Fig. 24.1
A 73-year-old man with an 18-month history of esophageal adenocarcinoma presented in April 2013 with right hemiparesis. a (postcontrast T1 MRI) reveals a mass that preoperatively was felt to represent a dural metastasis. Resection confirmed this diagnosis. He then received fractionated whole brain radiotherapy. Five months later he re-presented with personality changes and weakness. b demonstrates a new hemorrhagic parenchymal metastasis that was subsequently resected
Major risk factors for squamous cell carcinoma include smoking and alcohol consumption, while Barrett’s esophagus, gastroesophageal reflux disease, smoking and high body mass index increase the risk of adenocarcinoma [41–43]. Patients usually presented with progressive dysphagia (especially to solid foods) and weight loss. Many patients receive trimodality treatment with chemotherapy (including agents such as carboplatin, paclitaxel and 5-FU), radiation and surgery [44].
Brain Metastases
Brain metastases from esophageal cancer are rare, occurring in 1–5% of cases. Spread to the brain probably occurs via Batson’s vertebral venous plexus which provides communication between the esophagus and the brain [20, 45]. Weinberg and coworkers identified 27 patients (1.7%) with esophageal cancer brain metastases from 1588 treated at MD Anderson Cancer Center between 1993 and 2001 [46]. Nineteen of these patients (70%) had concurrent systemic metastatic disease and 75% presented with neurologic symptoms. Median survival was 3.8 months. The only risk factor for brain metastasis was increased tumor size in association with local invasion and lymph node metastases. Ogawa and coworkers reported on 36 esophageal cancer patients with brain metastases; only 5 survived more than one year (all treated with both SRS and WBRT), but 80% of these patients had no extracranial metastatic disease, excellent KPS, and solitary brain lesions [45].
A more recent review at MD Anderson Cancer Center by Wadhwa and coworkers identified 20 patients (3.9%) with brain metastasis from a population of 518 with esophageal adenocarcinoma given trimodality treatment (chemoradiation followed by surgery) between 2000 and 2010 [47]. Twelve patients (60%) had solitary metastasis while 8 (40%) had multiple metastases; 16 (80%) had CNS symptoms at diagnosis. Extracranial metastases were documented in 9 patients (45%). Seventeen of the 20 patients received treatment (4 had surgery alone, 8 had surgery followed by WBRT, 3 had WBRT alone, and 2 had SRS); median OS for all patients was 10.5 months. Additional recent clinical reviews of patients with esophageal cancer brain metastases similarly found that the frequency of brain metastases was higher in adenocarcinoma patients compared to those with squamous cell carcinoma histology [48, 49].
Leptomeningeal Metastases
Two case series each identified seven patients with leptomeningeal disease from primary esophageal cancer [50, 51]. There was a predominance of male patients with adenocarcinoma histology. Presenting symptoms included headache, visual changes, vertigo, nausea, and vomiting. Overall survival was poor—0 to 28 weeks in the first series and 2.5–16 weeks in the second.
Paraneoplastic Syndromes
A patient with esophageal squamous cell cancer was reported to have opsoclonus–myoclonus syndrome with symptoms improving after IVIG [52]. Another patient presented with limbic encephalitis and was subsequently diagnosed with esophageal adenocarcinoma [53]. An anti-Hu antibody was identified in a woman with encephalomyelitis and esophageal small cell carcinoma [54]. Two patients with paraneoplastic cerebellar degeneration (PCD) due to anti-Yo antibody have been reported [55, 56]. Lastly, one patient with numbness and fever was found to have vasculitis on muscle biopsy with symptoms resolving after esophagectomy [57].
Gastric Cancer
Approximately 22,220 patients are diagnosed with gastric cancer annually in the USA, with an estimated 10,990 deaths [1]. Worldwide, rates of disease are highest in Eastern Asia, Eastern Europe, and South America. Gastric ulcers, adenomatous polyps, and intestinal metaplasia are associated with increased risk of gastric cancer [58]. Additional risk factors include H. pylori infection, diet (nitroso compounds, high salt diet with low vegetables), smoking, and alcohol use. Gastric cancer is also associated with specific inherited cancer syndromes such as Lynch syndrome (hereditary nonpolyposis colorectal cancer), familial adenomatous polyposis (FAP), and Li–Fraumeni syndrome.
Early gastric cancer often does not have associated symptoms, but advanced disease may cause indigestion, nausea or vomiting, dysphagia, postprandial fullness, loss of appetite, and weight loss. Late complications include peritoneal or pleural effusions, obstructions, bleeding from esophageal varices, and jaundice.
Most gastric malignancies are adenocarcinoma, and diagnosis is usually made by imaging or endoscopy followed by biopsy or resection. Prognosis is good with resection of early gastric cancer. Patients with at least stage IB disease will often require postoperative chemoradiation.
Brain Metastases
Brain metastases from gastric cancer are very rare and have been reported in less than 1% of cases. York and coworkers identified only 24 brain metastasis patients (0.7%) of the 3320 gastric cancer patients treated at MD Anderson Cancer Center 1957–1997 [59]. There was a greater incidence of brain metastases from primary tumors originating in the proximal stomach, and all 24 patients had concurrent systemic metastatic disease (most commonly bone, liver, and lung). Mean interval from gastrectomy to the diagnosis of brain metastasis was 9 months. Median survival was only 2.4 months.
Kasakura et al. [60] reported brain metastasis in only 11 of 2322 (0.47%) of Japanese patients treated between 1980 and 1998. They noted median survival of 24 weeks in patients who had surgical resection, compared with 10.8 weeks with WBRT and 54 weeks for those who had both surgery and WBRT.
Leptomeningeal Metastases
Oh and colleagues reported 54 cases of cytologically confirmed leptomeningeal metastasis from gastric adenocarcinoma at four institutions in Korea from 1994 to 2007 [61]. The most common presenting symptoms were headache and nausea or vomiting. Opening pressure on lumbar puncture was elevated in 29 patients (58%), and MRI demonstrated leptomeningeal enhancement in 45 (82%). The median interval from diagnosis of the primary gastric cancer to the diagnosis of leptomeningeal disease was 6.3 months. Thirty-six patients received intrathecal chemotherapy with methotrexate alone or in combination with hydrocortisone or cytarabine. Twenty of these patients also received chemotherapy or radiation. Median overall survival was dismal at 6.7 weeks, and only conversion to negative cytology was predictive of relatively longer survival duration (14.6 weeks) on multivariate analysis. Other smaller series similarly suggest extremely poor prognosis as well as a possible modest benefit of intrathecal treatment [50, 62–66]. Leptomeningeal metastasis has also been reported as the presenting manifestation of gastric malignancy in several cases [67–71].
Paraneoplastic Syndromes
Two patients with gastric adenocarcinoma were reported to have paraneoplastic cerebellar degeneration associated with anti-Yo antibody; titers dropped in one patient after resection of the tumor [72, 73]. Another patient with paraneoplastic cerebellar degeneration due to anti-Ri antibody had a mixed tumor of neuroendocrine (reactive part of tumor) and adenocarcinoma [74]. Other cases include a sensorimotor neuropathy and encephalopathy with an antibody to alpha-enolase [75], peripheral neuropathy with arteritis of the sciatic nerve [76], and opsoclonus–myoclonus syndrome [77].
Hepatocellular Carcinoma (HCC)
The incidence of HCC continues to increase rapidly in the USA, especially in men. Approximately 20,000 patients are diagnosed with HCC each year. Worldwide, the highest incidences occur in sub-Saharan Africa and Asia. Important risk factors for the development of HCC include hepatitis B viral (HBV) infection, chronic hepatitis C virus (HCV) infection, hereditary hemochromatosis, and cirrhosis of almost any cause [78].
Patients with HCC typically present with symptoms related to chronic liver disease. There should be high suspicion for the diagnosis in patients with underlying liver disease with rising alpha-fetoprotein (AFP) levels. Most patients who develop HCC have cirrhosis and possibly thrombocytopenia, hypoalbuminemia, hyperbilirubinemia, and/or hypoprothrombinemia.
Surgery remains the only possible cure for HCC, but few patients have fully resectable disease. Additional treatment options for patients who cannot undergo resection or transplantation include radiofrequency ablation, percutaneous ethanol injection, transarterial chemoembolization, radiation therapy, and systemic chemotherapy. Studies have shown some efficacy for sorafenib in advanced HCC [79].
Brain Metastases
Earlier retrospective studies have reported an incidence of brain metastases in 0.2–2.2% of HCC patients [80–83]. However, a more recent review by Shao and colleagues identified brain metastases in 11 (7%) of 158 advanced HCC cases [84], which may be related to improved survival in the setting of new molecular targeted agents such as sorafenib. Median overall survival was poor at 4.6 months. Lim and colleagues reviewed 118 patients with HCC-brain metastases to develop an HCC-specific graded prognostic assessment (GPA) [85]. Patients with a single brain metastasis, Child–Pugh grade of A, and AFP less than 400 had the best prognosis with a median survival of 27 weeks. Sixty-five (55.1%) had associated brain hemorrhage and 101 (85.6%) had extracranial metastases. Studies suggest that treatment with surgery or radiation does improve survival [86]. Xu et al. [87] reported a median survival time of 5.0 months in 14 patients treated with gamma knife radiosurgery. However, Han et al. [88] noted better survival with surgical resection (with or without WBRT) compared to patients who received just stereotactic radiosurgery and or WBRT on analysis of 33 HCC-brain metastasis cases.
Leptomeningeal Metastases
Leptomeningeal disease with HCC is rare. One woman with HCC and headaches, hoarseness, dysphagia, and vomiting was diagnosed with leptomeningeal metastasis by CSF cytology in the setting of concomitant systemic and parenchymal brain metastases [89]. Her symptoms improved with intrathecal methotrexate and WBRT, but she passed away four months after diagnosis.
Gallbladder and Bile Duct (Cholangiocarcinoma) Carcinomas (Fig. 24.2)
Gallbladder cancer is rare although highly fatal. About 5000 cases are diagnosed annually in the USA [1]. Higher rates of gallbladder cancer are present in South America and East Asia. Most are adenocarcinomas, and risk factors are related to chronic gallbladder inflammation including gallstones, gallbladder polyps, and chronic infection. Patients are often asymptomatic but may present with jaundice, pain, and fever. Surgery is the only potentially curative option for gallbladder cancer, but most patients are ineligible for curative intent surgery because of local invasion and/or metastatic spread. For more advanced disease, palliation with radiation and chemotherapy is often considered.
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Fig. 24.2
A 39-year-old woman with no past medical history presented with 3 months of left scalp tenderness and an enlarging mass. Post-Gd T1 MRI shows an extra-axial mass invading through the calvarium. Body CT showed a large hepatic mass with satellite lesions. Resection of the calvarial mass demonstrated metastatic adenocarcinoma consistent with intrahepatic cholangiocarcinoma
Cholangiocarcinoma is even less common with fewer than 3000 cases a year in the USA; it is curable by surgery in less than 10% of cases. It can be difficult to treat as it is often characterized by early metastatic spread to lymph nodes and surrounding organs. The main risk factors are primary sclerosing cholangitis and choledochal cysts, but hepatobiliary flukes contribute to the high incidence in Southeast Asia. Most patients present with painless jaundice, abdominal pain, and weight loss [98]. As with gallbladder cancer, radiation and chemotherapy are given for locally advanced and metastatic disease.
Brain Metastases
Leptomeningeal Metastases
Although generally more rare than BM, several cases of leptomeningeal metastasis have been published. One patient with gallbladder cancer presented with psychosis [103], while others presented with headaches and cranial neuropathies [104, 105] and a meningitic picture [106]. Two patients with cholangiocarcinoma and LM have been described [107, 108].
Paraneoplastic Syndromes
One case of Guillain–Barré syndrome that may have been paraneoplastic has been described in association with gallbladder cancer; patients with polymyositis and opsoclonus have also been reported [109–111]. Another patient was diagnosed with an anti-Hu paraneoplastic sensory neuropathy related to small cell carcinoma of the gallbladder [112].
Pancreatic Cancer
Approximately 48,960 patients are diagnosed with exocrine pancreatic cancer (arising from the exocrine cells of the pancreas) annually, most of which are adenocarcinomas originating from the ductal epithelium [1]. Unfortunately, survival is often poor given the aggressive nature of the disease. Risk factors for the development of pancreatic cancer include obesity, cigarette smoking, chronic pancreatitis (hereditary and nonhereditary), pancreatic cysts, and potentially germline mutations in specific genes such as BRCA1, BRCA2, and STK11 [113, 114].
Patients often present late in the course of the disease with abdominal pain, jaundice, and weight loss. Surgical resection is the only potentially curative treatment, but only 15–20% of patients can get pancreatectomy. Patients who cannot undergo full resection often receive chemotherapy and radiation with limited results.
Brain Metastases
Pancreatic metastases to the brain are very rare (reported incidence of 0.33–0.57%) potentially related to poor overall survival [20, 115]. Kumar et al. [116] reported eight cases of CNS involvement with pancreatic adenocarcinoma at Johns Hopkins between 2004 and 2012. Six of the eight had other systemic metastases, and median time to diagnosis of brain metastasis was 29 months. Lemke et al. [117] retrospectively analyzed 12 patients with pancreatic cancer brain metastases reported in the literature. They identified two patients who underwent pancreatectomy with curative intent who developed solitary brain metastases (one 11 months and the other 6 years after initial diagnosis). These were surgically resected with subsequent extended survival (5 years and 4 years from diagnosis of the brain metastasis, respectively).
Leptomeningeal Metastases
Peripheral Nervous System Complications
A rare complication of colorectal cancer is lumbosacral plexopathy. This may be a direct effect of the tumor or a secondary complication of radiation therapy. Direct compression from tumor causes back and leg pain followed by sensory changes and weakness. In a review of 85 patients with lumbosacral plexopathy, 17 had colon and 2 gastric cancer [124]. Symptoms differed slightly between colon and rectal cancers. Colon cancer produced radicular pain down the posterior aspect of the leg from lower plexus compression, while rectal cancer was associated with perineal sensory changes from coccygeal plexus involvement. Patients did poorly with a median survival of 5 months from diagnosis of plexopathy. Radiation-induced lumbosacral plexopathy is characterized by painless weakness that progresses and ultimately stabilizes with a fixed deficit. Myokymia may be seen on EMG and provide a clue that neurologic dysfunction is a complication of radiation.
Metabolic Abnormalities
Volume depletion from vomiting or diarrhea results in the secretion of antidiuretic hormone (ADH), which when coupled with free water intake may lead to hypo-osmotic hyponatremia. Low serum sodium levels can manifest symptomatically as lethargy, confusion, seizures, or even coma. Continued volume depletion can further lead to deceased renal perfusion with hypokalemia and azotemia. Severe and persistent emesis can lead to hypokalemic metabolic alkalosis. Hypokalemia and hyperkalemia can present as muscle weakness, while uremia can result in mental status changes. McKittrick–Wheelock syndrome is the constellation of dehydration, hyponatremia, hypokalemia, and azotemia that is directly associated with malignancies in the rectum, most commonly a villous adenoma, although rectal adenocarcinoma has also been implicated [125].
Treatment of volume depletion and electrolyte disorders is supportive and often can be managed with isotonic fluids. Electrolyte replacement should be done with care; it is recommended that the correction rate of serum sodium not exceed 10–12 mEq/L per day in order to prevent osmotic demyelination. Treatment for the underlying cause of the electrolyte imbalance may require surgical intervention to relieve a small bowel obstruction or resect the rectal tumor as the case of McKittrick–Wheelock syndrome. The administration of octreotide or sandostatin LAR can be very helpful in reducing the diarrhea associated with carcinoid syndrome and VIPomas.
Some of the physiologic changes that occur with gastric cancer are related to surgery [126]. One complication is a “gastric dumping” syndrome, where there is a delay in the transportation of food into the small intestine due to loss of a functional pylorus. A second complication is iron and B12 deficiency, the latter due to the loss of intrinsic factor which can cause pernicious anemia, peripheral neuropathy, and subacute combined degeneration of the spinal cord. This has a delayed onset, and patients have loss of proprioception and vibration, ataxia, and loss of deep tendon reflexes. Treatment is with parenteral vitamin B12 replacement.
Neurologic Complications of Chemotherapy
The available treatments for GI malignancy are rapidly expanding, and clinicians must be alert for neurologic complications associated with therapy. The most commonly used agents are covered here.
5-Fluorouracil (5-FU)
Intravenous fluorouracil (5-FU) can rarely be associated with acute and chronic neurotoxicities. The acute toxicities have two clinical presentations: the acute cerebellar syndrome characterized by ataxia, confusion, drowsiness, disorientation, euphoria, headache, nystagmus, and visual disturbances or an encephalopathy with the notable biochemical changes: hyperammonemia and lactic acidosis [14]. These toxicities usually develop shortly after therapy and persist for 48–72 h after therapy has stopped. Dihydropyrimidine dehydrogenase (DPD), which is necessary in clearing 5-FU, is deficient in 2.4% of cancer patients; its absence has been linked to an increase in neurotoxicity [127].
In early studies combining levamisole and 5-FU in the treatment of metastatic colorectal cancer, some patients developed a subacute multifocal leukoencephalopathy manifested as cognitive abnormalities, disturbances of consciousness, dysarthria, focal extremity weakness, and gait and limb ataxia 3–5 months post-therapy [128, 129]. Brain MRI revealed multifocal enhancing white matter lesions, which were both supra and infratentorial. Discontinuation of levamisole generally results in improvement.
Other reported side effects include ophthalmoplegia, optic neuropathy, encephalopathy, focal dystonias, and parkinsonism [28].
Bevacizumab
Bevacizumab is a monoclonal antibody against VEGF. It has been associated with reversible posterior leukoencephalopathy syndrome (RPLS) , which may present with varied neurologic symptoms including headaches, seizures, lethargy, confusion, blindness, or other visual disturbances. Hypertension may precede the symptoms but is not necessary for diagnosis. Magnetic resonance imaging is used to confirm the diagnosis based on characteristic findings. The incidence is less than 0.1% [130]. Bevacizumab increases the risk of arterial thromboembolic events including stroke, transient ischemic attacks, and myocardial infarctions. Although less common than venous thrombotic disease in general, the morbidity associated with arterial events can be quite significant. The bevacizumab study AVF2107 g reported 13 (3.3%) events compared to 5 (1.3%) when treated with and without bevacizumab [131]. Similarly, AVF2192 g reported an absolute doubling of the rate of arterial thrombotic events when bevacizumab was used (10 vs. 4.8%). Of note, the study population had median age of 70 years [87]. In practice, clinicians must exercise caution in prescribing bevacizumab for patients with risk factors for or with known vascular disease. Intratumoral bleeding is another side effect that may occur in tumors; for intracranial tumors, this could be fatal.
Oxaliplatin
Oxaliplatin is a third-generation platinum compound that causes acute and chronic peripheral neuropathies. The acute neurotoxicity may occur during, shortly after, or 1–2 days postinfusion of the drug and is associated with paresthesias, hypesthesias, and dysesthesias. These usually begin in the hands or feet, but may occur around the mouth or in the throat as well. Acute side effects occur at a dose of about 130 mg/m2 [132]. Patients may also have a sense of dyspnea or dysphagia without bronchospasm, wheezing, stridor, or laryngospasm. Patients have described an unusual sensation in the tongue, jaw spasms, eye pain, and muscle spasms or cramps, which are sometimes described as stiffness in the hands or feet or an inability to release grip. Cold temperature may exacerbate symptoms, and patients are educated to avoid cold drinks, wear gloves when handling refrigerated items, and avoid inhaling cold air. Symptoms usually last only a few days post-therapy [133].
One suggestion for the mechanism by which oxaliplatin causes an acute neurotoxicity has been coined “channelopathy.” Oxaliplatin has been shown to be associated with the prolonged opening of sodium-gated channels on peripheral nerves that leads to hyperexcitability [134–136]. Whether this is a direct effect or not is unclear but may be related to the sequestration of calcium by the oxaliplatin–oxalate metabolite.
There are little published data on how to prevent and treat the acute neurotoxicity associated with oxaliplatin. Using a lower dose or increasing the infusion time has been thought to lessen the occurrence of these symptoms [137]. Administering calcium and magnesium salts like calcium gluconate and magnesium chloride has reportedly decreased the occurrence of pharyngolaryngeal dysesthesia (1.6 vs. 26%) [132, 138], although subsequent studies did not confirm this. Amifostine has also been studied as a preventative measure in reducing acute oxaliplatin-induced neuropathy. Patients receiving oxaliplatin, 5-FU, and leucovorin (a common first- or second-line therapy for metastatic colon cancer) in addition to amifostine reported less cold-induced sensitivity. However, there are significant toxicities associated with the administration of intravenous amifostine including hypotension, nausea, and vomiting that may limit its practical use; therefore, a subcutaneous preparation is recommended [139].
Symptoms associated with a more prolonged administration of oxaliplatin (total doses of ≥540–850 mg/m2) include paresthesia, hypesthesia, dysesthesia, and changes in proprioception that do not resolve between cycles. Proprioceptive dysfunction may present with difficulties in fine motor coordination required for writing, holding objects, picking up coins, and buttoning shirts. The chronic neuropathy is cumulative with a reported incidence of grade 3 toxicity occurring in 10% after nine cycles and in roughly 50% after 12–14 cycles (based on oxaliplatin doses of 85 mg/m2 infused over 2 h every 14 days) [140, 141]. Lhermitte’s phenomenon, an electric sensation experienced with neck flexion, has also been reported as a manifestation of chronic oxaliplatin-induced neuropathy [142]. Other central neuropathic symptoms such as urinary retention have also been reported less commonly. Symptoms usually last months with most resolving completely or to grade 1–2 toxicity within 12 months [143]. Rare symptoms include optic neuritis and visual field deficits [144].
Preventive strategies such as those outlined above (e.g., longer infusion time) have some reported efficacy in helping to prevent or at least minimize the chronic neuropathic effects of oxaliplatin. Gabapentin has also been shown to reduce the acute neuropathic toxicity but also prevents the chronic form as well.
Capecitabine
Capecitabine is a prodrug metabolized to 5-FU by thymidine phosphorylase. Neurologic toxicity is rare and limited to one case of peripheral neuropathy and several cases of encephalopathy. The latter is different from that seen with 5-FU/levamisole, as this is a reversible process with diffusion-restricted changes that do not enhance on brain MRI. This process starts earlier than that of 5-FU/levamisole [145, 146]. Capecitabine can cause an erythpalmar dysesthia that may mimic symptoms of neuropathy or give a sense that an underlying neuropathy is worsening.
Gemcitabine
Cetuximab/Panitumumab
Cetuximab and panitumumab are anti-EGFR monoclonal antibodies. Neither carries significant neurologic toxicity, but both have been noted to cause headache in recent trials with metastatic colorectal cancer [149].
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