The most effective treatment for cancer patients with newly diagnosed brain metastases is either surgical resection or stereotactic radiosurgery followed by whole-brain radiation, according to new evidence-based guidelines issued by the American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons (CNS) in a special open-access issue of the Journal of Neuro-Oncology.
The American Cancer Society reports that up to 40% of all newly diagnosed cancer patients develop one or more brain metastases. In a given year, this represents approximately 500,000 individuals in the U.S. alone.
The AANS and CNS developed the comprehensive new guidelines to identify the best treatments for brain metastases and to rank them based on survival, recurrence, and quality of life outcomes. The objective of the AANS, the CNS, and the joint AANS/CNS Section on Tumors is to minimize confusion about the many treatment options available, and to provide a set of evidence-based guidelines that can be used by clinicians at academic cancer treatment centers and community healthcare facilities alike.
The new guidelines address radiation therapy, surgical resection, stereotactic radiosurgery, and chemotherapy for newly diagnosed brain metastases, retreatment modalities for recurrent and/or progressive brain metastases, the role of prophylactic anticonvulsants, the role of steroid therapy, and novel and investigational therapies for brain metastases.
Process and participants
A 20-member multidisciplinary panel of experts developed the guidelines over a 16-month period starting in February 2008. The panel included clinicians from neuro-oncology, stereotactic radiosurgery, medical oncology, and radiation oncology, and they worked with the McMaster University Evidence-Based Practice Center in Hamilton, Ontario.
The panel analyzed 25,000 peer-review articles of clinical studies published since 1990, using 400 to make their guideline decisions. They highlighted and ranked every clinical treatment scenario involving brain metastases using a three-tier scale (class) to rate the quality of evidence, as well as a three-tier scale (level) to rate the strength of recommendations.
Dr. Steven Kalkanis, a neurosurgeon and co-director of the Hermelin Brain Tumor Center at Henry Ford Health System in Detroit, headed the panel, in conjunction with the chairman of the AANS/CNS Joint Guidelines Committee, Dr. Mark Linskey, program director of the department of neurological surgery at University of California, Irvine Healthcare in Orange, CA.
In addition to Kalkanis and Linskey, primary authors of the guideline chapters include:
- Dr. Mario Ammirati, neurosurgeon at the James Cancer Hospital of the Ohio State University Medical Center in Columbus
- Dr. Charles Cobbs, neurosurgeon at the California Pacific Medical Center in San Francisco
- Dr. Laurie Gaspar, professor of radiation oncology at the University of Colorado Hospital in Aurora
- Dr. Minesh Mehta, radiation oncologist at the Carbone Cancer Center of the University of Wisconsin School of Medicine and Public Health in Madison
Key recommendations and guidelines
Surgical resection and whole-brain radiation therapy
Surgical resection followed by whole-brain radiation therapy is a superior treatment modality to improve tumor control both at the original site of the metastasis and in the brain overall. This combination is superior to surgical resection alone or whole-brain radiation therapy alone.
This treatment is recommended for patients with limited extracranial disease, and with newly diagnosed single-brain metastases amenable to surgical resection. Patients should also have good performance status, which the panel defines as a patient being able to function independently and to be out of bed at least 50% of the time.
The guidelines do not apply to patients with relatively radiosensitive tumor histologies, such as small cell lung cancer, leukemia, lymphoma, germ cell tumors, and multiple myeloma.
There is also not enough evidence to make a recommendation for either surgical resection plus whole-brain radiation therapy versus radiation therapy alone for patients with poor performance scores, advanced systemic disease, or multiple brain metastases.
When comparing "standard" doses and fractions for whole-brain radiation therapy, defined as a dose of 30 Gy in 10 fractions or a biologically equivalent dose (BED) of 39 Gy10, the committee found no evidence that altered doses and/or fractionation schedules result in significant differences in median survival, local control, or neurocognitive outcomes among patient cohorts.
Evidence was insufficient to support the choice of any particular dose or fractionation regimen based on tumor histopathology.
Stereotactic radiosurgery
Both surgical resection and stereotactic radiosurgery, followed by whole-brain radiation therapy, are effective treatment strategies, resulting in relatively equal survival rates.
Single-dose stereotactic radiosurgery followed by whole-brain radiation therapy leads to significantly longer patient survival compared with whole-brain radiation therapy alone for patients with a single metastatic brain tumor with a Karnofsky Performance Scale (KPS) score of 70 or greater.
Single-dose stereotactic radiosurgery followed by whole-brain radiation therapy may also lead to significantly longer patient survival than whole-brain radiation therapy alone for patients with two to three metastatic brain tumors. And some evidence exists that this combined treatment may improve patient survival for patients with single or multiple brain metastases and a KPS score less than 70.
However, the team evaluating the specific role of surgical resection, headed by Kalkanis, also added the caveat that stereotactic radiosurgery has not been assessed from an evidence-based standpoint for lesions larger than 3 cm, or for those causing significant mass effect, with more than 1 cm midline shift.
Whether stereotactic radiosurgery alone provides equivalent functional and survival outcomes compared with surgical resection followed by whole-brain radiation therapy is open to debate. Stereotactic radiosurgery is defined as being either a traditional single dose, as well as up to five doses.
The panel could only identify "underpowered class I evidence along with a preponderance of conflicting class II evidence" in favor of using stereotactic radiosurgery alone. The panel therefore stated that stereotactic radiosurgery alone might provide comparable outcomes, so long as ready detection of distant site failure and salvage stereotactic radiosurgery was possible for a patient.
Class I evidence is defined as evidence provided by one or more well-designed randomized controlled clinical trials, as compared to well-designed observational studies with concurrent controls (class II evidence).
When comparing the outcomes of surgical resection plus whole-brain radiation therapy to outcomes of a combination treatment using stereotactic radiosurgery plus whole-brain radiation therapy, the panel could only identify four retrospective cohort studies. These studies yielded conflicting results in terms of overall survival and local recurrence outcomes.
The task force recommended that stereotactic radiosurgery be used for single surgically inaccessible lesions measuring less than 3 cm in maximum diameter. The group noted that surgical resection of lesions larger than 3 cm in maximum diameter, or those causing significant mass effect, produces better outcomes than stereotactic radiosurgery, based on class II evidence from well-designed observational studies with concurrent controls.
In situations when surgical resection is not an option, single-dose stereotactic radiosurgery appears to be superior to whole-brain radiation therapy in terms of survival advantage for patients with up to three metastatic brain tumors.
Chemotherapy
The panel did not recommend routine use of chemotherapy following whole-brain radiation therapy because it has not been shown to increase survival. This recommendation does not, however, apply to exquisitely chemosensitive tumors, such as germinomas metastatic to the brain.
The panel noted that lack of sufficient data does not mean that patients with tumor histologies other than breast cancer and non-small lung cancer may not benefit from this treatment. The group referenced the use of temozolomide as a reasonable treatment in combination with whole-brain radiation therapy for patients with melanoma-related brain metastases.
Retreatment for recurrent or progressive brain metastases
Due to insufficient evidence to make definitive treatment recommendations, the panel recommends that treatment should be individualized based on a patient's functional status, extent of disease, volume/number of metastases, recurrence or progression at original versus nonoriginal site, previous treatment, and type of primary cancer.
Once this analysis has been made, patients should either undergo surgical excision; reirradiation using either whole-brain radiation therapy, stereotactic radiation therapy, or both; chemotherapy; or be advised that no further treatment can help them.
Free access to guidelines
The guidelines consist of 13 chapters and a supplemental letter published online December 4, 2009, in the Journal of Neuro-Oncology. AANS/CNS spokespersons recommend that medical professionals interested in accessing the free-of-charge guidelines begin with the editorial comments of Linskey and Kalkanis, accessible by clicking here.
By Cynthia E. Keen
AuntMinnie.com staff writer
January 20, 2010
Related Reading
Prophylactic RT decreases risk of brain metastases, November 3, 2009
Whole brain radiation for mets may be ineffective, September 24, 2009
Cranial irradiation decreases brain metastases, June 2, 2009
Stereotactic radiosurgery adequate for treating brain metastases, January 7, 2009
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