Digestive system emergencies
Neutropenic appendicitis
Neutropenic appendicitis is seen in patients with hematologic malignancies or solid tumors treated with high doses of chemotherapeutic agents. It can be caused by chemotherapy with paclitaxel, cisplatin, oxaliplatin, irinotecan, and anthracyclines and is characterized by inflammation of the entire intestinal wall, usually involving the ileocecal region, with bone marrow suppression and marked neutropenia.
The pathophysiological mechanism of neutropenic appendicitis has not been fully elucidated, but it is usually thought that cytotoxic drugs cause acute mucosal injury, leading to secondary infection of the intestinal wall in immunosuppressed patients, resulting in abscesses and intestinal perforation. The cecum has a poor blood supply and can be dilated, increasing the chance of infection. The patient’s autopsy and surgical specimens showed dilated edema of the intestinal wall, mucosal ulceration and necrosis, and common bacterial foci, but no leukocytes among them.
The typical clinical presentation of neutropenic appendicitis is pain and fever in the right lower abdomen, similar to acute appendicitis, and signs of peritonitis and abscesses may be present. The diagnosis of this emergency is made mainly by clinical manifestations. Laboratory tests may reveal neutropenia, and most patients have normal abdominal plain films, which may also show thickening of the intestinal wall or thumbprint signs. Abdominal CT shows thickening of the colonic wall, peri-colonic inflammation, cystic pneumatosis of the intestinal wall and ascites. Ultrasound of the abdomen typically shows thickening of the intestinal wall (>4 mm) with abundant blood flow. Stool and blood cultures are useful for diagnosis.
Initial treatment does not recommend surgery, but fasting with fluids and broad-spectrum (covering anaerobes) antibiotics and granulocyte colony-stimulating factor for patients with signs of systemic infection. The efficacy of surgery is unclear, but it is still an option when conservative treatment is ineffective, the disease worsens, and complications such as intestinal obstruction, perforation, or necrosis occur. Follow-up chemotherapy with the same drugs again is not recommended because of the risk of recurrence and serious complications.
Toxic megacolon
The mechanism of toxic megacolon may be due to chemotherapy-induced intestinal wall damage, presumably related to ischemic injury, but the exact mechanism is unknown. toxic megacolon has occurred with the MACE regimen for acute myeloid leukemia, the ChlVPP regimen for Hodgkin’s lymphoma, and the FEC regimen for breast cancer.
Patients present clinically with abdominal pain, abdominal distension, fever, palpitations or other septic manifestations such as shock, and abdominal plain radiographs show a markedly dilated colon (usually >6 cm). The diagnosis must first exclude infections, especially those of Clostridium difficile.
Initial treatment is symptomatic and supportive, including rehydration, correction of electrolyte disturbances, fasting and broad-spectrum antibiotics, and, if necessary, analgesia and blood products. If the bowel dilatation increases further, intestinal decompression must be attempted to reduce the risk of bowel perforation. If conservative treatment is ineffective, surgical treatment is required, preceded by palliative colostomy until the patient recovers from the allocytopenic state and, if necessary, total colectomy. Considering the seriousness of this toxic side effect, subsequent chemotherapy with the same drug is not recommended.
Toxic megacolon flat tablets
Acute pancreatitis
Although cases of pancreatitis secondary to chemotherapy have been reported, it is difficult to identify the specific drugs that cause pancreatitis because supportive drugs, such as steroid hormones and 5-hydroxytryptamine 3 receptor antagonists, are often combined with chemotherapy regimens. In addition, pancreatic metastases from tumors can also induce pancreatitis. Acute pancreatitis has been found to be associated with paclitaxel, isocyclophosphamide, vincristine, cisplatin, cytarabine, vincristine, and levomucoidase.
Patients tend to develop epigastric pain within hours of drug administration (and possibly up to 1 month after chemotherapy), mostly with nausea and vomiting. The diagnosis of acute pancreatitis can be made if the patient is found to have elevated plasma amylase and lipase concentrations that are more than three times the upper limit of normal, and other causes such as cholelithiasis or bile duct dilatation must be excluded. Blood glucose, liver and kidney function, lactate dehydrogenase, calcium and triglyceride concentrations, and arterial blood gas analysis should be performed to assess the severity of the disease using the Ranson score. Plain abdominal radiographs usually show normal, but sometimes there is a typical presentation of anterior intestinal collaterals, and abdominal CT shows pancreatic inflammation and edema.
Most chemotherapy-induced pancreatitis is treated conservatively, including intravenous rehydration, analgesia, and parenteral nutrition. Given the high risk of recurrence in this acute condition, each patient should be evaluated individually for severity of pancreatitis, primary disease, and whether to continue treatment. If chemotherapy is necessary, medication must be changed to avoid recurrence of pancreatitis and reduce the risk of death.
Neurological emergencies
Cerebrovascular events
Patients with malignancy are at high risk of cerebrovascular events. In addition to progression of the primary disease, some chemotherapeutic agents increase the risk of stroke, the most common being cisplatin, followed by methotrexate, fluorouracil and levomepromazine.
In a retrospective study, Li et al. followed 10,963 patients with tumors treated with chemotherapy for 1 month and showed that the incidence of ischemic stroke after chemotherapy was 0.137%, with 75% occurring within 10 days of chemotherapy and 63% after the first course of chemotherapy; cisplatin-based chemotherapy regimens were also associated with an increased risk of stroke. Cisplatin-based chemotherapy regimens mostly lead to cerebrovascular events; the median survival of patients after stroke is 4 weeks and the prognosis is poor.
The mechanism of ischemic stroke due to cisplatin may be due to renal tubular dysfunction, hypomagnesemia, vasospasm, ischemia, and reduced magnesium concentration secondary to hyperreninemia. In patients with testicular tumors, long-term use of cisplatin-based chemotherapy regimens increases serum cholesterol levels and increases the risk of cerebrovascular events, especially when other cardiovascular risk factors are present. Cisplatin may also decrease fibrinolytic enzyme activity and increase fibrinopeptide A concentrations, placing the blood in a hypercoagulable state and thereby increasing the risk of vascular disease.
Fluorouracil can cause vasospasm, and the combination of cisplatin and fluorouracil may increase the risk of cerebrovascular events. High doses of intravenous and intrathecal methotrexate have also been associated with stroke, possibly secondary to a direct neuronal toxic response, while elevated cysteine concentrations have a direct effect on the vascular endothelium. L-menthaminase increases the risk of both hemorrhagic and ischemic cerebrovascular events, and patients treated with menthaminase are susceptible to cerebral hemorrhage or thrombosis affecting cerebral arteries or dural sinuses, which is associated with reduced plasma concentrations of proteins associated with coagulation and fibrinolysis.
Patients who develop signs and symptoms of cerebrovascular disease after chemotherapy should be admitted to the hospital for testing. Initial investigations include coagulation screening to rule out malignancy-associated DIC; CT or MRI of the brain to clarify whether the stroke is ischemic or hemorrhagic, and to rule out tumor brain metastases. Correction of risk factors (e.g. hypertension, hypercholesterolemia, electrolyte disturbances) is important to reduce the risk of subsequent cerebrovascular events. In thromboembolic stroke due to levomepsy, after exclusion of hemorrhage, anticoagulation therapy for 3-6 months is recommended, and if the patient does not respond to anticoagulant drugs, antithrombin therapy is recommended. The anticoagulant may be used prophylactically along with levomepromazin therapy. Chemotherapy with other drugs that have produced toxicity is not recommended again.
Reversible posterior leukoencephalopathy syndrome
Reversible posterior leukoencephalopathy syndrome (RPLS) is a neurological disorder with clinical manifestations of headache, altered state of consciousness, epileptic seizures, visual abnormalities, and typical white matter abnormalities on imaging. The syndrome was initially seen in patients with immunosuppressed states, renal insufficiency, and hypertension, and was later found to be associated with the use of cisplatin, gemcitabine, cytarabine, methotrexate, cyclophosphamide, isocyclophosphamide, and etoposide.
CT manifestations of RPLS
The pathophysiological mechanism of RPLS is not known, but the mechanism of RPLS in hypertensive patients may be due to secondary cerebrovascular The risk factors for RPLS include blood volume load >10% of baseline body weight, mean blood pressure >25% of baseline, and creatinine concentration >0.16 mmol/L.
In most patients, after removal of the causative factors, such as controlled blood pressure in hypertensive patients, the lesion is reversible and MRI abnormalities can be recovered within a few months. In a few cases, if this symptom is unrecognized or untreated, persistent neurological symptoms progress to cerebral infarction, cerebral hemorrhage and death. Chemotherapy (including intrathecal injections) may be continued after symptoms have completely resolved. However, if symptoms reappear, blood pressure must be tightly controlled and discontinued, and subsequent treatment is best switched to other drugs.
Acute skin reactions
Stevens-Johnson syndrome and toxic epidermal necrolysis can cause acute skin reactions with both chemotherapeutic and supportive care drugs, so it is sometimes difficult to determine which drug is causing the skin reaction. Skin reactions can also be caused by infection, so it is difficult to determine whether the malignant disease itself or the drug is causing the patient to be at increased risk for an infectious skin reaction. Drugs that can cause acute skin reactions include bleomycin, cyclophosphamide, paclitaxel, capecitabine, fluorouracil, methotrexate, azelnine, and etoposide; supportive therapies include allopurinol, anti-inflammatory drugs, and a variety of antibiotics (sulfonamides and penicillins).
The mechanism of acute skin reactions associated with chemotherapy may be due to immune-mediated skin damage, resulting in skin mucosal exfoliation and necrosis; Stevens-Johnson syndrome is a mild skin reaction with limited lesions and <10% of the skin involved, whereas severe skin reactions with toxic epidermal necrosis typically involve more than 30% of the skin and are almost always associated with mucosal involvement. Skin involvement is accompanied by systemic symptoms of fever and malaise.
The mortality rate for Stevens-Johnson syndrome is 1% to 3%, and the mortality rate for toxic epidermal necrolysis is as high as 20% to 30%. If this type of acute skin reaction occurs, immediate supportive treatment is required, including extensive rehydration, care of the skin breakdown, nutritional support, eye protection, and antibiotic therapy, and most patients are treated individually. It is not clear whether steroid hormone therapy is effective. Re-use of chemotherapy with the same drug is not recommended.
Hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura
These two syndromes are very rare chemotherapeutic emergencies, but have been clearly reported. Their common features are thrombocytopenia and microangiopathic hemolytic anemia with multisystem involvement and organ failure. Hemolytic uremic syndrome (HUS) is characterized by acute renal failure due to renal cortical necrosis, whereas thrombotic thrombocytopenic purpura (TTP) is characterized by neurological symptoms such as seizures and coma.
Pathological features of TTP
Cisplatin, vincristine and gemcitabine have been found to be associated with both diseases, but the incidence is less than 1% in both cases. The pathological mechanism is mainly due to drug damage to endothelial cells, which is related to the drug dose. The main treatment measures are discontinuation of the suspected drug, strict blood pressure control and, if necessary, hemodialysis. Usually, plasma exchange is ineffective if the disease is caused by chemotherapy, while when it is caused by other causes, plasma exchange can be attempted if the patient’s condition is deteriorating despite aggressive management. Re-chemotherapy with the same drug is not recommended.
Drug-related hepatotoxicity
Although elevated transaminases are common with chemotherapy, only a few cases of drug reactions resulting in acute fulminant liver failure and death have been reported. This acute illness was associated with gemcitabine, docetaxel and liposomal doxorubicin. There are multiple mechanisms of liver failure, including drug-induced cholestasis, hepatic necrosis, and veno-occlusive disease. Veno-occlusive disease is associated with high-dose chemotherapy regimens, particularly bone marrow pretreatment regimens at the time of bone marrow transplantation. 10-20% of patients treated with high-dose cyclophosphamide, leucovorin, cetapide, melphalan and vincristine develop these complications.
Patients with abnormal liver function after chemotherapy should be distinguished from viral hepatitis, progression of tumor metastases, and systemic toxicity due to decreased drug excretion in liver failure by performing liver ultrasound and screening for acute viral hepatitis. Management is immediate discontinuation of the drug and hepatoprotective therapy, but if fulminant liver failure is determined to exist, liver transplantation is the only viable option if appropriate. Reintroduction of any drug that may cause fatal liver injury is not recommended, and extra care should be taken when choosing chemotherapy regimens again, as many drugs require dose adjustment in the presence of hepatic insufficiency.
Acute vascular events
Chemotherapeutic agents, especially cisplatin, have been associated with the occurrence of vascular events (cerebrovascular events, venous thromboembolism, pulmonary embolism, and myocardial infarction). Some drugs, particularly cisplatin and fluorouracil, can cause acute arterial vasospasm, such as acute coronary artery spasm.
Acute arterial obstruction
Post-chemotherapy arterial obstruction leading to acute limb ischemia is seen with cisplatin-based chemotherapy regimens and can also occur with carboplatin combination chemotherapy regimens. The mechanism is the same as that of cisplatin leading to cerebrovascular events.
Patients present with progressively more severe pain, numbness, pallor, coldness of the affected limb, loss of pulse, diminished capillary refill, skin floridities, and in severe cases, paralysis.
Treatment includes intravenous heparin anticoagulation and, if necessary, surgical removal of the embolus. Angiography can help to understand the extent of the blockage, and revascularization can be achieved by percutaneous endovascular angioplasty. If there are no contraindications, thrombolytic therapy and, if necessary, open surgery to recanalize the vessel are possible. In addition, cardiac ultrasound must be performed to exclude emboli of cardiac origin, and coagulation disorders must also be excluded. Acute limb ischemia usually occurs in patients with a history of atherosclerosis and peripheral vascular disease. Reintroduction of chemotherapy with the same drug is not recommended, and caution should be exercised with subsequent chemotherapy with other drugs (especially platinum-based drugs).
Acute arterial obstruction
Acute mesenteric ischemia
Treatment with cisplatin, fluorouracil, cyclophosphamide, and methotrexate is associated with acute mesenteric artery obstruction, resulting in mesenteric ischemia.
The typical clinical presentation of the disease is an acute onset of abdominal pain, and most patients also have signs of peritonitis. CT angiography can be used to confirm the diagnosis, but usually in the setting of open surgery to remove the infarcted and necrotic bowel. The mortality rate of acute mesenteric ischemia is high and therefore chemotherapy with the same drug is not recommended again.
In summary, the most common drugs that cause these rare emergencies are familiar and frequently used chemotherapeutic agents and deserve the attention of clinicians. When these emergencies occur, it is important to not only diagnose and treat them in a timely manner, but also to keep in mind that subsequent chemotherapy should be carefully selected or avoided with the same drug.
With the increasing incidence of tumors and the widespread use of chemotherapy drugs, clinicians should be more alert to rare and life-threatening chemotherapy emergencies, and early diagnosis and timely and correct management are very important to achieve the best therapeutic efficacy and improve patient prognosis. While there are relatively few articles on the treatment of rare complications of chemotherapy in oncology, it is therefore necessary to emphasize that oncologists actively report rare chemotherapy toxic reactions in clinical practice, which is important to improve clinicians’ ability to identify chemotherapy drug side effects and determine the best treatment plan.