Page 1291 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

898 PART 7: Hematologic and Oncologic Disorders

metoclopramide), dopamine receptor antagonists (prochlorperazine, steatohepatitis demonstrates a postoperative mortality odds ratio of
haloperidol), and newer neurokinin-1 receptor antagonists (aprepitant). 10.5 and postoperative liver failure odds ratio of 7.7. Adjuvant, locally
64
Neutropenic enterocolitis, or typhlitis, is a necrotizing process involving delivered chemotherapy with floxuridine via a hepatic artery pump is
the bowel as a result of neutropenia most commonly resulting from che- associated with damage to bile ducts and can lead to biliary sclerosis in
motherapeutic treatment of leukemia. Onset is within the first month of up to 35%. Due to this side effect and lack of clear survival advantage,
initiation of chemotherapy and may be occult as in most cases or present use of hepatic artery pump is less common in recent years.
with diarrhea, abdominal pain, and fever. The incidence of neutropenic Of the platinum agents, both carboplatin and oxaliplatin have one
enterocolitis in leukemic patients approaches 46% on autopsy series. 30 or more case reports describing fulminant liver failure, while 15% of
Various forms of hepatotoxicity may occur as a result of anticancer patients treated with carboplatin can experience a transient, reversible
therapies. Venoocclusive or sinusoidal obstructive syndrome is a feared elevation of LFTs (AST, alkaline phosphatase, and bilirubin).
62
complication of bone marrow transplant, which will be discussed below. Dacarbazine has also been implicated in case reports as causing fulmi-
Other manifestations of hepatotoxicity include cholestasis; elevations in nant hepatic failure in patients with melanoma via proposed mechanism
transaminases due to hepatocellular injury; steatosis as seen with treat- of small vein thrombosis.
ment with L-asparaginase; and hepatitis B reactivation and increased High-dose cytoreductive chemotherapy in anticipation of stem cell
hepatitis C viremia as a result of chemotherapy-induced immunosup- transplantation is associated with hepatic venoocclusive disease or
pression particularly in patients being treated for hematologic malig- sinusoidal obstruction syndrome. Incidence ranges from 5% to 60%
nancies and NHL (18% and 40% incidence, respectively). Underlying and clinical diagnosis requires painful hepatomegaly, jaundice, ascites,
liver disease (cirrhosis and viral hepatitis) also increases the risks of fluid retention, and weight gain. The mechanism of disease involves
hepatotoxicity due to dependence of cytochrome P450 oxidation for chemotherapy-induced injury to sinusoidal endothelial cells followed
chemotherapy drug metabolism. Fulminant hepatic failure has been by sinusoidal hemostasis, obstruction, and eventual hepatocyte ischemia
described with IFN-α, though is rare. 62 and necrosis. Secondary effects of sinusoidal obstruction include portal
Many of the anticancer therapies have been found to occasionally hypertension, liver failure, encephalopathy, multiorgan dysfunction,
cause asymptomatic, transient elevations in LFTs. The more common and death with mortality rates up to 98% to 100% in severe cases. 65,66
agents known to cause elevations in bilirubin and transaminases include Until recently, treatment was largely supportive including diuresis and
carboplatin, 6-MCP, 5-FU, pentostatin, and taxanes. The mechanisms dialysis, while efforts toward prevention centered on reduced-intensity
of these LFT abnormalities are largely unclear and incidences are dif- conditioning. Experimental therapies such as t-PA, heparin, and anti-
ficult to determine due to comorbid conditions that may be present. thrombin III have showed little promise in investigational studies.
Vincristine and dactinomycin have been shown to precipitate more Defibrotide is an experimental agent with antithrombotic activity that
severe hepatotoxicity following radiation treatment and dose adjust- has shown response rates of 36% to 76% and improved survival rates in
ments should be considered as in any individual with compromised clinical trials of adult and pediatric patients with VOD. 66,67 A summary
liver function prior to beginning chemotherapy due to increased risks of these GI and hepatotoxicities is available in Table 95-5.
of developing toxicity. 62
topic of intense investigation in the setting of colon cancer with isolated ■ RENAL AND BLADDER TOXICITIES
The hepatotoxic effects of chemotherapy have been a more recent
liver metastasis. With the advent of new chemotherapeutic combina- The bladder and kidneys are at particular risk of toxicity due to anti-
tions, neoadjuvant treatment has shown improved response rates as well cancer therapies because they are the route of elimination for many
as 5-year survival rates after surgical resection. However, with the use of of these agents. Comorbid diseases such as hypertension, diabetes,
new chemotherapeutic regimens came the concern of hepatotoxic side hypovolemia, concomitant nephrotoxic drug use such as nonsteroidal
effects that would affect the function of remaining liver parenchyma. As anti-inflammatory agents, and advanced age may increase the risk of
a result, many studies in the past 5 to 10 years have tried to elucidate the developing chemotherapeutic-induced kidney injury. Acute renal failure
precise hepatotoxic effects of anticancer therapies and how they impact may be precipitated by capillary leak syndrome (prerenal failure), acute
outcome following resection. 63 tubular necrosis (intrinsic failure), or obstruction (postrenal failure).
Steatosis (fat accumulation within hepatocytes) has been associated Examples of therapies causing acute renal failure by these mechanisms
with floxuridine, 5-FU, folinic acid, IFN-α, levamisole while agents are IL-2 (prerenal), ifosfamide and cisplatin (intrinsic), and methotrex-
inducing oxidative stress such as 5-FU, platinums, taxanes, and irino- ate (postrenal).
tecan have been associated with more severe steatohepatitis (fat accu- The heavy metal makeup of platinum drugs results in dose-limiting
mulation associated with inflammation). The impact of steatosis on nephrotoxicity. Cisplatin causes proximal renal tubular impairment
long-term liver function following hepatic resection is unclear, while in reabsorption of water and sodium and increased renal vascular

TABLE 95-5 GI and Hepatotoxicities
Toxicity Common Agents Treatment Comments
Mucositis Anthracyclines, taxanes, platinums Supportive nutrition and hydration; • Risk increases significantly in the setting of concomitant
analgesia; airway protection radiation therapy
• Stem cell transplant recipients most commonly affected
Transient elevations in LFTs Carboplatin, 6-MP, 5-FU, pentostatin, Supportive • Patients with underlying liver dysfunction at higher risk
taxanes, vincristine, dactinomycin of developing LFT abnormalities
Steatohepatitis 5-FU, platinums, taxanes, irinotecan Supportive • Presence of steatohepatitis increases postoperative liver
failure and mortality in patients undergoing hepatic
resection
Biliary sclerosis Floxuridine via hepatic artery pump Supportive • Local delivery causes direct damage to bile ducts
Venoocclusive disease (sinusoidal Alkylating agents, antimetabolites, Supportive; discontinue drug; • Patients undergoing high-dose cytoreductive therapy for
obstructive syndrome) high-dose cyclophosphamide defibrotide (experimental) stem cell transplant most commonly affected

section07.indd 898 1/21/2015 7:43:07 AM