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Effective Health Care Program

Radiation Therapy for Brain Metastases

Key Questions Draft

Background

It is estimated that 10–30% of adults with cancer will eventually develop brain metastases (BM) and approximately 200,000 to 300,000 Americans are diagnosed with the condition each year.1-3 The incidence of brain metastases is growing as diagnostic tools improve and cancer treatments extend patients' lifespans.3 The brain is thought to be a common location of metastasis because it is a sanctuary site protected from systemic treatments by the blood brain barrier. While a minority of brain metastases manifest as a single tumor (10–20%) at the time of detection, the rest arise as multiple tumors. Primary tumors that most commonly metastasize to the brain are lung cancer (30–60% of all BMs), breast cancer (5–30% of all BMs in women) and melanoma (5–21% of all BMs). Melanoma is reported to have the highest propensity to metastasize to the brain of all cancer types.2,4 In consultation with expert clinical opinion and in order to manage the scope of the review, the population has been limited to individuals with BMs arising from these three primary tumor sites.3

In the past, an individual who developed brain metastases had a poor prognosis with median survival of less than six months.1 However, the development of prognostic tools such as the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) and the diagnostic-specific Graded Prognostic Assessment (DS-GPA) have helped physicians differentiate patients based on expected survival time (which can vary markedly) using risk factors such as age, number of brain metastases, performance status, disease status and primary tumor site.1 Treatment plans have become more individualized and, particularly for those patients with a good prognosis, focused on effectively managing the brain metastasis(es) while minimizing neurotoxicity and quality of life disruptions.

Whole brain radiation therapy (WBRT) is a type of radiation therapy administered to the entire brain over multiple visits; it may also be delivered in medium-dose fractions in more sessions ("hypofractionation"). WBRT, sometimes preceded by surgery, was the standard of care for many years.1 It was widely used because it treats the known tumor(s) along with any unknown microscopic disease; the therapy can be started quickly; it is commonly available; and it is helpful for symptom relief.1 WBRT can be used alone or in combination with surgery, stereotactic radiotherapy or systemic therapies. However, WBRT is associated with negative short- and long-term side effects including fatigue and irreversible neurocognitive deficits. As systemic therapies have improved and patients with brain metastases have started living months or years longer, the longer-term side effects of WBRT have become more apparent. As a result, researchers, clinicians and patients have explored other promising therapies.1

Surgery, during which a surgeon removes as much of the tumor as possible, remains an important component of therapy for brain metastases. Surgery is particularly effective for single tumors larger than 3 cm, tumors not located in speech or motor areas, and/or tumors causing symptoms.1,3  WBRT or stereotactic radiosurgery (SRS) is often administered after surgery.

SRS was introduced in the 1980s. It applies focused beams of high doses of radiation to the tumor(s) while sparing the surrounding tissue. It is often administered in one session of high dose radiation but it may also be given in more sessions of medium-dose fractions ("hypofractionation").5 The role of SRS in treating brain metastases continues to expand. Acute side effects may include nausea, dizziness, seizures or headache. A longer-term harm which may uncommonly occur is radiation necrosis.5

Research has shown that certain tumors may respond well to particular systemic agents (i.e., chemotherapy or immunotherapies). Chemotherapy and immunotherapy may also be used in combination with radiation. Ascertaining the histology of the tumor and presence of certain molecular markers before determining the treatment plan is increasingly common.3 This is a rapidly evolving area in the management of brain metastases.

Draft Key Questions

  • KQ1: What is the effectiveness of whole brain radiation therapy (WBRT), alone or in combination with stereotactic radiosurgery (SRS) or systemic therapies, as initial treatment in patients with brain metastases on patient-relevant outcomes, such as overall survival and quality of life?
    • KQ1a: How does effectiveness vary by dose fractionation schedule?
    • KQ1b: How does effectiveness differ by patient prognosis (i.e., limited/favorable versus extensive brain metastases) and primary tumor site?
  • KQ2: What is the effectiveness of SRS/fractionated stereotactic radiation as initial treatment in patients with brain metastases on patient-relevant outcomes? 
    • KQ2a: How does effectiveness vary by dose fractionation schedule?
    • KQ2b: How does effectiveness differ by the addition of systemic therapies?
  • KQ3: What is the effectiveness (or comparative effectiveness) of postoperative SRS compared to WBRT or observation in patients with brain metastases on patient-relevant outcomes?
    • KQ3a: How does effectiveness vary by dose fractionation schedule?
  • KQ4: What are the adverse effects (i.e., serious harms) of WBRT, SRS, and systemic therapies for patients with brain metastases (either alone or in combination)?
    • KQ4a: Do adverse effects vary by important patient characteristics (i.e., age, performance status, patient prognosis, disease status, primary tumor site) or dose fractionation schedule?

Draft Analytic Framework

Figure 1: This figure depicts the key questions within the context of the PICOTS described below. In general, the figure illustrates how WBRT, SRS and systemic therapies may result in intermediate and final outcomes such as recurrence, overall and disease specific survival, quality of life, and functional status, as well as adverse effects that may occur at any point after patients receive the treatment.

Abbreviations: WBRT: Whole brain radiation therapy; SRS: stereotactic radiosurgery

 

Draft Inclusion and Exclusion Criteria

PICOTS Element

Inclusion Criteria

Exclusion Criteria

Populations

  • Adults (age ≥18 years of age)
  • Patients with metastases in the brain resulting from one of the following primary, extracranial cancers:
    • Lung cancer
    • Breast cancer
    • Melanoma
  • KQ4: Patient characteristics of interest include: age, performance status, patient prognosis, disease status, primary tumor site
  • Patients with primary brain tumors (e.g., glioblastomas)

Interventions

  • KQ 1: Initial WBRT (in varying dose fractionation schedules)
  • KQ 2: Initial SRS (in varying dose fractionation schedules)
  • KQ 3: Postoperative SRS (in varying dose fractionation schedules)
  • KQ 4: WBRT (in varying dose fractionation schedules), systemic therapy (i.e., immunotherapy and chemotherapy), and SRS (in varying dose fractionation schedules)

Other interventions not listed as included

Comparators

KQ 1:

  • Initial WBRT (in varying dose fractionation schedules)
  • Initial WBRT in combination with SRS (in varying dose fractionation schedules)
  • Initial WBRT (in varying dose fractionation schedules) in combination with systemic therapy (i.e. immunotherapy and chemotherapy)
  • Placebo or usual care

KQ2:

  • Initial SRS (in varying dose fractionation schedules)
  • Initial SRS (in varying dose fractionation schedules) in combination with systemic therapies (i.e., immunotherapy and chemotherapy)
  • Placebo or usual care

KQ 3:

  • Postoperative WBRT (in varying dose fractionation schedules)
  • Observation

KQ 4:

  • WBRT (in varying dose fractionation schedules), systemic therapy (i.e., immunotherapy and chemotherapy), and SRS (in varying dose fractionation schedules) 

Other comparators not listed as included

Outcomes

  • Overall survival from all causes
  • Disease-specific survival
  • Recurrence/cancer control (local tumor control: as defined by either a complete response, partial response, or stable response of all metastases)
  • Progression-free survival
  • Adverse events: acute and late toxicity (e.g., radiation necrosis, new neurologic deficit, peritumoral edema)
  • Quality of life as measured using a clinically validated scale
  • Functional status
  • Neurocognition

Study does not include any outcomes of interest

Timing

  • Timing of follow-up not limited

None

Setting

  • Inpatient and outpatient

None

Study design

  • All sample sizes
  • RCTs
  • KQ4 only: Include prospective observational studies of ≥ 200 participants
  • All other study designs

Publications

  • English-language publications
  • Relevant systematic reviews, meta-analyses, or methods articles (used for background only)
  • Published on or after January 1, 2000*
  • Non-English-language publications

*2000 was the date of the publication of RTOG 9005, a landmark study of SRS that influenced its use in U.S. clinical practice.6

References

  1. Arvold ND, Lee EQ, Mehta MP, Margolin K, Alexander BM, Lin NU, et al. Updates in the management of brain metastases. Neuro Oncol. 2016;18(8):1043-65. PMID: 27382120; PubMed Central PMCID: 4933491.
  2. Lin X, DeAngelis LM. Treatment of Brain Metastases. J Clin Oncol. 2015;33(30):3475-84. PMID: 26282648; PubMed Central PMCID: 5087313 online at www.jco.org. Author contributions are found at the end of this article.
  3. American Brain Tumor Association. Metastatic Brain Tumors. American Brain Tumor Association,, 2017.
  4. Fox BD, Cheung VJ, Patel AJ, Suki D, Rao G. Epidemiology of metastatic brain tumors. Neurosurg Clin N Am. 2011;22(1):1-6, v. PMID: 21109143.
  5. Loeffler J. Overview of the treatment of brain metastases: UptoDate; 2018 [updated Dec 11, 2018; cited Jan 15, 2019].
  6. Shaw E, Scott C, Souhami L, Dinapoli R, Kline R, Loeffler J, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys. 2000;47(2):291-8. PMID: 10802351.