DOS 741: Clinical Protocol

Presentation

Collin Nappi
ALLIANCE-A071801: Phase III Trial of Post-Surgical Single Fraction
Stereotactic Radiosurgery (SRS) Compared with Fractionated SRS
(FSRS) for Resected Metastatic Brain Disease

NCT04114981
About the Study
Sponsors and collaborators
• Alliance for Clinical Trials in Oncology
• Mission statement: Develops and conducts clinical trials with promising new cancer therapies, and utilizes the best science to develop
optimal treatment and prevention strategies for cancer, as well as research methods to alleviate side effects of cancer and cancer
treatments1
• National Cancer Institute (NCI)
• Collection of organizations and clinicians that coordinates and supports cancer trials1

201 participating study locations

Interventional (clinical trial)

208 participants

Study date start: October 3, 2019

Estimated completion date: March 2028

Study Rationale2

It is estimated that 16-18% of the 200,000 newly diagnosed brain

metastases cases undergo surgical resection to remove these metastases

Brain metastases are the most common problem in neuro-oncology and

the resected brain metastasis population is similar in size, per year, to
newly diagnosed glioblastoma

This clinical trial aims to find the best option for durable control of the
surgical bed of these resected lesions
Purpose2

• To compare how well single fraction

stereotactic radiosurgery works
versus fractionated stereotactic
radiosurgery in treating patients
with resected brain metastases
• Single fraction is the standard, but
this study aims to determine if the
standard of care should be changed
by comparing fractionated
stereotactic radiosurgery to single
fraction stereotactic radiosurgery
 Comparing a new treatment to the standard treatment
and focuses on learning how a new treatment compares
to the standard

What does Participants are randomized and assigned to one of two or

more groups (arms) where one group (control) will receive
phase III the standard treatment while the other (investigational
group) receives the new treatment being tested
mean?3
Single fraction is the control group while fractionated is
the experimental group
SRS vs. FSRS4

Stereotactic radiosurgery is a technique in radiation therapy where

very high doses of radiation are given in a high dose per fraction

They often range from 1 to 5 fractions at a high dose rate

SRS aims to cause less damage to normal tissue by delivering only one
high dose of radiation directly to the tumor

FSRS delivers multiple, smaller doses of radiation over time – these

doses are still high compared to normal fractionation schemes, so
extensive immobilization is required for both techniques
 • Active comparator (control): Arm I Single
Arms of the fraction stereotactic radiosurgery

Study5 • Experimental: Arm II Fractionated

stereotactic radiosurgery
• Both arms will undergo a quality-of-life (QOL)
assessment and functional independence
assessments compared to each patient’s
baseline QOL assessments
• Patients are followed up at 30 days, at 3, 6, 9,
12, 16, and 24 months, then every 6 months
until five years from randomization
Primary Outcome Measures5

• Surgical bed recurrence-free survival (SB-RFS)

• From the time of randomization up to 2 years post radiation
• Surgical bed control is the absence of new nodular contrast enhancement in
the surgical bed
• Stratified log-rank test to compare the two techniques
 • Change in functional assessment of cancer
Highlights of therapy-brain (FACT-BR)

Secondary • Functional assessment of FACT-BR total score (9

and 12 months)

Outcome • Linear analog self assessment overall quality of

life (9 and 12 months)
Measures (14)5 • Karnofsky performance status (up to 24 months)
• Barthel activities of daily living (up to 24 months)
• Overall survival (up to 5 years)
• Incidence of adverse events (up to 24 months)
 Patients with or without active disease outside the nervous system

Inclusion Three or fewer unresected brain metastases at time of screening

Unresected lesions must measure < 4.0 cm in maximal extent on contrasted post-operative (unresected lesions

Criteria5
will be treated with SRS)

One brain metastasis must be completely resected < 30 days prior to pre-registration

Resected brain metastasis must measure 2 cm or larger on the pre-op MRI

Resection cavity must measure < 5.0 cm in maximal extent and resection must be complete

Karnofsky performance status of > 60

Ability to complete an MRI of head with contrast

Brain metastasis must be located > 5 mm of the optic chiasm and outside of the brain stem

Must be fluent in English, Spanish, or French

Completion of all baseline electronic patient reported quality of life measures and Montreal Cognitive
Assessment (MoCA)
Exclusion Criteria5
Must not have any prior whole brain radiation therapy; past
radiosurgery to other lesions is allowed if it is not in the same
location
May not have primary germ cell tumor, small cell carcinoma, or
lymphoma

No evidence of leptomeningeal metastasis

 • Permitted equipment include Gamma Knife or x-rays with 4 MV or
Treatment greater capabilities for accelerator-based treatments
Considerations6 • Extensive immobilization is required
Target Volumes6

• The GTV includes the adjacent meningeal

surfaces and any adjacent meningeal surfaces
adjacent to the resection bed up to 2 to 5 mm
along the bone flap
• Total prescribed dose to surgical cavity
determined by GTV volume
• CTV = GTV + 2 mm expansion; PTV = CTV
(optional 1 mm margin)
Target Dose6

• 95% of the protocol dose should encompass the

target
• Variation acceptable: 90% of protocol dose
encompasses target
• Deviation unacceptable: < 90% of protocol
dose encompasses target
• For lesions 5 mm or greater, the ratio of
prescription isodose volume to target volume
should be between 1.0 and 2.0
• Deviation unacceptable: ratio is > 3.0
• For lesions less than 5 mm, a ratio up to 3.0 is
acceptable
• Deviation unacceptable: ratio is above 5.0
Beam Arrangements

• 6 MV FFF with partial arcs

• Avoids entrance and exit dose overlap by
providing unique fields each time
• Allows for mid and low dose to be tight and
spherical
• If we do not use kicks then only high dose
would be conformal
Critical Structure
Tolerances – 1
Fraction6,7
Normal tissue tolerances are based
on AAPM TG 101
Critical Structure
Tolerances – 3
Fractions6,7
Normal tissue tolerances are based
on AAPM TG 101
Critical Structure
Tolerances – 5
Fractions6,7
Normal tissue tolerances are based
on AAPM TG 101
Variations
and
Deviations
of Normal
Tissue6
Outcome Analysis

SB-RFS, FACT-BR, Linear

Analysis of the primary Compare results of tests
Analog Self-Assessment
and secondary outcomes to baseline tests prior to
(LASA), Barthel ADL Index,
in a range of 9 months to radiation technique and
Karnofsky Performance
5 years after then compare results of
Scale, Montreal Cognitive
randomization each technique
Assessment (MoCA)5
Ancillary Studies6
 • Benefits
• Regardless of the group, the patient will receive
Benefits, the best standard treatment and if the new
proven treatment is better, the patient is the
Risks, and first to benefit
• Risks
Moving • Potential side effects
Forward3 • The treatment could be worse or less effective
than the standard
• Moving to phase IV
References

1. NCTN: NCI’s National Clinical Trials Network. National Cancer Institute.

https://www.cancer.gov/research/infrastructure/clinical-trials/nctn#the-need Accessed June 28, 2021.
2. Alliance Trial to Focus on Care for Patients with Resected Brain Metastases. Alliance for Clinical Trials in Oncology.
https://www.allianceforclinicaltrialsinoncology.org/main/public/standard.xhtml?path=%2FPublic%2FAbout Accessed June 28, 2021.
3. Lenards, N. Clinical Trials. [SoftChalk]. La Crosse, WI: UW-L Medical Dosimetry Program; 2021.
4. A Study to Compare Single Fraction Stereotactic Radiosurgery Compared with Fractionated Stereotactic Radiosurgery in Treating Patients with
Resected Metastatic Brain Disease. Mayo Clinic. https://www.mayo.edu/research/clinical-trials/cls-20477457 Accessed June 28, 2021.
5. Single Fraction Stereotactic Radiosurgery Compared with Fractionated Stereotactic Radiosurgery in Treating Patients with Resected Metastatic
Brain Disease. U.S. National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT04114981 Accessed June 28, 2021.
6. Brown, P. Phase III Trial of Post-Surgical Single Fraction Stereotactic Radiosurgery (SRS) Compared with Fractionated SRS (FSRS) for Resected
Metastatic Brain Disease. Alliance for Clinical Trials in Oncology. Published October 3, 2019. Accessed June 28, 2021.
7. Single Fraction Stereotactic Radiosurgery Compared with Fractionated Stereotactic Radiosurgery in Treating Patients with Resected Metastatic
Brain Disease. The James.
https://cancer.osu.edu/for-patients-and-caregivers/learn-about-cancers-and-treatments/innovation-at-the-james/clinical-trials/find-a-clinical-trial
/phase-iii-trial-of-post-surgical-single-fraction
Accessed June 28, 2021.