Carter's Cancer Thrusts SRS for Brain Mets into Limelight

Roxanne Nelson, RN, BSN

September 02, 2015

When former President Jimmy Carter recently discussed the cancer treatment he is receiving, it was clear that he was receiving state-of-the-art treatment.

He was diagnosed with melanoma, and said he is being treated with one of the newest immunotherapies, pembrolizumab (Keytruda, Merck & Co.), which, in September 2014, became the first programmed cell death inhibitor for melanoma to be approved in the United States. The cancer has already metastasized to four regions in his brain, and for this he is undergoing stereotactic radiosurgery (SRS), a relatively new approach that has been gaining ground in recent years.

SRS is a more targeted approach than whole-brain radiation therapy (WBRT), which has long been considered the standard of care in the treatment of identifiable brain metastases and prophylaxis for microscopic disease. However, the use of WBRT has been declining in recent years because of advances in radiation technology and growing concerns about the late-toxicity profile associated with WBRT.

Adding SRS to WBRT has been shown to improve survival and local tumor control in selected patients. But there has also been an increasing trend to forgo WBRT completely, at least in patients with limited metastases, as more data are published, guidelines are updated, and SRS becomes more geographically available. Needless to say, the move away from WBRT has generated a great deal of discussion among experts.

 
In the case of Jimmy Carter, there are several factors that make radiosurgery and not whole-brain radiation the preferred therapeutic choice.
 

"In the case of Jimmy Carter, there are several factors that make radiosurgery and not whole-brain radiation the preferred therapeutic choice," said Arjun S. Sahgal, MD, associate professor of radiation oncology and surgery deputy chief at the University of Toronto Sunnybrook Health Sciences Centre. "He has a limited number of metastases and all are small, from what I heard in the news, plus melanoma is considered to be a relatively resistant cancer type that needs higher biologic doses of radiation than what whole brain on its own can offer."

Guideline Changes and Growing Data

Professional organizations have been updating guidelines to take into account the shift away from WBRT and the recognition that it may not be needed for all patients.

Last year, the American Society for Radiation Oncology recommended that oncologists not routinely add adjuvant WBRT to SRS for limited brain metastases as part of their second Choosing Wisely list. The society noted that randomized studies have not demonstrated a survival benefit from adding WBRT to SRS in the management of selected patients with good performance status and brain metastases stemming from solid tumors. In addition, combining WBRT with SRS was associated with diminished cognitive function and worse patient-reported fatigue and quality of life.

Updates to the National Comprehensive Cancer Network (NCCN) guidelines now indicate support for SRS in cases of multiple metastases and state that the strategy is no longer limited to patients with three or fewer lesions because data suggest that total disease burden, rather than number of lesions, is predictive of survival benefits associated with the technique (J Natl Compr Canc Netw. 2014;12:1517-1523).

Findings from recent studies also lend support to limiting the use of WBRT in some populations.

A meta-analysis published in March demonstrated a survival advantage for SRS alone in patients with one to four metastases, a Karnofsky performance status of 70 or higher, and who are 50 years and younger.

That analysis comprised patient data on 364 patients from the three largest randomized clinical trials of SRS and WBRT conducted to date. Dr Sahgal, who was lead author in this study, and colleagues found that in patients older than 50 years, WBRT decreased the risk for new brain metastasis, as expected, but without affecting survival.

For survival, age was a significant effect modifier (P = .04), favoring SRS alone in patients 50 years and younger, and no significant differences were observed in older patients.

Patients 50 years and younger who received SRS alone had a median survival of 13.6 months after treatment, compared with 8.2 months for patients 50 and younger who were treated with SRS plus WBRT.

Another study, presented earlier this year during the plenary session at the American Society of Clinical Oncology 2015 annual meeting, showed that WBRT should be avoided in patients with a limited number of brain metastases because it does not prolong survival, reduces quality of life, and causes cognitive decline.

That study (N0574) involved 208 patients with one to three metastases who were recruited from 34 institutions during a 12-year period (2002 to 2013). After stratification by age, extracranial disease status, number of brain metastases, and institution, the patients were randomly assigned to receive SRS alone or in combination with WBRT.

After a median follow-up of 7.2 months, the study showed that patients who were treated with WBRT were significantly more likely to have stable disease at 3 months, but this did not translate to better survival.

Specifically, WBRT significantly improved time to intracranial progression in terms of central nervous system (CNS) failure at both 3 and 6 months (6.3% vs 24.7% and 11.6% vs 35.4%, respectively) and beyond (P < .0001).

But that did not translate to a survival benefit. Median overall survival was 7.4 months in the WBRT group and 10.4 months in the control group (hazard ratio, 1.02; P = .92).

"The recent information and overall focus on patient well-being and quality of life has led multiple societies to recommend radiosurgery alone as the first-line therapy for patients with limited brain metastases," said Dr Sahgal. "Moreover, recent systemic therapies are showing effectiveness in the brain in particular with melanoma. It is thought by some that this is an even stronger rationale to support radiosurgery alone, as the radiosurgery can focally control the gross tumor and drugs treat the microscopic disease that otherwise would be the rationale for using whole-brain radiation."

Still a Role for WBRT?

Clearly, there are patients who will definitely benefit from SRS and who can also be spared the adverse effects of WBRT. But is there still a potential role for WBRT?

Definitely, Dr Sahgal told Medscape Medical News. "There are benefits to whole-brain radiation to consider and these are improved intracranial control."

He pointed out that some increase in local control is seen with additional WBRT, although the local control rates are still high with radiosurgery alone and local control rates would be much less effective with WBRT on its own.

"More important, whole-brain radiation reduces the risk of new metastases emerging typically from 50% to 30%," he explained. "But given this information and the toxicity profile of whole-brain radiation, the rationale to overtreat half of all patients for an absolute risk reduction of 20% to 30% in developing new metastases is the issue at hand."

Dr Sahgal notes that if new metastases occur after SRS, patients can receive further radiosurgery or undergo WBRT at that time. "This option gives patients a chance of avoiding the whole radiation, as there can be serious consequences that impair the patients' functioning," he said.

He pointed out that the next generation of trials is looking at radiosurgery alone for multiple metastases (five or more) and it may be that WBRT is reserved only as a last-resort therapy for cases not eligible for radiosurgery, and all patients can be offered this treatment option aimed at preserving cognitive capacity and quality of life.

Christopher R. Loiselle, MD, a radiation oncologist with the Swedish Medical Group in Seattle, echoed some of Dr Sahgal's opinions. "Many experts in the field and centers of expertise have moved away from WBRT, and the rest of the medical community is catching up," he said in an interview.

"There are some really old metrics that are really no longer relevant to modern practice that are still leftover in many guidelines and some insurance carrier policies," he explained.

One of these is that the number of brain metastases is still a cardinal factor in deciding who should get SRS and who should not. "It really has little to no bearing on the clinical situation," Dr Loiselle said.

 
Counting metastases is dinosaur methodology, and goes back to the prehistoric times before we had MRI.
 

As an example, if a patient has a single 3 cm metastasis in the brain stem, that would be a classic criteria for SRS, but that person may not be a good candidate at all, he pointed out. "Whereas a patient who is asymptomatic and has four small metastases should certainly have SRS, and the fact that they have more than three is irrelevant in their functional status, quality of life, and prognosis. It is so arcane," he said. "Counting metastases is dinosaur methodology, and goes back to the prehistoric times before we had MRI."

"That method doesn't take into account whether a patient has symptoms, the size and volume of the lesions, or where they are located in the brain, and those are the most important factors," he added.

Burden of Proof

However, another expert is a little more cautious about completely relegating WBRT to the back burner for all patients with brain metastases.

H. Jack West, MD, a thoracic oncologist at Swedish Cancer Institute in Seattle, pointed out that the burden of proof generally isn't placed on the established and less expensive standard of care, but on the new, less proven, and more expensive intervention.

 
Why is gamma knife being used in every situation in which it hasn't been proven to be wrong.
 

Therefore, the question should be, "Why is gamma knife being used in every situation in which it hasn't been proven to be wrong, rather than just having a very tenuous rationale?" he said. "Stereotactic radiosurgery happens to be associated with remarkably higher rates of recurrence in the brain than WBRT, which is discussed about 1/20th as much as the cognitive risk of WBRT."

Dr West explained that from his viewpoint, the cognitive adverse effects of WBRT are not a major concern for diseases with a very high risk for future multifocal brain metastases, such as in patients with small-cell lung cancer or anyone with more than 10 to 15 identified brain metastases, and who also tend to "have an anticipated survival that is likely to be more limited than their quality of life or cognitive ability in the likely period of typically months that they may remain alive."

"The goal here is to temporize by controlling CNS disease long enough to put it on the back burner and be able to focus on extracranial disease that is more likely to limit survival and quality of life," he noted. "Gamma knife makes sense for treating patients with fewer than three lesions, probably fewer than 10 lesions, and in patients with an anticipated survival of more than 1 year, but in truth, that's not the vast majority of patients with brain metastases."

For patients with a good performance status and many metastatic lesions, WBRT arguably remains the most appropriate tool for the job, Dr West added.

Access and Cost

But for patients who meet the criteria for SRS and are potentially good candidates, cost and accessibility are two areas that can affect the ultimate choice in treatment.

As with most newer technologies, SRS is not still not universally available, cost may be higher than older strategies, and payers may have restrictions on coverage. In one study, which compared the cost of SRS plus WBRT with SRS plus observation, SRS alone had a higher average cost ($74,000 vs $119,000), but also a higher average effectiveness (0.60 vs 1.64 life-years saved) with an incremental cost-effectiveness ratio of $44,231 per life-years saved, or $41,783 per quality-adjusted life-year (10-year horizon) (Am J Clin Oncol. 2012;35:45-50).

Another study looked at the ratio of radiation therapy costs per patient receiving SRS for brain metastases to radiation therapy costs per patient not receiving SRS, for Medicare beneficiaries. The average cost per patient treated with SRS was 2.19 times greater than the average cost per patient without SRS (Int J Radiat Oncol Biol Phys. 2013;85:e109-e116).

Generally speaking, SRS is not that much more expensive than WBRT, said Dr Loiselle. "It's probably on the order of thousands of dollars, and it's not like SRS is $100,000 and WBRT is $4000."

As far as coverage, Dr Loiselle explained that most private insurers have "updated their policies so that they make sense and have moved or are moving toward coverage with appropriate assessment tools."

Medicare is more complicated because it is not a universal coverage across the United States but, instead, contracts to intermediaries, and they vary considerably by geographic location. "Some of them have updated policies and moved beyond counting metastases, while others have not," he said. "An example is Noridian Healthcare Services, which covers Medicare beneficiaries in the Seattle area and has reasonable coverage. Their coverage is based on reasonable criteria."

But others still use very arcane methods for decision making, such as saying that SRS is inappropriate for more than three metastases, so patients covered by those networks may have barriers to access, Dr Loiselle said.

The 2013 study looking at Medicare beneficiaries with brain metastases also demonstrated that patients living in higher socioeconomic-status census tracts (third and fourth quartiles) were more likely to receive SRS than those in the lowest quartile (odds ratio, 1.58 and 1.61, respectively; P = .004. SRS use also varied by geographic region and the teaching status of the admitting hospital.

The study population consisted of patients diagnosed with non-small-cell lung cancer from 1995 to 2005, and of this group, 7684 were treated with radiation therapy without neurosurgic resection after diagnosis with brain metastases from 2000 to 2007. A total of 469 (6.1%) received SRS. Overall, the annual use of patients receiving this treatment increased from 3.0% in 2000 to 8.2% in 2005, and use varied considerably by geographic location, ranging from 3.4% (Detroit and Kentucky) to 12.5% (Los Angeles).

NCCN and other guidelines have changed recently, so that will change practice patterns, contends Dr Loiselle. "But we do know there are geographic variations, especially for those who may live far from a radiosurgery center," he said. "Some people, for instance, don't have the means to travel or they may be too ill to even travel a short distance, so for them, receiving WBRT at a local facility may be the best option."

Dr Sahgal feels that brain radiosurgery has been developed to the point that it is now mainstream, at least in North America, and available in both community and academic centers. "If not in one specific center, there typically is a major cancer center within a reasonable distance that can offer this therapy," he said. "There is need for specialized equipment and training, but it is widely available in US and Canada. It is paid for by insurance for patients with limited metastases, as it is recognized that this is an evidence-based treatment with benefits for patients."

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