Dos 741 Protocols & Studies in Rad Onc 2011 Charles Poole Phase III Randomized Trial of the Role of Whole Brain Radiation Therapy in Addition to Radiosurgery in Patients with One to Three Cerebral Metastases Dos 741 Protocols & Studies in Rad Onc 2011 Charles Poole

Background Information 100,000 to 170,000 new patients with brain metastasis in U.S. each year. Brain metastasis is an increasing management problem due to the inability of chemotherapy agents to pass the blood brain barrier. If untreated, brain metastasis survival is less than seven weeks. Brain metastases cause significant mortality and morbidity, including significant cognitive impairment at the time of presentation”(1).

Whole Brain Radiation Therapy (WBRT) Palliative whole brain radiation therapy (WBRT) extend median survival time from three to six months and also delays neurologic progression. Previous RTOG trials conducted different WBRT regimens. Whole brain radiation therapy dosing regimens are variable with no definitive results in survival regarding dose escalation beyond 30 Gy in 10 fractions.

Stereotactic Radiosurgery (SRS) “Stereotactic radiosurgery (SRS) is a single-fraction radiation therapy procedure for treating intracranial lesions using a combination of a stereotactic apparatus and narrow multiple beams delivered through noncoplanar isocentric arcs”(2). SRS delivers a high dose of radiation precisely focused on a target within the brain while delivering significantly lower dose to brain tissue outside the target area (3). Brain metastases are ideal targets for SRS because most lesions are small pseudo-spherical and well demarcated from the surrounding brain tissue.

Example of Stereotactic Radiosurgery (SRS)

Objectives of Phase III Trial N0574 Objectives of Arm A (SRS alone) compared to Arm B (SRS + WBRT) Primary - Less neurocognitive progression at three months post radiosurgery in patents in Arm A compared to patients in Arm B. Compare overall survival. Secondary - Greater or equal time to CNS (brain) failure. Improved quality of life (QOL) with longer duration of functional independence. Better long term neurocognitive status. Compare post treatment adverse events with associated interventions Compare overall survival in patients who receive SRS alone versus SRS combined with WBRT.

At what stage is clinical trial N0574? Clinical trial N0574 is a randomized phase III trial. Arm A (SRS alone) or Arm B (SRS + WBRT). “Phase III trials focus on learning how a new treatment compares to standard, or the most widely accepted, treatment”(4). Participants are from hundreds of people to thousands of people. Participants also range from newly diagnosed patients to patients with advanced clinical disease(4). Target enrollment for trial N0574 is 238 patients.

Trial N0574 Inclusion Criteria Patients with one to three brain metastases from an extra cerebral tumor site. The lesion measures < 3.0 cm in maximum extent from an MRI scan approximately 28 days prior to randomization. Use of standard tumor-staging procedures to define extra cranial disease. 18 years of age or greater. Have an ECOG status of 0,1, or 2. Grooved peg board for Neurocognitive Testing. SRS treatment has been approved by RPC for the facility on a Gamma Knife or Linac-based radiosurgery program.

Trial N0574 Exclusion Criteria Pregnant women, men or women of childbearing potential must use effective contraception. Pacemakers or other MRI non-compatible metal in the body. Allergic to gadolinium. Prior resection of cerebral metastasis. Lesions that are located less than or equal to 5 mm of the optic chiasm or within the brainstem. Chemotherapy starting prior to registration of the trial. Planned chemotherapy during SRS and WBRT. Prior cranial radiation therapy. Leptomeningeal metastasis. Primary germ cell tumor, small cell carcinoma, or lymphoma.

What does trial N0574 address? This study is designed to test the hypothesis that in patients with one to three metastases, WBRT adds no additional benefit to SRS. The purpose of this research study is to compare overall survival and compare the effect (good and bad) of stereotactic radiosurgery (SRS) to stereotactic radiosurgery plus whole brain radiation therapy (WBRT) on brain metastases. Also, to determine if adding WBRT to SRS will be of any benefit versus receiving SRS alone in treating microscopic tumor deposits in the brain. “They want to determine whether adding whole-brain radiotherapy provides any benefit in terms of preventing additional metastases and how whole-brain radiotherapy affects patient quality of life and cognition”(5).

What is the control for trial N0574? The control for this trial is Arm A (SRS alone). Arm B is investigational: Patients undergo SRS as in arm A and within 14 days, patients then undergo WBRT for 5 days a week for 2.5 weeks. Quality of life, functional independence, and neurocognitive status are assessed for a baseline, at the beginning of each treatment, at weeks 6 and 12, and then at 6, 9, 12, 16, 24 , 36, 48, and 60 months.

Sponsor and Collaborators of trial N0574 Sponsor of trial N0574 is North Central Cancer Treatment Group (NCCTG). Collaborators include: National Cancer Institute (NCI). American College of Surgeons. Eastern Cooperative Oncology Group. Radiation Therapy Oncology Group.

Benefits to NCCTG “Clinical trial N0574 is the largest study at NCCTG evaluating the cognitive function and quality of life aspects”(6). SRS + WBRT benefits; cognitive function and QOL. “Researchers want to evaluate the costs of this additional treatment to the patient: how does it impact their cognitive function or quality of life”(6).

Who will benefit from trial N0574? Patients who have one to three brain metastases may benefit from the addition of SRS to WBRT. Radiation oncologists and other physicians such as neurosurgeons. Researchers conducting other trials that involve multiple brain metastasis subjects.

How will they benefit? Patients with one to three metastases would demonstrate increased local control and no further evidence of additional metastases. Improved QOL and neurocognitive assessments at three months post treatment. The FACT-BR QOL questionnaire and objective assessments of cognitive changes will be studied. Increased functionality. The ability to perform daily activities.

Stereotactic Radiosurgery (SRS) Regimen (Arm A) SRS dose (Table 1) is selected to provide a high rate of local control with minimum risk of radionecrosis. SRS dose is decreased when WBRT is given in addition due to the additive effects. Table 1. Arm A doses. Arm A (SRS only) Lesions < 2 cm receive 24 Gy. Lesions 2 – 2.9 cm receive 20 Gy.

Whole Brain Radiation Therapy WBRT Regimen (Arm B) Patients randomized to Arm B: SRS and WBRT (Table 2), initiation of WBRT is less than 14 days following SRS. Table 2. Arm B doses. Arm B (SRS + WBRT) Lesions < 2 cm receive 22 Gy. Lesions 2 – 2.9 cm receive 18 Gy. WBRT = 30 Gy delivered in 12 fractions at 2.5 Gy / fx.

Stereotactic Radiosurgery (SRS) Treatment Planning Protocol (Arm A) Arm A (SRS only): Gamma Knife or greater than 4 MV energy for linear accelerator treatments with Multi-leaf Collimators (MLC’s). Machine needs to be calibrated by RPC. Volumes defined by a planning MRI brain scan Identified by ICRU-50 nomenclature. Gross Tumor Volume (GTV) – defined by contrast enhanced tumor seen on planning MRI. Diameter must be < 3.0 cm. Clinical Target Volume (CTV) – Defined as GTV for this study. Dose should be prescribed to the highest isodose line encompassing the CTV ~ 50% to 80% of maximum dose.

Stereotactic Radiosurgery (SRS) Treatment Planning Protocol (Arm A) Dose Uniformity: Efforts should be made to cover the GTV with as uniform a dose as possible. Dose conformity: The ratio of the prescription isodose volume to the target volume (GTV) should be between 1.0 and 2.0. Goal to minimize dose to normal tissue and critical structures. The dose to the Optic Chiasm should be less than 8 Gy. Dose Volume Histogram (DVH) should be submitted for all volumes and critical structures.

Whole Brain Radiation Therapy WBRT Treatment Planning Protocol (Arm B) Arm B (SRS + WBRT): X-ray beams with energies between 4 and 6 MV. Target Volume consists of the entire brain, posterior halves of the globes of the eyes, optic nerves. The caudal border is below the skull base at the top of C2 vertebral level. The prescription point in the cranial volume is near the center. Dose uniformity: Dose within the target volume shall be within +7% (-5% of the prescription-point dose). Recommended patient is treated supine with two lateral equally weighted beams. Field borders should be 1.0 cm beyond the periphery of the scalp and MLC’s are allowed.

References Consulted: Phase III Randomized Study of Stereotactic Radiosurgery With Versus Without Whole-Brain Radiotherapy in Patients With Cerebral Metastases. Cancer.gov Web site. http://www.cancer.gov/clinicaltrials/search/view?cdrid=499633&version=HealthProfessional&protocolsearchid=9746041#Objectives_CDR0000499633. September, 10 2006. Assessed October 18, 2011. Cited: 1. Jenkinson M, Haylock B, Shenoy A, Husband D, Javadpour M. Management of cerebral metastasis: Evidence-based approach for surgery, stereotactic radiosurgery and radiotherapy. http://www.sciencedirect.com/science/article/pii/S0959804910011597. March 2011. Accessed October 18, 2011. 2. Khan F. The physics of radiation therapy. 4th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2010: 453. Stereotactic Radiosurgery (SRS); The UCLA Radiosurgery Program, One of the Most Advanced Facilities in the World. UCLA educational Web site. http://radonc.ucla.edu/body.cfm?id=33. 2011. Accessed October 19, 2011. National Cancer Institute Cancer Clinical Trials: The Basic Workbook. National Cancer Institute. Web site. http://www.cancer.gov/clinicaltrials/learningabout/basicworkbook/Allpages. 2002. Accessed October 24, 2011. Radiation Therapies to Treat Brain Metastases. National Cancer Institute Web site. http://www.cancer.gov/clinicaltrials/featured/trials/ncctg-n0574. August 21, 2007. Accessed October 24, 2011. 6. Insights. NCCTG publication for members. Docstoc Web site. http://www.docstoc.com/docs/66277465/Insights. 2010. Accessed October 25, 2011.