Palliative radiotherapy in the brain

Brain metastases

Affecting up to 30% of all patients with solid tumors, brain metastases are a common indication for radiotherapy (RT) consultation. Presentation of brain metastases may be asymptomatic (screening/surveillance-detected, or otherwise incidental finding) or associated with focal neurologic symptoms (up to 40% of patients) or generic symptoms of intracranial mass effect and edema, such as altered mentation, headache (up to 50%), seizure (15%–20%) or a stroke-like presentation (5%–10%). Clinical suspicion should be high for any new neurologic symptoms in a patient with known malignancy, particularly those with a high predisposition for brain metastases. The imaging study of choice to detect brain metastases is a gadolinium-enhanced magnetic resonance imaging (MRI) of the brain ( Table 21.1 ), although a head computed tomography (CT) can be faster and still helpful in detecting large lesions, significant edema, or certain emergencies necessitating rapid diagnosis and treatments.

The treatment modalities for the management of brain metastases can include surgery and RT combined, RT alone, systemic therapy alone, or supportive care. The decision regarding the optimal treatment is patient-specific and must take multiple disease and patient factors into consideration. Optimal management of patients with brain metastases requires a multidisciplinary team consisting of radiology, surgery, medical oncology, and radiation oncology, at a minimum. Other specialties worthy of inclusion are social work, palliative care, physical/occupational therapy, and nutrition, among others. There is no single ideal model for establishing and conducting a multidisciplinary clinic, but a published experience has shown that same-day consultations with core specialties can send patients home with a comprehensive care plan and support enrollment in clinical trials.

Somewhat unique to other common uses of palliative radiation, brain metastases may be treated regardless of symptoms. Historically, this was due to the poor response rate of intracranial disease to systemic agents. As further discussed later in this chapter, some newer agents have been found to have better intracranial penetration, which may allow for avoidance or delay of RT.

Primary brain tumors

Approximately 80,000 primary brain tumors are diagnosed annually in the US, with malignant tumors accounting for 30%. Gliomas (WHO grades I–IV) comprise the majority of malignant tumors (approximately 20,000 per year), while meningiomas, pituitary tumors, and nerve sheath tumors account for a majority of benign lesions (approximately 30,000, 13,000, and 7000 annually, respectively). High-grade gliomas are typically managed with curative intent but frequently recur and progress, warranting consideration of palliative management options. Additionally, there may be patients who present with advanced disease and are thus not candidates for curative intent but may still benefit from palliative treatment. While low-grade gliomas and benign lesions are less likely to recur after definitive management, patients with advanced or recurrent disease may also still benefit from palliation. Management options for advanced or recurrent disease include combinations of surgery, RT, and systemic therapies. As with brain metastases, these patients are best managed in a multidisciplinary setting.

Brain metastases

Brain metastases are quite common in patients with malignancy, either at the time of diagnosis or at future progression. Although determining the precise incidence and prevalence of brain metastases is difficult in the absence of national reporting systems for metastatic progression, brain metastases are clearly increasing in incidence, likely due to improved systemic therapies prolonging the survival of patients with metastatic disease. ^,

Series noting the barriers to more precise estimates have utilized multiple approaches to overcome the shortcomings in reporting. Numerous population-based studies rely on older data from the 1950s to 1990s that likely reflect a different population of patients than those managed with contemporary staging and therapies. A modern analysis of brain metastases at diagnosis using Surveillance, Epidemiology, and End Result (SEER) reporting data found small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) as the only malignancies with greater than 10% risk of brain metastases at diagnosis. However, when the denominator of the incidence proportion included only patients with de novo metastatic disease, melanoma, NSCLC, SCLC, and renal cell carcinoma (RCC) were all found to have incidence rates greater than 10%. Other cancers with high incidence rates were breast (7.6%) and testicular (7.6%), suggesting there may be a role for increased post-treatment surveillance of these patients.

While these data fail to account for brain metastases occurring after initial diagnosis, other series elucidate the clear impact of histology on the development of brain metastases throughout one’s disease course. Melanoma is estimated to develop clinically apparent metastasis in up to 40% of patients, and altogether up to 70% of patients are found to harbor metastatic disease on autopsy specimens. Randomized evidence from SCLC demonstrates high rates of brain metastases within the first 18 to 24 months after diagnosis in both limited and extensive stage disease—approximately 30% to 40% and 60% to 70% with and without treatment, respectively. ^, Similarly, an estimated 25% to 50% of patients with NSCLC will be diagnosed with brain metastases during their disease course. Breast cancers have estimated de novo and 15-year respective brain metastases incidences ranging from 0.2/2.2% for Luminal A subtypes to 1.0/14.3% for Her-2 positive/ER-PR negative subtypes. ^, Brain metastases from RCC may develop in up to 17% of patients. Other prevalent cancers with relatively infrequent progression to brain metastases include bladder cancer (4.1%), colorectal cancer (1.2%–3.2%), cervical cancer (0.5%–1.2%), endometrial cancer (0.3%–1.16%), and prostate cancer (conservatively 0.6% prior to the era of modern systemic therapies). Among a pediatric population, brain metastases were a relatively uncommon occurrence (1.4% in one series). Brain metastases incidence rates are summarized in Table 21.2 . These data are further reinforced by treatment billing data showing a 21% increase in billed stereotactic radiosurgery (SRS) procedures between 2012 and 2015, suggesting radiation oncologists are likely to see more of these patients with increasingly complex oncologic histories as more effective therapies enter the clinic.

Primary brain tumors

WHO grade IV glioma (previously known as glioblastoma) not only represents the most common malignant primary brain tumor but is also an aggressive disease with near uniform rates of recurrence after definitive management with surgery followed by chemoradiation. Therefore, the bulk of evidence supporting palliative interventions for primary brain tumors derives from glioblastoma experiences. Anaplastic (WHO grade III astrocytomas and oligodendrogliomas) and lower grade tumors may be managed according to similar paradigms. Even tumors considered to be benign, such as meningioma, pituitary tumors, and nerve sheath tumors, can result in significant morbidity and possibly mortality depending on the site and extent of disease involvement.

Brain metastases

While the limitations of clinical prognostication are well-documented, the development of brain metastases is widely understood to portend a poor prognosis. Multiple systems inclusive of disease-specific prognostic elements have been developed to improve clinical assessment, with age, performance status (PS), number of brain metastases, extracranial metastases, and certain mutations common to many of these grading systems. Notably, the mortality curve for many cancers has shifted with modern systemic therapies, and patients with the best prognoses can have median survivals 3 years or longer with breast cancer, RCC, and melanoma as well as NSCLC.

Elderly patients with brain metastases who may not be fit for certain therapies require special consideration. A SEER analysis of patients 65 or older with brain metastases found survival was even worse than otherwise suggested by prior analyses. An updated prognostic system for these patients based on age, PS, and the number of involved extracranial organs determined patients with the worst prognoses had 6-month survival rates less than 5%. See Table 21.3 for more prognosis data.

Primary brain tumors

Table 21.4 summarizes the clinical data informing the prognosis of patients with primary brain tumors. Randomized trials inform the outcomes of curative-intent therapy for most tumors, with some offering good data on recurrence rates and salvage, and other available prognostic systems predicting which patients will do worse and in what timeframe. Management and outcomes for various tumors are highly variable and dependent on a disease-free interval, patterns/extent of recurrence, prior treatment(s), and other patient-specific factors. In some cases, retrospective series have established prognostic information.

The prognosis for glioma depends on the grade of disease as well as outcomes of upfront management, which can be estimated from the outcomes in randomized trials as well as prognostic systems developed based on curative paradigms. ^, Estimating prognosis for recurrent or advanced disease is more challenging. In recurrent high-grade glioma, the prognosis is influenced by PS, extent of recurrence, and disease-free interval. Even patients with the best prognostic features have prognoses on the order of months, and many may survive only weeks. Prognosis of recurrent low-grade gliomas depends on many of the same features in addition to isocitrate dehydrogenase (IDH) and O6-methylguanine-DNA methyltransferase (MGMT) status. Reported outcomes following treatment for recurrence vary widely, with some suggesting progression-free survival can be as short as 6 to 12 months or as long as 5 years. Similarly, overall survival can range from 1 to more than 7 years.

Meningioma also represents a spectrum of disease. Benign (WHO grade I; ~78% of meningiomas) lesions have low rates of recurrence but can present clinical challenges if located in poorly-accessible anatomic locations. No well-established prognostic system exists given their nonmalignant characterization, but recurrence rates ranging from 14% to 31% suggest that recurrent or advanced disease may warrant palliation. Atypical (WHO grade II; 20% of meningiomas) and anaplastic (WHO grade III, 2%) lesions are more likely to be aggressive, and therefore more prone to recurrence, local anatomic invasion, and shortened survival. Survival from atypical meningioma can vary, while anaplastic tumors are typically fatal within a few years. Retrospective series suggest overall survival following the recurrence of atypical meningioma is 4 to 5 years, and likely less for recurrent anaplastic tumors, which have reported median survival of 1.5 years at initial diagnosis.

Brain metastases

Optimal management of patients with brain metastases requires a multidisciplinary team consisting of radiology, surgery, medical oncology, and radiation oncology, at a minimum. Other specialties worthy of inclusion are social work, palliative care, physical/occupational therapy, and nutrition, among others. There is no single ideal model for establishing and conducting a multidisciplinary clinic, but a published experience has shown that same-day consultations with core specialties can send patients home with a comprehensive care plan and support enrollment in clinical trials. The ideal treatment for a specific patient may involve surgery, radiation, systemic therapy, supportive care, or a combination of any of the modalities.