Stereotactic radiosurgery (SRS) is a reasonable and effective treatment for cancer patients with extensive brain metastases, according to recent research from the Centre hospitalier universitaire de Sherbrooke in Quebec, Canada,1 and University of Pittsburgh.2 These studies add to data needed for the development of SRS treatment guidelines that identify factors impacting positive outcome and better survival for these patients.
With its ability to deliver extremely targeted radiation to a tumor while sparing radiation dose exposure to normal brain parenchyma, Gamma Knife (Elekta, Stockholm, Sweden) radiosurgery is increasingly performed as an initial or salvage treatment subsequent to whole-brain radiation therapy (WBRT). Improvements in systemic treatments for advanced primary cancers have extended survival for many patients. Although 10% to 40% of patients develop brain metastases from their primary cancers, this may not be an immediate death sentence. In fact, SRS has become the initial recommended treatment for patients with up to 4 brain metastases and who have an anticipated life expectancy of 6-plus months because of better local control, a lower risk of neurocognitive damage, less radiotoxicity and fewer complications, and better quality of life compared to WBRT.
The Sherbrooke study: SRS treatment for 5-plus brain metastases1
With the objective of identifying patients with multiple brain metastases who might benefit from SRS, the Canadian research team conducted a retrospective study of all patients who underwent SRS for 5-plus brain metastases between September 2005 and March 2016 at the Centre hospitalier universitaire de Sherbrooke to identify factors influencing overall survival, local recurrence, and distant recurrence. They identified 103 patients, 79% of whom had 5-9 brain metastases, and 21% of whom had 10-19. The mean volume of the largest brain tumor of each patient was 1.1 cm3, with tumors ranging 0.02 cm3 to 16 cm3.
More than half (57%) of the patients had non-small cell lung cancer (NSCLC), followed by breast cancer (28%), melanoma (12%), and colorectal cancer (3%). Fewer than 30% of these patients had stable or responding systemic disease. Fifty-six patients had undergone irradiation for up to 4 brain metastases 6 months or more prior to the SRS treatment included in the study.
The number of brain metastases a patient had had no effect on their length of survival, which was a median of 6 months following SRS treatment, according to principal investigator Laurence Masson-Côté, MD, professor of radiation oncology, and colleagues. However, patients with a cumulative volume of treated brain metastases < 6 cm3 lived longer. Interestingly, absence of extracranial metastases also had no effect on remaining life span.
SRS treatment did not stop the development of additional brain metastases for this patient cohort. More than one-fourth of the patients developed >10, 13% developed 5-10, and 17% developed up to 4. The patients had a mean of two SRS treatments, with at least one patient undergoing up to 10 treatments. No patients experienced complications or long-term side effects.
In their article, Dr. Masson-Côté and colleagues recommended that a large prospective trial be undertaken to improve the management of patients with extensive brain metastases. The Centre hospitalier universitaire de Sherbrooke is now participating in an open-label randomized phase III clinical trial (NCT03550391) comparing SRS with WBRT for patients with 5-15 brain metastases, at 1 of 7 Canadian cancer treatment center sites. Sponsored by the Canadian Clinical Trials Group, the trial launched in May 2018 and has a recruitment goal of 206 participants in 5 provinces.
The study’s primary objectives are to measure overall survival and neurocognitive progression-free survival over 3.5 years. Secondary outcomes include comparisons of time to central nervous system (CNS) failure, difference in CNS failure patterns, number of salvage procedures following radiation therapy treatment, quality of life, and overall cost of treatment.
The patients cannot have any brain metastasis > 2.5 cm or a total tumor volume > 30 cm3. They also cannot have undergone prior cranial radiation therapy. The patients will be assigned to either receive a single SRS radiation dose of 18-20 Gy or 22 Gy, or 3000 cGy in 10 fractions of WBRT with memantine medication.
“I think this clinical trial is very important and will add much needed information on this topic,” said Dr. Masson-Côté. “In the future, we will continue our research efforts on the question of which types of patients with more than 5 brain metastases would receive the greatest benefit from SRS.”
University of Pittsburgh: SRS Treatment for 15-plus Brain Metastases2
University of Pittsburgh researchers conducted a detailed analysis of the survival outcomes of 93 patients who received Gamma Knife SRS from 2009 through 2017 for 15- 67 brain metastases. The patient cohort included 39 patients with lung cancer, 32 with breast cancer, and 21 with melanoma. The lung cancer patients had a median of 21 tumors with as many as 48. Breast cancer patients had a median of 23 tumors, and as many as 67. The melanoma patients had a median of 21 tumors, with as many as 67. The median volume of metastatic brain tumors did not exceed 7.53 cm3 for each cancer subgroup.
The overwhelming majority of patients had active primary disease that had metastasized to other organs in addition to the brain. Approximately two-thirds of the breast and lung cancer patients died from systemic factors. By comparison, the majority (62%) of melanoma patients appeared to die from intracranial disease.
Breast cancer patients had the longest survival following SRS treatment for brain metastases, a median of 16 months, and a 12-month survival rate of 63%. The median for lung cancer patients was 4.6 months, with a 12-month survival rate of 18%, and 3.1 months for melanoma patients, with a 12-month survival rate of 11%. For all, a higher Karnofsky Performance Score (KPS) was associated with increased survival. Fifty-six percent of patients with breast cancer, 35% of those lung cancer, and 24% of melanoma patients had repeat SRS for local or distant progression; repeat SRS treatment was also associated with better survival outcomes.
“Primary tumor type, systemic disease, and performance status heavily influence survival outcomes,” wrote the authors. “Careful patient selection should occur regarding systemic disease status, and a discussion of palliative approaches [should be] at least considered.”
“Literature has clearly demonstrated that our ability to determine survival in patients with a significant disease burden is very difficult. Therefore, patients should receive the best care available,” said Greg Bowden, MD, principal investigator and clinical assistant professor of neurological surgery. “These patients have no realistic surgical option, and systemic treatments do not adequately treat intracranial disease.
“Our goals are tumor control, patient care, quality of life, and survival,” he told Applied Radiation Oncology. “The Gamma Knife represents the gold standard for radiation treatments to the brain, which is an area where most patients would prefer to have things done right.”
As for the future, Dr. Bowden hopes to build onto their research relating to SRS treatment for extensive brain metastases. “We are actively working on associated papers to increase the statistical power, to provide guidelines for methodology in this subset of patients, and to increase outcome analysis,” he said.
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Gamma Knife radiosurgery treatment for numerous brain metastases. Appl Rad Oncol.