Whole Brain Radiotherapy (WBRT) Versus Stereotactic Radiosurgery (SRS) for 4 Upto 10 Brain Metastases (WBRTvsSRS)

Whole Brain Radiotherapy vs. Stereotactic Radiosurgery for 4 - 10 Brain Metastases:a Phase III Randomized Multicenter Trial

Recently stereotactic radiosurgery (SRS) in 5 up to 10 brain metastases showed to have equal survival as in 2 up to 4 brain metastases. Whole brain radiotherapy (WBRT) is currently the gold standard for patients with more than 3 brain metastases, but has significant side effects. In this prospective randomized phase III trial WBRT is compared to SRS for patients with 4 up to 10 BM.

Study Overview

• Status: Terminated
• Conditions: Neoplasm Metastasis
• Intervention / Treatment: Radiation: Stereotactic Radiosurgery; Radiation: Whole Brain Radiotherapy

Detailed Description

Dutch guideline advices stereotactic radiosurgery (SRS) for patients with 1 up to 3 brain metastases (BM) and whole brain radiotherapy (WBRT) for patients with 4 or more BM. The interim analysis from the QUARTZ study showed that WBRT did not provide benefit in quality of life nor survival over best supportive care. WBRT has significant side effects, such as hair loss, fatigue, and cognitive dysfunction which may impair quality of life. A recently published study showed that SRS in patients with 5 up to 10 BM had a comparable survival to patients treated with 2 up to 4 BM. Many systemic therapies do not have a satisfactory intracranial response, because of the blood-brain barrier. The potential advantages of SRS i.e, limiting radiation doses to the uninvolved brain and a high rate of local tumour control by just a single treatment. Next logic step would be to compare WBRT with SRS alone in patients with 4-10 BM and evaluate whether SRS is superior to WBRT with regard to QOL.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1081HV
    • VUMC
  • Amsterdam, Netherlands, 1105AZ
    • AMC
  • Den Haag, Netherlands, 2262BA
    • Haaglanden MC
  • Maastricht, Netherlands, 6202 AZ
    • Maastricht Radiation Oncology (MAASTRO clinic)
  • Rotterdam, Netherlands, 3015CE
    • Erasmus MC
  • Tilburg, Netherlands, 5042BS
    • Instituut Verbeeten
  • Vlissingen, Netherlands, 4382EK
    • ZRTI

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Minimal 4 up to a maximum of 10 BM on diagnostic MRI scan
• Max diameter of single GTV 2.5cm
• Max cumulative GTV of 30cm3
• Karnofsky performance status ≥ 70
• Any solid primary tumour. Small cell lung carcinoma, germinoma, and lymphoma are excluded
• Ability to provide written informed consent

Exclusion Criteria:

• Contra-indication for MRI
• Prior treatment for BM (i.e. surgery, SRS or WBRT)
• Concurrent use of systemic therapy
• Maximum cumulative GTV of more than 30cm3 on planning-MRI
• More than 10 BM on planning-MRI
• A brainstem metastasis with a PTV of more than 20 cm3

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: Stereotactic Radiosurgery; Stereotactic Radiosurgery for patients with 4 up to 10 brain metastases:	Radiation: Stereotactic Radiosurgery; Stereotactic Radiosurgery for patients with 4 up to 10 brain metastases
Other: Whole Brain Radiotherapy; Whole Brain Radiotherapy for patients with 4 up to 10 brain metastases:	Radiation: Whole Brain Radiotherapy; Whole Brain Radiotherapy for patients with 4 up to 10 brain metastases

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of life in patients with 4 - 10 brain metastases comparing WBRT and SRS	Quality of life is measured by the EQ-5D-5L, a descriptive system of health-related quality of life states consisting of five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression)	Change in quality of life measured from baseline to 3 months after radiotherapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival steroid use (mg), toxicity including hair loss and fatigue.	Overall survival	1 year
Time that patient is functioning independently (Karnofsky ≥ 70)	Time that patient is functioning independently (Karnofsky ≥ 70)	Change in Karnofsky index from baseline to 3 months after radiotherapy
Steroid use	Steroid use in mg over time	Change in steroid use from baseline to 3 months after radiotherapy
Toxicity measured by hair loss and fatigue	Toxicity measured by hair loss and fatigue using CTCAE version 4.0	Change in toxicity from baseline to 3 months after radiotherapy
Degree of independence	Degree of independence of patients using the Barthel index	Change in independence from baseline to 3 months after radiotherapy

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain salvage during follow-up	Brain salvage during follow-up, type of salvage, and time to salvage after randomisation	1 year
Verbal learning	Verbal recall and verbal regognition is measured using the Hopkins Verbal Learning Test - Revised	Change in verbal recall and verbal recognition from baseline to 3 months after radiotherapy
Quality of life of cancer patients	QoL will be measured using the EORTC QLQ-C30	Change in Quality of life from baseline to 3 months after radiotherapy
Quality of life of cancer patients with brain neoplasms	QoL will be measured using the EORTC QLQ-BN20	Change in Quality of life from baseline to 3 months after radiotherapy
Quality of life of cancer patients measuring cancer-related fatigue	QoL will be measured using the EORTC QLQ-FA13	Change in Quality of life from baseline to 3 months after radiotherapy

Collaborators and Investigators

• Sponsor: Maastricht Radiation Oncology

Publications and helpful links

General Publications

• Zindler JD, Rodrigues G, Haasbeek CJ, De Haan PF, Meijer OW, Slotman BJ, Lagerwaard FJ. The clinical utility of prognostic scoring systems in patients with brain metastases treated with radiosurgery. Radiother Oncol. 2013 Mar;106(3):370-4. doi: 10.1016/j.radonc.2013.01.015. Epub 2013 Mar 20.
• Gijtenbeek JM, Ho VK, Heesters MA, Lagerwaard FJ, de Graeff A, Boogerd W. [Practice guideline 'Brain metastases' (revision)]. Ned Tijdschr Geneeskd. 2011;155(52):A4141. Dutch.
• Yamamoto M, Serizawa T, Shuto T, Akabane A, Higuchi Y, Kawagishi J, Yamanaka K, Sato Y, Jokura H, Yomo S, Nagano O, Kenai H, Moriki A, Suzuki S, Kida Y, Iwai Y, Hayashi M, Onishi H, Gondo M, Sato M, Akimitsu T, Kubo K, Kikuchi Y, Shibasaki T, Goto T, Takanashi M, Mori Y, Takakura K, Saeki N, Kunieda E, Aoyama H, Momoshima S, Tsuchiya K. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 2014 Apr;15(4):387-95. doi: 10.1016/S1470-2045(14)70061-0. Epub 2014 Mar 10.
• Langley RE, Stephens RJ, Nankivell M, Pugh C, Moore B, Navani N, Wilson P, Faivre-Finn C, Barton R, Parmar MK, Mulvenna PM; QUARTZ Investigators. Interim data from the Medical Research Council QUARTZ Trial: does whole brain radiotherapy affect the survival and quality of life of patients with brain metastases from non-small cell lung cancer? Clin Oncol (R Coll Radiol). 2013 Mar;25(3):e23-30. doi: 10.1016/j.clon.2012.11.002. Epub 2012 Dec 2.
• Hartgerink D, Bruynzeel A, Eekers D, Swinnen A, Hurkmans C, Wiggenraad R, Swaak-Kragten A, Dieleman E, van der Toorn PP, van Veelen L, Verhoeff JJC, Lagerwaard F, de Ruysscher D, Lambin P, Zindler J. Quality of life among patients with 4 to 10 brain metastases after treatment with whole-brain radiotherapy vs. stereotactic radiotherapy: a phase III, randomized, Dutch multicenter trial. Ann Palliat Med. 2022 Apr;11(4):1197-1209. doi: 10.21037/apm-21-1545. Epub 2021 Nov 18.
• Zindler JD, Bruynzeel AME, Eekers DBP, Hurkmans CW, Swinnen A, Lambin P. Whole brain radiotherapy versus stereotactic radiosurgery for 4-10 brain metastases: a phase III randomised multicentre trial. BMC Cancer. 2017 Jul 25;17(1):500. doi: 10.1186/s12885-017-3494-z.

Study record dates

Study Major Dates

• Study Start: July 1, 2016
• Primary Completion (Actual): April 1, 2019
• Study Completion (Actual): December 1, 2019

Study Registration Dates

• First Submitted: January 16, 2015
• First Submitted That Met QC Criteria: January 28, 2015
• First Posted (Estimate): February 2, 2015

Study Record Updates

• Last Update Posted (Actual): June 1, 2020
• Last Update Submitted That Met QC Criteria: May 29, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasm Metastasis; Brain Neoplasms
• Other Study ID Numbers: 01-2015

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No