ACR Appropriateness Criteria® Follow-up and Retreatment of Brain Metastases

Patel, Samir H. MD*; Robbins, Jared R. MD; Gore, Elizabeth M. MD; Bradley, Jeffrey D. MD§; Gaspar, Laurie E. MD, MBA; Germano, Isabelle MD; Ghafoori, Paiman MD#; Henderson, Mark A. MD**; Lutz, Stephen T. MD††; McDermott, Michael W. MD‡‡; Patchell, Roy A. MD§§; Robins, H. Ian MD, PhD∥∥; Vassil, Andrew D. MD¶¶; Wippold, Franz J. II MD##; Videtic, Gregory M. MD, CM***; Expert Panel on Radiation Oncology–Brain Metastases

American Journal of Clinical Oncology: June 2012 - Volume 35 - Issue 3 - p 302–306
doi: 10.1097/COC.0b013e31824be246
Review Articles

Multiple options for retreatment are available, which include whole-brain radiation therapy, stereotactic radiosurgery, surgery, chemotherapy, and supportive care. Size, number, timing, location, histology, performance status, and extracranial disease status all need to be carefully considered when choosing a treatment modality. There are no randomized trials examining the retreatment of brain metastases. Repeat whole-brain radiation has been examined in a single-institution experience, showing the potential for clinical responses in selected patients. Local control rates as high as 91% using stereotactic radiosurgery for relapses after whole-brain radiation are reported. Surgery can be indicated in progressive and/or hemorrhagic lesions causing mass effect. The role of chemotherapy in the recurrent setting is limited but some agents may have activity on the basis of experiences on a smaller scale. Supportive care continues to be an important option, especially in those with a poor prognosis. Follow-up for brain metastases patients is discussed, examining the modality, frequency of imaging, and imaging options in differentiating treatment effect from recurrence. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of the current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

*Mayo Clinic Arizona, Scottsdale

§§Barrow Neurological Institute, American Academy of Neurology, Phoenix, AZ

Henry Ford Hospital, Detroit, MI

Medical College of Wisconsin, Milwaukee, WI

∥∥University of Wisconsin, Paul P. Carbone Comprehensive Cancer Center, American Society of Clinical Oncology, Madison, WI

§Alvin J. Siteman Cancer Center, St. Louis, MO

##Mallinckrodt Institute of Radiology, St Louis, MO

University of Colorado Denver, Aurora, CO

Mount Sinai School of Medicine, American Association of Neurological Surgeons/Congress of Neurological Surgeons, New York, NY

#Duke University Medical Center, Durham, NC

**Indiana University School of Medicine, Indianapolis, IN

††Blanchard Valley Regional Cancer Center, Findlay

¶¶Cleveland Clinic, Strongsville, OH

***Cleveland Clinic Foundation, Cleveland, OH

‡‡University of California-San Francisco, American Association of Neurological Surgeons/Congress of Neurological Surgeons, San Francisco, CA

The American College of Radiology seeks and encourages collaboration with other organizations on the development of the ACR Appropriateness Criteria through society representation on expert panels. Participation by representatives from collaborating societies on the expert panel does not necessarily imply individual or society endorsement of the final document.

This article is a revised version of the American College of Radiology Appropriateness Criteria Follow-Up and Retreatment of Brain Metastases, excerpts of which are reprinted here with permission. Practitioners are encouraged to refer to the complete version at

The authors declare no conflicts of interest.

Reprints: Samir H. Patel, MD, American College of Radiology, 1891 Preston White Drive, Reston, VA 20191. E-mail:

Article Outline
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Recent progress in the management of various metastatic cancers has led to the emergence of increasing numbers of patients with brain metastases. Current estimates suggest that nearly 200,000 new patients develop brain metastases annually in the United States. It has also been estimated that up to 40% of patients with cancer will develop brain metastases.1 Hence, although progress has been made in decreasing the incidence of lung cancer deaths (largely due to fewer smokers) and prolonging survival in other systemic cancers such as breast and colorectal, the incidence of brain metastases continues to increase as patients with metastatic disease live longer.

The most common source of brain metastases is lung cancer. A recent report on 177 patients with surgically staged IIIA non–small-cell lung cancer (NSCLC) found that 34% of them had cancer recurrence in the brain as the first site of failure, and that 40% developed brain metastases at some point in their course.2 In the past, brain metastases were thought to herald the onset of a rapidly fatal course in patients with cancer due to the limited efficacy of systemic therapies and whole-brain radiation therapy (WBRT) (median survival 4 to 7 mo; 2-year survival ≤10%). Survival rates for patients with brain metastases becomes significant only when extracranial disease is controlled, as pointed out by Tan and Black.3

There are now several reports of brain metastasis patients surviving >1 or 2 years after treatment,4,5 and recently, a single-institution report from the Cleveland Clinic documented the incidence of 5- and 10-year survivors in a series of nearly 1300 patients with brain metastases. Thirty-two patients (2.5%) survived ≥5 y, and 15 of them had recurrence of local or distant brain cancer.6 Thus, as a growing percentage of treated patients may live long enough to experience relapse in the brain, there is a greater need for appropriate follow-up and management of recurrent brain metastases.

Retreatment for brain metastases may be required following a variety of initial treatments such as WBRT, surgery, radiosurgery, chemotherapy, and combinations of these. The choice of treatment modality after recurrence will depend on the size, number, timing, and location of the recurrent metastases and the patient’s performance status and extent of disease beyond the central nervous system. There seems to be an increasing number of patients who have received only surgery or radiosurgery as their initial management of brain metastases. This trend is likely driven by the increasing availability of stereotactic radiosurgery (SRS) and improvements in neuroimaging and surgical techniques.

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Repeat WBRT

Repeat WBRT has not been routinely administered for retreatment after previous WBRT, primarily because of concerns about severe neurotoxicity. However, 1 institution recently reported a retrospective review of its database that involved 72 patients who underwent 2 courses of WBRT for brain metastases.7 The most common initial fractionation scheme was 20 Gy in 5 fractions, whereas the most frequent reirradiation schedule was 25 Gy in 10 fractions. The median survival time after reirradiation was 4.1 months. Performance status (Eastern Cooperative Oncology Group criteria), neurological function class (Radiation Therapy Oncology Group classification), and documented response to reirradiation were predictive of survival times. An analysis of the time interval between initial treatment and retreatment with cranial irradiation and of patient age at diagnosis of brain metastases showed that these factors did not affect the survival time after repeat radiotherapy. However, a response to the first course of brain irradiation did significantly affect survival time after reirradiation to the brain. Although toxicity data were limited, this study suggests that there may be a role for WBRT in the retreatment of progressive brain metastases (Table 1).

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Radiosurgery for recurrent brain metastases is a viable option if size and number permit. In patients undergoing radiosurgery for recurrence after initial WBRT, Noel et al and Chao et al reported 1-year local control rates of 91% and 68% and 2-year rates of 84% and 58%, respectively.8,9 Good local control, as high as 90%, has been reported in patients who underwent repeat gamma knife SRS to previously treated or newly developed sites, but risk for radiation necrosis increased with repeat treatments to same areas.10 Radiographic responses after salvage radiosurgery have been well documented, although evidence for a survival benefit is not strong.11 This modality is increasingly available at many centers. Moreover, a recent review of 10 series totaling 363 patients treated with surgical excision, followed by radiosurgery as an alternative to WBRT showed crude local control rates of about 79%, with a median survival time of 14.2 months and a 52% rate of new metastasis after SRS.12 In this cohort, SRS was well tolerated with low rates of necrosis. These data suggest that SRS is one valid approach in managing patients having brain relapses even after prior WBRT and especially if no more than 3 metastatic foci are present (Tables 2, 3).

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Surgery may be indicated for palliation of mass effect from progressive or hemorrhagic brain metastases,13 and may also be an important diagnosis and management tool in determining the nature of a progressive lesion after radiation treatment. Factors to consider regarding the use of surgical resection after prior irradiation include clinical or radiographic evidence of a progressive lesion, Karnofsky performance status >60, and stable or absent extracranial disease.14 Crude reported local control rates range from 69% to 79%,13–15 and 1 retrospective study comparing resection to no resection showed a modest survival benefit.14

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Chemotherapy has occasionally been a successful strategy for chemosensitive tumors.16 Limited evidence suggests that some chemotherapy and biological treatments may be effective in brain metastases. These studies, which are based on smaller experiences, are summarized here. The chemotherapy agents include paclitaxel, cisplatin, carboplatin, docetaxel, etoposide, and topotecan.17 Temozolomide, capecitabine, and gefitinib have also been reported to be used in treating brain metastases from melanoma, breast cancer, and lung cancer, respectively.18 The response of brain metastases to antiepidermal growth factor inhibitors such as gefitinib or erlotinib provides some new alternatives for the management of brain metastases.19 These targeted agents may be particularly attractive for patients with less symptomatic, smaller recurrent brain metastases. Dual tyrosine kinase inhibitors (eg, lapatinib) have recently been shown to benefit some Her2neu-positive breast cancer patients and also those with recurrent brain metastases.20 Recent evidence also suggests that bevacizumab may be safe and effective in patients with active brain metastasis from NSCLC.21

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Supportive Care

Best supportive care is always an option for select patients with recurrent brain metastases. Factors important in evaluating prognosis in these patients include, but are not limited to, performance status, status of extracranial disease, number of brain metastases, and age. Patients with a poorer prognosis may be better served with an earlier discussion of best supportive care considering their reduced survival rates.

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Follow-up of Brain Metastases

After the treatment of brain metastasis, determining the proper timing and modality of follow-up imaging and distinguishing treatment response from recurrence are major management considerations. This issue is complicated by the lack of reliable early indicators of response versus progression. Sheehan et al22 reported a median time of 8.8 months to new metastasis after initial gamma knife radiosurgery. They recommended close surveillance with a 3-month interval between magnetic resonance imaging (MRI), for identifying new metastasis early in order to facilitate the most effective treatment. They found that patients with 3 or more lesions and cancer histologies other than NSCLC were more likely to have additional future metastasis. These patients may benefit most from close surveillance and additional treatments. The most appropriate frequency and choice of imaging modality after treatment of a patient with brain metastases are matters of debate. Given its wide availability in this country and superior sensitivity over computed tomography, MRI is the preferred imaging modality, especially with newer applications such as spectroscopy, diffusion-weighted imaging, and perfusion-weighted imaging. It is an expensive option, however, and its frequency of use should depend on the likelihood of obtaining useful information that is not otherwise available and that could be acted upon for the patient’s benefit.

A not uncommon problem after the treatment of brain metastases is the difficulty of differentiating between tumor recurrence and radiation-induced scar tissue or necrosis. This is particularly vexing in asymptomatic patients with a high performance status. Although invasive pathologic evaluation remains the only definitive test to make this distinction, it is not always practical or feasible. In an attempt to address this problem, several imaging modalities have been investigated, with most data advocating fluorine-18 fluorodeoxyglucose (FDG) and carbon-11 methyl methionine positron emission tomography (PET) scanning for this purpose.23–25 Ross et al26 reported on the imaging changes after SRS and found that 22% of 35 metastatic tumors appeared larger on MRI at a mean of 10 weeks after SRS. Eleven had FDG-PET performed for enlarging lesions. Eight of them showed increased brain activity, whereas 3 showed decreased activity. Of the 8, however, 6 were incorrectly predicted on the basis of the patient’s subsequent course (alive, mean follow-up of 27 mo). A later study showed that FDG-PET imaging is especially effective in detecting tumor recurrence compared with radiation changes in patients with brain metastases from lung cancer.25 In addition to the previously mentioned imaging studies, dynamic susceptibility-weighted contrast-enhanced MRI has been suggested to improve the prediction of tumor response after treatment for brain metastases and help distinguish between necrosis or recurrence.27 These findings suggest that examination of cerebral blood volume ratios can predict tumor recurrence.28,29 Further research in this arena will likely contribute to better determination of imaging changes after radiation treatments. When recurrence of brain metastasis is confirmed, surgery, and particularly radiosurgery, may be useful in improving disease control (Table 4).9,30–33

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The issues regarding postirradiation management and retreatment of brain metastases revolve around 3 concerns:

* First is the need to assess the effects of and manage the treatment of sequelae.

* Second is the need for appropriate surveillance and the ability to accurately distinguish late treatment effects from recurrence, so that further treatment can be administered as appropriately as possible.

* Third is the goal of detecting recurrences before the onset of symptoms, when patients may best tolerate additional treatment, and when the lesion size does not preclude the use of radiosurgery, arguably the most effective option.

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brain metastases; recurrence; appropriateness criteria; radiation therapy; radiosurgery

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