Whole Brain Radiotherapy Versus Volumetric Modulated Arc Therapy for Brain Metastases

NCT ID: NCT02220491

Last Updated: 2020-05-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-10-01
• Study Completion Date: 2020-05-18

Brief Summary

Patients with brain metastases with expected life expectancy of 3-6 months are typically treated with radiotherapy to the whole brain giving a dose of 20 Gy over a 5 day period. This study will compare this with volumetric modulated arc therapy (VMAT) which is capable of delivering 15 Gy in one single session to identified disease within the brain but sparing the normal surrounding brain tissue. Primarily the study will assess whether it is possible to recruit sufficient patient numbers to a trial of this type. It will also compare effectiveness, side effects and quality of life between the two treatment methods.

Detailed Description

This is a Phase II prospective clinical trial. Pre treatment evaluations include estimation of life expectancy, Creatinine (GFR) and MRI brain with contrast. An assessment of cognitive function using Montreal Cognitive Assessment questionnaire, assessment of daily living activities using the Modified Barthel's index and quality of life assessment using EORTC QLQ-PAL-15 & BN-20 questionnaires will be performed in clinic. Karnofsky Performance Status will also be assessed by the clinician. If all assessments are within the eligibility criteria then the patient can be recruited. Before treatment begins a history documenting baseline symptoms using NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 and a neurological examination documenting baseline deficits must be obtained.

If patient is randomized to standard treatment of whole brain radiotherapy (WBRT) then subjects will have a non-contrast CT scan using a slice thickness of 2.5 mm or less to plan radiotherapy. If patient are randomized to single fraction radiotherapy then a contrast CT will be used as this aids in identifying metastatic tumours within the brain. Also for the single fraction arm if a contrast-enhanced diagnostic MRI was obtained ≤ 10 days before the CT planning scan, with a single-plane high-resolution sequence or low-resolution sequences in two planes, it can be used for treatment planning. If the contrast-enhanced diagnostic MRI was obtained > 10 days before the CT planning scan or there is no diagnostic MRI, the subject requires a gadolinium-enhanced, high-resolution MRI sequence for fusion in the treatment planning system. During treatment, patients will have daily online cone beam CT scans to apply setup corrections to ensure treatment accuracy. To ensure minimal movement during radiotherapy all subjects will be immobilized lying on their back in a plastic headshell with an integrated bite block.

For subjects in the single-fraction arm that are not requiring steroids before radiotherapy, dexamethasone 8 mg 1 hour before the radiotherapy and for 5 days afterwards is required. For subjects in the single-fraction arm that are requiring corticosteroids for symptom management before radiotherapy, dexamethasone 8 mg before treatment and 8 mg 2 times daily for 2 days is required. Beginning three days after radiotherapy, a taper back to the pre-radiotherapy dose can be done swiftly over 4-6 days. However, for subjects who have been on dexamethasone for more than 2 weeks at this time point, slow tapering from the pre-radiotherapy dose using decrements of 0.5 - 2 mg every 3-5 days should be used to prevent a hypocortisolemia. For subjects in the 5-fraction arm, corticosteroids will be prescribed according to the preference of the treating radiation oncologist. Anti-sickness medication and steroids will be prescribed are required before each fraction in both arms.

Following therapy completion, all patients will be seen at 6 weeks, 3, 6, 9 and 12 months. At each visit history and neurological examination will be performed. Cognitive Function, Karnofsky Performance Status, Quality of life and Adverse Events will all be assessed and recorded. Activities of Daily Living and steroid use will be assessed by telephone consultation every 4 weeks (monthly) for 1 year. Steroid use will be confirmed by evaluating the pharmacy prescription database.

Patients will have contrast-enhanced MRI brain at every time point with a creatinine 1 week before each MRI to ensure safety of intravenous contrast administration. Steroid use will be recorded in a patient diary for first 6 weeks post treatment and monthly by telephone discussion.

Conditions

Brain Metastases

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Whole-brain radiotherapy

All subjects will have a non-contrast CT scan using a slice thickness of 2.5mm or less.

The Brain contour will be generated using the segmentation wizard and edits as required.

PTV_Brain is an expansion of the Brain by 5mm. 99% of PTV_Brain is to be covered by 95% of 20 Gy in 5 fractions using 6-10 MV photons in a parallel-opposed pair lateral beam arrangement.

Group Type: ACTIVE_COMPARATOR

Whole-brain radiotherapy

Intervention Type: RADIATION

Whole brain radiotherapy delivering 20 Gy in five fractions to brain metastases

Single-fraction radiotherapy

Immobilized in the mask, the subject will be imaged for radiotherapy planning with a CT slice thickness of 1.25 mm or less and an axial resolution of \< 0.7 mm (CT field of view \< 35 cm). Subjects that require contrast with GFR 45-59 will have pre-hydration, contrast dose modification and/or Mucomyst administration to preserve renal function, according to standard practice for radiological imaging at the institution.

Group Type: EXPERIMENTAL

Single-fraction radiotherapy

Intervention Type: RADIATION

Volumetric modulated arc therapy (VMAT) delivering 15 Gy in one fraction to brain metastases

Interventions

Single-fraction radiotherapy

Volumetric modulated arc therapy (VMAT) delivering 15 Gy in one fraction to brain metastases

Intervention Type: RADIATION

Whole-brain radiotherapy

Whole brain radiotherapy delivering 20 Gy in five fractions to brain metastases

Intervention Type: RADIATION

Eligibility Criteria

Inclusion Criteria

• Age ≥ 18
• Pathologically confirmed solid malignancy
• 1-10 brain or brainstem metastases on MRI with a maximum of 4 cm diameter
• Documented extracranial disease
• Anticipated median survival 3-6 months (Graded Prognostic Assessment: Appendix I)
• Available for regular clinical and imaging follow up (< 1 hour from a cancer centre)
• Montreal Cognitive Assessment score ≥ 20 (Appendix II)
• Karnofsky Performance Score (KPS) ≥ 70 (Appendix III)
• Barthel Activities of Daily Living score ≥ 90 (Appendix IV)
• Able to complete EORTC quality of life questionnaires (Appendix V)

Exclusion Criteria

• A metastasis located within 5 mm of the optic nerves or optic chiasm
• Requiring craniotomy to relieve mass effect
• Cytotoxic systemic therapy administered within one week before radiotherapy or planned within one week after radiotherapy
• Neurological decline since starting corticosteroids
• Metastatic germinoma, small cell carcinoma, multiple myeloma, lymphoma or leukaemia
• Systemic lupus erythematosis, scleroderma, or other connective tissue disorders not in remission
• Multiple sclerosis
• Glomerular Filtration Rate < 45 ml/minute
• Contra-indications to MRI
• Pregnancy
• AST, ALT or Bilirubin > 3 times upper limit of normal
• Haemorrhagic Metastases

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

British Columbia Cancer Agency

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nichol Alan, MD

Role: PRINCIPAL_INVESTIGATOR

British Columbia Cancer Agency

Locations

British Columbia Cancer Agency

Vancouver, British Columbia, Canada

Countries

Canada

References

Mekhail T, Sombeck M, Sollaccio R. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. Curr Oncol Rep. 2011 Aug;13(4):255-8. doi: 10.1007/s11912-011-0180-1. No abstract available.

Reference Type: BACKGROUND

PMID: 21584645 (View on PubMed)

Soon YY, Tham IW, Lim KH, Koh WY, Lu JJ. Surgery or radiosurgery plus whole brain radiotherapy versus surgery or radiosurgery alone for brain metastases. Cochrane Database Syst Rev. 2014 Mar 1;2014(3):CD009454. doi: 10.1002/14651858.CD009454.pub2.

Reference Type: BACKGROUND

PMID: 24585087 (View on PubMed)

Soffietti R, Kocher M, Abacioglu UM, Villa S, Fauchon F, Baumert BG, Fariselli L, Tzuk-Shina T, Kortmann RD, Carrie C, Ben Hassel M, Kouri M, Valeinis E, van den Berge D, Mueller RP, Tridello G, Collette L, Bottomley A. A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results. J Clin Oncol. 2013 Jan 1;31(1):65-72. doi: 10.1200/JCO.2011.41.0639. Epub 2012 Dec 3.

Reference Type: BACKGROUND

PMID: 23213105 (View on PubMed)

Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, Arbuckle RB, Swint JM, Shiu AS, Maor MH, Meyers CA. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009 Nov;10(11):1037-44. doi: 10.1016/S1470-2045(09)70263-3. Epub 2009 Oct 2.

Reference Type: BACKGROUND

PMID: 19801201 (View on PubMed)

Rodrigues G, Warner A, Zindler J, Slotman B, Lagerwaard F. A clinical nomogram and recursive partitioning analysis to determine the risk of regional failure after radiosurgery alone for brain metastases. Radiother Oncol. 2014 Apr;111(1):52-8. doi: 10.1016/j.radonc.2013.11.015. Epub 2014 Jan 17.

Reference Type: BACKGROUND

PMID: 24444529 (View on PubMed)

Tsao MN, Lloyd N, Wong RK, Chow E, Rakovitch E, Laperriere N, Xu W, Sahgal A. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2012 Apr 18;2012(4):CD003869. doi: 10.1002/14651858.CD003869.pub3.

Reference Type: BACKGROUND

PMID: 22513917 (View on PubMed)

Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, Werner-Wasik M, Demas W, Ryu J, Bahary JP, Souhami L, Rotman M, Mehta MP, Curran WJ Jr. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet. 2004 May 22;363(9422):1665-72. doi: 10.1016/S0140-6736(04)16250-8.

Reference Type: BACKGROUND

PMID: 15158627 (View on PubMed)

Shaw E, Scott C, Souhami L, Dinapoli R, Bahary JP, Kline R, Wharam M, Schultz C, Davey P, Loeffler J, Del Rowe J, Marks L, Fisher B, Shin K. Radiosurgery for the treatment of previously irradiated recurrent primary brain tumors and brain metastases: initial report of radiation therapy oncology group protocol (90-05). Int J Radiat Oncol Biol Phys. 1996 Feb 1;34(3):647-54. doi: 10.1016/0360-3016(95)02106-x.

Reference Type: BACKGROUND

PMID: 8621289 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24621620 (View on PubMed)

Clark GM, Popple RA, Young PE, Fiveash JB. Feasibility of single-isocenter volumetric modulated arc radiosurgery for treatment of multiple brain metastases. Int J Radiat Oncol Biol Phys. 2010 Jan 1;76(1):296-302. doi: 10.1016/j.ijrobp.2009.05.029.

Reference Type: BACKGROUND

PMID: 19836151 (View on PubMed)

Stieler F, Fleckenstein J, Simeonova A, Wenz F, Lohr F. Intensity modulated radiosurgery of brain metastases with flattening filter-free beams. Radiother Oncol. 2013 Dec;109(3):448-51. doi: 10.1016/j.radonc.2013.10.017. Epub 2013 Nov 11.

Reference Type: BACKGROUND

PMID: 24231243 (View on PubMed)

Audet C, Poffenbarger BA, Chang P, Jackson PS, Lundahl RE, Ryu SI, Ray GR. Evaluation of volumetric modulated arc therapy for cranial radiosurgery using multiple noncoplanar arcs. Med Phys. 2011 Nov;38(11):5863-72. doi: 10.1118/1.3641874.

Reference Type: BACKGROUND

PMID: 22047350 (View on PubMed)

Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod CM, editor. Evaluation of Chemotherapeutic Agents. Columbia University Press; 1949. p. 196.

Reference Type: BACKGROUND

Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005 Apr;53(4):695-9. doi: 10.1111/j.1532-5415.2005.53221.x.

Reference Type: BACKGROUND

PMID: 15817019 (View on PubMed)

Shah S, Vanclay F, Cooper B. Improving the sensitivity of the Barthel Index for stroke rehabilitation. J Clin Epidemiol. 1989;42(8):703-9. doi: 10.1016/0895-4356(89)90065-6.

Reference Type: BACKGROUND

PMID: 2760661 (View on PubMed)

Taphoorn MJ, Claassens L, Aaronson NK, Coens C, Mauer M, Osoba D, Stupp R, Mirimanoff RO, van den Bent MJ, Bottomley A; EORTC Quality of Life Group, and Brain Cancer, NCIC and Radiotherapy Groups. An international validation study of the EORTC brain cancer module (EORTC QLQ-BN20) for assessing health-related quality of life and symptoms in brain cancer patients. Eur J Cancer. 2010 Apr;46(6):1033-40. doi: 10.1016/j.ejca.2010.01.012. Epub 2010 Feb 22.

Reference Type: BACKGROUND

PMID: 20181476 (View on PubMed)

Caissie A, Nguyen J, Chen E, Zhang L, Sahgal A, Clemons M, Kerba M, Arnalot PF, Danjoux C, Tsao M, Barnes E, Holden L, Danielson B, Chow E. Quality of life in patients with brain metastases using the EORTC QLQ-BN20+2 and QLQ-C15-PAL. Int J Radiat Oncol Biol Phys. 2012 Jul 15;83(4):1238-45. doi: 10.1016/j.ijrobp.2011.09.025. Epub 2011 Dec 13.

Reference Type: BACKGROUND

PMID: 22172909 (View on PubMed)

Groenvold M, Petersen MA, Aaronson NK, Arraras JI, Blazeby JM, Bottomley A, Fayers PM, de Graeff A, Hammerlid E, Kaasa S, Sprangers MA, Bjorner JB; EORTC Quality of Life Group. The development of the EORTC QLQ-C15-PAL: a shortened questionnaire for cancer patients in palliative care. Eur J Cancer. 2006 Jan;42(1):55-64. doi: 10.1016/j.ejca.2005.06.022. Epub 2005 Sep 12.

Reference Type: BACKGROUND

PMID: 16162404 (View on PubMed)

Hsieh YW, Wang CH, Wu SC, Chen PC, Sheu CF, Hsieh CL. Establishing the minimal clinically important difference of the Barthel Index in stroke patients. Neurorehabil Neural Repair. 2007 May-Jun;21(3):233-8. doi: 10.1177/1545968306294729. Epub 2007 Mar 9.

Reference Type: BACKGROUND

PMID: 17351082 (View on PubMed)

Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, Bhatt A, Jensen AW, Brown PD, Shih H, Kirkpatrick J, Schwer A, Gaspar LE, Fiveash JB, Chiang V, Knisely J, Sperduto CM, Mehta M. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010 Jul 1;77(3):655-61. doi: 10.1016/j.ijrobp.2009.08.025. Epub 2009 Nov 26.

Reference Type: BACKGROUND

PMID: 19942357 (View on PubMed)

Raman S, Mou B, Hsu F, Valev B, Cheung A, Vallieres I, Ma R, McKenzie M, Beaton L, Rackley T, Gondara L, Nichol A. Whole Brain Radiotherapy Versus Stereotactic Radiosurgery in Poor-Prognosis Patients with One to 10 Brain Metastases: A Randomised Feasibility Study. Clin Oncol (R Coll Radiol). 2020 Jul;32(7):442-451. doi: 10.1016/j.clon.2020.02.001. Epub 2020 Feb 19.

Reference Type: DERIVED

PMID: 32085923 (View on PubMed)

Other Identifiers

H14-02032

Identifier Type: -

Identifier Source: org_study_id