Oncological emergencies associated with gastrointestinal tumors

Neutropenic fever (NF)

NF is defined as fever in a neutropenic patient either one episode of above 38.3°C or a temperature above 38°C sustained for more than 1 h [5]. The definition of neutropenia is not uniform but neutropenia is usually defined as an absolute neutrophil count (ANC) below 1000 cells/μL and severe neutropenia as <500 cells/μL or an ANC that is expected to decrease below 500 cells/μL [5]. Although mortality from NF has decreased, it still remains significant with a 5% mortality rate in high-risk and 1% in low-risk patients [6]. Most patients with GI tumors treated with chemotherapy are expected to be neutropenic (<500 cells/μL) for ≤7 days which makes them less at risk for complications [5]. However, patients with comorbidities such as pulmonary and cardiovascular diseases and patients with hepatic or renal dysfunction are considered high risk for complications requiring hospitalization, regardless of the duration of neutropenia. The Multinational Association for Supportive Care in Cancer (MASCC) has developed a MASCC risk index, which is a validated tool for estimating the risk for NF-related complications [7]. Patients with NF with a MASCC score ≥21, without clinical alarm signs, can be safely managed in the outpatient setting and are treated with a combination of oral fluoroquinolones and amoxicillin/clavulanate [8]. An alternative is the use of oral moxifloxacin [9]. High-risk patients with NF require hospitalization and treatment with intravenous antibiotics. It is important that antibiotics are started within 1 h from NF diagnosis after taking blood and urine cultures. The source of infection is only identified in about 20% of patients and most of the identified infections are believed to arise from the endogenous flora. In high-risk patients fungal pathogens are also more common than in low-risk patients. The use of colony stimulating factors (CSF) did not show any effect on the overall survival, but induced a faster recovery from fever and shorter hospital stay [10]. Most guidelines do not recommend the use of CSF for the management with NF except in patients with high-risk features such as older age, pneumonia, hypotension, sepsis and being hospitalized at the time of development of fever [11].

Neutropenic enterocolitis (NE, typhlitis)

NE is a life-threatening condition caused by mucosal injury by chemotherapy in combination with profound neutropenia and impaired host defense to invasion by microorganisms [12]. The syndrome is most often associated with hematological malignancies but can also occur in patients with solid tumors receiving chemotherapy. The cause of death in these patients is usually sepsis and mortality rate is extremely high. NE must be considered in all severely neutropenic patients with fever and abdominal pain (usually right lower quadrant). A CT scan can reveal the characteristic findings such as bowel wall thickening, bowel dilatation, pneumatosis coli and mesenteric stranding. Treatment consists of broad-spectrum antibiotics (ex. piperacillin-tazobactam), nasogastric suction as well as fluid and nutritional support. In case of perforation, abscess formation or persistent bleeding, surgery is the only option.

Disseminated intravascular coagulation (DIC)

DIC is a potentially life-threatening condition, characterized by an abnormal activation of coagulation and fibrinolysis leading to thrombosis and hemorrhage simultaneously [13]. It occurs in a variety of diseases, including cancer [14]. About 10-15% of metastatic cancer patients have some evidence of DIC. It is mostly associated with acute leukemia, but can also occur in mucinous tumors such as pancreatic and gastric cancer [15]. Some patients have only a mild clinical course with consumption of coagulation factors while others present with life-threatening bleeding. Treatment consists of treating the underlying cause in combination with supportive measures such as hemodynamic support, hydration and transfusion.

Spinal cord compression (SCC)

SCC occurs in approximately 5% of cancer patients and is most often due to extradural spread from vertebral metastases [16]. It can cause pain and irreversible loss of neurologic function. Although all tumors can cause SCC, it most often occurs in patients with cancers with a tendency to metastasize to the spinal column such as breast cancer, lung cancer, lymphoma, prostate cancer and myeloma [17]. In tumors of the digestive tract SCC is rather rare, for example only 2% of all cases with SCC had colorectal cancer as a primary tumor [17]. However, because of the increased overall survival of colon cancer patients due to the recent advances in the treatment of systemic disease and because of the poor delivery of chemotherapeutic drugs across the blood-brain barrier, chances to develop SCC secondary to vertebral metastases are likely to rise.

Pain is usually the first symptom of SCC and precedes neurologic symptoms. Prompt diagnosis and immediate treatment might impact neurological outcome. MRI is the preferred imaging modality to diagnose SCC. Treatment consists of administration of glucocorticoids [18] followed by either surgery and/or radiotherapy depending on the presence of spinal instability, radiosensitivity of the tumor and degree of SCC.

Brain metastases

Due to advances in the efficacy of systemic chemotherapy, there is an increase in the incidence of brain metastases as patients with metastatic cancer have an improved overall survival the last decades [19]. Still, in most GI tumors, such as for example colon cancer, incidence of brain metastases remains low. The clinical features of brain metastases are very variable, but most patients develop symptoms related to increased intracranial pressure, such as headache in combination with nausea and vomiting. A smaller percentage (15%) of patients develops seizures or focal neurologic dysfunction [20]. The manifestation of symptoms depends on the localization of the metastases. In rare cases patients present with stroke caused by a hemorrhage in metastases or embolization of tumor cells. For diagnosis, contrast-enhanced MRI is the preferred imaging study. Patients with signs of increased intracranial pressure should be treated with intravenous corticosteroids. Further treatment depends on the patients overall prognosis. In patients with limited extracranial disease and chemotherapeutic options, brain surgery and/or radiotherapy (whole brain or stereotactic) can be indicated. Systemic therapy is generally not adequate for brain metastases although the blood-brain barrier is not always impermeable as it is sometimes disrupted. Thus, in case of no other options and when the tumor is still chemosensitive, systemic therapy can be an option in those patients.

Some patients also develop leptomeningeal carcinomatosis, which can be confirmed by either imaging and/or evaluation of cerebrospinal fluid. The prognosis of these patients is very poor with a survival of only a few months. Sometimes intrathecal chemotherapy is given, although its superiority to systemic chemotherapy has never been established in clinical trials especially in patients with GI tumors and can therefore only be recommended in selected cases.

Superior vena cava (SVC) syndrome

SVC syndrome results from a mechanical obstruction of the blood flow through the SVC. This can be caused either by external compression of the SVC by an adjacent tumoral process or by thrombosis within the SVC. Although most commonly SVC syndrome is caused by lung cancer (75% of cases) and non-Hodgkin lymphoma it can rarely also occur in other solid tumors with mediastinal lymph node metastases [21]. The symptoms of facial swelling, dyspnea and distended neck veins depend upon the rate at which obstruction of the SVC occurs and thus the time for development of venous collaterals. In case of airway obstruction of laryngeal edema urgent treatment is indicated. Chest CT is the mainstay of diagnosis. Treatment depends upon the type of cancer, prognosis and whether or not the patient was already pretreated. In case tumors present with SVC syndrome, a histological diagnosis is obligatory to define the best treatment plan. In chemotherapynaïve patients in whom a rapid clinical response is expected (for example germ cell tumors or lymphoma), chemotherapy can be the first choice. In other patients, either radiotherapy or endovenous stenting are valuable alternatives. Corticosteroids are often used in conjunction with radiotherapy to decrease edema. When SVC syndrome is caused by an extensive thrombosis, either catheter-directed thrombolysis or mechanical thrombectomy is the preferred choice of treatment [22].

Intestinal obstruction

GI tumors can often cause mechanical small bowel obstruction either by intrinsic or extrinsic compression. Especially some tumors, e.g. located in the colon, pancreas and stomach, are more likely to disseminate in the peritoneum and subsequently cause mechanical obstruction. Tumors can also impair bowel motility by invasion of the celiac plexus. There are no guidelines on the role of palliative surgery versus medical management. However, we feel that in the absence of urgent indications for surgery (such as perforation, bowel infarction), preference should be given to medical treatment including GI decompression using a nasogastric tube, adequate hydration and controlling nausea and vomiting. A randomized, doubled blind, placebo-controlled phase III study also showed efficacy of the somatostatin analog lanreotide in patients with inoperable bowel obstruction resulting from peritoneal carcinomatosis [23]. Palliative surgery should only be considered in selected patient with limited metastatic disease. In most metastatic cancer patients palliative surgery is associated with high mortality [24]. In cases with isolated gastric outlet or colonic obstruction, endoscopic stent placement should be considered although there is a risk of stent migration, re-occlusion or bowel perforation.

Hypercalcemia

Hypercalcemia is the most common metabolic emergency in cancer patients, occurring in approximately 20-30% of patients [27]. Most common tumor types associated with hypercalcemia are breast, kidney and lung cancer, and multiple myeloma, although it also occurs in digestive tumors such as esophageal cancer [28]. Patients with hypercalcemia of malignancy often have a bad prognosis. Hypercalcemia occurs either by osteolytic metastases or by tumor production of calcitriol (1,25-dihydroxyvitamin D) or parathyroid hormone-related peptide. Clinically, patients are often asymptomatic until reaching high levels. Then neurologic changes occur such as fatigue, muscle weakness, stupor and coma. Hypercalcemia may also cause cardiac abnormalities such as arrhythmias, heart block and even cardiac arrest [29]. GI symptoms include anorexia, nausea, vomiting, ileus, constipation, and, in rare cases, pancreatitis. Often patients complain of polyuria and polydipsia due to inability of concentrating the urine, and, as the hypercalcemia persists, progressive renal insufficiency occurs (caused by calcium deposits in the kidney).

Aggressive treatment should be initiated as quickly as possible depending on the severity of the hypercalcemia. In general, patients with calcium >14 mg/dL (3.5 mmol/L) require therapy with volume expansion with isotonic saline to maintain sufficient urine output. For short-term management (in the first 48 h), calcitonin can be used which increases renal calcium excretion an decreases bone resorption via interference with osteoclast function [30]. Furthermore, biphosphonates (preferably zoledronic acid) should be administered for longer term control of hypercalcemia [31], with a maximum effect after 2-4 days. Since bisphosphonates are potentially nephrotoxic, caution is warranted when used in patients with impaired renal function. Dose reduction in combination with adequate hydration may minimize the risk. As a last option, hemodialysis is an effective treatment.

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

SIADH occurs in approximately 1-2% of cancer patients. It should be suspected in any cancer patient with hyponatremia in combination with hypo-osmolality and high urine osmolality. It results from ADH-induced retention of ingested water. Ectopic production of ADH by a tumor is most often associated with lung carcinoma (especially small cell) but can also occur in other tumors such as head and neck cancer and rarely in GI tumors such as esophageal, gastric, pancreatic, and colon cancer [32]. Antineoplastic drugs such as cisplatin are also well known to cause hyponatremia by a mechanism that may involve SIADH. Clinical symptoms depend on the level of hyponatremia and the rapidity of onset. Symptoms include changes in mental status, apathy, fatigue, headache, seizures and ultimately coma. Management involves control of the underlying tumor as well as fluid restriction of 500 mL to 1 L/day. In severe cases patients can be treated with hypertonic saline by slow infusion at a rate to increase the serum sodium level by 0.5-1.0 mEq/L/h. Sometimes isotonic saline is used as an alternative, however the electrolyte concentration of the administered fluid has to be greater than the concentration in urine, otherwise isotonic saline will not be effective and will even lead to further lowering of the serum sodium [33]. Loop diuretics are only recommended when urine osmolality is more than twice the plasma osmolality thereby increasing water excretion.