Natural History and Management Options of Cerebral Metastases

22 Natural History and Management Options of Cerebral Metastases

Anthea H. O’Neill, Mendel Castle-Kirszbaum, Cristian Gragnaniello, and Leon T. Lai

Abstract

Cerebral metastases are the most commonly encountered brain tumors in clinical practice. The majority of patients have a known primary malignancy at presentation, and 70% have multiple cerebral metastases. The natural history of untreated cerebral metastases is dismal, and thus treatment should be offered to all but the most severely ill patients. Treatment modality is determined by surgical aims (such as acute relief of mass effect or need for tissue diagnosis), functional status, and patient wishes. Patients with radiosensitive histology, a large burden of intracranial disease, or those with poor functional status are treated with radiotherapy. Solitary, surgically accessible metastases should be offered microsurgical resection with adjuvant radiotherapy to the tumor bed. Treatment is associated with a significant survival benefit, particularly in patients with lung, breast, or renal primary. The management of patients with cerebral metastases is complex and evolving, and is best executed by an experienced multidisciplinary team of surgeons, medical and radiation oncologists, and palliative care physicians.

Keywords: metastases brain radiotherapy radiosurgery microsurgery biopsy natural history

22.1 Introduction

Cerebral metastases are the most encountered brain tumor in clinical practice, comprising up to 50% of cerebral malignancies. An aging population, improved treatment for primary disease, and increasing surveillance of individuals with cancer have seen cerebral metastases increasingly outnumber primary brain tumors in recent years.1 In decreasing order of frequency, lung, breast, melanoma, renal, and colorectal cancers account for the majority of brain metastases.² This list reflects not only the prevalence of the primary malignancy but also its propensity for metastatic spread, tropism for the brain, and ability to establish a metastatic seed in the cerebral microenvironment.

Melanoma appears particularly trophic to brain tissue, with nearly half of all patients developing brain metastases. In approximately 15% of all cases, symptomatic cerebral metastasis is the first indication of malignancy, and by the time cerebral metastases become symptomatic, approximately 70% of patients will have multiple cerebral lesions.³

Carcinomatous malignancies are a disease of older age, and it should come as no surprise that the incidence of brain metastases peaks in the 5th to 7th decades.⁴ A much smaller spike in incidence occurs in the first decade of life, where leukemia, lymphoma, sarcoma, and germ cell tumors are the most common primary cancer. Brain metastases occur with equal prevalence in both sexes; however, the type of primary cancer responsible differs somewhat, with lung cancer more common in males and breast cancer in females.⁵

The distribution of brain metastases corresponds to the relative volume and blood flow of different parts of the brain,⁶ with the exception that the region supplied by the terminal branches of the middle cerebral artery is more greatly affected, presumably as embolic tumor aggregates follow the center of the blood flow column. Clinical studies show that 80% of solitary metastases are in the cerebral hemispheres (Table 22.1), while 16% are situated in the cerebellum. Intracranial metastases cause symptoms due to the mass effect of the tumor itself, or the intense vasogenic edema they induce. Symptoms thus depend on the location and eloquence of their bed. Rarely, hormonal dysfunction can occur from metastases to the sella.⁷ Symptoms of increased intracranial pressure may develop from obstructive hydrocephalus, large tumor burden, or lesional hemorrhage. In most series, headache is the most common symptom; however, altered cognition, weakness, and seizures all occur in greater than 20% of cases.⁸ The latter may be especially common in melanoma given its propensity to involve the cortex and to hemorrhage.

Fig. 22.1 Intraoperative images demonstrating (a) a preresection view of a metastatic melanoma involving the cerebral cortex, (b) dissection of the tumor, and (c) posttumor resection cavity.

Magnetic resonance imaging (MRI) with gadolinium is the gold standard imaging technique to assess brain metastases.⁹ Multiplicity, mass effect, marked vasogenic edema, and contrast enhancement are typical of cerebral metastases, with the addition of gadolinium increasing the sensitivity for detection of small lesions (Fig. 22.2).¹⁰ Metastases are usually iso- or hypointense on T1 and hyperintense on T2; however, the paramagnetic effects of melanin in melanoma and iron in hemorrhagic lesions may cause intrinsic T1 hyperintensity.

Fig. 22.2 Cerebral metastasis. (a) Axial T1 non–contrast-enhanced, (b) axial fluid-attenuated inversion recovery (FLAIR), and (c) axial T1-weighted contrast-enhanced magnetic resonance images demonstrating a rim-enhancing lesion with surrounding edema.

Diffusion-weighted imaging is helpful in the differential diagnosis of brain metastases. The nonenhancing T2 hyperintense area surrounding a metastasis represents vasogenic edema, whereas in high-grade glioma, it may additionally represent tumor invasion, and thus peritumoral apparent diffusion coefficient (ADC) values are typically higher in metastases. Cerebral abscess, another differential, generally demonstrated markedly restricted diffusion in their central necrotic (nonenhancing) region.11

22.2 Selected Papers on the Natural History of Cerebral Metastases

Mulvenna P, Nankivell M, Barton R, et al. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet 2016;388(10055):2004–2014

Fife KM, Colman MH, Stevens GN, et al. Determinants of outcome in melanoma patients with cerebral metastases. J Clin Oncol 2004;22(7):1293–1300

22.3 Natural History of Cerebral Metastases

The natural history of cerebral metastases is difficult to elucidate as most patients in the modern era, even those with poor functional status, will receive some form of therapy. The overall prognosis, in general, is poor and brain metastases are generally the harbinger to end-stage metastatic disease. An overview of currently published case series regarding the survival and cause of death in patients with cerebral metastases is presented in Table 22.1.¹²^, ¹³^, ¹⁴^, ¹⁵^, ¹⁶^, ¹⁷^, ¹⁸^, ¹⁹^, ²⁰^, ²¹^, ²²^, ²³^, ²⁴^, ²⁵^, ²⁶^, ²⁷^, ²⁸^, ²⁹^, ³⁰^, ³¹ Based on our pooled analysis of 1,724 patients over 20 studies, the median survival time of untreated cerebral metastases, or those managed with best supportive care only, is guarded (5.9 weeks from diagnosis; 95% confidence interval [95%CI]: 2.0–8.0). Most patients (72.7%) die from neurological causes, whereas the remaining minority (18.2%) die due to complications of their systemic disease.

Table 22.1 Natural history of cerebral metastases

Studies	Patients	Primary malignancy, n (%)						Median survival, wk (range)	Cause of death
Studies	Patients	Lung	Breast	Melanoma	Renal	GIT	Other	Median survival, wk (range)	Neurological, n (%; 95%CI)	Systemic, n (%; 95%CI)	Unknown, n (%; 95%CI)	Other, n (%; 95%CI)
Madajewicz et al²⁴	15	0	0	15	0	0	0	3.0 (0–12.0)	ne	ne	ne	ne
Pladdet et al²⁹	107	ne	ne	ne	ne	ne	ne	11.0 (ne)	ne	ne	ne	ne
Gambardella et al¹⁶	13	0	0	0	0	0	13	8.0 (ne)	ne	ne	ne	ne
Cormio et al¹³	6	0	0	0	0	0	6	4.0 (4.0–8.0)	ne	ne	ne	ne
Farnell et al¹⁴	17	0	0	0	0	17	0	2.0 (0–7.8)	ne	ne	ne	ne
Lagerwaard et al²⁰	118	0	0	0	0	0	118	5.2 (ne)	ne	ne	ne	ne
Tremont-Lukats et al³⁰	68	0	0	0	0	0	61	4.0 (ne)	ne	ne	ne	ne
Fife et al¹⁵	327	0	0	327	0	0	0	6.8 (ne)	ne	ne	ne	ne
	210	0	0	210	0	0	0	8.4 (ne)	ne	ne	ne	ne
Choi et al¹²	25	0	0	0	0	0	25	2.0 (1.6–2.4)	21	4	0	0
Lee et al²¹	9	0	9	0	0	0	0	8.4 (ne)	ne	ne	ne	ne
Nieder et al²⁶	7	4	0	2	1	0	0	5.7 (1.7–12.3)	2	0	2	3
Jung et al¹⁸	20	0	0	0	0	20	0	1.5 (ne)	ne	ne	ne	ne
Jiang et al¹⁷	23	0	0	0	0	0	23	1.5 (ne)	17	6	0	0
Langley et al⁹¹	76	76	0	0	0	0	0	7.3 (ne)	ne	ne	ne	ne
Nieder et al²⁷	41	23	2	9	2	3	2	6.8 (ne)	ne	ne	ne	ne
	17	17	0	0	0	0	0	7.6 (ne)	ne	ne	ne	ne
Lim and Lin²²	41	0	0	0	0	0	41	2.0 (1.6–2.4)	ne	ne	ne	ne
Ostheimer et al²⁸	16	0	16	0	0	0	0	6.0 (ne)	ne	ne	ne	ne
Lin et al²³	38	0	0	0	0	38	0	1.2 (ne)	ne	ne	ne	ne
Mulvenna et al²⁵	269	269	0	0	0	0	0	8.5 (ne)	ne	ne	ne	ne
Ryoo et al³¹	261	261	0	0	0	0	0	9.9 (ne)	ne	ne	ne	ne
	1,724	650 (37.7)	27 (1.6)	563 (32.7)	3 (0.2)	78 (4.5)	289 (16.8)	5.9 (95%CI: 2.0–8.0) (0–12.3)	40 (72.7; 95%CI: 59.7–82.7)	10 (18.2; 95%CI: 10.2–30.3)	2 (3.6; 95%CI: 1.0–12.3)	3 (5.5; 95%CI: 1.9–14.9)
Abbreviations: CI, confidence interval; GIT, gastrointestinal tract; ne, not extractable.

Prognostic factors include performance status (e.g., high Karnofsky performance scale), number of brain metastases, number of systemic metastases, control of primary tumor, and age,³² the former likely being the most important factor.³³

22.4 Selected Papers on the Treatment Outcomes of Cerebral Metastases

Patel KR, Burri SH, Boselli D, et al. Comparing pre-operative stereotactic radiosurgery (SRS) to post-operative whole brain radiation therapy (WBRT) for resectable brain metastases: a multi-institutional analysis. J Neurooncol 2017;131(3):611–618

Yoshida S, Morii K. The role of surgery in the treatment of brain metastasis: a retrospective review. Acta Neurochirurgica 2004;146(8):767–770³⁴

Bowden G, Kano H, Caparosa E, et al. Gamma Knife radiosurgery for the management of cerebral metastases from non-small cell lung cancer. J Neurosurg 2015;122(4):766–772

Jeene PM, de Vries KC, van Nes JGH, et al. Survival after whole brain radiotherapy for brain metastases from lung cancer and breast cancer is poor in 6325 Dutch patients treated between 2000 and 2014. Acta Oncol 2018;57(5):637–643

22.5 Treatment Options for Cerebral Metastases

Management options for cerebral metastases include supportive care, microsurgical resection, stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT), systemic treatments, or a combination thereof. The results of a literature review performed of the available treatment options published between 1952 and 2018 are presented in Table 22.2 and Table 22.3.¹⁴^, ¹⁵^, ¹⁸^, ²⁰^, ²¹^, ²⁵^, ²⁷^, ³¹^, ³⁴^, ³⁵^, ³⁶^, ³⁷^, ³⁸^, ³⁹^, ⁴⁰^, ⁴¹^, ⁴²^, ⁴³^, ⁴⁴^, ⁴⁵^, ⁴⁶^, ⁴⁷^, ⁴⁸^, ⁴⁹^, ⁵⁰^, ⁵¹^, ⁵²^, ⁵³^, ⁵⁴^, ⁵⁵^, ⁵⁶^, ⁵⁷^, ⁵⁸^, ⁵⁹^, ⁶⁰^, ⁶¹^, ⁶²^, ⁶³^, ⁶⁴^, ⁶⁵^, ⁶⁶^, ⁶⁷^, ⁶⁸^, ⁶⁹^, ⁷⁰^, ⁷¹^, ⁷²^, ⁷³^, ⁷⁴^, ⁷⁵^, ⁷⁶^, ⁷⁷^, ⁷⁸^, ⁷⁹^, ⁸⁰^, ⁸¹^, ⁸²^, ⁸³^, ⁸⁴^, ⁸⁵^, ⁸⁶^, ⁸⁷^, ⁸⁸^, ⁸⁹^, ⁹⁰^, ⁹¹^, ⁹²^, ⁹³^, ⁹⁴^, ⁹⁵^, ⁹⁶^, ⁹⁷^, ⁹⁸^, ⁹⁹^, ¹⁰⁰^, ¹⁰¹^, ¹⁰²^, ¹⁰³^, ¹⁰⁴^, ¹⁰⁵^, ¹⁰⁶^, ¹⁰⁷^, ¹⁰⁸^, ¹⁰⁹^, ¹¹⁰^, ¹¹¹^, ¹¹²^, ¹¹³^, ¹¹⁴^, ¹¹⁵^, ¹¹⁶^, ¹¹⁷^, ¹¹⁸^, ¹¹⁹^, ¹²⁰^, ¹²¹^, ¹²²^, ¹²³^, ¹²⁴^, ¹²⁵^, ¹²⁶^, ¹²⁷^, ¹²⁸^, ¹²⁹^, ¹³⁰^, ¹³¹^, ¹³²^, ¹³³^, ¹³⁴^, ¹³⁵^, ¹³⁶^, ¹³⁷^, ¹³⁸^, ¹³⁹^, ¹⁴⁰^, ¹⁴¹^, ¹⁴²^, ¹⁴³^, ¹⁴⁴^, ¹⁴⁵^, ¹⁴⁶^, ¹⁴⁷^, ¹⁴⁸^, ¹⁴⁹^, ¹⁵⁰^, ¹⁵¹^, ¹⁵²^, ¹⁵³^, ¹⁵⁴^, ¹⁵⁵^, ¹⁵⁶^, ¹⁵⁷^, ¹⁵⁸^, ¹⁵⁹^, ¹⁶⁰^, ¹⁶¹^, ¹⁶²^, ¹⁶³^, ¹⁶⁴^, ¹⁶⁵^, ¹⁶⁶^, ¹⁶⁷^, ¹⁶⁸^, ¹⁶⁹^, ¹⁷⁰^, ¹⁷¹^, ¹⁷²^, ¹⁷³^, ¹⁷⁴^, ¹⁷⁵^, ¹⁷⁶^, ¹⁷⁷^, ¹⁷⁸^, ¹⁷⁹^, ¹⁸⁰^, ¹⁸¹^, ¹⁸²^, ¹⁸³¹⁸⁴

Table 22.2 Summary of the literature regarding the management of cerebral metastases according to primary malignancy

	Lung (56 studies)	Breast (37 studies)	Melanoma (25 studies)	Renal (14 studies)	GIT (12 studies)
Study period	1974–2015	1970–2014	1952–2015	1974–2014	1974–2012
No. of patients (n)	19,020	7,523	7,874	1,225	1,229
Treatment modality^a
Surgery (%)	2.8	4.5	5.2	4.1	5.0
Surgery + radiotherapy (%)	0.8	1.8	10.3	1.7	9.4
Surgery + systemic (%)	0.0	0.0	0.0	0.0	0.0
Systemic (%)	11.8	26.9	22.1	39.8	0.5
Systemic + radiotherapy (%)	6.9	5.3	1.4	3.3	4.1
SRS (%)	29.2	24.0	43.3	45.0	41.7
WBRT (%)	46.5	66.2	27.1	15.2	33.7
SRS + WBRT (%)	4.2	1.8	5.3	4.3	3.2
Other radiotherapy (%)	4.5	0.0	0.0	0.0	0.0
Median OS, mo (95%CI) (range)	10.7 (95%CI: 8.5–13.0) (0–175.0)	11.3 (95%CI: 9.0–13.8) (0–126.0)	7.0 (95%CI: 6.4–8.9) (0–114.3)	10.8 (95%CI: 8.1–12.9) (ne)	6.8 (95%CI: 4.9–9.8) (ne)
Mean 12-mo actuarial survival (%)	44.9 (95%CI: 37.6–52.3)	38.0 (95%CI: 29.9–36.1)	15.9 (95%CI: 3.1–26.7)	40.5 (95%CI: –57.8 to 135.8)	9.6 (95%CI: –111.8 to 130.9)
Median PFS, % (95%CI) (range)	7.2 (95%CI: 5.7–11.6) (0–85.0)	5.5 (95%CI: 2.4–7.4) (ne)	2.8 (95%CI: 1.1–4.3) (0–10.9)	5.6 (na) (ne)	Ne
Abbreviations: CI, confidence interval; GIT, gastrointestinal tract; na, not applicable; ne, not extractable; OS, overall survival; PFS, progression-free survival; SRS, stereotactic radiosurgery; WBRT, whole brain radiation therapy. ^aSome patients underwent treatment with multiple therapies.

Table 22.3 Summary of the literature regarding the management of cerebral metastases according to treatment modality

	Surgery (21 studies)	Surgery + radiotherapy (29 studies)	SRS (70 studies)	WBRT (53 studies)	SRS + WBRT (7 studies)	Systemic (20 studies)	All treatments (166 studies)
Study period	1952–2016	1952–2016	1975–2016	1952–2016	1985–2015	1970–2015	1952–2016
No. of patients (n)	2,782	2,817	29,411	17,537	1,984	2,775	63,553
Primary cancer
Lung (%)	34.8	19.6	54.2	52.7	53.0	44.5	50.1
Breast (%)	9.8	9.9	14.3	24.6	10.5	16.0	17.7
Melanoma (%)	14.2	24.4	11.7	6.9	15.7	24.2	12.7
Renal (%)	2.1	2.8	5.8	0.8	3.5	15.3	4.2
GIT (%)	8.3	5.4	7.1	2.1	2.9	0.0	4.9
Other (%)	9.1	9.5	5.2	1.6	4.0	0.0	4.0
Combined (%)	21.7	28.9	2.2	11.3	10.8	0.0	6.4
Median OS (mo) (95%CI) (range)	8.5 (95%CI: 7.2–11.3) (0.1–116.0)	12.7 (95%CI: 11.0–13.8) (0.6–114.0)	9.2 (95%CI: 8.3–10.4) (0.1–175.0)	4.4 (95%CI: 3.7–5.8) (0–86.0)	9.0 (95%CI: 7.1–14.0) (0.2–64.8)	9.2 (95%CI: 5.7–13.9) (0–98.0)	8.9 (95%CI: 8.3–10.0) (0–175.0)
Mean 12-mo actuarial survival (%) (95%CI)	44.7 (95%CI: 29.4–60.0)	57.6 (95%CI: 54.0–61.2)	42.1 (95%CI: 36.7–47.6)	27.2 (95%CI: 20.2–34.1)	48.9 (95%CI: 33.3–64.4)	34.5 (95%CI: 17.7–51.4)	39.4 (95%CI: 36.0–42.9)
Response rate
Complete response (%)	na	83.3*	20.4	9.0	30.5	4.6	16.7
Partial response (%)	na	na	36.4	30.1	31.8	25.0	31.3
Stable disease (%)	na	0.0	18.8	21.8	24.5	31.9	22.6
Progression (%)	na	16.7	14.0	34.1	8.9	33.5	21.4
Degree of resection
Gross total resection (%)	61.2	81.5	na	na	na	na	72.4
Subtotal resection (%)	38.8	18.5	na	na	na	na	27.6
Median PFS, % (95%CI) (range)	6.5 (95%CI: 3.6–8.1) (ne)	10.4 (95%CI: 6.0–27.5) (3.0–17.0)	8.5 (95%CI: 5.3–12.4) (6.0–42.0)	6.9 (95%CI: 4.8–11.3) (0–85.0)	8.1 (na) (ne)	5.2 (95%CI 3.1–8.6) (0–10.9)	6.0 (95%CI 5.2–8.0) (0–85.0)
Abbreviations: CI, confidence interval; GIT, gastrointestinal tract; na, not applicable; ne, not extractable; OS, overall survival; PFS, progression-free survival; SRS, stereotactic radiosurgery; WBRT, whole brain radiation therapy.

Treatment recommendations should be offered in the view to improve the quality and quantity of the patient’s remaining life. The selection of treatment modality must be tailored to the individual, considering factors such as the type of primary malignancy, their functional status, the size, multiplicity, and location of metastases, but most importantly the patient’s and family’s attitudes and wishes.

Fig. 22.3 Simplified recommended treatment algorithm for management of patients with new brain metastases (ICP, intracranial pressure; SRS, stereotactic radiosurgery; WBRT, whole brain radiation therapy).

Only gold members can continue reading. Log In or Register to continue