Whole Brain Radiation Therapy With Boost to Metastatic Tumor Volume Using RapidArc

• Sponsor: Emory University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01218542
• Collaborator: (none)
• Enrollment: 22
• Locations: 2
• Arm: 1
• Actual Duration (Months): 116.4
• Patients Per Site: 11
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Brain metastases are the most common adult intracranial tumor, occurring in approximately 10% to 30% of adult cancer patients, and represent an important cause of morbidity and mortality. The most widely used treatment for patients with multiple brain metastases is whole brain radiation therapy (WBRT). The use of WBRT after resection or stereotactic radiosurgery (SRS) has been proven to be effective in terms of improving local control of brain metastases.

RapidArc (RA) (Varian Medical Systems, Palo Alto, CA) is a new method of delivering radiation that uses "arcs" to deliver highly conformal intensity modulated three dimensional dose distributions. The purpose of this investigation is to evaluate an alternative strategy for giving WBRT with highly focal boost to gross visible lesions in patients with brain metastasis.

Given the limitations of the SRS boost technique, the purpose of our investigation is to evaluate an alternative strategy for giving WBRT with highly focal boost to gross visible lesions in patients with brain metastasis. In this study, we plan to assess the tolerability of using volumetric modulated arc therapy (RapidArc) on patients with brain metastasis to simultaneously treat the entire brain with a concomitant focal boost to grossly identified lesions on MRI scan to try to improve local control and reduce neurocognitive toxicities.

This previous version of this study was a phase I dose escalation trial giving 25 Gy in 10 fractions to the whole brain with simultaneous infield boost (SIB) to a total of 45 Gy in 10 fractions to gross brain metastatic disease. Prior to this, patients were enrolled onto one of two cohorts with whole brain dose of 30 Gy in 10 fractions with SIB to total of 45 Gy in 10 fractions to gross brain metastatic disease or whole brain dose of 37.5 Gy in 15 fractions with SIB to total of 52.5 Gy in 15 fractions to gross brain metastatic disease. A total of 12 patients have been previously enrolled on this trial. No patients have experienced a dose limiting toxicity (grade 3 or above) at least possibly due to study therapy. Also, no patients experienced local brain failure/progression at a site of treated metastatic brain disease. Based on this, we no longer feel that dose escalation to the gross brain disease is warranted and would proceed with a single arm pilot study treating patients with 25 Gy in 10 fractions to the whole brain with simultaneous infield boost (SIB) to a total of 45 Gy in 10 fractions to gross brain metastatic disease.

Condition or Disease	Intervention/Treatment	Phase
Neoplasm Metastasis	Radiation: Volumetric modulated arc therapy	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 22 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Whole Brain Radiation Therapy With Simultaneous Boost to Gross Metastatic Tumor Volume Using Volumetric Modulated Arc Therapy (RapidArc)
• Actual Study Start Date: Sep 22, 2010
• Actual Primary Completion Date: Jun 3, 2020
• Actual Study Completion Date: Jun 3, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Volumetric modulated arc therapy Single arm pilot study treating patients with 25 Gy in 10 fractions to the whole brain with simultaneous infield boost (SIB) to a total of 45 Gy in 10 fractions to gross brain metastatic disease.	Radiation: Volumetric modulated arc therapy; Using volumetric modulated arc therapy to give simultaneous infield boost to gross metastatic brain lesions during whole brain radiation therapy.

Outcome Measures

Primary Outcome Measures

1. Percent of Participants With Locoregional Control of Treating Brain Metastasis Patients [Locoregional control at 1 year]

   The cumulative incidences of recurrence locally and in the whole brain were reported at the patient level.

Secondary Outcome Measures

1. Brain Progression-free Survival [11 months median follow up period.]

   Defined as period of time from study entry to to death from any cause or brain tumor recurrence or progression.

2. Overall Survival [11 months median follow up period.]

   Defined time from study entry to death from any cause.

3. Neurocognitive Effects [11 months median follow up period.]

   Neurological test score were assessed using the Hopkins Verbal Learning Test-Revised (HVLT). In the HVLT 12 words are read and the participant is asked to recall them, this is completed 3 times. Total words recalled are summed to give a score for Total Recall (0-36, higher scores demonstrated better recall). Delayed recall is conducted 20-25 minutes later on the same list of 12 words (scored 0-12 with higher scores demonstrating better recall). Retention is calculated as the percent of words recalled (scored 0-100, higher scores representing better recall). Recognition Discrimination is tested by a series of yes/no responses from the participant identifying 12 target words from a list of 24 and calculated by the number of true positives minus the number of true negatives with higher scores indicating a better outcome.

4. Quality of Life as Measured by the FACT-Br Subscales [11 month median follow up]

   The Functional Assessment of Cancer Therapy-Brain (FACT-Br) were summed to create the FACT brain trial outcome index (FACT-BR TOI), FACT general (FACT-G), and FACT brain total (FACT-BR Total). Three FACT scales were calculated. The higher the value the better the score, i.e., the better the quality of life perceived by patient. FACT BR TOTAL (FACT-G + BrCS, possible range 0 - 200) FACT-BR TOI (Trial Outcome Index = Physical Well Being _ Functional Well Being +BrCS, possible range 0 - 148) FACT-G (Fact General, possible range 0 - 108)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Pathologic proven diagnosis of solid tumor malignancy.

• Age ≥ 18.

• KPS ≥ 70.

• Mini Mental Status Exam (MMSE) ≥ 18 prior to study entry.

• RPA class I (KPS ≥ 70, primary cancer controlled, age < 65, metastases in brain only) or class II (lack of one or more of class I criteria).

• One to ten brain metastatic lesions.

Exclusion Criteria:

• Previous whole brain radiation therapy.

• Previous radiosurgery to any currently progressive gross metastatic disease.

• Previous radiosurgery to any intracranial site within the prior 6 weeks.

• Recursive partitioning analysis (RPA) class III (KPS < 70).

• Radiosensitive (eg. small cell lung carcinomas, germ cell tumors, leukemias, or lymphomas) or unknown tumor histologies.

• Concurrent chemotherapy (no chemotherapy starting 14 days before start of radiation).

• Evidence of leptomeningeal disease by MRI and/or cerebrospinal fluid (CSF) cytology.

• Current pregnancy.

• No metastases to brain stem, midbrain, pons, or medulla or within 7 mm of the optic apparatus (optic nerves and chiasm).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University Hospital Midtown	Atlanta	Georgia	United States	30308
2	Emory University/Winship Cancer Institute	Atlanta	Georgia	United States	30322

Sponsors and Collaborators

• Emory University

Investigators

• Principal Investigator: Hui-Kuo Shu, MD, PhD, Emory University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 9, 2013

More Information

Publications

• 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.
• Arbit E, Wroński M, Burt M, Galicich JH. The treatment of patients with recurrent brain metastases. A retrospective analysis of 109 patients with nonsmall cell lung cancer. Cancer. 1995 Sep 1;76(5):765-73.
• Bauman G, Yartsev S, Fisher B, Kron T, Laperriere N, Heydarian M, VanDyk J. Simultaneous infield boost with helical tomotherapy for patients with 1 to 3 brain metastases. Am J Clin Oncol. 2007 Feb;30(1):38-44.
• CHAO JH, PHILLIPS R, NICKSON JJ. Roentgen-ray therapy of cerebral metastases. Cancer. 1954 Jul;7(4):682-9.
• Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, McKenna WG, Byhardt R. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997 Mar 1;37(4):745-51.
• Lagerwaard FJ, van der Hoorn EA, Verbakel WF, Haasbeek CJ, Slotman BJ, Senan S. Whole-brain radiotherapy with simultaneous integrated boost to multiple brain metastases using volumetric modulated arc therapy. Int J Radiat Oncol Biol Phys. 2009 Sep 1;75(1):253-9. doi: 10.1016/j.ijrobp.2009.03.029. Epub 2009 Jul 4.
• Patchell RA, Regine WF. The rationale for adjuvant whole brain radiation therapy with radiosurgery in the treatment of single brain metastases. Technol Cancer Res Treat. 2003 Apr;2(2):111-5. Review.
• Sundström JT, Minn H, Lertola KK, Nordman E. Prognosis of patients treated for intracranial metastases with whole-brain irradiation. Ann Med. 1998 Jun;30(3):296-9.
• Zimm S, Wampler GL, Stablein D, Hazra T, Young HF. Intracerebral metastases in solid-tumor patients: natural history and results of treatment. Cancer. 1981 Jul 15;48(2):384-94.

• Responsible Party: Hui-Kuo Shu, MD, PhD, MD, Principal Investigator, Emory University
• ClinicalTrials.gov Identifier: NCT01218542
• Other Study ID Numbers: IRB00045035; WCI1784-10
• First Posted: Oct 11, 2010
• Last Update Posted: Jun 29, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Hui-Kuo Shu, MD, PhD, MD, Principal Investigator, Emory University: Secondary brain malignancies; RapidArc; Volumetric modulated arc therapy
• Additional relevant MeSH terms: Neoplasm Metastasis

Study Results

Participant Flow

Recruitment Details	Patients were recruited at Winship Cancer Institute of Emory University from September 2010 to September 2015.

Arm/Group Title	Volumetric Modulated Arc Therapy
Arm/Group Description	Single arm pilot study treating patients with 25 Gy in 10 fractions to the whole brain with simultaneous infield boost (SIB) to a total of 45 Gy in 10 fractions to gross brain metastatic disease. Volumetric modulated arc therapy: Using volumetric modulated arc therapy to give simultaneous infield boost to gross metastatic brain lesions during whole brain radiation therapy.
Period Title: Overall Study
STARTED	22
COMPLETED	13
NOT COMPLETED	9

Baseline Characteristics

Arm/Group Title	Volumetric Modulated Arc Therapy
Arm/Group Description	Single arm pilot study treating patients with 25 Gy in 10 fractions to the whole brain with simultaneous infield boost (SIB) to a total of 45 Gy in 10 fractions to gross brain metastatic disease. Volumetric modulated arc therapy: Using volumetric modulated arc therapy to give simultaneous infield boost to gross metastatic brain lesions during whole brain radiation therapy.
Overall Participants	22
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	13 59.1%
>=65 years	9 40.9%
Sex: Female, Male (Count of Participants)
Female	13 59.1%
Male	9 40.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	10 45.5%
White	12 54.5%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	22 100%

Outcome Measures

1. Primary Outcome

Title	Percent of Participants With Locoregional Control of Treating Brain Metastasis Patients
Description	The cumulative incidences of recurrence locally and in the whole brain were reported at the patient level.
Time Frame	Locoregional control at 1 year

Outcome Measure Data

Analysis Population Description

Feasibility by our criteria was met for all participants.

Arm/Group Title	Volumetric Modulated Arc Therapy
Arm/Group Description	Single arm pilot study treating patients with 25 Gy in 10 fractions to the whole brain with simultaneous infield boost (SIB) to a total of 45 Gy in 10 fractions to gross brain metastatic disease. Volumetric modulated arc therapy: Using volumetric modulated arc therapy to give simultaneous infield boost to gross metastatic brain lesions during whole brain radiation therapy.
Measure Participants	13
1-year Local Control	92 418.2%
Lesion Level Control	98.6 448.2%
1-year Regional Control	46 209.1%
Intracranial Control	46 209.1%
Distant Intracranial Recurrence	87.5 397.7%

2. Secondary Outcome

Title	Brain Progression-free Survival
Description	Defined as period of time from study entry to to death from any cause or brain tumor recurrence or progression.
Time Frame	11 months median follow up period.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Volumetric Modulated Arc Therapy
Arm/Group Description	Single arm pilot study treating patients with 25 Gy in 10 fractions to the whole brain with simultaneous infield boost (SIB) to a total of 45 Gy in 10 fractions to gross brain metastatic disease. Volumetric modulated arc therapy: Using volumetric modulated arc therapy to give simultaneous infield boost to gross metastatic brain lesions during whole brain radiation therapy.
Measure Participants	13
Median (Full Range) [months]	5.7

3. Secondary Outcome

Title	Overall Survival
Description	Defined time from study entry to death from any cause.
Time Frame	11 months median follow up period.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Volumetric Modulated Arc Therapy
Arm/Group Description	The 2-year neurocognitive effect was not collected. We collected and reported neurocognitive data up to 6 months after treatment.
Measure Participants	13
Median (Full Range) [months]	8.6

4. Secondary Outcome

Title	Neurocognitive Effects
Description	Neurological test score were assessed using the Hopkins Verbal Learning Test-Revised (HVLT). In the HVLT 12 words are read and the participant is asked to recall them, this is completed 3 times. Total words recalled are summed to give a score for Total Recall (0-36, higher scores demonstrated better recall). Delayed recall is conducted 20-25 minutes later on the same list of 12 words (scored 0-12 with higher scores demonstrating better recall). Retention is calculated as the percent of words recalled (scored 0-100, higher scores representing better recall). Recognition Discrimination is tested by a series of yes/no responses from the participant identifying 12 target words from a list of 24 and calculated by the number of true positives minus the number of true negatives with higher scores indicating a better outcome.
Time Frame	11 months median follow up period.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Volumetric Modulated Arc Therapy
Arm/Group Description	Single arm pilot study treating patients with 25 Gy in 10 fractions to the whole brain with simultaneous infield boost (SIB) to a total of 45 Gy in 10 fractions to gross brain metastatic disease. Volumetric modulated arc therapy: Using volumetric modulated arc therapy to give simultaneous infield boost to gross metastatic brain lesions during whole brain radiation therapy.
Measure Participants	13
Total Recall	1.0
Delayed Recall	1.09
Retention	0.99
Recognition Discrimination	0.96

5. Secondary Outcome

Title	Quality of Life as Measured by the FACT-Br Subscales
Description	The Functional Assessment of Cancer Therapy-Brain (FACT-Br) were summed to create the FACT brain trial outcome index (FACT-BR TOI), FACT general (FACT-G), and FACT brain total (FACT-BR Total). Three FACT scales were calculated. The higher the value the better the score, i.e., the better the quality of life perceived by patient. FACT BR TOTAL (FACT-G + BrCS, possible range 0 - 200) FACT-BR TOI (Trial Outcome Index = Physical Well Being _ Functional Well Being +BrCS, possible range 0 - 148) FACT-G (Fact General, possible range 0 - 108)
Time Frame	11 month median follow up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Volumetric Modulated Arc Therapy
Arm/Group Description	Single arm pilot study treating patients with 25 Gy in 10 fractions to the whole brain with simultaneous infield boost (SIB) to a total of 45 Gy in 10 fractions to gross brain metastatic disease. Volumetric modulated arc therapy: Using volumetric modulated arc therapy to give simultaneous infield boost to gross metastatic brain lesions during whole brain radiation therapy.
Measure Participants	13
FACT-BR Total	1.0
FACT-BR TOI	0.98
FACT-G	0.98

Adverse Events

Time Frame	Adverse events were collected thorughout the study assessed up to 2 year follow-up
Arm/Group Title	Volumetric Modulated Arc Therapy
Arm/Group Description	Single arm pilot study treating patients with 25 Gy in 10 fractions to the whole brain with simultaneous infield boost (SIB) to a total of 45 Gy in 10 fractions to gross brain metastatic disease. Volumetric modulated arc therapy: Using volumetric modulated arc therapy to give simultaneous infield boost to gross metastatic brain lesions during whole brain radiation therapy.
All Cause Mortality
	Volumetric Modulated Arc Therapy
	Affected / at Risk (%)	# Events
Total	10/13 (76.9%)
Serious Adverse Events
	Volumetric Modulated Arc Therapy
	Affected / at Risk (%)	# Events
Total	0/13 (0%)
Other (Not Including Serious) Adverse Events
	Volumetric Modulated Arc Therapy
	Affected / at Risk (%)	# Events
Total	13/13 (100%)
General disorders
Radiation Necrosis	2/13 (15.4%)	2
Fatigue	8/13 (61.5%)	8
Nausea	5/13 (38.5%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.