SEARCH

SEARCH BY CITATION

Keywords:

  • gastrointestinal cancer;
  • brain metastasis;
  • colorectal cancer;
  • esophageal cancer;
  • gastric cancer;
  • gallbladder cancer;
  • small bowel cancer;
  • pancreatic cancer;
  • whole brain radiation therapy;
  • radiosurgery

Abstract

  1. Top of page
  2. Abstract
  3. Esophageal Cancer
  4. Gastric Cancer
  5. Gallbladder Cancer
  6. Pancreatic Cancer
  7. Small Bowel Cancer
  8. Colorectal Cancer
  9. Conclusions
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Metastatic brain tumors represent 20% to 40% of all intracranial neoplasms and are found most frequently in association with lung cancer (50%) and breast cancer (12%). Although brain metastases occur in <4% of all tumors of the gastrointestinal (GI) tract, the incidence of GI brain metastasis is rising in part due to more effective systemic treatments and prolonged survival of patients with GI cancer. Data were collected from 25 studies (11 colorectal, 7 esophageal, 2 gastric, 1 pancreatic, 1 intestinal, 3 all-inclusive GI tract cancer) and 13 case reports (4 pancreatic, 4 gallbladder, and 5 small bowel cancer). Brain metastases are found in 1% of colorectal cancer, 1.2% of esophageal cancer, 0.62% of gastric cancer, and 0.33% of pancreatic cancer cases. Surgical resection with whole brain radiation therapy (WBRT) has been associated with the longest median survival (38.4-262 weeks) compared with surgery alone (16.4-70.8 weeks), stereotactic radiosurgery (20-38 weeks), WBRT alone (7.2-16 weeks), or steroids (4-7 weeks). Survival in patients with brain metastasis from GI cancer was found to be diminished compared with metastases arising from the breast, lung, or kidney. Prolonged survival and improvement in clinical symptoms has been found to be best achieved with surgical resection and WBRT. Although early treatment has been linked to prolonged survival and improved quality of life, brain metastases represent a late manifestation of GI cancers and remain an ominous sign. Cancer 2011;117:3630–3640. © 2011 American Cancer Society.

Metastatic brain tumors are among the most common lesions found in the brain, outnumbering primary brain tumors by 10:1 and accounting for approximately 20% to 40% of all intracranial masses in adults.1 An estimated 25% to 35% of cancer cases are complicated by brain metastasis, the development of which is associated with a poor prognosis and an overall median survival of 4.2 months.2 Although brain metastases are frequently diagnosed in patients with lung cancer (48%), breast cancer (15%), testicular cancer (10% to 15%), and malignant melanoma (6% to 10%),3, 4 they rarely arise from gastrointestinal (GI) tract cancers. Bartelt et al5 reported brain metastases in <4% of malignancies affecting the esophagus, stomach, colon, and rectum. However, the reported incidence of brain metastasis from GI cancers is rising due in part to an increased use of brain imaging modalities in these patients and prolonged survival associated with more effective systemic treatments.6

Gait disturbances, altered mental status or personality changes, and focal neurologic deficits are the most common clinical manifestations of metastatic brain disease, whereas memory loss and seizures are less common.3, 7 Brain metastases are a late manifestation of GI cancer5 and associated with a median survival of 3.8 months compared with <7 months in similarly affected patients with primary breast or lung cancer.3

This report provides a comprehensive review of the incidence, prevalence, epidemiology, risk factors, management, and prognosis of brain metastasis arising from esophageal, gastric, gallbladder, pancreatic, small bowel, and colorectal cancer.

Esophageal Cancer

  1. Top of page
  2. Abstract
  3. Esophageal Cancer
  4. Gastric Cancer
  5. Gallbladder Cancer
  6. Pancreatic Cancer
  7. Small Bowel Cancer
  8. Colorectal Cancer
  9. Conclusions
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Esophageal cancer (including squamous cell carcinoma and adenocarcinoma) is currently the fastest growing malignancy in the United States with an annual incidence of 4.0 per 100,000 people.1, 8 In 2010, the American Cancer Society estimates that there will be 16,640 new cases of esophageal cancer and 14,500 deaths from esophageal cancer.9 Worldwide, esophageal cancer is more prevalent, reaching an incidence of 160 to 540 per 100,000 people in South Africa, China, and Kazakhstan.1 Fifty percent of newly diagnosed patients have unresectable or metastatic disease at the time of diagnosis, typically to the lungs, liver, and adrenal glands.8, 10-12 Brain metastasis from esophageal cancer remains a rare occurrence with approximately 100 clinical cases reported in the world literature (Table 1). Metastatic spread to the brain likely occurs via Batson's vertebral venous plexus, which provides communication between the esophagus and central nervous system (CNS).5, 8, 10 Clinical cohort studies have identified brain metastases in up to 2.1% of esophageal cancer cases and in 1% to 5% of patients in postmortem studies.13-16 Weinberg et al8 reported on 1588 patients treated at The MD Anderson Cancer Center between 1993 and 2001, and identified only 27 patients (1.7%) with esophageal cancer brain metastases, 19 (70%) of whom had concurrent systemic disease.

Table 1. Published Clinical and Autopsy Reports of Esophageal Cancer Patients With Brain Metastases
StudyNo.Patients With Brain Metastasis No. (%)Median Time to Diagnosis (Months)a
  • N/A indicates not applicable; NR, not reported.

  • a

    Interval between diagnosis of primary esophageal cancer and detection of brain metastasis.

  • b

    Central nervous system metastasis; no differentiation between the brain and spinal cord were specified.

Clinical   
 Agrawal et al, 2009515041 (0.20)30
 Yoshida et al, 200711114117 (1.5)12.3
 Bartelt et al, 200459160 (0.0)N/A
 Almasi et al, 2004523011 (0.33)9
 Weinberg et al, 20038158827 (1.7)5.6
 Ogawa et al, 200210255436 (1.4)6.7
 Gabrielsen et al, 19951472215 (2.1)5.8
 Quint et al, 1995531473 (2.0)NR
Autopsy   
 Chan et al, 1986542312 (0.9)NR
 Sons and Borchard, 1984551713 (1.8)NR
 Anderson and Lad, 198215791 (1.3)NR
 Mandard et al, 198113b985 (5.1)NR
 Bosch et al, 197916821 (1.2)NR
 Appelqvist, 1975561541 (0.6)NR
 Attah and Hajdu, 1968571130 (0.0)NR

Available data would suggest that the brain disease-free interval (bDFI) for esophageal cancer, defined as the interval between diagnosis of the primary tumor and discovery of brain metastasis, ranges from 5.6 to 12.3 months (Table 1). Risk factors for the development of brain metastases in patients with esophageal cancer include advanced stage and size of the primary tumor.8, 10, 14 Ogawa et al10 reported that 26 of 32 (81%) esophageal cancer patients with brain metastases had stage III or stage IV esophageal cancer, whereas Weinberg et al8 noted that 19 of 27 (70%) such patients had stage IV disease. In a retrospective analysis of 496 patients with primary esophageal tumors, Gabrielsen et al14 studied the correlation between primary esophageal tumor size and the presence of brain metastasis and reported a mean tumor size of >8.63 cm (standard deviation [SD] ± 2.79 cm) among 15 patients diagnosed with brain metastasis compared with <5.12 cm (SD ± 2.56 cm) in those with no metastases (P < .001).

Several studies analyzing brain metastasis in patients with primary esophageal cancer have originated in Asia. Yoshida et al11 reported brain metastases in 17 of 1141 (1.5%) Japanese patients diagnosed with primary esophageal cancer between 1993 and 2005; 13 of these patients had systemic disease (76%). During the same period, a cohort of 803 patients receiving treatment for metastatic brain tumors were surveyed, and it was noted that 17 (2.1%) patients among this group had primary esophageal cancer.11 In Western series, the majority of brain metastases are found among patients with esophageal adenocarcinoma,8, 14 whereas in Japan they are more common among patients with esophageal squamous cell carcinoma10, 11 (Table 2). These results likely reflect the higher incidence of adenocarcinoma in the United States and squamous cell carcinoma in Asia and suggest tumor histology is not an independent risk factor for esophageal brain metastasis.8

Table 2. Histologic Features of the Primary Esophageal Cancer Among Patients Who Develop Brain Metastases in the United States and Japan
StudyPatients No. (%)Patients With Brain Metastases No. (%)
AdenocarcinomaSquamous Cell CarcinomaAdenocarcinomaSquamous Cell Carcinoma
  1. NR indicates not reported.

United States
 Weinberg et al, 200381085 (68.3)405 (25.5)22 (82)2 (7)
 Gabrielsen et al, 199514230 (68.9)104 (31.1)10 (67.7)2 (13.3)
Japan
 Yoshida et al, 200711NRNR3 (18)12 (71)
 Ogawa et al, 200210NRNR1 (2.8)33 (92)

Gabrielsen et al14 investigated the utility of pre-operative brain computed tomography (CT) to detect occult metastases in a cohort of 240 patients who were candidates for esophagectomy. No patient was found to have occult metastases. This group also evaluated the value of routine CT brain imaging in a separate cohort of 388 patients who were not candidates for esophagectomy and found brain metastases in only 3 patients (0.8%). Given the low incidence of brain metastasis in both groups, as well as the associated costs, routine pre-operative neuroimaging is not recommended as part of the staging work-up for patients with esophageal cancer.14

Rare reports of surgical resection (SR) of isolated esophageal cancer brain metastases, with or without whole brain radiation therapy (WBRT), have resulted in a 15- to 262-week median survival in several small studies (Table 3). The 262-week median survival reported by Yoshida et al11 included only 3 patients with esophageal cancer who underwent both SR and WBRT. Ogawa et al10 reported on 5 patients (14%) surviving >1 year, all of whom were treated with both SR and WBRT. Of note, none of those 5 patients had extracranial metastasis, 4 patients had a Karnofsky Performance Score (KPS) of 90% to 100%, and 4 patients had solitary brain lesions.

Table 3. All Published Reports Detailing Survival Among Patients With Brain Metastases From Esophageal, Gastric, and Colorectal Cancer
StudyPrimary LocationNo.TreatmentMedian Survival (Weeks)a
  • SR indicates surgical resection; WBRT, whole brain radiation therapy; SRS, stereotactic radiosurgery; GIT, gastrointestinal tract.

  • a

    Length of survival from diagnosis of brain metastasis.

  • b

    Radiotherapy included both WBRT and gamma knife therapy in these patients.

  • c

    No differentiation between esophagus, stomach, and colon/rectum specified.

  • d

    Surgical resection before (after) WBRT.

Yoshida et al, 200711Esophagus3SR+WBRT262
  7SR70.8
  4SRS38
Weinberg et al, 20038Esophagus4SR+WBRT38.4
  6SR15.2
Ogawa et al, 200210Esophagus12SR+WBRT38.4
  24WBRT7.2
Kasakura et al, 200019Gastric1SR+WBRT28
  2SR18.8
  3SRS+WBRTb10.8
York et al, 199918Gastric3SR+WBRT54
  11WBRT9
  4Steroids7
Da Silva et al, 20096GITc40SRS27.6
Hasegawa et al, 200358GITc39SRS20
Schoeggl et al, 200259Colon/rectum35SRS24
Wronski et al, 199942Colon/rectum42SR+WBRT36.0 (28.0)d
  26SR33.2
Hammoud et al, 199645Colon/rectum22SR+WBRT36
  14SR36
  57WBRT12
  7Steroids4
Farnell et al, 19963Colon/rectum39SR+WBRT42
  11SR45
  79WBRT16
  21Steroids6
Alden et al, 199660Colon/rectum5SR16.4
  14WBRT11.2
Cascino et al, 198343Colon/rectum4SR+WBRT44.0 (26.0)d
  7SR37
  29WBRT9

Brain metastases from esophageal cancer are rare, occurring in <2% of patients. Surgery with or without WBRT is the most common treatment modality used. High KPS (90% to 100%), solitary brain lesion, and absence of extracranial metastasis are associated with prolonged survival in up to 14% of patients. Pre-operative neuroimaging is not indicated for routine staging of patients with esophageal cancer except perhaps in the setting of large tumors (>8 cm) that demonstrate evidence of local invasion or lymph node metastasis.

Gastric Cancer

  1. Top of page
  2. Abstract
  3. Esophageal Cancer
  4. Gastric Cancer
  5. Gallbladder Cancer
  6. Pancreatic Cancer
  7. Small Bowel Cancer
  8. Colorectal Cancer
  9. Conclusions
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Gastric cancer is the 14th most common cancer in the United States with approximately 21,000 new cases each year, resulting in >10,000 deaths annually.9 Worldwide, gastric cancer remains a leading cause of cancer death (803,000 deaths annually), second only to lung cancer (1.3 million deaths annually).1, 17 At the time of diagnosis, 20% to 30% of gastric cancer patients have stage IV disease, most commonly to the liver, lung, and bone.1 Brain metastases from gastric cancer are exceedingly rare and have been reported in <1% of clinical cases, the majority of which are included in 2 large, single-institution retrospective studies.18, 19 York et al18 reported on 3320 gastric cancer patients treated over a 40-year period (1957-1997) at The MD Anderson Cancer Center and identified brain metastases in only 24 patients (0.7%). In Japan, where the incidence of gastric cancer is amongst the highest in the world (62.0 per 100,000 men, 26.1 per 100,000 women20) and second only to Korea (68.1 per 100,000 men, 29.0 per 100,000 women21), Kasakura et al19 identified brain metastasis in only 11 of 2322 (0.47%) patients treated between 1980 and 1998.

Among gastric cancer patients with brain metastasis, the mean interval from gastrectomy to the diagnosis of brain metastasis was 9 months (range, 1-23 months) in the US study18 and 9.6 months (range, 0.1-43.7 months) in the Japanese study.19 York et al18 observed a greater incidence of primary tumors in the proximal stomach (67%) among patients with brain metastases. Similarly, Bartelt et al5 also reported that 50% of gastric cancer patients who developed brain metastases had primary tumors in the gastric cardia. Concurrent systemic metastases were present in all patients with gastric cancer brain metastases and most commonly involved the bone (46%), liver (42%), and lung (29%).18, 19

Response to treatment is poor among patients with brain metastasis arising from gastric cancer18 (Table 3). York et al18 noted neurologic improvement in only 4 of 24 (16.7%) patients treated with either SR+WBRT (n = 3) or WBRT alone (n = 1). Median survival among the WBRT group did not differ from patients who received steroid monotherapy (9.0 weeks with WBRT vs 7.0 weeks with steroids, P > .05). Kaskura et al19 reported a median survival of 24.0 weeks in the surgical group (SR, n = 2; SR+WBRT, n = 1) compared with 10.8 weeks in the WBRT group (n = 3) (P < .05). The longest median survival was observed in patients treated with both surgery and WBRT (54 weeks; range, 22-83 weeks).18 In general, the prognosis of gastric cancer patients who present with brain metastasis is dismal, and treatment is palliative.18 Younger patients and patients with less extensive systemic disease may benefit most (if at all) from surgical palliation.18

Brain metastases in the setting of gastric cancer are exceedingly rare and diagnosed in <1% of affected patients. Response to treatment is poor, with neurologic improvement achieved in only 16.7% of patients treated with SR and/or WBRT. Combination SR+WBRT has been associated with a small survival advantage; nevertheless, aggressive treatment should be reserved for younger patients with less extensive systemic disease.

Gallbladder Cancer

  1. Top of page
  2. Abstract
  3. Esophageal Cancer
  4. Gastric Cancer
  5. Gallbladder Cancer
  6. Pancreatic Cancer
  7. Small Bowel Cancer
  8. Colorectal Cancer
  9. Conclusions
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Cancer of the gallbladder is estimated to have resulted in approximately 9800 deaths in the US in 2010.9 Gallbladder cancer typically presents at an advanced and unresectable stage at diagnosis and has a very poor prognosis (5-year survival of <5%; mean survival of 4.5 months).22 Sons et al23 reported distant metastases in 92% of patients at autopsy, most commonly to the para-aortic and portal lymph nodes, liver, lungs, and peritoneum.22 Brain metastasis arising from primary gallbladder tumors is extremely rare and only 4 cases have been reported in the English literature since 1980 (Table 4). Other large series have reported that <0.5% of brain metastases originate from gallbladder cancer.22

Table 4. Published Clinical Reports of Gallbladder, Pancreatic, and Small Bowel Cancer Patients With Brain Metastases
StudyNo.Primary Tumor LocationHistologic TypeTreatmentbDFI (Months)Survival (Weeks)aExtracranial Metastases
  • bDFI indicates brain disease-free interval; AC, adenocarcinoma; SR, surgical resection; NR, not reported; PALN, para-aortic lymph nodes; LN, lymph node; WBRT, whole brain radiation therapy; RT, radiation therapy; GIST, gastrointestinal stromal tumor.

  • a

    Interval between diagnosis of primary small intestine cancer and detection of brain metastasis.

  • b

    Brain tumor diagnosed before primary tumor.

  • c

    Patient still alive at the time of report.

  • d

    Mean bDFI encompassing 34 cases of GI tract cancer overall (small intestine+colon+rectum); range, 8-52 months.

  • e

    Median survival encompassing 34 cases of GI tract cancer overall (small intestine+colon+rectum); range, 12-112 weeks.

Agrawal et al, 2006241GallbladderACSRUnknownbNRLiver
Kawamata et al, 1999251GallbladderACSRUnknownbNRLiver
Takano et al, 1991221GallbladderACSR4.0208cNone
Smith et al, 1983261GallbladderACConservativeUnknownb1.4Pancreas, liver, PALN
Caricato et al, 2006301PancreasACSR24.064.0cLN
Park et al, 2003274PancreasACWBRT4.511.6Lungs, liver, bone, LN
El Kamar et al, 2003311PancreasACConservative6.01.7Liver, LN
Kuratsu et al, 1990282PancreasACSR5.02.0Liver
Local RT, SR15.036.0LN
Watanabe et al, 2004351Duodenum (2nd portion)ACSRUnknownbNRAdrenal gland, mediastinum, clavicular LN
Maiuri et al, 2004371IleumCarcinoidSR+WBRT14.036.0None
Hughes et al, 2004381JejunumGISTSR, imatinib mesylate42.076.0Liver, gluteus
Salvati et al, 19953410Not specifiedACSR24.0d40.0eLung, liver
Raymond et al, 1992361IleumCarcinoidWBRTUnknownbNRNone
Miyamoto et al, 1989321Duodenum, jejunumACSRUnknownb47.2None

Neurologic symptoms were the initial manifestations of malignancy in 3 of 4 reported cases of brain metastases from gallbladder cancer. Symptoms included hemiparesis and aphasia,24 hypoesthesia,25 and sagittal sinus thrombosis presenting with papilledema, proptosis, and 6th cranial nerve palsy.26

Takano et al22 reported the only case in which brain metastasis was detected after the diagnosis of the primary gallbladder cancer. This patient had a solitary brain lesion, with no evidence of extracranial involvement,22 whereas metastases to the liver, pancreas, or para-aortic lymph nodes were present in all other cases.24-26 Takano et al22 reported a survival rate of >4 years following SR in this patient, which is likely attributed to the absence of extracerebral metastases rather than the management of the brain metastasis. Smith et al26 reported a survival of only 10 days in a patient who presented with sagittal sinus thrombosis as a result of gallbladder cancer brain metastasis. In the other 2 cases, the cerebral mass was surgically removed; however, no patient follow-up was provided.24, 25

Brain metastasis arising from gallbladder cancer represents an advanced stage of disease and is almost always associated with systemic metastases. Prognosis is poor and treatment is generally palliative.

Pancreatic Cancer

  1. Top of page
  2. Abstract
  3. Esophageal Cancer
  4. Gastric Cancer
  5. Gallbladder Cancer
  6. Pancreatic Cancer
  7. Small Bowel Cancer
  8. Colorectal Cancer
  9. Conclusions
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Pancreatic adenocarcinoma is among the most aggressive cancers in adults with a disease-free 5-year survival rate of approximately 6%.9 In 2010, an estimated 43,000 Americans will be diagnosed with pancreatic cancer, with 18,700 people succumbing to the disease.9 Given the absence of early signs or symptoms of pancreatic cancer, 65% to 70% of all patients will have nodal or distant metastases to the liver, lungs, or bone at the time of diagnosis.1 Despite this fact, pancreatic cancer metastases to the brain are exceedingly rare (0.33% of pancreatic adenocarcinoma cases), perhaps owing to the aggressive nature of pancreatic adenocarcinoma and the fact that most patients do not survive long enough to experience clinical manifestations of brain metastasis.27 However, recent advances in the detection and treatment of pancreatic adenocarcinoma have resulted in prolonged survival and an increased incidence of brain metastasis.28 Kuratsu et al28 reported 2 patients with pancreatic adenocarcinoma with a mean bDFI of 10 months and mean overall survival of 19 weeks following diagnosis of brain metastasis.

Demchuk et al29 was the first to report an antemortem diagnosis of brain metastasis in a patient with pancreatic adenocarcinoma. Since then, only 8 cases of pancreatic adenocarcinoma with antemortem metastasis to the brain (1 retrospective study, 4 case reports) have been reported in the English literature (Table 4). The bDFI ranged from 5 to 24 months among these patients and survival ranged from 2 weeks to >16 months after diagnosis of brain metastasis (Table 4).27, 28, 30

In a retrospective analysis of 1229 pancreatic adenocarcinoma patients treated at Seoul National University Hospital between 1980 and 2000, Park et al27 reported only 4 patients (0.33%) with metastasis to the brain. Although all 4 patients had concurrent metastasis to the lung, liver, and/or bone, neurologic symptoms was the first manifestation of pancreatic cancer in 2 patients. The bDFI was 4.5 ± 0.7 months (P < .05) and the overall median survival was 2.9 ± 1.0 months (P < .05) after diagnosis of brain metastasis. All 4 patients were treated with WBRT, which did not alter their clinical course, though none died of neurologic causes.

Presenting symptoms for brain metastasis due to pancreatic adenocarcinoma are similar to those arising from other cancers and include headache, hemiparesis, ataxia, vertigo, and rarely, personality changes.27, 28, 30, 31 Caricato et al30 reported on a patient who presented with intractable vomiting 2 years after diagnosis and treatment of pancreatic adenocarcinoma. These symptoms were initially attributed to peritoneal carcinomatosis but was later confirmed by magnetic resonance imaging (MRI) to be a brain metastasis. The authors concluded that, although vomiting in a patient with pancreatic adenocarcinoma usually suggests intra-abdominal local recurrence, metastases, or peritoneal carcinomatosis, neuroimaging is indicated if an intra-abdominal explanation for vomiting is not found.30

Given the rarity of pancreatic cancer brain metastasis, neuroimaging surveillance is not indicated. Serum carcinoembryonic antigen (CEA) and cancer antigen (CA) 19-9 levels may be useful for identifying aggressive primary tumor growth or recurrence but have no demonstrable utility in predicting or diagnosing brain metastasis.28, 30 CEA and CA 19-9 levels were within normal limits among all patients reported by both Caricato et al and Kuratsu et al at the time of their brain metastasis diagnosis.28, 30

Treatment of pancreatic adenocarcinoma brain metastasis has included SR,28, 30 WBRT,27 local radiotherapy,28 and placement of an Ommaya reservoir for hydrocephalus.28 Survival ranged from 2 weeks (following a 5-month bDFI) to >16 months (following a 24-month bDFI) in 2 patients treated surgically for solitary cerebellar brain metastasis.28, 30 In the former case, the patient had stage IV primary adenocarcinoma,28 whereas the latter patient had stage III disease that had been treated aggressively with pancreaticoduodenectomy plus chemoradiation.30

Pancreatic adenocarcinoma is an aggressive malignancy with an extremely poor prognosis. Metastases to the brain are a rare phenomenon, occurring in <1% of patients. Surgery may have a very limited role in patients with limited systemic metastases and whose primary tumor is controlled. Given the radioresistant nature of most pancreatic adenocarcinoma, radiation therapy appears to offer little benefit.27, 28

Small Bowel Cancer

  1. Top of page
  2. Abstract
  3. Esophageal Cancer
  4. Gastric Cancer
  5. Gallbladder Cancer
  6. Pancreatic Cancer
  7. Small Bowel Cancer
  8. Colorectal Cancer
  9. Conclusions
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Cancer of the small intestine represents only 1% to 2% of GI tract malignancies.1 Nearly 7000 new cases of cancer arising from the duodenum (excluding the Ampulla of Vatar), jejunum, or ileum will be diagnosed in the US this year, resulting in 1000 deaths.9 Although the duodenum is the primary site for 75% of all small intestine cancers,32 an autopsy series by Cortese et al33 reported a low duodenal cancer incidence of only 0.02% to 0.5% of cancer cases overall. Adenocarcinoma is the most common histology and accounts for approximately 50% of small intestine malignancies, most commonly in the foregut. By comparison, carcinoid tumors, gastrointestinal stromal tumors (GIST) and lymphomas show predilection for the distal small intestine.1 Distant metastases to the liver, lungs, and/or bone are common at presentation and are present in 1/3 of patients at the time of surgery for the primary tumor.1

Brain metastases arising from small intestine malignancies have been reported in only 15 cases (1 retrospective cohort study, 5 case reports) in the English literature (Table 4). These included 12 cases of small bowel adenocarcinoma,32, 34, 35 2 ileal carcinoid tumors,36, 37 and 1 GIST.38 Survival after diagnosis of brain metastases is dependent upon tumor type with adenocarcinoma having the poorest prognosis and a 5-year survival rate of 15% to 20%.1 Salvati et al34 reported 34 cases of solitary cerebral metastases from 24 tumors originating in the colon-rectum and 10 tumors in the small intestine. The median survival was 10 months among this group (range, 3-28 months), although they did not differentiate between tumors of the small intestine and the colon and rectum. Survival among patients with ileal carcinoids37 and GIST38 brain metastasis has been reported as 9 and 19 months, respectively. The mean bDFI for these tumors was 24 months (range, 8-52 months), 14 months, and 42 months among adenocarcinomas (no differentiation between small intestine and colon/rectum),34 ileal carcinoids,37 and GIST cases,38 respectively.

The clinical presentation of brain metastases associated with small intestinal malignancies is variable and includes hemiparesis, extremity weakness, headache, blurry vision, cranial nerve palsies, and foot drop.35-38 Neurologic symptoms from brain metastasis were the first manifestations of small intestine cancer in only 3 patients,32, 35, 36 including 2 patients with no additional systemic metastases.32, 36

Unlike other small intestinal malignancies, the metastatic potential of a carcinoid tumor (regardless of the primary location) is directly correlated to the size of the primary tumor.36, 37 Metastases are seen in only 2% to 7% of carcinoids ≤1 cm in diameter, whereas systemic metastasis are seen in 70% to 80% of carcinoids >2 cm.39, 40 Brain metastases are most common when tumor diameter reaches >3 to 4 cm (and often up to 7 to 8 cm).37

Surgery and/or WBRT is the most common treatment modality used for brain metastasis due to small bowel cancer,32, 34-38 although the lack of data precludes formal outcomes analysis between various forms of intervention. Imatinib mesylate has been used to treat small bowel GIST brain metastasis, although its effectiveness in maintaining local control of intracranial metastases is conflicting.38, 41 Hughes et al38 reported a case of a jejunal GIST that metastasized to the brain while the patient was on imatinib mesylate therapy. Multiple intracranial recurrences occurred despite repeated resection and good systemic disease control, leading these authors to conclude that the CNS may provide a sanctuary site in which imatinib mesylate fails to achieve adequate levels.38 In contrast, Brooks et al41 reported on a patient with a mesenteric GIST who had extensive intra-abdominal and meningeal metastasis who underwent therapy with imatinib mesylate. Complete resolution of CNS abnormalities and a dramatic improvement in intra-abdominal disease was confirmed radiologically 60 days after initiation of treatment.41

Brain metastases arising from small intestinal adenocarcinoma, carcinoids, and GISTs are rare and represent a late complication of advanced disease. Treatment of small intestine cancer brain metastasis generally involves SR and/or WBRT, although targeted therapy with imatinib mesylate may be an effective treatment for GIST brain metastases.

Colorectal Cancer

  1. Top of page
  2. Abstract
  3. Esophageal Cancer
  4. Gastric Cancer
  5. Gallbladder Cancer
  6. Pancreatic Cancer
  7. Small Bowel Cancer
  8. Colorectal Cancer
  9. Conclusions
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Despite a steady decline in incidence and mortality over the past 20 years, colorectal cancer (CRC) remains a significant worldwide health concern, accounting for an estimated 639,000 deaths annually.17 The American Cancer Society estimates that CRC will account for 142,500 new cases and 51,000 deaths in the United States in 2010.9 Distant metastases develop in 10% to 15% of patients, most commonly to the liver (20% to 30%) and lung (10% to 20%).42 In contrast, brain metastases from CRC are rare, occurring in only 4% of cases43 (Table 5) and are concomitant with lung metastases in 55% to 85% of patients7 and liver metastases in up to 75%.44 Postmortem studies have shown that an additional 2% to 3% of patients who die of colorectal cancer will harbor occult brain metastases at autopsy.42

Table 5. Published Clinical Reports of Colorectal Cancer (CRC) Patients With Brain Metastases
StudyNo.Brain Metastasis No. (%)Median Time to Diagnosis (Months)a
  • NR indicates not reported.

  • a

    Time between diagnosis of primary CRC and detection of brain metastasis.

  • b

    Radiographic confirmation of brain metastasis. CRC was subsequently found to be the primary cancer.

  • c

    Autopsy study.

Mongan et al, 20097162039 (2.3)25.0
Tan et al, 200947437827 (0.62)27.5
Bartelt et al, 20045b91647 (5.1)22.6
Wronski et al, 199942b70973 (10.3)27.6
Ko et al, 199948377353 (1.4)36.0
Hammoud et al, 1996458632150 (1.7)26.0
Weiss et al, 198661c154138 (2.5)NR
Cascino et al, 198343100640 (4.0)24.5
Temple et al, 198244c99929 (2.9)NR
Floyd et al, 196662168730 (1.8)NR

The cerebellum is the site of intracranial metastasis in up to 55% of affected CRC patients,42, 43 which may explain the high prevalence of gait abnormalities reported. Wronski et al42 have also reported infratentorial masses in 6 of 73 (8.2%) patients with CRC brain metastasis who presented with obstructive hydropcephalus.

The bDFI between diagnosis of CRC and discovery of brain metastasis has been shown to correlate with subsequent survival.45 For CRC, the bDFI ranges from 22.6 to 27.6 months (Table 5), which is considerably longer than for other GI cancers (range, 5.6-30 months)5, 46 and lung cancer (average 4 months) but shorter than breast cancer (average 3 years).45 Hammoud et al45 investigated factors affecting bDFI for CRC and identified Dukes' stage and treatment status of extracerebral metastatic disease.45 Median bDFIs in patients with Dukes' stage B (n = 28), C (n = 48), and D CRC (n = 24) was 40 months, 26 months, and 8 months, respectively (P < .05). Among patients who received radiotherapy (n = 7), chemotherapy (n = 35), or no treatment (n = 31) for their extracerebral metastatic disease, the mean bDFI was 49 months, 27 months, and 13 months, respectively (P < .05). Notably, age, gender, primary tumor location, primary tumor treatment modality and site(s), and treatment of systemic metastasis showed no correlation with bDFI.45

Several authors have reported that the primary location of the CRC tumor is an independent factor relating to incidence and survival following development of brain metastasis.5, 42, 45 The distal colon, represented by the sigmoid, rectosigmoid junction, and rectum, is the primary tumor site in approximately 60% of all reported CRC brain metastases.5, 42, 45 Hammoud et al45 analyzed 150 CRC patients with brain metastasis and found that proximal colonic lesions, which are more often associated with liver metastasis, resulted in shorter survival compared with distal lesions (3 vs 6 months, P < .005). This finding is likely the consequence of concurrent hepatic involvement and supports the hypothesis that most patients with liver metastasis die before brain metastasis develops.45

The worldwide incidence of CRC varies as does the incidence of CRC brain metastasis. A retrospective report on 1006 patients with CRC treated at the Memorial Sloan-Kettering Cancer Center (MSKCC) between 1977 and 1980 identified brain metastasis in only 40 patients with colon cancer (4.0%), 62.5% of whom had primary tumors located at the rectosigmoid junction (n = 25).43 A similar German study5 reviewed a cohort of 916 patients treated for brain metastasis between 1985 and 2000 and identified 47 patients (5.1%) who were diagnosed with primary CRC, 64% of which originated in the sigmoid (n = 6) or rectum (n = 24). In contrast, Asian countries have noted a lower incidence of colorectal brain metastasis. In Singapore, where the incidence of colorectal cancer is amongst the highest in the world (35.1 per 100,000 men, 29.9 per 100,000 women46), brain metastases were identified in only 27 of 4378 (0.62%) CRC cases diagnosed between 1995 and 2003,47 even though 71% of these patients had a primary tumor located in the sigmoid or rectum. Ko et al48 reported on a 27-year Taiwanese experience (1970 to 1996) in which brain metastases were identified in only 53 of 7153 (0.74%) patients with CRC, 79% of whom had primary tumors occurring in the left colon or rectum.

Additional factors that have been associated with prolonged survival among CRC patients with brain metastases include age <65 years, presence of a solitary CNS lesion, absence of systemic disease, and bone metastasis and memory loss at presentation.3 In contrast, gender, KPS at diagnosis of brain metastasis, tumor size, tumor grade, and seizures at presentation did not positively or negatively influence survival.3, 45 Despite its utility as a serum marker for CRC recurrence, carcinoembryonic antigen (CEA) level is of limited use in predicting survival from brain metastasis.7, 43 Current studies evaluating the relation between bDFI and overall survival report conflicting results. Hammoud et al45 reported that an increased interval between primary tumor diagnosis and the diagnosis of brain metastasis was associated with a significant increased survival. In contrast, among a cohort of 150 patients with CRC brain metastasis reported by Farnell et al,3 no correlation between a prolonged bDFI and long-term survival was established. Current guidelines regarding systemic surveillance after surgery for CRC are controversial with respect to the need for routine chest and liver imaging.49, 50 Nonetheless, all patients diagnosed with systemic metastasis, particularly patients with pulmonary involvement, should undergo neuroimaging for early detection of subclinical intracranial metastasis.47 Routine imaging of the brain for staging purposes in patients with no evidence of metastatic disease is neither beneficial nor cost-effective regardless of the site of the primary tumor.47

Without treatment, median survival among patients with colorectal brain metastasis is 4 to 6 weeks.3, 45 Steroids are often used palliatively to treat neurologic symptoms but have not been shown to influence survival.42 Whole brain radiation therapy offers only modest increases in median survival (9-16 weeks, Table 3). Several authors have reported that colorectal brain metastases are unusually resistant to radiation therapy; however, there is no consensus surrounding this view.3, 42, 43, 45 Surgery, with or without WBRT, is the optimal initial management for isolated CRC brain metastasis in patients who are good surgical candidates. This combination can yield significant improvement in quality of life and prolong median survival up to 45 weeks.3 Of note, the addition of radiotherapy to surgical resection did not affect overall survival or recurrence rate (surgery alone = 36%; surgery + WBRT = 32%, P < .05), adding further support to the radioresistant hypothesis regarding CRC brain metastases.3 Within a cohort of 150 patients with CRC brain metastases, Farnell et al3 noted 24 patients who survived >1 year (range, 13-153 months) after diagnosis. Among these 24 long-term survivors, 19 (79%) were treated surgically (16 received adjuvant radiotherapy), 9 (38%) had no additional systemic disease, and 9 (38%) had only pulmonary metastases.3

CRC brain metastases are rare and diagnosed in <4.0% of CRC cases. Surgery is the optimal treatment for CRC brain metastases and is associated with prolonged survival and improved quality of life. The addition of WBRT appears to offer no survival benefit or reduction in recurrence. Neuroimaging for early detection of subclinical intracranial lesions is indicated in all patients diagnosed with extracranial metastasis, whereas routine neuroimaging for staging purposes is not beneficial.

Conclusions

  1. Top of page
  2. Abstract
  3. Esophageal Cancer
  4. Gastric Cancer
  5. Gallbladder Cancer
  6. Pancreatic Cancer
  7. Small Bowel Cancer
  8. Colorectal Cancer
  9. Conclusions
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Brain metastases from gastrointestinal cancers are rare, and their presence represents an ominous prognostic sign. Nonetheless, the incidence is increasing due to earlier diagnosis and prolonged survival as a result of more effective intracranial and extracranial treatment modalities. The cerebellum is the most common site of metastasis, thus new onset gait difficulties in patients with gastrointestinal cancer should be evaluated immediately because early recognition of focal neurologic symptoms can lead to prolonged survival and improved quality of life. Pre-operative neuroimaging is only indicated in patients with neurologic symptoms or those with large, late-stage GI tumors.

Survival among patients with brain metastases from primary GI cancers is significantly diminished compared with breast, lung, or renal cell cancers. However, increased survival and improvement in clinical symptoms allowing greater functional dependence is achievable with both SR and SRS in select patients.3, 6, 45, 58-60 It is important to emphasize, however, that patients who are considered for neurosurgical intervention are those who demonstrate good prognostic factors, and this selection bias may be responsible for the apparent success of surgical intervention in prolonging survival. Although the addition of WBRT does not significantly enhance postoperative survival following SR or SRS, it may reduce the likelihood of recurrence, increase the time to recurrence, and minimize the chance of death from neurologic complications. Da Silva et al6 have reported 1 of only a few studies evaluating the efficacy of gamma knife surgery (GKS) for the treatment of GI brain metastasis. The authors reported a median survival of 6.7 months (n = 40) and local tumor control rates of 91% for patients. Among a cohort of 19 patients who were given WBRT prior to GKS, there was no significant increase in survival (6.9 months) (P > .05).6

No single, optimal treatment modality for brain metastasis has been established, although an aggressive approach entailing SR with postoperative WBRT is recommended for patients with solitary, accessible brain tumors, limited extracranial disease, and an expected survival of ≥3 months. Stereotactic radiosurgery may be a viable option for patients with good functional status (KPS ≥ 70) who cannot tolerate surgery and have brain lesions <3.5 cm in diameter.6, 58, 59 Although early treatment is linked to prolonged survival and improved quality of life, brain metastasis represents an advanced manifestation of GI cancer that is uniformly fatal.

REFERENCES

  1. Top of page
  2. Abstract
  3. Esophageal Cancer
  4. Gastric Cancer
  5. Gallbladder Cancer
  6. Pancreatic Cancer
  7. Small Bowel Cancer
  8. Colorectal Cancer
  9. Conclusions
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES