This is the current release of the guideline.

This guideline updates a previous version: Loeffler JS, Bloomer WD, Malcolm AW, Larson D, Gasper LE, Lewin AA, Mendenhall WM, Schneider JF, Simpson JR, Wharam MD Jr, McDermott MW, Rogers L, Mauch PM, Expert Panel on Radiation Oncology-Brain Metastases Work Group. Single brain metastasis. [online publication]. Reston (VA): American College of Radiology (ACR); 2006. 7 p. [22 references]

The appropriateness criteria are reviewed biennially and updated by the panels as needed, depending on introduction of new and highly significant scientific evidence.

Single brain metastasis

To evaluate the appropriateness of radiologic treatment procedures for patients with a single brain metastasis

Patients with a single brain metastasis

Literature Search Procedure

The Medline literature search is based on keywords provided by the topic author. The two general classes of keywords are those related to the condition (e.g., ankle pain, fever) and those that describe the diagnostic or therapeutic intervention of interest (e.g., mammography, MRI).

The search terms and parameters are manipulated to produce the most relevant, current evidence to address the American College of Radiology Appropriateness Criteria (ACR AC) topic being reviewed or developed. Combining the clinical conditions and diagnostic modalities or therapeutic procedures narrows the search to be relevant to the topic. Exploding the term "diagnostic imaging" captures relevant results for diagnostic topics.

The following criteria/limits are used in the searches.

1. Articles that have abstracts available and are concerned with humans.
2. Restrict the search to the year prior to the last topic update or in some cases the author of the topic may specify which year range to use in the search. For new topics, the year range is restricted to the last 5 years unless the topic author provides other instructions.
3. May restrict the search to Adults only or Pediatrics only.
4. Articles consisting of only summaries or case reports are often excluded from final results.

The search strategy may be revised to improve the output as needed.

The total number of source documents identified as the result of the literature search is not known.

Strength of Evidence Key

Category 1 - The conclusions of the study are valid and strongly supported by study design, analysis and results.

Category 2 - The conclusions of the study are likely valid, but study design does not permit certainty.

Category 3 - The conclusions of the study may be valid but the evidence supporting the conclusions is inconclusive or equivocal.

Category 4 - The conclusions of the study may not be valid because the evidence may not be reliable given the study design or analysis.

The topic author drafts or revises the narrative text summarizing the evidence found in the literature. American College of Radiology (ACR) staff draft an evidence table based on the analysis of the selected literature. These tables rate the strength of the evidence for all articles included in the narrative text.

The expert panel reviews the narrative text, evidence table, and the supporting literature for each of the topic-variant combinations and assigns an appropriateness rating for each procedure listed in the table. Each individual panel member forms his/her own opinion based on his/her interpretation of the available evidence.

More information about the evidence table development process can be found in the American College of Radiology (ACR) Appropriateness Criteria® Evidence Table Development document (see "Availability of Companion Documents" field).

Modified Delphi Technique

The appropriateness ratings for each of the procedures included in the Appropriateness Criteria topics are determined using a modified Delphi methodology. A series of surveys are conducted to elicit each panelist's expert interpretation of the evidence, based on the available data, regarding the appropriateness of an imaging or therapeutic procedure for a specific clinical scenario. American College of Radiology (ACR) staff distributes surveys to the panelists along with the evidence table and narrative. Each panelist interprets the available evidence and rates each procedure. The surveys are completed by panelists without consulting other panelists. The ratings are a scale between 1 and 9, which is further divided into three categories: 1, 2, or 3 is defined as "usually not appropriate"; 4, 5, or 6 is defined as "may be appropriate"; and 7, 8, or 9 is defined as "usually appropriate." Each panel member assigns one rating for each procedure per survey round. The surveys are collected and the results are tabulated, de-identified and redistributed after each round. A maximum of three rounds are conducted. The modified Delphi technique enables each panelist to express individual interpretations of the evidence and his or her expert opinion without excessive bias from fellow panelists in a simple, standardized and economical process.

Consensus among the panel members must be achieved to determine the final rating for each procedure. Consensus is defined as eighty percent (80%) agreement within a rating category. The final rating is determined by the median of all the ratings once consensus has been reached. Up to three rating rounds are conducted to achieve consensus.

If consensus is not reached, the panel is convened by conference call. The strengths and weaknesses of each imaging procedure that has not reached consensus are discussed and a final rating is proposed. If the panelists on the call agree, the rating is accepted as the panel's consensus. The document is circulated to all the panelists to make the final determination. If consensus cannot be reached on the call or when the document is circulated, "No consensus" appears in the rating column and the reasons for this decision are added to the comment sections.

Not applicable

A formal cost analysis was not performed and published cost analyses were not reviewed.

Criteria developed by the Expert Panels are reviewed by the American College of Radiology (ACR) Committee on Appropriateness Criteria.

ACR Appropriateness Criteria®

Clinical Condition: Single Brain Metastasis

Variant 1: 77-year-old man, PET scan demonstrated widely metastatic melanoma with a 2 cm right thalamic lesion. Neurosurgeon believes surgery would be high risk. KPS 60. Patient refuses further systemic therapy.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 2: 54-year-old man found to have wide spread metastatic small cell carcinoma to lung, bone, and liver by PET/CT imaging with a 2 cm asymptomatic left anterior temporal lobe lesion. KPS 70. Systemic therapy is planned. No prior WBRT.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.  

Variant 3: 68-year-old woman status-post chemotherapy/radiotherapy and surgery for esophageal carcinoma. No evidence of extracranial disease with 5 cm lesion in right anterior frontal lobe with 15 mm midline shift. KPS 90 on high dose steroids.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 4: 48-year-old man status-post left upper lobe resection for NSCLC one year earlier, now with 3 cm right frontal lobe lesion. No clinical or radiographic evidence of extracranial disease. The right frontal lesion was completely resected, confirmed by contrast MRI scan 24 hours after surgery. Two weeks after surgery, KPS is 80.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 5: 35-year-old woman with metastatic breast cancer to multiple bony sites with a 3 cm left parietal lesion. Systemic disease is no longer responding to chemo-hormonal therapy. Surgical resection was subtotal in nature, confirmed by postoperative MRI. KPS 90.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 6: 49-year-old woman (non-smoker) recently diagnosed with 2 cm NSCLC left upper lobe with no hilar and mediastinal lymphadenopathy, and asymptomatic 2 cm right frontal lesion. Abdominal CT and bone scan were negative. KPS 90.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 7: 42-year-old woman status-post nephrectomy for renal cell carcinoma six years earlier with a 1 cm lesion in the right lateral cerebellum found incidentally after MRI for head injury. CT of chest/abdomen and bone scan was negative. KPS 90.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Summary of Literature Review

Introduction

The appropriate treatment for a patient with a single brain metastasis has become controversial given the number of management strategies that are currently available and the strong opinions that are associated with each option. As a result, there is no clear consensus regarding optimal or ideal treatment for these patients despite class I evidence suggestive of best therapy.

Prognostic Factors

To help categorize patients into prognostic groups, a number of clinical factors have been evaluated to help guide treatment decisions. The most commonly used prognostic scale for patients with brain metastases is from the Radiation Therapy Oncology Group (RTOG®) Recursive Partitioning Analysis of three consecutive phase III brain metastases trials. This study determined the four most important factors were Karnofsky performance score (KPS), age, control of primary and status of extracranial disease. More recently, a less subjective, more quantifiable scale (Graded Prognostic Assessment) from five phase III RTOG® trials revealed that extracranial disease status, age and KPS were still prognostic. This analysis, however, demonstrated the importance of the number of lesions (1 vs 2-3 vs >3) in determining outcomes for patients with brain metastases.

Surgery

Advances in surgery and imaging have allowed for safer resection of brain metastases. If the patient is suffering from significant mass effect or has no pathologic confirmation of the primary, then surgical resection of the lesion, if feasible, is warranted. For patients with a single lesion who are relatively asymptomatic, the decision process is somewhat more complicated. The decision to use aggressive therapy depends on the extent and activity of extracranial disease, number of brain lesions as well as the patient's general medical condition, performance status, and patient's preference. For patients with stable or absent extracranial disease, two randomized studies have clearly shown the benefit of surgical resection followed by whole brain radiotherapy (WBRT). The benefits are expressed not only in terms of freedom from neurologic progression but also in terms of overall survival. However, a third study failed to show a survival advantage with the addition of surgery, or an advantage in terms of quality-of-life. Thus, two of three randomized studies have shown a benefit of surgical resection and WBRT versus WBRT alone.

Whole Brain Radiation Therapy

The dose used with WBRT in patients with single brain metastasis is based mainly on studies performed in patients with multiple brain metastases. Prospective, randomized phase III clinical trials in patients with multiple brain metastases have included 1000 cGy in one fraction (1000/1), 1200/2, 1800/3, 2000/5, 3000/10, 3600/6, 4000/20, 5000/20, and 5440/34 (160 cGy twice a day [BID]). Since none of these regimens has proved superior in terms of survival or efficacy (about half of patients have an improvement in their neurologic symptoms), 3000 cGy in 10 fractions or 3750 cGy in 15 fractions represent frequently utilized dose/fractionation schedules. A randomized trial in patients with one to three brain metastases by the RTOG® used 3750 cGy in 15 fractions WBRT (i.e., 250 cGy per fraction) as the standard treatment arm. This schedule is an extrapolation from two other series in the literature, one of which suggests that 300 cGy fractions given following resection of a single brain metastasis are associated with a greater likelihood of late effects to the normal brain, and another in which prophylactic cranial irradiation given in case of small-cell lung cancer with 250 cGy fractions (10 fractions) was not associated with late effects. WBRT alone can provide excellent palliation for many patients with brain metastases.

Surgery versus Stereotactic Radiosurgery

Whether stereotactic radiosurgery (SRS) is as effective as surgical resection has not been evaluated within a Phase III randomization trial for patients with single brain metastasis. A multi-institutional outcome study was performed on patients treated with radiosurgery and WBRT who met the same entry criteria as the patients treated in the two positive randomized trials of surgery and WBRT vs. WBRT alone. The results of this non-randomized study indicate that radiosurgery plus WBRT produces the same local control, freedom from neurological deterioration, and overall survival as surgery plus WBRT. Another retrospective study showed improved median and 1-year survival for those undergoing surgery as compared to SRS. The rates of local recurrence and neurologic death were lower in the surgery group. More recent studies have suggested that the results of SRS and WBRT are equivalent to surgery and WBRT. For tumors greater than 4 cm in greatest diameter or causing significant mass effect, surgery rather than SRS is the preferred treatment.

Brachytherapy

Some studies looking at stereotactic interstitial brachytherapy for patients with single lesions indicate that control rates are similar to those obtained with radiosurgery. However, stereotactic brachytherapy is an invasive procedure and requires hospitalization. A more recent phase II trial evaluating balloon brachytherapy demonstrated local control rates of 80% but higher rates of radiation necrosis. Given the invasive nature of brachytherapy, this approach is not routinely practiced.

Surgery with or without Whole Brain Radiation Therapy

The use of WBRT for patients with a single metastasis has been a subject of controversy. The question of whether surgical resection can be performed without the addition of WBRT was tested in a Phase III randomized trial. This trial demonstrated that the overall local and distant recurrence rates in the brain were 46% and 70% in the surgery arm versus 10% and 18%, in the surgery and WBRT arm. Overall survival was not improved; however, the study was not powered to detect such a difference.

Stereotactic Radiosurgery with or without Whole Brain Radiation Therapy

The analogous question, of whether radiosurgery can be performed without the addition of WBRT, has been studied retrospectively in several institutional and multi-institutional studies. Several radiosurgery studies investigating patients treated with radiosurgery alone versus radiosurgery plus WBRT for single and multiple lesions have not shown an improvement in survival with the addition of WBRT. One study suggested that patients without extracranial disease had a trend toward better median survival of 15.4 months for the WBRT plus SRS group versus 8.3 months survival for the SRS alone group. A phase III trial conducted in Japan randomizing patients with one to four brain metastases between radiosurgery and radiosurgery plus WBRT demonstrated significantly improved local and distant brain control for the WBRT plus radiosurgery arm. Since the primary end point of the study was local control and not overall survival, the study was not powered properly to evaluate survival differences. More recently, a randomized phase III trial of SRS versus SRS and WBRT demonstrated a decline in neurocognitive outcome based on Hopkins Verbal Learning Test (HVLT) at 4 months for patients undergoing WBRT and SRS. The North Central Cancer Treatment Group (NCCTG) has an ongoing phase III trial for patients with 1-3 brain metastases of SRS versus SRS followed by WBRT. The primary endpoint is neurocognitive function.

Whole Brain Radiation Therapy with or without Stereotactic Radiosurgery

Another question, whether patients receiving WBRT for a single brain metastasis benefit from the addition of radiosurgery, has recently been answered in an RTOG® randomized trial in patients with one to three brain metastases. In patients with a single brain metastasis, the addition of radiosurgery increased median survival from 4.9 months to 6.5 months (p=0.04). Local control was significantly improved for all patients. Based on the results of this trial, the RTOG® started a phase III trial (RTOG® 0320) for patients with non-small-cell lung cancer with one to three brain metastases, which closed secondary to poor accrual.

Neurocognitive Effect of Whole Brain Radiation Therapy

Concerns about the potential neurocognitive effects of WBRT have received much attention and scrutiny. As part of a phase III trial evaluating the use of a novel radiation sensitizer with WBRT, all patients underwent evaluation of neurocognitive function using a battery of tests. Baseline neurocognitive testing demonstrated that 91% of patients had a significant decline in at least one domain prior to WBRT. Further analysis of the 208 patients in the WBRT arm of the study demonstrated WBRT-induced tumor shrinkage correlated with better survival and neurocognitive function. In addition, neurocognitive deterioration preceded quality of life declines, which suggests that strategies that delay neurocognitive decline appear worthwhile. When Mini-Mental Status Examination was used to evaluate neurocognitive function as part of the phase III trial of SRS versus SRS plus WBRT for patients with one to four brain metastases, the omission of WBRT led to faster time to neurologic deterioration based on Mini-Mental State Examination. In addition, the omission of WBRT significantly increased the risk for tumor recurrence and decline in neurologic function. A pilot study of neurocognitive function in patients with one to three brain metastases treated with SRS alone showed 60% of the patients had impairment at presentation. A recent phase III trial demonstrated worse neurocognitive outcomes at 4 months as measured by HVLT for patients randomized to the WBRT and SRS arm versus SRS alone.

Stereotactic Radiosurgery to Resection Cavity

The use of SRS to the resection cavity has also been investigated. This study showed actuarial local control rates at 6 and 12 months of 88% and 79%, respectively. Since less conformal plans led to better local control, the authors recommended inclusion of a 2 mm margin around the resection cavity. When the inclusion of a 2 mm margin was retrospectively evaluated for 93 patients with a single metastasis undergoing SRS for an unresected metastasis, higher rates of severe complications were reported.

Long Term Survival after Surgery or SRS

More aggressive treatment with surgery or SRS has led to greater number of patients being long-term survivors. Retrospective review of patients undergoing SRS reported that 6.5% survived at least 4 years. Another review of long-term survivors showed that 2.6% of patients in a large single institution database survived a minimum of 5 years.

Summary

Compelling evidence suggests that aggressive local therapy for patients with a single brain metastasis is beneficial for survival. There is also evidence to suggest that aggressive local therapy for a patient with a single lesion improves quality of life. If patients have no evidence of progressive extracranial disease, surgical resection or radiosurgery is appropriate therapy. While it appears that the addition of WBRT does not add to survival or duration of functional independence, it does reduce the risk of further intracranial failure and delays neurocognitive decline, particularly for those patients whose tumors have responded to WBRT. Recently completed and ongoing studies will help address the impact of WBRT on neurocognitive function and quality of life, which have been major reasons why WBRT is being omitted despite class I evidence supporting the use of WBRT after surgery or SRS.

Since much controversy exists regarding optimal treatment for a patient with a single brain metastasis, patient participation in clinical trials is important to evaluate best treatment. For those patients who do not participate in clinical trials, the roles of surgery and SRS in improving outcomes for patients with a single lesion are evident.

Abbreviations

• CT, computed tomography
• KPS, Karnofsky Performance Status
• MRI, magnetic resonance imaging
• NSCLC, non-small cell lung cancer
• PET, positron-emission tomography
• RCC, renal cell carcinoma
• RT, radiotherapy

Algorithms were not developed from criteria guidelines.

The recommendations are based on analysis of the current literature and expert panel consensus.

Selection of appropriate radiologic treatment procedures for patients with a single brain metastasis

The American College of Radiology (ACR) Committee on Appropriateness Criteria and its expert panels have developed criteria for determining appropriate imaging examinations for diagnosis and treatment of specified medical condition(s). These criteria are intended to guide radiologists, radiation oncologists, and referring physicians in making decisions regarding radiologic imaging and treatment. Generally, the complexity and severity of a patient's clinical condition should dictate the selection of appropriate imaging procedures or treatments. Only those examinations generally used for evaluation of the patient's condition are ranked. Other imaging studies necessary to evaluate other co-existent diseases or other medical consequences of this condition are not considered in this document. The availability of equipment or personnel may influence the selection of appropriate imaging procedures or treatments. Imaging techniques classified as investigational by the U.S. Food and Drug Administration (FDA) have not been considered in developing these criteria; however, study of new equipment and applications should be encouraged. The ultimate decision regarding the appropriateness of any specific radiologic examination or treatment must be made by the referring physician and radiologist in light of all the circumstances presented in an individual examination.

An implementation strategy was not provided.

Not applicable: The guideline was not adapted from another source.

The American College of Radiology (ACR) provided the funding and the resources for these ACR Appropriateness Criteria®.

Committee on Appropriateness Criteria, Expert Panel on Radiation Oncology-Brain Metastases

Panel Members: John H. Suh, MD (Principal Author); Laurie E. Gaspar, MD, MBA (Panel Chair); Gregory M. M. Videtic, MD (Panel Vice-Chair); Amr M. Aref, MD; Isabelle Germano, MD; Brian J. Goldsmith, MD; Joseph P. Imperato, MD; Karen J. Marcus, MD; Michael W. McDermott, MD; Mark W. McDonald, MD; Roy A. Patchell, MD; H. Ian Robins, MD, PhD; C. Leland Rogers, MD; Aaron H. Wolfson, MD; Franz J. Wippold II, MD

Not stated

This is the current release of the guideline.

This guideline updates a previous version: Loeffler JS, Bloomer WD, Malcolm AW, Larson D, Gasper LE, Lewin AA, Mendenhall WM, Schneider JF, Simpson JR, Wharam MD Jr, McDermott MW, Rogers L, Mauch PM, Expert Panel on Radiation Oncology-Brain Metastases Work Group. Single brain metastasis. [online publication]. Reston (VA): American College of Radiology (ACR); 2006. 7 p. [22 references]

The appropriateness criteria are reviewed biennially and updated by the panels as needed, depending on introduction of new and highly significant scientific evidence.

Electronic copies: Available in Portable Document Format (PDF) from the American College of Radiology (ACR) Web site.

Print copies: Available from the American College of Radiology, 1891 Preston White Drive, Reston, VA 20191. Telephone: (703) 648-8900.

The following are available:

• ACR Appropriateness Criteria®. Overview. Reston (VA): American College of Radiology; 2 p. Electronic copies: Available in Portable Document Format (PDF) from the American College of Radiology (ACR) Web site.
• ACR Appropriateness Criteria®. Literature search process. Reston (VA): American College of Radiology; 1 p. Electronic copies: Available in Portable Document Format (PDF) from the ACR Web site.
• ACR Appropriateness Criteria®. Evidence table development. Reston (VA): American College of Radiology; 4 p. Electronic copies: Available in Portable Document Format (PDF) from the ACR Web site.

None available

This summary was completed by ECRI on January 30, 2001. The information was verified by the guideline developer as of February 20, 2001. This NGC summary was updated by ECRI on August 17, 2006. This NGC summary was updated most recently by ECRI Institute on December 22, 2010.

Instructions for downloading, use, and reproduction of the American College of Radiology (ACR) Appropriateness Criteria® may be found on the ACR Web site .