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

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC (Other)

Overall Status

Unknown status

CT.gov ID

NCT00039338

Collaborator

(none)

686

Enrollment

Locations

Arms

28.6

Patients Per Site

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Cervical Cancer	Procedure: conventional surgery Procedure: neoadjuvant chemotherapy Radiation: brachytherapy Radiation: radiation therapy Drug: cisplatin	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

686 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Mar 1, 2002

Anticipated Primary Completion Date :

Jul 1, 2019

Arms and Interventions

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. 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. Drug: cisplatin Minimal cumulative 225 mg/m2 (experimental arm). Cumulative 200-240 mg/m2 (comparator arm).

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.

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.

Drug: cisplatin

Minimal cumulative 225 mg/m2 (experimental arm). Cumulative 200-240 mg/m2 (comparator arm).

Outcome Measures

Primary Outcome Measures

Overall survival at 5 years [5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Karl-Franzens-University Graz	Graz		Austria
2	Kaiser Franz Josef Hospital	Vienna		Austria
3	Universitair Ziekenhuis Antwerpen	Edegem		Belgium
4	U.Z. Gasthuisberg	Leuven		Belgium
5	Centre Hospitalier Regional de la Citadelle	Liege		Belgium	4000
6	Centre Regional Francois Baclesse	Caen		France
7	Istituto Europeo Di Oncologia	Milano		Italy
8	Ospedale San Gerardo	Monza		Italy
9	Istituto Nazionale Per Lo Studio E La Cura Dei Tumori	Naples		Italy
10	Ospedale Mauriziano Umberto I	Torino		Italy	10128
11	Clinica Universitaria	Turin		Italy	10126
12	Ospedale di Circolo e Fondazione Macchi	Varese		Italy
13	Academisch Medisch Centrum at University of Amsterdam	Amsterdam		Netherlands	1105 AZ
14	Vrije Universiteit Medisch Centrum	Amsterdam		Netherlands
15	Medisch Spectrum Twente	Enschede		Netherlands
16	Leiden University Medical Center	Leiden		Netherlands
17	Universitair Medisch Centrum St. Radboud - Nijmegen	Nijmegen		Netherlands
18	Erasmus MC - Daniel den Hoed Cancer Center	Rotterdam		Netherlands	3008 AE
19	Universitair Medisch Centrum - Academisch Ziekenhuis	Utrecht		Netherlands
20	Hospitais da Universidade de Coimbra (HUC)	Coimbra		Portugal
21	Hospital Universitario San Carlos	Madrid		Spain
22	Queen Elizabeth The Queen Mother Hospital	Margate	England	United Kingdom
23	NHS Greater Glasgow and Clyde - Beatson West of Scotland Cancer Centre	Glasgow	Scotland	United Kingdom
24	Mid Kent Oncology Centre	Maidstone, Kent		United Kingdom

Sponsors and Collaborators

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