Gastrointestinal Cancer and Brain Metastasis Outcomes and Management

Introduction

The most common adult intracranial neoplasms are metastatic brain tumors. Metastatic tumors account for approximately 20–40% of all brain tumors and outnumber primary brain tumors 10 to 1 ( ). Two hundred thousand new cases of metastatic brain tumors are estimated to occur in the United States annually, although the exact incidence of brain metastasis is unknown ( ). The majority of epidemiologic studies underestimate the incidence of brain metastasis given the fact that many brain metastases are asymptomatic, and even when symptomatic, they are ignored by patients with advanced cancer and often never diagnosed.

The most common primary sites for brain metastases include primary tumors of the lung (40–50%), breast (15–25%), and melanoma (5–20%). Primary gastrointestinal (GI) tumors rarely metastasize to the brain. In a retrospective study by , 916 patients with brain metastases treated with whole-brain radiation therapy (WBRT) between January 1985 and December 2000 were analyzed. reported that 57 (6.2%) of the 916 patients had brain metastasis from the GI tract upon presentation. The rectum was the most common primary cancer site with brain metastasis (24 patients, 42%), followed by the colon (excluding rectosigmoid, 17 patients, 30%), stomach (10 patients, 17.5%), and sigmoid colon (6 patients, 10.5%); none of the 916 patients analyzed had esophageal brain metastases. Although the incidence of cancer in the United States has plateaued, the incidence of brain metastasis from the GI tract is increasing. The escalation of brain metastasis from GI cancers is likely due to the increased use of brain imaging techniques and prolonged patient survival associated with more effective treatments for many GI cancers.

Symptoms of metastatic GI brain tumors resemble those of primary brain tumors. Clinical manifestations frequently include headache, weakness, mental disturbances (sometimes mimicking psychiatric abnormalities), and focal or generalized seizures ( ). studied 284 consecutive patients treated for brain metastases at Memorial Sloan-Kettering Cancer Center and identified headaches in 24% of patients ( n = 68), motor weakness in 20% ( n = 56), cognitive and behavioral disturbances in 14% ( n = 40), focal or generalized seizures in 12% ( n = 35), and ataxia in 7% ( n = 21), whereas 7% were asymptomatic ( n = 21). The metastatic propagation of any solid tumor to the brain is typically associated with a very poor prognosis, and GI tumors with brain metastases are no exception. reported a median overall survival of only ( n = 916) 3.4 months for all patients with brain metastasis and a 3.2-month median survival for patients with GI brain metastases. This chapter provides a comprehensive review of the incidence, prevalence, epidemiology, risk factors, management, and outcomes of brain metastasis arising from esophageal, gastric, gallbladder, pancreatic, small bowel, and colorectal cancer.

Esophageal cancer

Esophageal cancer is commonly divided into two types: (1) adenocarcinoma and (2) squamous cell carcinoma. Notably different risk factors and geographic variation are associated with each type. It is well recognized that esophageal adenocarcinoma primarily affects the Western world while squamous cell carcinoma comprises the majority of esophageal cancer in the Asia-Pacific region. Barrett’s esophagus, gastroesophageal reflux, and obesity are risk factors associated with adenocarcinoma whereas esophageal squamous cell carcinoma risk factors include tobacco use, alcohol consumption, and nutritional imbalance.

The annual incidence of esophageal cancer is 4.0 per 100 000 people and it is currently the fastest-growing malignancy in the United States ( ). According to the , 17 990 new cases of esophageal cancer and 15 210 deaths from esophageal cancer are estimated to occur in 2013. Worldwide, esophageal cancer is even more prevalent, with incidence ranging from 160 to 540 per 100 000 people in South Africa, China, and Kazakhstan ( ). Each year, more than half of all esophageal cancer cases occur in China, with 50% of all esophageal cancer patients presenting with unresectable or distant metastasis at diagnosis ( ). Esophageal cancer characteristically metastasizes to the lungs, liver, and adrenals, and only rarely goes to the brain ( Table 15.1 ; ; ; ). Published cohort studies have reported brain metastases in 2.1% of esophageal cancer cases (1–5% of patients in post-mortem studies) noting that nearly all esophageal cancer patients with brain metastasis had additional systemic disease ( ; ; ). reported that 27 of 1588 esophageal cancer patients (1.7%) treated at the MD Anderson Cancer Center between 1993 and 2001 had esophageal brain metastasis. Nineteen of these patients (70%) had concurrent systemic metastases. In a recently published study also from MD Anderson, identified 20 patients (3.9%) with brain metastasis among 518 esophageal cancer patients who received surgery and chemoradiation for their primary tumor between 2000 and 2010. noted that 45% of these patients had extracranial metastases. reported on 1141 Japanese patients diagnosed with primary esophageal cancer, identifying 17 patients (1.5%) with brain metastasis among whom 13 had coexisting systemic disease (76%). Recently, reported on 26 of 1612 esophageal carcinoma patients in China who had brain metastasis and were treated between 2000 and 2010. In summary, brain metastasis rates from primary esophageal cancer range between 0.6% and 2.1% ( Table 15.1 ), with concurrent extracranial metastases present in a majority of cases.

Esophageal cancer brain metastases are predominantly detected shortly after identification of the primary tumor, with the brain disease-free interval (bDFI) ranging from 5.6 to 30.0 months ( Table 15.1 ). The bDFI is defined as the measurement of time from the diagnosis of the primary tumor to the discovery of brain metastasis. In esophageal cancer, both stage and size of the primary tumor are risk factors useful for determining the likelihood of brain metastasis in esophageal cancer patients ( ; ; ). reported that 19 of 27 (70%) esophageal cancer patients with brain metastasis had Stage IV disease and found that 26 of 32 (81%) esophageal cancer patients with brain metastases had either Stage III or Stage IV disease. Furthermore, analyzed 496 patients and reported a mean tumor size of 8.63 cm (standard deviation [SD] = ±2.79 cm) among 15 patients diagnosed with brain metastases compared with 5.12 cm (SD = ±2.56 cm) in those with no metastases ( p < 0.001). Of note, and have independently documented that the majority of esophageal cancer brain metastases in Japanese patients were squamous cell carcinoma, whereas adenocarcinoma is far more common in the United States ( Table 15.2 ). This difference reflects the higher incidence of adenocarcinoma in the United States and squamous cell carcinoma in Asia and insinuates that brain metastasis is not dependent on a specific histology ( ). On the other hand, have reported that the incidence of brain metastasis among Chinese patients with squamous cell esophageal carcinoma was slightly lower than adenocarcinoma (1.4% [22/1560] vs. 12% [4/33]).

explored the ability of preoperative brain computed tomography (CT) to detect brain metastases in a cohort of 240 patients who were candidates for esophagectomy. Among these patients, none were found to have brain metastases. simultaneously evaluated 388 patients who were not candidates for esophagectomy, and 3 patients (0.8%) were identified with brain metastasis. Given this low incidence of esophageal cancer brain metastasis routine preoperative neuroimaging is an unnecessary part of the routine workup for esophageal cancer.

Treatment modalities employed for brain metastases predominantly include surgical resection alone (SR), SR+WBRT, WBRT alone, and stereotactic radiosurgery (SRS) alone or in combination. Multiple small studies have reported median survival times ranging from 15 to 262 weeks using various treatment modalities ( Table 15.3 ). reported a median survival of 262 weeks among three patients treated with SR+WBRT. reported survival >1 year in five patients (14%), all of whom were treated with both SR and WBRT. None of these patients had extracranial metastases, four patients had superior Karnofsky performance status (KPS) scores of 90–100%, and four patients had solitary brain lesions. Additionally, Song et al. (2014) described five (19.2%) patients who received SR and WBRT with a mean survival of 28.0 weeks, four of whom had KPS ≥ 70% and all had fewer than three cerebral metastatic lesions on initial presentation.