvant cisplatin-based chemotherapy on day 1. Treatment repeats every 21 days. Within 6 weeks after the last chemotherapy course, patients undergo a type III-V Piver-Rutledge radical hysterectomy. Patients with positive lymph nodes or tumor invasion into the parametria or less than 5 mm from the resection borders after surgery receive standard adjuvant external beam radiotherapy once daily, 5 days a week, for 5-5.6 weeks (25-28 treatment days) followed by external boost radiotherapy or brachytherapy for 1 or 2 days.
• Arm II: Patients receive standard therapy comprising radiotherapy as in arm I concurrently with cisplatin-based chemotherapy once weekly for 6 weeks. Adjuvant hysterectomy is allowed, but not recommended, in case of histologically proven residual tumor.

Treatment in both arms continues in the absence of disease progression or unacceptable toxicity. For patients in both arms, cisplatin may be combined with other chemotherapeutics as long as the minimum platinum dose is given.

Quality of life is assessed at baseline and at 6, 12, 18, and 24 months.

Patients are followed every 3 months for 1 year, every 6 months for 4 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 686 patients (343 per treatment arm) will be accrued for this study within 3.8 years.

• Study Type: Interventional
• Enrollment (Anticipated): 686
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria
    • Karl-Franzens-University Graz
  • Vienna, Austria
    • Kaiser Franz Josef Hospital
• Belgium
  • Edegem, Belgium
    • Universitair Ziekenhuis Antwerpen
  • Leuven, Belgium
    • U.Z. Gasthuisberg
  • Liege, Belgium, 4000
    • Centre Hospitalier Regional de la Citadelle
• France
  • Caen, France
    • Centre Regional Francois Baclesse
• Italy
  • Milano, Italy
    • Istituto Europeo Di Oncologia
  • Monza, Italy
    • Ospedale San Gerardo
  • Naples, Italy
    • Istituto Nazionale per lo Studio e la Cura dei Tumori
  • Torino, Italy, 10128
    • Ospedale Mauriziano Umberto I
  • Turin, Italy, 10126
    • Clinica Universitaria
  • Varese, Italy
    • Ospedale di Circolo e Fondazione Macchi
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Academisch Medisch Centrum at University of Amsterdam
  • Amsterdam, Netherlands
    • Vrije Universiteit Medisch Centrum
  • Enschede, Netherlands
    • Medisch Spectrum Twente
  • Leiden, Netherlands
    • Leiden University Medical Center
  • Nijmegen, Netherlands
    • Universitair Medisch Centrum St. Radboud - Nijmegen
  • Rotterdam, Netherlands, 3008 AE
    • Erasmus MC - Daniel den Hoed Cancer Center
  • Utrecht, Netherlands
    • Universitair Medisch Centrum - Academisch Ziekenhuis
• Portugal
  • Coimbra, Portugal
    • Hospitais da Universidade de Coimbra (HUC)
• Spain
  • Madrid, Spain
    • Hospital Universitario San Carlos
• United Kingdom
  • Maidstone, Kent, United Kingdom
    • Mid Kent Oncology Centre
  • England
    • Margate, England, United Kingdom
      • Queen Elizabeth the Queen Mother Hospital
  • Scotland
    • Glasgow, Scotland, United Kingdom
      • NHS Greater Glasgow and Clyde - Beatson West of Scotland Cancer Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed cervical cancer, including the following subtypes:

  • Squamous cell carcinoma
  • Adenosquamous cell carcinoma
  • Adenocarcinoma (excluding small cell, clear cell, and other rare variants of the classical adenocarcinoma)
• FIGO stage IB2, IIA (greater than 4 cm), or IIB

PATIENT CHARACTERISTICS:

Age:

• 18 to 75

Performance status:

• WHO 0-2

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count greater than 1,500/mm^3
• Platelet count greater than 100,000/mm^3

Hepatic:

• Bilirubin less than 1.46 mg/dL

Renal:

• Creatinine clearance greater than 60 mL/min

Other:

• No other prior or concurrent malignancy except adequately treated basal cell skin cancer
• No psychological, familial, sociological, or geographical condition that would preclude study
• Not pregnant

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy

Surgery:

• Not specified

Other:

• No other concurrent anticancer agent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Chemotherapy followed by surgery; neoadjuvant chemotherapy (Cisplatin) followed by surgery (radial hysterectomy)	Procedure: conventional surgery; Radial hysterectomy; Procedure: neoadjuvant chemotherapy; Experimental arm: minimal cumulative cisplatin dose of 225 mg/m2. Comparator arm: cumulative cisplatin dose of 200-240 mg/m2.; Drug: cisplatin; Minimal cumulative 225 mg/m2 (experimental arm). Cumulative 200-240 mg/m2 (comparator arm).
Active Comparator: Radio-chemotherapy; Concomitant radiotherapy (external radiotherapy combined with external boost or brachytherapy) and chemotherapy (cisplatin)	Procedure: neoadjuvant chemotherapy; Experimental arm: minimal cumulative cisplatin dose of 225 mg/m2. Comparator arm: cumulative cisplatin dose of 200-240 mg/m2.; Drug: cisplatin; Minimal cumulative 225 mg/m2 (experimental arm). Cumulative 200-240 mg/m2 (comparator arm).; Radiation: brachytherapy; Brachytherapy at the end of external radiation. Minimal total dose (external with or without external boost + brachytherapy) of 75 Gy EQD2 to point A. Overall treatment less than 50 days.; Radiation: radiation therapy; Between 45-50 Gy, in fractions of 1.8 to 2 Gy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival at 5 years	5 years

Collaborators and Investigators

• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Investigators: Study Chair: Fabio Landoni, MD, Istituto Europeo Di Oncologia, Milano; Study Chair: Alessandro Colombo, MD, Ospedale Alessandro Manzoni, Lecco; Study Chair: Stefano Greggi, MD, PhD, Istituto Nazionale per lo Studio e la Cura dei Tumori, Napoli; Study Chair: Gemma G. Kenter, MD, Academisch Medisch Centrum - Universiteit van Amsterdam

Study record dates

Study Major Dates

• Study Start: March 1, 2002
• Primary Completion (Anticipated): July 1, 2019

Study Registration Dates

• First Submitted: June 6, 2002
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): December 5, 2016
• Last Update Submitted That Met QC Criteria: December 2, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: cervical squamous cell carcinoma; stage IIB cervical cancer; stage IB cervical cancer; stage IIA cervical cancer; cervical adenocarcinoma; cervical adenosquamous cell carcinoma
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Cervical Diseases; Uterine Diseases; Uterine Cervical Neoplasms; Antineoplastic Agents; Cisplatin
• Other Study ID Numbers: EORTC-55994; 2008-003396-52 (EudraCT Number)