Induction Chemotherapy Plus Chemoradiation as First Line Treatment for Locally Advanced Cervical Cancer (INTERLACE)

A Phase III Multicentre Trial of Weekly Induction Chemotherapy Followed by Standard Chemoradiation Versus Standard Chemoradiation Alone in Patients With Locally Advanced Cervical Cancer

Chemoradiation has been the standard treatment for advanced cervical cancer for a decade, but one third of women still die from a failure to control systemic disease. In a recent multicentre phase II trial of 46 women the investigators found that, 68% of women had tumours that responded to weekly induction chemotherapy prior to chemoradiation. The induction chemotherapy had acceptable toxicity and did not compromise the standard chemoradiation treatment. In addition, the overall survival and progression free survival at 3 years was 66% (95% CI 4779). These results, together with acceptable toxicity, provide justification for evaluating induction chemotherapy prior to chemoradiation in a randomised phase III trial. The investigators aim to investigate in a randomised trial whether additional induction chemotherapy given on a weekly schedule immediately before standard chemoradiation leads to an improvement in overall survival. The investigators plan to recruit 770 women with locally advanced cervical cancer who are eligible for standard chemoradiation, they will be randomised to weekly carboplatin and paclitaxel chemotherapy for 6 weeks followed by chemoradiation or to chemoradiation alone. The trial will recruit for 4 years with 5 years of follow up period.

Study Overview

• Status: Active, not recruiting
• Conditions: Cervical Cancer
• Intervention / Treatment: Radiation: Radiotherapy; Drug: Cisplatin; Drug: Paclitaxel; Drug: Carboplatin

• Study Type: Interventional
• Enrollment (Actual): 500
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • São Paulo, Brazil, 01246-000
    • Instituto do Cancer do Estado de São Paulo
• India
  • Kolkata, India
    • Chittaranjan National Cancer Institute (CNCI)
  • Kolkata, India
    • Saroj Gupta Cancer Centre and Research Institute
• Italy
  • Lombardy
    • Milan, Lombardy, Italy, 20141
      • Istituto Europeo di Oncologia
• Mexico
  • Mexico City, Mexico
    • Instituto Nacional de Cancerología (INCan)
• United Kingdom
  • Belfast, United Kingdom
    • Belfast City Hospital
  • Boston, United Kingdom
    • Pilgrim Hospital
  • Brighton, United Kingdom
    • Royal Sussex County Hospital
  • Cardiff, United Kingdom
    • Velindre Cancer Centre
  • Cheltenham, United Kingdom
    • Cheltenham General Hospital
  • Derby, United Kingdom
    • Royal Derby Hospital
  • Exeter, United Kingdom, EX2 5DY
    • Royal Devon and Exeter NHS Foundation Trust
  • Glasgow, United Kingdom
    • Beatson WOSCC
  • Gloucester, United Kingdom
    • Gloucester Royal Hospital
  • Grantham, United Kingdom
    • Grantham and District Hospital
  • Hull, United Kingdom
    • Castle Hill Hospital
  • Leicester, United Kingdom
    • Leicester Royal Infirmary
  • Lincoln, United Kingdom
    • Lincoln County Hospital
  • London, United Kingdom
    • Imperial College Healthcare NHS Trust
  • London, United Kingdom
    • Guy's and St Thomas' NHS Foundation Trust
  • London, United Kingdom
    • St Bart's Hospital
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust
  • Middlesbrough, United Kingdom
    • James Cook University Hospital
  • Northampton, United Kingdom
    • Northampton General Hospital
  • Norwich, United Kingdom
    • Norfolk and Norwich University Hospital
  • Nottingham, United Kingdom, NG5 1PB
    • Nottingham University Hospitals NHS Trust
  • Plymouth, United Kingdom
    • Derriford Hospital
  • Southampton, United Kingdom
    • Southampton General Hospital
  • Stoke-On-Trent, United Kingdom
    • Royal Stoke University Hospital
  • Truro, United Kingdom
    • Royal Cornwall Hospital
  • Wirral, United Kingdom
    • The Clatterbridge Cancer Centre
  • Wolverhampton, United Kingdom
    • New Cross Hospital
  • Devon
    • Barnstaple, Devon, United Kingdom, EX31 4JB
      • North Devon District Hospital
  • Greater London
    • London, Greater London, United Kingdom, NW1 2BU
      • University College London Hospital
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S10 2SJ
      • Weston Park Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically confirmed FIGO stage Ib2-IVa squamous, adeno or adenosquamous carcinoma of the cervix (except FIGO IIIA). Patients with histologically confirmed FIGO stage IB1 and positive lymph nodes are also eligible
• Deemed suitable and fit for radical chemoradiation
• Medically fit to receive carboplatin and paclitaxel
• ECOG performance status 0 - 1
• No evidence of active TB
• Aged 18 and over
• Adequate renal function, defined as a GFR ≥ 60 ml/min calculated using the Wright equation (or ≥ 50 ml/min for radioisotope GFR assessment)
• Adequate liver function, as defined by ALT or AST < 2.5 ULN and bilirubin < 1.25 ULN
• Adequate bone marrow function as defined by ANC ≥1.5 x 109/L, platelets ≥ 100 x 109/L
• Using adequate contraception precautions if relevant
• A documented negative HIV test (patients recruited from high risk countries or who have moved within the past 10 years from high risk countries)
• A documented negative pregnancy test (if applicable)
• Capable of providing written or witnessed informed consent

Patients with positive (pelvic/para-aortic/both) nodes (either histologically/PET positive ≥15 mm on CT/MRI) at or below the level of the aortic bifurcation may be included in the study provided none of the exclusion criteria apply.

Exclusion Criteria:

• Previous pelvic malignancy (regardless of interval since diagnosis)
• Previous malignancy not affecting the pelvis (except basal cell carcinoma of the skin) where disease free interval is less than 10 years
• Positive lymph nodes (imaging or histological) above the aortic bifurcation*
• Hydronephrosis which has not undergone ureteric stenting or nephrostomy except where the affected kidney is non-functioning
• Evidence of distant metastasis i.e. any non-nodal metastasis beyond the pelvis
• Previous pelvic radiotherapy
• Prior diagnosis of Crohn's disease or Ulcerative colitis
• Uncontrolled cardiac disease (defined as cardiac function which would preclude hydration during cisplatin administration and any contraindication to paclitaxel)
• Pregnant or lactating * i.e. PET any size, CT/MRI ≥ 15mm

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
Active Comparator: Chemoradiation; Radiotherapy (external beam and brachytherapy) plus concurrent Cisplatin weekly for 5 weeks	Radiation: Radiotherapy; Radiotherapy comprising external beam 40-50.4Gy in 20-28 fractions plus intracavity brachytherapy to achieve a minimum total EQD2 dose of 78-86Gy.; Drug: Cisplatin; Cisplatin 40 mg/m2 (capped at 70mg total dose) weekly for five weeks maximum, commencing in the first week of radiotherapy or as soon as blood counts have recovered from induction chemotherapy.
Experimental: Induction Chemotherapy + Chemoradiation; 6 cycles of weekly Paclitaxel and Carboplatin followed by Chemoradiation as per Active Comparator	Radiation: Radiotherapy; Radiotherapy comprising external beam 40-50.4Gy in 20-28 fractions plus intracavity brachytherapy to achieve a minimum total EQD2 dose of 78-86Gy.; Drug: Cisplatin; Cisplatin 40 mg/m2 (capped at 70mg total dose) weekly for five weeks maximum, commencing in the first week of radiotherapy or as soon as blood counts have recovered from induction chemotherapy.; Drug: Paclitaxel; Paclitaxel 80 mg/m2 (capped at 162mg maximum total dose) weekly for 6 weeks i.e. on days 1, 8, 15, 22, 29 & 36.; Drug: Carboplatin; Carboplatin AUC 2 (capped at 270mg maximum total dose) weekly for 6 weeks i.e. on day 1, 8, 15, 22, 29, & 36.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall Survival	5 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Progression free survival	12 weeks post treatment and then as required
Adverse events (AE) as assessed by the Common Terminology Criteria for Adverse Events v4.03	To be assessed at every timepoint i.e. baseline; at every chemotherapy cycle, at all follow up visits.
Quality of Life (UK and Ireland only) as assessed by EORTC QLQ-C30, QLQ-CX24 and EQ-5D	Baseline, during induction chemotherapy (Week 4), day 1 of chemoradiation, during chemoradiation (Weeks 3), 4 weeks post end of treatment, and as part of follow up (3 monthly for 2 years; 6 monthly for 3 years until 5 years post randomisation)
Patterns of first relapse (local and/or systemic)	12 weeks post treatment and as required

Collaborators and Investigators

• Sponsor: University College, London
• Collaborators: Cancer Research UK
• Investigators: Principal Investigator: Mary Dr McCormack, MBBS, FRCR, University College London Hospitals

Study record dates

Study Major Dates

• Study Start (Actual): November 8, 2012
• Primary Completion (Estimated): February 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: March 27, 2012
• First Submitted That Met QC Criteria: March 28, 2012
• First Posted (Estimated): March 29, 2012

Study Record Updates

• Last Update Posted (Actual): December 5, 2024
• Last Update Submitted That Met QC Criteria: December 4, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Chemoradiation; Cisplatin; Radiotherapy; Cervical Cancer; Carboplatin; Brachytherapy; Chemotherapy; Paclitaxel; Stage IB2 Cervical Cancer; Stage IIA Cervical Cancer; Stage IIB Cervical Cancer; Stage IIIB Cervical Cancer; Stage IVA Cervical Cancer
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Uterine Diseases; Genital Diseases, Female; Genital Neoplasms, Female; Uterine Cervical Diseases; Uterine Neoplasms; Uterine Cervical Neoplasms; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Carboplatin; Paclitaxel
• Other Study ID Numbers: UCL 11/0034; 2011-001300-35 (EudraCT Number); C37815/A12832 (Other Grant/Funding Number: CRUK)