Nephrotoxicity and hemorrhagic cystitis
Drug toxicity, along with drug resistance, remains one of the most significant barriers to the delivery of curative doses of cancer chemotherapy. The most common toxicities of individual chemotherapeutic agents are included in Appendix 2. Several toxicities, eg, those affecting the heart, kidneys, liver, and lungs, are frequently encountered, however. These common toxicities will be discussed in more detail in this chapter.
Chemotherapeutic agents may cause direct injury to the heart, either acutely, in the form of myocardial tissue injury or dysrhythmias, or in a delayed or chronic fashion associated with congestive heart failure. Agents frequently associated with cardiac toxicity are listed in Table 1, along with the doses at which toxicity is commonly encountered.
Principal among the cardiotoxic agents are the anthracyclines, for which cardiac toxicity is the major dose-limiting toxicity.
Acute toxicity These agents can result in acute cardiac dysfunction, particularly supraventricular tachyarrhythmias, within hours of bolus administration. The arrhythmia may be associated with ECG changes, including ST-T segment changes, decreased voltage, T-wave flattening, and atrial and ventricular ectopy. These acute effects occur in up to 40% of patients receiving bolus doxorubicin and are usually transient.
Chronic toxicity Of greatest concern, however, is the chronic toxicity of anthracyclines that occurs weeks or months after administration. The pathogenesis of anthracycline-related cardiotoxicity is mediated, in part, by free radical formation with derangement of mitochondrial function.
Chronic toxicity is manifested as a cardiomyopathy that is dose- and schedule-dependent. Above cumulative bolus doses of 550 mg/m2, the risk of congestive heart failure increases rapidly. Doses < 450 mg/m2 pose a risk of < 10%. Peak plasma levels appear to be important; less cardiac toxicity is seen with continuous infusion schedules.
Mediastinal radiation increases the risk of cardiac toxicity. The cardiac toxicity is only minimally reversible.
A variety of techniques can be used to monitor cardiac function and detect evidence of chemotherapy-induced injury. Noninvasive studies include the echocardiogram and radionuclide ventriculogram (multiple-gated acquisition [MUGA] scan). Percutaneous endomyocardial biopsy can detect subclinical injury to the heart.
Late toxicity Long-term follow-up of patients receiving anthracyclines has also demonstrated late-appearing cardiac toxicity occurring > 5 years after exposure to doxorubicin. Cardiac dysfunction is manifested as congestive heart failure or dysrhythmias and can occur in persons who were previously asymptomatic. It is estimated that ~5% of patients surviving 10 years after exposure to doxorubicin will experience this toxicity.
Toxicity modifiers Two approaches are now available to mitigate anthracycline-induced cardiotoxicity: the administration of liposomal anthracycline preparations and the use of the cardioprotectant dexrazoxane (Zinecard).
Liposomal anthracycline preparations Recent technologic advances have enabled the use of liposomes as carriers for antineoplastic drugs. Preliminary studies show that major toxicities associated with the free drugs are altered and frequently less severe with liposomal formulations.
Liposomal preparations of doxorubicin (Doxil) and daunorubicin (DaunoXome) appear to ameliorate cardiotoxicity without sacrificing antitumor effect. Liposomal drug delivery may allow for the enhancement of dose intensity, selective uptake into tumor cells, and the achievement of concentrations that overcome multidrug resistance.
Dexrazoxane, a derivative of ethylenediamine tetra-acetic acid (EDTA) is a potent intracellular antioxidant and chelating agent. It is believed to act by interfering with iron-mediated free radical generation thought to be responsible for anthracycline-induced cardiac toxicity.
Dexrazoxane is indicated for patients with metastatic breast cancer in whom the cumulative anthracycline dose is > 300 mg/m2 and who would benefit from continued doxorubicin therapy. Dexrazoxane is given in a 10:1 dosing ratio to doxorubicin (eg, dexrazoxane, 500 mg/m2; doxorubicin, 50 mg/m2), administered prior to and within 30 minutes after doxorubicin.
Drugs producing urinary tract toxicity are outlined in Table 2. In general, most agents causing toxic injury to the kidney produce injury to the renal tubules.
Most important among renal tubular toxins is cisplatin (Platinol), which causes injury to both the proximal and distal tubules. Methods to reduce cisplatin toxicity include aggressive hydration with saline at a rate of 2-3 L over 8-12 hours on the day of therapy, often with the addition of mannitol. Hypertonic saline has also been used but does not provide additional renal protective effects and can be deleterious if not administered properly.
Management of acute toxicity of cisplatin, manifested by azotemia and oliguria, includes reducing the dose or discontinuing the drug and aggressive hydration. Dialysis is poorly effective in reversing cisplatin-induced renal failure, and chronic renal insufficiency may persist indefinitely.
Cisplatin is also associated with electrolyte abnormalities, including hypomagnesemia and renal sodium wasting. Management includes oral or IV magnesium replacement and careful replacement of sodium or free water.
Toxicity modifier Amifostine (Ethyol) is a thiol ester that acts as a cytoprotective agent. The active free thiol metabolite can reduce the toxic effects of cisplatin on the kidney (as well as toxic effects in many other organ systems exposed to chemotherapy and radiation therapy) by binding to free radicals generated in the tissues.
Amifostine is indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin. It does not interfere with the effectiveness of cisplatin. Doses range from 200 to 910 mg/m2, given by rapid IV infusion within minutes of chemotherapy or radiation therapy. It is rapidly metabolized, can cause transient hypotension, and is emetogenic.
Cyclophosphamide and ifosfamide
Cyclophosphamide (Cytoxan, Neosar) and ifosfamide (Ifex) are associated with hemorrhagic cystitis in ~10% of patients being treated with standard doses. Incidence may increase to as high as 40% in patients receiving high-dose chemotherapy with bone marrow transplantation (BMT). Patients may exhibit microscopic hematuria (93%) or gross hematuria (78%).
Also associated with ifosfamide use is a proximal renal tubular defect, which manifests as low serum bicarbonate with losses of uric acid, phosphate, glucose, calcium, and free amino acids. Ifosfamide and cyclophosphamide are associated with hyponatremia and a syndrome similar to the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Multiple chemotherapeutic agents require dose alterations with impaired renal function. A general guideline is provided in Table 3.
Toxicity modifier The uroprotective agent mesna (Mesnex) is often given with ifosfamide and cyclophosphamide to protect against acrolein, the metabolite that is toxic to bladder mucosa and results in hemorrhagic cystitis. The appropriate dose of mesna is controversial, and recommended doses range from 60%-160% of the cyclophosphamide dose. The optimal schedule of mesna uroprotection is not well defined, but administration should begin prior to or concurrent with alkylating agent administration.
Once hemorrhagic cystitis develops, conservative therapies, such as clot evacuation, continuous bladder irrigation with saline or hydrocortisone, or systemic aminocaproic acid, can be used. Other more aggressive therapies include cystoscopy and fulguration, intravesical formalin, intravesical prostaglandins, oral or parenteral estrogens, or intravesical administration of silver nitrate, phenol, or aluminum hydroxide. Intractable cases may require urinary diversion, internal iliac artery ligation or embolization, or cystectomy.
The liver is the site of metabolism of most chemotherapeutic agents (Table 4), and many agents are directly hepatotoxic (Table 5). Hepatotoxicity can be acute or chronic and is most often manifested as an elevation of transaminases. Veno-occlusive disease of the liver can be observed in the setting of high-dose chemotherapy and BMT or radiotherapy to the liver. Pathologically, it is characterized by nonthrombotic obliteration of small intrahepatic veins by loose connective tissue. Clinical features include acute upper abdominal pain, hepatomegaly, ascites, weight gain, and jaundice.
Guidelines for the adjustment of common chemotherapeutic agents in the setting of hepatic dysfunction are outlined in Table 6. A clinical study is currently underway to define the use of the taxanes in patients with altered hepatic function.
Agents that commonly result in pulmonary toxicity are outlined in Table 7.
Notable among these agents is bleomycin (Blenoxane), which produces severe pulmonary fibrosis. Bleomycin concentrates in the lung and skin because of negligible hydrolase for bleomycin inactivation in these organs. Therefore, bleomycin has a direct effect on the pulmonary capillary endothelium and type I pneumocytes. Bleomycin produces free radicals through an oxidative shunt between ferrous and ferric ions, and this free radical oxidation is responsible for the toxic injury to capillary endothelium.
Risk factors for the development of pulmonary toxicity with the use of bleomycin include the total dose administered, increasing age of the patient, prior pulmonary function abnormalities, prior or concomitant radiotherapy, exposure to high-dose oxygen, and concomitant administration of other chemotherapeutic drugs, including doxorubicin, cyclophosphamide, vincristine, dexamethasone, and methotrexate.
Supplemental oxygen may cause severe pulmonary damage. Patients undergoing surgery should not have oxygen concentrations exceeding a fraction of the inspired oxygen (FIO2) of 30%. Pulmonary toxicity appears to be related to dose, with an increased incidence when the total dose is > 400 units. Pulmonary function tests should be followed routinely during bleomycin therapy and the drug discontinued for significant (> 10%-15%) changes in function.
Skin changes associated with chemotherapy drugs can have a wide variety of manifestations including rashes, dermatitis, hyperpigmentation, urticaria, photosensitivity, nail changes, alopecia, and radiation recall. Table 8 lists some of the commonly associated dermatologic toxicities associated with selected drugs.
Hand-foot syndrome, or palmar-plantar erythrodysesthesia, involves dry, painful, erythematous, hyperpigmented skin conditions commonly associated with continuous infusion of fluorouracil (5-FU); liposomal preparations, such as liposomal doxorubicin; or prolonged therapy with hydrea or high-dose methotrexate.
Rashes Infusion of carmustine (BCNU), cytarabine (Ara-C), gemcitabine (Gemzar), asparaginase (Elspar), and procarbazine (Matulane) can cause transient rashes. These are often responsive to diphenhydramine or steroids.
Photosensitivity Mitomycin, 5-FU, methotrexate, vinblastine, and dacarbazine (DTIC) can induce photosensitivity.
Nail changes A variety of nail changes can result from chemotherapy. Usually, changes in nail pigmentation are noted, with banding and streaks starting at the base of the nail as it grows out. Cyclophosphamide, doxorubicin, and 5-FU cause nail pigment changes, and these are more common in black patients. Bleomycin and, more recently the weekly administration of taxanes, have been noted to produce excessive nail brittleness and nail loss.
Skin hyperpigmentation can occur with a variety of drugs, most notably, busulfan, bleomycin, thiotepa, 5-FU, and methotrexate.
Radiation recall is a phenomenon in which a skin reaction is observed after chemotherapy administration in areas that were previously irradiated. DTIC and doxorubicin are the usual agents associated with radiation recall. Methotrexate and 5-FU can also cause this effect.
The oral mucosa is very sensitive to chemotherapeutic drugs because the tissue is subject to rapid turnover. Stomatitis (mucositis) usually begins within days of the initiation of chemotherapy, and symptoms of mucositis often parallel hematologic toxicity. Painful ulcerations can occur throughout the GI tract, from the lips to the anus.
Agents that are commonly associated with stomatitis include bleomycin, doxorubicin, 5-FU, and methotrexate. The dose and schedule of these drugs influence the severity of toxicity. Continuous infusions of 5-FU and doxorubicin can cause severe stomatitis; therefore, at the earliest signs of mouth soreness, infusions of these drugs should be discontinued.
Management Prevention with good dental care, salt and mouthwash, and chewing ice during chemotherapy can help diminish stomatitis. A variety of oral analgesics can be utilized for more severe cases.
Diarrhea occurs quite frequently during chemotherapy and can stem from a number of causes. Certain chemotherapeutic agents frequently cause diarrhea; these include the cell-cycle–specific agents 5-FU, methotrexate, Ara-C, and irinotecan (CPT-11 [Camptosar]).
In most cases, the diarrhea is self-limiting and resolves within several days once the drugs are withheld. Irinotecan can cause a profound secretory diarrhea that has both acute and chronic phases.
Management If aggressive antidiarrheal prophylaxis is taken, including atropine for the acute phase and regular diphenoxylate hydrochloride/atropine sulfate (Lomotil and others) starting at the earliest onset of loose stools, such complications as dehydration and electrolyte imbalances can be minimized.
Most cases of chemotherapy-induced diarrhea can be controlled with dietary measures (low-residue, bland diet, and plenty of noncarbonated beverages), diphenoxylate hydrochloride/atropine sulfate, loperamide (Imodium and others), and camphorated tincture of opium (Paregoric). In refractory cases, octreotide (Sandostatin) can be utilized.
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