Clinical trial NCT00182819: Radiation Therapy or Temozolomide in Treating Patients With Gliomas
Official title: Primary Chemotherapy With Temozolomide Versus Radiotherapy in Patients With Low Grade Gliomas After Stratification for Genetic 1p Loss: A Phase III Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Brain and Central Nervous System Tumors
Keywords: adult oligodendroglioma
adult diffuse astrocytoma
adult mixed glioma
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
Collaborators: name: NCIC Clinical Trials Group
name: British Medical Research Council
name: Trans Tasman Radiation Oncology Group
First posted: 2005-09-16
Enrollment: 709
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether radiation therapy is more effective than temozolomide in treating gliomas.

PURPOSE: This randomized phase III trial is studying radiation therapy to see how well it works compared to temozolomide in treating patients with gliomas.

Detailed description: OBJECTIVES:

Primary

* Compare the progression-free survival of patients with low-grade gliomas treated with radiotherapy vs temozolomide.

Secondary

* Compare the overall survival of patients treated with these regimens.
* Determine whether the incidence of late toxicity can be decreased in patients who are randomized to receive temozolomide.
* Compare the toxic effects of these regimens in these patients.
* Compare the quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, controlled, multicenter study. Patients are stratified according to participating center, chromosome 1p status (deleted vs normal vs undeterminable), contrast enhancement on MRI (yes vs no), age (\< 40 years vs ≥ 40 years), and WHO performance status (0 or 1 vs 2). Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients undergo radiotherapy once daily, 5 days a week, for a total of 28 fractions (i.e., 5½ weeks).
* Arm II: Patients receive oral temozolomide once daily on days 1-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline and then every 3 months until disease progression.

After completion of study treatment, patients are followed every 6 months for survival.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: A minimum of 699 patients (a total of 466 randomized \[233 per treatment arm\]) will be accrued for this study within 5 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed low-grade glioma, including any of the following types:

  * Astrocytoma (gemistocytic, fibrillary, or protoplasmatic)
  * Oligoastrocytoma
  * Oligodendroglioma
* WHO grade II disease
* Supratentorial tumor location only
* RTOG neurological function 0-3
* Not a candidate for surgical treatment alone
* Requires treatment, as determined by ≥ 1 of the following criteria:

  * Age ≥ 40 years
  * Radiologically-proven progressive lesion
  * New or worsening neurological symptoms other than seizures only (e.g., focal deficits, signs of increased intracranial pressure, or mental deficits)
  * Intractable seizures, defined by both of the following criteria:

    * Experiences persistent seizures that interfere with everyday life activities except driving a car
    * Failed 3 anti-epileptic drug regimens, including ≥ 1 combination regimen
* Tumor material (paraffin-embedded) or histopathologic slides available

PATIENT CHARACTERISTICS:

Age

* 18 and over

Performance status

* WHO 0-2

Life expectancy

* Not specified

Hematopoietic

* Absolute neutrophil count ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3

Hepatic

* No chronic hepatitis B or C infection
* Bilirubin ≤ 1.5 times upper limit of normal (ULN)
* AST or ALT ≤ 2.5 times ULN
* Alkaline phosphatase ≤ 2.5 times ULN

Renal

* Creatinine ≤ 1.5 times ULN

Other

* Not pregnant or nursing
* Fertile patients must use effective contraception during and for 6 months after completion of study treatment
* No known HIV positivity
* No other serious medical condition
* No other prior or concurrent malignancy except surgically cured carcinoma in situ of the cervix or nonmelanoma skin cancer
* No psychological, familial, sociological, or geographical condition that would preclude study participation
* No medical condition that would preclude receiving oral medication (e.g., frequent vomiting or partial bowel obstruction)

PRIOR CONCURRENT THERAPY:

Biologic therapy

* No concurrent growth factors for elevating absolute neutrophil counts for the purpose of temozolomide administration
* No concurrent epoetin alfa
* No concurrent immunotherapy or biologic therapy

Chemotherapy

* No prior chemotherapy
* No other concurrent chemotherapy, including adjuvant chemotherapy for patients randomized to undergo radiotherapy

Endocrine therapy

* Not specified

Radiotherapy

* No prior radiotherapy to the brain
* No concurrent integrated boost with intensity-modulated radiotherapy

Surgery

* Recovered from prior surgery
* No concurrent surgical tumor debulking

Other

* No prior randomization to this study
* No other concurrent investigational drugs
* No concurrent regular use of agents known to be radiosensitizers or radioprotectors (e.g., cyclooxygenase-2 inhibitors, thalidomide, or amifostine) during study radiotherapy

  * Occasional use of nonsteroidal anti-inflammatory drugs for pain allowed

Primary outcomes:
measure: Progression-free survival
timeFrame: 5 years
Secondary outcomes:
measure: Overall survival
timeFrame: 5 years
measure: Quality of life as measured by QLQ-C30 v3.0 and EORTC BN-20
timeFrame: every 3 months until progression, and then every 6 months until death
measure: Mini-Mental State Examination
timeFrame: every 3 months until progression, and then every 6 months until death
measure: Adverse events as measured by CTCAE v3.0
timeFrame: As indicated in the protocol
Other outcomes:
Locations:
city: Randwick
country: Australia
facility: Prince of Wales Private Hospital
state: New South Wales
city: St. Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Sydney Cancer Centre at Royal Prince Alfred Hospital
state: New South Wales
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: South Brisbane
country: Australia
facility: Mater Adult Hospital
state: Queensland
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Heidelberg West
country: Australia
facility: Austin and Repatriation Medical Centre
state: Victoria
city: Prahran
country: Australia
facility: Alfred Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital - Nedlands
state: Western Australia
city: Liverpool
country: Australia
facility: Liverpool Hospital
city: Vienna
country: Austria
facility: Medical University Vienna - General Hospital AKH
city: Brussels
country: Belgium
facility: Hopital Universitaire Erasme
city: Brussels
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Leuven
country: Belgium
facility: U.Z. Leuven - Campus Gasthuisberg
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre - Calgary
state: Alberta
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Saint John
country: Canada
facility: Saint John Regional Hospital
state: New Brunswick
city: Halifax
country: Canada
facility: Nova Scotia Cancer Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: Margaret and Charles Juravinski Cancer Centre
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Program at London Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Edmond Odette Cancer Centre at Sunnybrook
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Montreal
country: Canada
facility: Hopital Notre-Dame du CHUM
state: Quebec
city: Montreal
country: Canada
facility: Mcgill University Health Centre - Gerald Bronfman Centre - Dept Of Oncology
state: Quebec
city: Regina
country: Canada
facility: Allan Blair Cancer Centre at Pasqua Hospital
state: Saskatchewan
city: Vancouver
country: Canada
facility: BC Cancer Agency
city: Cairo
country: Egypt
facility: National Cancer Institute of Egypt
city: Bordeaux
country: France
facility: CHU de Bordeaux - Groupe Hospitalier Saint-André - Hopital Saint-Andre
city: Bordeaux
country: France
facility: Institut Bergonie
city: Grenoble
country: France
facility: CHU de Grenoble - Hopital de la Tronche
city: Marseille
country: France
facility: CHU de la Timone
city: Nantes-Saint Herblain
country: France
facility: Centre Regional Rene Gauducheau
city: Paris
country: France
facility: Assistance Publique - Hopitaux de Paris - La Pitie Salpetriere
city: Rennes
country: France
facility: Centre Eugene Marquis
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Villejuif
country: France
facility: Gustave Roussy
city: Heidelberg
country: Germany
facility: Universitatsklinikum Heidelberg
city: Leipzig
country: Germany
facility: Universitaetsklinikum Leipzig
city: Regensburg
country: Germany
facility: Universitaetskliniken Regensburg
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen
city: Budapest
country: Hungary
facility: National Institute Of Neurosurgery
city: Haifa
country: Israel
facility: Rambam Health Care Campus, Oncology Institute
city: Bologna
country: Italy
facility: Ospedale Bellaria
city: Milano
country: Italy
facility: Ospedale San Raffaele
city: Roma
country: Italy
facility: Istituto Regina Elena / Istituti Fisioterapici Ospitalieri
city: Turin
country: Italy
facility: Azienda Sanitaria Ospedale San Giovanni Battista Molinette di Torino
city: Esch / Alzette
country: Luxembourg
facility: Centre Francois Baclesse
city: Amsterdam
country: Netherlands
facility: Vrije Universiteit Medisch Centrum
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum - Universiteit van Amsterdam
city: Den Haag
country: Netherlands
facility: Medisch Centrum Haaglanden - Westeinde
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Maastricht
country: Netherlands
facility: Maastro Clinic - Maastricht Radiation Oncology
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center Nijmegen
city: Rotterdam
country: Netherlands
facility: Erasmus MC Cancer Institute - location Daniel den Hoed
city: Tilburg
country: Netherlands
facility: Dr. Bernard Verbeeten Instituut
city: Christchurch
country: New Zealand
facility: Canterbury Health Laboratories
city: Lisbon
country: Portugal
facility: Instituto Portugues de Oncologia de Francisco Gentil - Centro Regional de Oncologia de Lisboa, SA
city: Singapore
country: Singapore
facility: National University of Singapore
city: Badalona - (Barcelona)
country: Spain
facility: ICO Badalona - Hospital Germans Trias i Pujol (Institut Catala D'Oncologia)
city: Barcelona
country: Spain
facility: Hospital General Vall D'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital Clinico Universitario de Barcelona
city: Girona
country: Spain
facility: ICO Girona - Hospital Doctor Josep Trueta (Institut Catala D'Oncologia)
city: L'Hospitalet de Llobregat
country: Spain
facility: ICO L'Hospitalet - Hospital Duran i Reynals (Institut Catala D'Oncologia)
city: Linkoping
country: Sweden
facility: University Hospital of Linkoping
city: Lund
country: Sweden
facility: Skane University Hospital
city: Umea
country: Sweden
facility: Umea Universitet
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
city: Bellinzona
country: Switzerland
facility: Oncology Institute of Southern Switzerland - Ospedale Regionale Bellinzona e Valli
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois - Lausanne
city: Zurich
country: Switzerland
facility: UniversitaetsSpital Zurich
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol NHS Foundation Trust - Bristol Haematology And Oncology Centre
state: Avon
city: Bebington, Wirral
country: United Kingdom
facility: Clatterbridge Centre for Oncology
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: England
city: Leeds
country: United Kingdom
facility: Leeds Cancer Centre at St. James's University Hospital
state: England
city: London
country: United Kingdom
facility: University College Hospital
state: England
city: London
country: United Kingdom
facility: Royal Marsden - London
state: England
city: Manchester
country: United Kingdom
facility: Christie Hospital
state: England
city: Middlesbrough
country: United Kingdom
facility: James Cook University Hospital
state: England
city: Sheffield
country: United Kingdom
facility: Cancer Research Centre at Weston Park Hospital
state: England
city: Sutton
country: United Kingdom
facility: Royal Marsden - Surrey
state: England
city: Cheltenham
country: United Kingdom
facility: Gloucestershire Hospital NHS Foundation Trust - Cheltenham General Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: London
country: United Kingdom
facility: Royal Free Hospital
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Trust - Churchill Hospital
city: Preston
country: United Kingdom
facility: Lancashire Teaching Hospitals NHS Foundation Trust - Royal Preston Hospital
Study officials:
affiliation: Maastricht University Medical Center
name: Brigitta Baumert, MD, PhD
role: STUDY_CHAIR
affiliation: Centre Hospitalier Universitaire Vaudois
name: Roger Stupp, MD
role: STUDY_CHAIR
References:
citation: Musat E, Roelofs E, Bar-Deroma R, Fenton P, Gulyban A, Collette L, Stupp R, Weber DC, Bernard Davis J, Aird E, Baumert BG. Dummy run and conformity indices in the ongoing EORTC low-grade glioma trial 22033-26033: First evaluation of quality of radiotherapy planning. Radiother Oncol. 2010 May;95(2):218-24. doi: 10.1016/j.radonc.2010.03.005. Epub 2010 Apr 6.
citation: Fairchild A, Weber DC, Bar-Deroma R, Gulyban A, Fenton PA, Stupp R, Baumert BG. Quality assurance in the EORTC 22033-26033/CE5 phase III randomized trial for low grade glioma: the digital individual case review. Radiother Oncol. 2012 Jun;103(3):287-92. doi: 10.1016/j.radonc.2012.04.002. Epub 2012 May 3.
citation: Gao Y, Weenink B, van den Bent MJ, Erdem-Eraslan L, Kros JM, Sillevis Smitt P, Hoang-Xuan K, Brandes AA, Vos M, Dhermain F, Enting R, Ryan GF, Chinot O, Ben Hassel M, van Linde ME, Mason WP, Gijtenbeek JMM, Balana C, von Deimling A, Gorlia T, Stupp R, Hegi ME, Baumert BG, French PJ. Expression-based intrinsic glioma subtypes are prognostic in low-grade gliomas of the EORTC22033-26033 clinical trial. Eur J Cancer. 2018 May;94:168-178. doi: 10.1016/j.ejca.2018.02.023. Epub 2018 Mar 20.
citation: Baumert BG, Hegi ME, van den Bent MJ, von Deimling A, Gorlia T, Hoang-Xuan K, Brandes AA, Kantor G, Taphoorn MJB, Hassel MB, Hartmann C, Ryan G, Capper D, Kros JM, Kurscheid S, Wick W, Enting R, Reni M, Thiessen B, Dhermain F, Bromberg JE, Feuvret L, Reijneveld JC, Chinot O, Gijtenbeek JMM, Rossiter JP, Dif N, Balana C, Bravo-Marques J, Clement PM, Marosi C, Tzuk-Shina T, Nordal RA, Rees J, Lacombe D, Mason WP, Stupp R. Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 2016 Nov;17(11):1521-1532. doi: 10.1016/S1470-2045(16)30313-8. Epub 2016 Sep 27.
citation: Reijneveld JC, Taphoorn MJB, Coens C, Bromberg JEC, Mason WP, Hoang-Xuan K, Ryan G, Hassel MB, Enting RH, Brandes AA, Wick A, Chinot O, Reni M, Kantor G, Thiessen B, Klein M, Verger E, Borchers C, Hau P, Back M, Smits A, Golfinopoulos V, Gorlia T, Bottomley A, Stupp R, Baumert BG. Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 2016 Nov;17(11):1533-1542. doi: 10.1016/S1470-2045(16)30305-9. Epub 2016 Sep 27.