Brain Metastasis from Renal Carcinoma: Locoregional and Systemic Treatments

Introduction

Kidney cancer is among the 10 most common cancers in Western communities and accounts for almost 3% of worldwide adult malignancies. Each year worldwide, around 270 000 cases of kidney cancer are diagnosed and 116 000 people die from the disease. The incidence per 100 000 people of kidney cancer varies geographically: rates of kidney cancer are highest in Europe, North America, and Australia but are low in India, Japan, Africa, and China. However, in the last 35 years, this incidence has increased by about 2% or more per year, one of the fastest-growing rates of all cancers. Risk factors for renal cancer include, among others, smoking, overweight and obesity, and germline mutations in specific genes ( ).

Kidney cancer among adults consists of malignant tumors arising from the renal parenchyma and renal pelvis. Whereas renal pelvis cancers are of the transitional cell type, and represent less than 10% of the microscopically confirmed kidney carcinomas, on the other hand, adenocarcinomas that arise primarily in the renal parenchyma renal cell carcinomas are mainly of clear cell type (ccRCC), followed by the papillary and chromophobe tumors ( ). RCC is the most common type of kidney tumor and accounts for 90% of all renal tumors. At initial diagnosis, approximately one-third of patients will have advanced or metastatic disease and 60% of locally diagnosed patients will develop a metastatic disease. Since the advent of antiangiogenic therapies, patients’ prognosis with ccRCC has improved, with an observed median overall survival up to 40 months ( ). This improvement has modified the classic natural history of metastatic RCC leading to more unusual metastatic localizations like brain metastasis.

Brain metastases occur during development of 20–40% of cancers and are more common than primary intracranial neoplasms, which accounts for 5% of adult’s cancers. These metastases result from hematogenous spread and 80% of brain lesions occur in the cerebral hemispheres, 15% in the cerebellum, and 5% in the brainstem. They are multiple brain metastases in 70% of cases ( ). RCC is one of the most common sources of brain metastases together with melanoma and breast, colorectal, and lung cancers ( ). Depending on studies, incidence of brain metastasis during RCC range between 4% and 48% ( ; ; Remon et al., 2011). Most of the brain lesions are clinically asymptomatic and are discovered during routine evaluation of primary cancer; such cases pose a unique therapeutic challenge. Incidence of occult metastases at the time of diagnosis or evaluation may range from 15% to 33% ( ). In fact, onset of brain metastasis development compromises the RCC prognosis because of the risk of spontaneous intracranial hemorrhage (retrieved in 70% of cases). The risk of bleeding of RCC brain metastases is actually higher than in other cancers’ brain metastases. The median survival of patients with untreated RCC brain metastases averages 3–4 months. Neurologic symptoms depend on the location of the metastases within the brain. Symptoms that should raise suspicion of brain metastases include headaches, confusion, altered behavior, mental status changes, motor and sensory deficits, and seizures.

Corticoids-based treatments allow control of peritumoral edema and seizures. Therapeutic approach of brain metastasis includes localized treatments (neurosurgery, whole-brain irradiation [WBI] and/or stereotactic radiosurgery [SRS]) and systemic treatments (targeted antiangiogenic therapies). To date, there is no optimal treatment procedure for brain metastases from ccRCC, and it must generally be adapted on an individual basis. Indeed, patient selection, and not only the type of treatment followed, has been shown to greatly influence outcome in patients undergoing radiosurgery or SRS of brain metastases. In a study that included 1200 patients from three Radiation Therapy Oncology Group (RTOG) trials on brain metastases, the authors used recursive partitioning analysis to analyze the prognostic significance of 18 pretreatment characteristics and three treatment-related variables ( ). According to Gaspar et al., the most influencing parameters of patient survival after diagnosis of brain metastases are the patient’s functional status (Karnofsky performance status [KPS] < 70%), the patient’s age (≥65 years), and extracranial extension of cancer (no control of the primary tumor and metastases in other organs). These results were subsequently validated in another RTOG trial that included 445 patients with brain metastases.

Three prognostic groups for overall survival were defined based on these criteria (see Table 14.1 ): (1) favorable (median survival 7.1 months), (2) intermediate (median survival 4.2 months), and (3) negative (median survival 2.3 months). Only patients with a favorable prognosis should benefit from an aggressive treatment based on neurosurgery and/or SRS. Targeted therapies, despite their proven effectiveness in the treatment of the primary tumor, appear to be little explored, to date, in the treatment of ccRCC brain metastases.

Locoregional approach

Locoregional treatments include neurosurgery, WBI, and split or single-fraction SRS. It is indicated for the treatment of localized and good-prognosis metastasis. The surrounding healthy tissue often limits indications for neurosurgery and WBI radiotherapy.