Page 1292 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 95: Toxicities of Chemotherapy 899

resistance leading to a decrease in creatinine clearance on an average hydrolyzing MTX to an inactive metabolite. A list of chemotherapeutic
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of 15% for up to 6 months after treatment. Forced diuresis (normal agent–induced toxicities is provided in Table 95-6.
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saline plus mannitol or furosemide to achieve 24-hour urine volume
avoid nephrotoxicity due to cisplatin by way of dilution and accelerating ■ NEUROLOGIC COMPLICATIONS
of >3 L) was developed in the late 1970s and is now routinely used to
transit time of the agent through the tubules to prevent damage. The glu- Chemotherapy-induced peripheral neuropathy can be a debilitating side
tathione analog, amifostine, has been used to prevent cisplatin-induced effect of cancer therapy. The incidence is likely underestimated as many
nephrotoxicity but not without its own side effects of nausea, vomiting, cases may go undiagnosed unless symptoms are significant prompting
and hypotension. In a study by Hartmann et al, 1000 mg of amifostine diagnostic evaluation. While most cases are reversible after discontinu-
given prior to chemotherapy with cisplatin-based regimens resulted in ation of the offending drug, severe cases may be permanent and have
maintained GFR compared to the control group, which experienced a significant effects on quality of life for a cancer survivor. The signs and
30% decline in GFR. 69,70 symptoms are typical of any peripheral neuropathy and include burning
Renal tubular damage also leads to electrolyte abnormalities such pain and hyperesthesias with loss of pain or temperature sense. With
as hyponatremia, hypocalcemia, and hypomagnesemia in up to 10% progression of neuropathy, involvement of larger nerve fibers can result
of patients due to impaired resorption and excess renal losses. Renal in loss of vibration, proprioception, reflexes, and muscular weakness.
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salt wasting syndrome (RSWS) due to cisplatin can occur as early as Toxicity is generally a dose-dependent, axonal degeneration occurring
12 hours after administration and may be difficult to distinguish from weeks to months after exposure to chemotherapy. Agents commonly
SIADH, which is also common in cancer patients. Therefore, the inci- associated with peripheral neuropathy include vincristine, methotrexate,
dence of RSWS is unclear with estimates anywhere from 1% to 10% in paclitaxel, cisplatin, oxaliplatin, thalidomide, and the newer proteasome
case reports. RSWS is characterized by hyponatremia, polyuria, hypo- inhibitor bortezomib. 78
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volemia, and high urinary sodium concentration with high fractional Vincristine neurotoxicity is predominantly sensory though one-third
excretion of sodium despite volume depletion. Treatment for RSWS is can have autonomic dysfunction as well characterized by orthostatic
restoration of volume and serum sodium via saline infusion (isotonic or hypotension and bladder dysfunction. More severe cases, typically at
hypertonic based on severity of hyponatremia) or salt tablets. Free water high cumulative doses, can begin to involve motor function leading to
restriction will not be effective since urinary losses include salt and water. reduced strength. 78
Carboplatin, due to alterations in chemical structure, compared to It is well established that platinum-based agents are associated with
cisplatin is less nephrotoxic unless used at high doses in anticipation of a dose-dependent sensory neuropathy at doses >500 mg/m in 50% to
2
stem cell transplantation. 90% of patients treated. Oxaliplatin has uniquely been associated with
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Ifosfamide and cyclophosphamide result in production of the renally an acute onset sensory neurotoxicity immediately after infusion. Clinical
cleared metabolite acrolein, which is toxic to the bladder epithelium symptoms include transient paresthesias and muscle spasms in the upper
resulting in hemorrhagic cystitis. Prevention of hemorrhagic cystitis limb and jaw. The mechanism of acute neurotoxicity is secondary to
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is accomplished by vigorous IV hydration and mesna, which binds to axonal hyperexcitability due to altered voltage-gated sodium channel
acrolein. In the event bleeding does occur, bladder irrigation to evacuate function. Chemoprotective agents such as amifostine, glutathione, and
clots is necessary. Ifosfamide can also cause a Fanconi-like syndrome, glutamine have been studied for their neuroprotective effects and while
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typically in children, via proximal tubular damage similar to cisplatin, some small observational studies show promise, larger randomized con-
resulting in electrolyte abnormalities and acidosis. 74 trolled trials need to be performed before their use can be advocated. 81
High-dose methotrexate (1-12 g/m ) causes nephrotoxicity by pre- Bortezomib also causes a dose-limiting peripheral neuropathy in up to
2
cipitation in the renal tubules where it is actively secreted as well as the 37% of those treated characterized by small-fiber axonal neuropathy caus-
collecting ducts resulting in renal failure due to ATN and renal obstruc- ing burning and paresthesias in the hands and feet as well as a debilitating
tion, respectively. Its solubility is pH and volume dependent requiring neuropathic pain and eventual sensory deficits. The onset of neuropathy
urine alkalinization with sodium bicarbonate and IVF prior to admin- occurs after a cumulative dose of 26 mg/m . The majority of patients expe-
2
istration. Adequate pretreatment with these strategies can decrease the rience resolution of symptoms within 3 to 4 months after discontinuation. 82
incidence of methotrexate nephrotoxicity to 1.8%. Treatment with leu- Liposomal cytarabine administered intrathecally for palliation in
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covorin rescue in the event of renal toxicity due to methotrexate is meant cases of lymphomatous meningitis, can cause arachnoiditis in 2% to
to mitigate the potentially harmful nonrenal effects of increased metho- 8% of patients and warrants prophylactic dexamethasone. Presenting
trexate levels that ensue when renal function is impaired. By providing symptoms are difficult to distinguish from those that would otherwise be
reduced folates to nontumor cells, effects on bone marrow suppression attributable to lymphomatous involvement and include headache, back
due to methotrexate may be prevented. In severe cases of renal failure pain, meningismus, and nausea. Other serious neurotoxic side effects
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and methotrexate toxicity (MTX serum level >1 µmol/L), carboxypep- reported include seizure, encephalitis, cauda equina syndrome, and pseu-
tidase has been shown to rapidly decrease serum levels of methotrexate by dotumor cerebri. Nelarabine also has significant neurotoxicity in 20% to
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TABLE 95-6 Renal and Bladder Toxicities
Toxicity Common Agents Treatment Comments
Tubular necrosis Platinums, methotrexate Forced diuresis to achieve urine output >3 L • Amifostine may be used to prevent nephrotoxicity but can
over 24 hours; electrolyte supplementation be associated with nausea, vomiting, and hypotension
Renal salt wasting Cisplatin, carboplatin, Restoration of volume and correction of serum • Distinguished from SIADH by presence of high FE despite
Na
syndrome cyclophosphamide sodium hypovolemia
SIADH Methotrexate, vinca alkaloids, Fluid restriction; serum sodium correction; • Careful attention should be paid to the rate of correction
cisplatin, ifosfamide vasopressin receptor antagonists (conivaptan) of hyponatremia
• SIADH due to chemotherapy may be difficult to distinguish
from SIADH due to underlying malignancy
Hemorrhagic cystitis Ifosfamide, cyclophosphamide Bladder irrigation; vigorous IV hydration • Preventive therapy with mesna and vigorous IV hydration

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