1. George, Saby MD, FACP
  2. Abad, Ajay MD

Article Content

Looking back just a few years, we had few good treatment options to offer patients diagnosed with advanced renal cell carcinoma (RCC). But with the addition of targeted therapies and, more recently, checkpoint inhibition immunotherapy, we're seeing even some patients with multiple metastases from their kidney cancer-who until recently would have been given a life expectancy of a few months-live with excellent quality of life for several years.

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It's been rewarding to see even patients with RCC that has metastasized to the brain, a type of spread that's been notoriously hard to treat, respond to clinical therapy to the extent they are simply followed with serial MRI scans of the brain every few months in routine follow up in the neurology clinic; we can approach their care as a chronic but manageable disease.


Incidence & Presentation

RCC can metastasize to virtually any organ in the body, often without evidencing clear symptoms. Out of the nearly 64,000 new U.S. cases annually (CA Cancer J Clin 2017;67(1):7-30), we can expect 20-25 percent of patients to present with metastasis at diagnosis, and approximately 11 percent of that total to have one or more metastatic brain lesions at diagnosis (Neuro Oncol 2017;19(11):1511-1521).


A 2015 analysis by some of our Roswell Park Comprehensive Cancer Center colleagues found that 70 percent of RCC patients diagnosed with brain metastases presented with referable central nervous system symptoms, persistent headache being the most common (Clin Exp Metastasis 2015;32(8):783-788). Focal weakness or sensory changes-typically in one or both limbs on one side of the body, or as evidenced by lateralizing lower facial droop or numbness-has also been seen in many of these patients. But regular surveillance has not proven to be advantageous. Results reported in 1990 show that, among 106 patients with routine brain imaging, brain metastasis was found in only 3.3 percent of asymptomatic subjects (Urology 1990;36(4):300-302). This research continues to hold up in clinical practice.


Key predictors for survival of patients with brain metastases include age, extent of extracranial disease, and performance status. A recursive partitioning analysis suggests that stratification of patients based on performance status is of prognostic value and should be considered when making decisions about treatment (Int J Radiat Oncol Biol Phys 1997;37(4):745-751). A diagnosis-specific graded prognostic assessment showed widely varying median survival estimates, from 3.3 months for those patients with a prognostic score of 1 or less, to 14.8 months for those patients with scores of 3.5 to 4-important metrics to consider when formulating a treatment strategy that often involves multiple modalities and consideration of treatment-related toxicities (J Clin Oncol 2012;30(4):419-425).


Treating Brain Metastasis in Patients With RCC

For patients who present with a single brain metastasis in an area of noneloquent cortex and in absence of widespread disease, surgical resection is usually indicated (N Engl J Med 1990;322:494-500). Advances in surgical technique and the use of specialized imaging such as functional MRI, which is routinely used by the neurosurgical team at Roswell Park, allow for more precise localization of critical areas in the brain that control motor function, sensation, and speech production and comprehension. This is important for surgical planning, allowing neurosurgeons to achieve maximal safe resection.


Kocher and colleagues demonstrated that surgery should be followed up by either stereotactic radiosurgery (SRS) or whole-brain radiotherapy (WBRT), as surgery alone typically will not achieve adequate local control (J Clin Oncol 2011;29(2):134-141). Where appropriate, SRS is favorable for local disease control with fewer adverse effects in terms of cognitive function (Cancer 2007;110(5):1077-1082).


Ongoing advances in terms of technology and methods of radiation allow for more precise and predictable delivery of high-dose radiation to the tumor bed with relative sparing of surround normal brain tissue (Lancet Oncol 2017;18(8):1049-1060). SRS, meanwhile, can be used to treat patients with multiple brain lesions traditionally thought to be more appropriate for WBRT (Lancet Oncol 2017;15(4):387-395). In cases of more widespread brain metastasis, techniques such as hippocampal sparing can limit radiation exposure to important memory centers in the brain in an effort to minimize the memory impairment often associated with this treatment modality.


For patients treated with targeted therapy who develop solitary brain metastases that are symptomatic and accessible surgically, surgical resection is still recommended, although effects of delayed wound healing in the case of therapies targeting vascular endothelial growth factor (VEGF)-often requiring washout periods of up to 1 month prior to any major surgery-must be taken into account.


Targeted therapy directed at VEGF blockade in particular has the added benefit of reducing swelling and inflammation related to prior radiation therapy, which can cause significant neurologic dysfunction. This is particularly true after SRS, where post-radiation localized necrosis can occur weeks to months after treatment in treated areas-a response seen less frequently in patients treated with WBRT.


Because it is no longer uncommon for RCC patients with brain metastases to live many years after detection and treatment of those metastatic lesions, it is important to avoid modalities like WBRT that may have long-lasting and irreversible effects to the brain that can have devastating effects on cortical functions like memory, multitasking, and judgement/impulsivity-balancing the important considerations of efficacy and tolerability.


Checkpoint Inhibition Changes Treatment

Systemic therapy is usually considered for metastatic RCC patients with brain metastases with or without surgery and/or radiation therapy. It is common for patients who develop metastases to the brain to experience concomitant disease progression systemically.


Until recently, the mainstay of systemic therapy for advanced metastatic RCC has been VEGF tyrosine kinase inhibitors. The checkpoint inhibitor nivolumab, an anti-PD-1 antibody, was approved for use in the second-line setting of metastatic RCC in 2015 based on its primary ability to prolong overall survival when compared to everolimus (N Engl J Med 2015;373:1803-1813). Today, the estimated median overall survival of advanced kidney cancer patients is estimated to be around 3-3.5 years-an improvement of 6-12 months, on average, from what we saw before checkpoint inhibitors became available.


Recently, two studies reporting on the combination of checkpoint inhibition with VEGF targeted agents showed promising results. Checkmate 214, first reported at ESMO 2017, was a randomized phase III trial comparing the anti CTLA-4 antibody ipilimumab in combination with nivolumab against sunitinib in treatment-naive patients with metastatic RCC (Annals of Oncology 2017; The study focused on intermediate-risk and poor-risk populations for the primary objectives and demonstrated superior overall response rate (42% vs. 27%, p=<0.0001), median overall survival (not reached vs. 26 months, p=0.00003), and trend in progression-free survival (11.6 months vs. 8.4 months, p=.0331). Moreover, the frequency of adverse events-those of any grade as well as grade 3-5 adverse events-was lower in the group treated with combination checkpoint inhibition.


A second trial compared the combination of bevacizumab with the anti-PD-L1 antibody atezolizumab against sunitinib in a large phase III trial, IMmotion 151-conducted in the treatment-naive setting (J Clin Oncol 2018; doi:10.1200/JCO.2018.36.6_suppl.578). Among the 915 randomized patients, 40 percent were PD-L1-positive. The interim analysis showed the co-primary endpoint of investigator-assessed progression-free survival in PD-L1-positive patients to be superior in the combination arm (11.2 months vs. 7.7 months, HR=.74, 95% CI, 0.57-0.96, p=0.02). The safety profile was also better for the atezolizumab-bevacizumab combination compared to sunitinib.


Steroid Use for Checkpoint Inhibition

When brain metastases are being treated surgically or utilizing gamma knife radiation, it has become a standard practice to suspend systemic therapies, as managing the brain metastasis takes precedence.


The VEGF inhibitors are held due to concerns of bleeding risk, and usually they are held for 1 week before and 1 week after gamma knife therapy. For surgical procedures, it is held for longer periods based on safety, as assessed by the team. Checkpoint inhibitors are held during gamma knife radiation or surgery, as the patients would need steroids that could suppress the T cells.


These systemic treatments may continue after the completion of local treatment for brain metastasis, if there is disease control elsewhere by the systemic therapy. VEGF inhibitors could be started after the above safety period. Checkpoint inhibition may be reinitiated after tapering off the steroid used for parenchymal edema management.


Key Takeaways

In short, the management of brain metastasis from RCC takes precedence over metastatic disease elsewhere, and the incorporation of new modalities of therapies like SRS have made it possible for patients to have long-term survival without losing considerable cranial function.


While relatively few patients with kidney cancer will experience brain metastases, the potential impacts on a patient's functioning and quality of life make these cases especially challenging. Thanks to advances in systemic therapies and radiotherapy and improved interdisciplinary management, we are seeing the outlook for kidney cancer patients with metastasis to the brain steadily and significantly improve.


With the ongoing development of combination immunotherapy regimens, we expect the long-term outlook for patients with kidney cancer that has metastasized to the brain to continually improve-a welcome and long overdue positive trend.


SABY GEORGE, MD, FACP, is Associate Professor of Oncology, Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and AJAY ABAD, MD, is Assistant Professor of Oncology and Neurology, Department of Neuro-Oncology, Roswell Park Comprehensive Cancer Center.


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