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  Most antineoplastic agents have toxic side effects.

  
  
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  New antineoplastic agents are frequently being developed and not all side effects are known.

  
  
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  Diagnosis or organ dysfunction due to drug toxicity is largely a diagnosis of exclusion.

  
  
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  Maintaining a level of clinical suspicion is key to detection of drug toxicity.

  
  
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  Therapy for drug-induced toxicity is largely supportive.

  
  
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  Myelosuppression is a common toxic side effect from high-dose combination chemotherapy regimens used in leukemia and bone marrow transplant patients.

  
  
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  Pulmonary toxicity may manifest as ARDS especially in patients undergoing treatment for hematologic malignancies (eg, cytarabine or gemcitabine) and pulmonary fibrosis (eg, bleomycin).

  
  
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  Cardiotoxic side effects of anthracyclines such as doxorubicin can lead to refractory heart failure if not identified and managed early, while treatment with 5-FU may precipitate symptoms of acute MI due to vasospasm in patients with underlying risk factors for heart disease.

  
  
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  Mucositis of the oropharynx and GI tract is painful and can lead to dehydration and malnutrition. Severe cases of oral mucositis may require intubation for airway protection.

  
  
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  Intractable nausea, vomiting, and diarrhea can lead to dehydration, hypovolemia, and electrolyte disturbances.

  
  
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  Nephrotoxicity is a dose-limiting side effect of cisplatin and causes renal salt wasting syndrome.

  
  
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  During treatment with methotrexate, special attention must be paid to urinary pH to avoid precipitation in the renal tubules resulting in ATN and renal obstruction.

  
  
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  Both peripheral and central nervous system toxicities, including posterior reversible encephalopathy syndrome (PRES), are reported after high-dose chemotherapy.

  
  
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  The spectrum of severity of hypersensitivity reactions ranges from flushing and rash to anaphylactic shock. Common causes of these reactions include paclitaxel, platinum compounds, and monoclonal antibodies.

  
  
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  Venous thromboembolic disease is a well-known complication of tamoxifen.

  
  
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  Thrombotic thrombocytopenic purpura (TTP) or thrombotic microangiopathy has been associated with mitomycin, cisplatin, and gemcitabine.

As treatment for cancer continues to evolve with the development of new therapies and improved survival, we can expect an ever-growing number of cancer patients to be admitted to intensive care units (ICUs). Whether they require ICU care due to acute complications of treatment or underlying illnesses, it is important for the intensivist to be aware of the myriad of anticancer therapies and their toxicities. The following chapter will review the classification of commonly used anticancer therapies and the various organ system toxicities they can cause. Organ systems commonly affected by antineoplastics include the bone marrow, pulmonary, cardiovascular, neurologic (both central and peripheral), dermatologic, and gastrointestinal. Less common reactions, though still of clinical importance, are those involving the liver, kidneys, and systemic reactions (infusion and anaphylactoid). While the focus will be on acute toxicities, certain subacute and chronic toxicities will also be discussed. As the long-term survival of cancer patients improves, these less acute complications may confound the presentation and diagnosis of elderly patients admitted to the ICU for seemingly unrelated acute illnesses. Importantly, the diagnosis of drug-related toxicity is most often a diagnosis of exclusion, relying on dose and temporal exposure to an agent known to cause organ toxicity, and management is largely supportive. Adding to the challenge of diagnosing drug toxicity is the continued development of new agents and combinations of therapies. Other acute complications of cancer treatment including tumor lysis syndrome will be discussed under oncologic emergencies.

Cancer therapies are classified by mechanism of action and the phase of the cell cycle during which the drug targets its action. Cell cycle–specific agents refer to drugs whose activity requires the target cell to be within a certain phase of cell division or proliferation. To review, the five phases of the cell cycle are Gap 0 (G0), Gap 1 (G1), synthesis (S), Gap 2 (G2), and mitosis (M). Cells in G0 are dormant cells with potential to be stimulated to proceed further in the cell cycle. G1 is a phase of RNA and protein synthesis in preparation for DNA synthesis and replication which occurs during S phase. Following DNA synthesis during G2 phase, the cell readies itself by RNA and protein synthesis in preparation of mitosis, or cell division. Chemotherapy agents that are cell cycle–specific include antimetabolites, vinca alkaloids, taxanes, and epipodophyllotoxins. All other classes of agents are cell cycle nonspecific (though some overlap) and include alkylating agents, nitrosoureas, antibiotics, hormones, and hormone antagonists. Biologic response modifiers are also cell cycle nonspecific and include interferons, recombinant interleukin-2, and tumor necrosis factor. Over the last decade, the development of targeted anticancer therapies has improved our ability to selectively damage malignant cells based on their unique characteristics. Examples of targeted therapies include tyrosine kinase inhibitors, mTOR kinase inhibitor, gene expression modulators, retinoic acid receptor modifiers, proteasome inhibitors, epidermal and vascular endothelial growth factor inhibitors, histone deacetylase inhibitors, and monoclonal antibodies. Several agents may overlap these rather indistinct classifications, while others defy classification, such as thalidomide and hydroxyurea.

Alkylating agents (including nitrogen mustards among others) alter and destroy DNA structure, leading to cell death. Nitrosoureas are alkylating agents that are lipid soluble, thus capable of crossing the blood-brain barrier. The platinum compounds have broad antineoplastic activity that also functions by binding and disrupting DNA structure, therefore they are classified under alkylating agents.

The antimetabolites are synthetic precursors of DNA synthesis that compete with naturally occurring purines, pyrimidines, and folates to interrupt the cell cycle and cause cell death. Because of their specificity for the S phase of the cell cycle, they are particularly effective against rapidly proliferating tumors.

Many anticancer therapies are naturally derived products such as enzymes or antibiotics. Several antibiotics, both natural and synthetic, have antitumor properties. The anthracycline antibiotics as well as their semisynthetic and synthetic derivatives act by intercalating DNA base pairs, thereby inhibiting DNA synthesis. The antibiotics bleomycin and dactinomycin generate reactive oxygen species resulting in DNA strand breaks while mitomycin cross-links DNA like the previously described alkylating agents. L-asparaginase is a naturally occurring enzyme that cleaves the amino acid L-asparagine on which tumor cells are dependent. Vinca alkaloids are plant extracts that bind microtubules and prohibit mitosis, leading to cell death. Taxanes also cause cell death by forming abnormal mitotic spindle fibers. Camptothecins inhibit topoisomerase I which prevents normal DNA transcription and replication from occurring. Epipodophyllotoxins interfere with topoisomerase II activity, thereby prohibiting proper condensation and packaging of DNA after cell division.

Newer agents of considerable interest are the targeted therapies and biologic response modifiers. Unique to this class of agents is their specificity for tumor cells, thus limiting the toxic side effects that are dose limiting for the traditional cytotoxic chemotherapeutic agents. Biological response modifiers (BRMs), or biologicals, accounted for 44% of cancer therapy sales in 2006, exceeding those of traditional cytotoxic agents.¹ BRMs modulate a host’s immune response resulting in antitumor effects. Examples include interferon alfa, tumor necrosis factor, and interleukin 2. Targeted therapies are developed through recombinant DNA technology, proteins closely mimicking those that naturally occur in humans are engineered to mediate antitumor effects. These agents include cytokines, monoclonal antibodies, and fusion proteins. Tyrosine kinase inhibitors disrupt signal transduction, gene transcription, and DNA synthesis in the tumor cells which overexpress their target (ie, ABL, EGFR, HER1/EGFR).

Some agents cannot be easily clarified into the above groups due to unique mechanisms of action. For example, all-trans-retinoic acid or tretinoin is an agent which induces malignant myeloid cells to differentiate, thereby decreasing the population of highly proliferative immature cells. Hydroxyurea is a synthetic enzyme that inhibits conversion of RNA to DNA, leading to cell death in rapidly dividing cells. Thalidomide, after being withdrawn from the market for its teratogenic effects, has been reintroduced along with its derivative lenalidomide, for cancer therapy due to antiangiogenic and immunomodulatory properties. Glucocorticoids are useful for their ability to suppress mitosis in lymphocytes.^2,3 For a summary of antineoplastic agents and their disease targets, please refer to Table 95-1.

MYELOSUPPRESSION

Myelosuppression due to cytotoxic chemotherapies is a frequent dose-limiting side effect, although it is difficult to identify the precise incidence of anemia, thrombocytopenia, and neutropenia due to potential disease-related effect on the bone marrow.

Severe anemia (hemoglobin <8 g/dL) can be found in over 70% of non-Hodgkin lymphoma (NHL) patients receiving CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) combination chemotherapy; however, the role of chemotherapy in causing the anemia is difficult to distinguish from the disease-related anemia in the patient population.⁴ In the absence of symptomatic anemia or evidence of impaired oxygen delivery, a hemoglobin level less than 7 g/dL should be transfused according to original guidelines published by the British Committee for Standards in Haematology in 2001; however, there is little available evidence to support ideal hemoglobin levels.^5,6

Thrombocytopenia has been described in case reports of 16 patients after treatment with rituximab. Mean onset of thrombocytopenia was 19 hours after administration and spontaneously resolved in an average of 4 days. The mean nadir of platelet count was 12,000/μL with only one case of major bleeding (GI) associated with thrombocytopenia. The mechanism remains unclear.⁷ Current practice among hematologists, based primarily on retrospective and few controlled trials more than 25 years ago, uses a platelet count of 10 to 20,000/μL, as a threshold for prophylactic transfusion. Incidence of severe bleeding events, RBC transfusions, and mortality were not statistically significant when thresholds of 10,000 versus 20,000/μL were compared.^8,9 Guidelines of the American Society of Clinical Oncology indicate that the threshold for prophylactic transfusion varies according to diagnosis, clinical condition, and treatment modality.¹⁰ In cases of actively bleeding thrombocytopenic patients, or those requiring invasive procedures commonly performed in the ICU such as central venous and arterial catheters or lumbar puncture, a platelet count greater than 40,000 to 50,000/μL is desired. More invasive surgical procedures with high risk of bleeding or placement of an epidural catheter may require a platelet count greater than 80,000 to 100,000/μL.

Neutropenia, defined as an absolute neutrophil count (ANC) ≤500 cells/mL, predisposes patients to febrile neutropenia and opportunistic infections, an oncologic emergency requiring close monitoring and hospitalization. Such intensive observation is necessary due to the lack of signs and symptoms of infection without the inflammatory response typically mediated by neutrophils. In the absence of clinical symptoms, there is a 50% likelihood that a patient with febrile neutropenia has an established or occult infection (most commonly within the GI tract, lungs, or skin), while 20% with ANC <500 cells/mL will be bacteremic. Causative organisms are typically gram-negative rods (E Coli, Klebsiella pneumoniae, Enterobacter sp, Pseudomonas aeruginosa, Citrobacter sp, Acinetobacter sp, and Stenotrophomonas maltophilia) or gram-positive cocci (Staphylococcus sp, Streptococcus sp, Enterococcus sp). Factors predicting the risk and morbidity of febrile neutropenia include age greater than 65 to 70 years, comorbid conditions (pneumonia, abdominal pain, neurologic changes), poor performance status, dose intensity of chemotherapy, as well as the severity (ANC ≤100cells/mL) and duration (>7 days) of the neutropenia. The risk of neutropenia is greatest for hematologic malignancies due to intensity of the treatment regimen and bone marrow involvement of disease. Contrary to what one might think, the risk of neutropenia is greatest earlier in treatment (7-14 days). In retrospective studies as well as clinical trials, in 63% to 65% and 75% of hospitalizations, febrile neutropenia occurred within the first two cycles of treatment for NHL and advanced breast carcinoma respectively.¹¹ Late onset (>3-4 weeks after the last treatment) neutropenia (LON) has been described in case reports following use of the monoclonal antibody rituximab. Wolach and colleagues presented a series of six patients treated with rituximab as part of a regimen for DLBCL or follicular lymphoma who developed neutropenia anywhere from 42 to 168 days after the last treatment.¹² All but one of these cases was associated with at least one episode of febrile neutropenia. In their review of the literature, they found an incidence range of 3% to 27% of late onset neutropenia associated with rituximab with a median onset of 38 to 175 days and duration of 5 to 77 days. Mortality rates associated with febrile neutropenia are 8.4% and up to 13.2% in patients with hematologic cancers.⁴

Neutropenia is also associated with dose reductions and treatment delays, potentially compromising desired goals of long-term survival in patients being treated with curative intent. This has been supported by studies demonstrating a direct relationship between dose intensity and disease-free as well as overall survival.¹³

Use of granulocyte colony-stimulating factor has been shown to both decrease nadir and duration of neutropenia if administered prior to its development. Hartman et al performed a randomized controlled clinical trial, which found no benefit (decreased rate of hospitalization, LOS, duration of antibiotics, or culture positive infections) to treating neutropenia with granulocyte colony-stimulating factor compared to placebo once it developed even though the median time to achieve ANC greater than 500 cells/mL was 2 days shorter.¹⁴ Current recommendations for use of granulocyte colony-stimulating factor are based on patient’s risk factors for developing neutropenia (age ≥65; poor performance status; existing cytopenia due to marrow involvement of malignancy; serious comorbidities; concurrent radiation therapy; extensive prior chemotherapy; previous episode of febrile neutropenia; and planned dose intensity >80%).¹³

Clinical practice guidelines for the management of febrile neutropenia were most recently updated by the Infectious Disease Society of America in 2010 and are summarized in Table 95-2.¹⁵ In addition to standard laboratory testing (CBC with differential, electrolytes, BUN/creatinine, and LFTs), at least two sets of blood cultures are recommended, including samples from each lumen of an indwelling catheter and chest x-ray and culture from other sites of suspected infection. Monotherapy with an antipseudomonal β-lactam (cefepime), carbapenem (meropenem or imipenem-cilastatin), or piperacillin-tazobactam is an A-I recommendation. Empiric vancomycin is not recommended (A-I) unless a specific clinical indication (catheter-related blood stream infection, skin-soft tissue infection, pneumonia, hemodynamic instability) is present and should be discontinued if after 2 days there is no evidence of gram-positive infection (A-II). In instances of suspected bacterial resistance, empiric coverage may be modified (B-III). If fever or hemodynamic instability persists, empiric antifungal coverage should be considered (A-II). In cases where there is a documented infection (clinically or microbiologically), the duration of treatment should continue until ANC ≥500 cells/mL or as long as clinically necessary (B-III). In instances where fever remains unexplained, the course should be continued until evidence of marrow recovery (ANC ≥500 cells/mL) (B-II).

PULMONARY TOXICITY

Due to the lack of definitive diagnostic testing, nonspecific clinical findings (dyspnea, hypoxemia, infiltrates), and significant overlap, diagnosing pulmonary toxicity due to anticancer agents is challenging as is determining the incidence of complications due to particular agents. The mechanisms by which chemotherapies can cause pulmonary toxicity include direct damage to pneumocytes or alveolar capillary endothelium, immunologic-mediated toxicity, and capillary leak. Any one or combination of these mechanisms can lead to clinical manifestations such as interstitial pneumonitis, hypersensitivity pneumonitis, noncardiogenic pulmonary edema, alveolar hemorrhage, BOOP, pleural effusions, bronchospasm, and pulmonary venoocclusive disease.¹⁶ Depending on the severity of the clinical findings, a diagnosis of ALI/ARDS may be met. Many pulmonary manifestations secondary to chemotherapy are beyond the scope of a critical care–oriented text and will not be addressed; rather the focus will be on agents with potentially life-threatening pulmonary toxicities. Hypersensitivity reactions in response to many chemotherapeutic infusions may result in respiratory symptomatology, and will be discussed later. In addition, complications due to underlying malignancy such as infection and metastatic disease may coexist and confound the diagnosis of treatment-induced lung disease.

Acute respiratory distress and failure can be caused by a number of anticancer therapies, and can be secondary to direct toxic drug effects or secondary to other complications caused by treatment side effects such as pancytopenia resulting in pulmonary hemorrhage and pneumonia, or pulmonary edema due to fluid overload. These entities are particularly notable for patients being treated for hematologic malignancies. Ameri et al performed a retrospective analysis at MD Anderson including over 1500 patients undergoing induction chemotherapy for AML or high-risk MDS (typically with an anthracycline plus cytarabine) and found an 8% incidence of acute respiratory failure requiring ventilator support within 2 weeks of initiation of treatment.¹⁷ Seventy-three percent of those patients who experienced respiratory failure died with a median survival of 3 weeks, indicating substantial mortality associated with the need for ventilatory support in this patient population. Significant predictors of developing respiratory failure were identified and included poor performance status, infiltrates on presentation, renal insufficiency, and male sex.

Direct injury to pneumocytes as well as the alveolar capillary endothelium and the resultant release of inflammatory mediators can result in leaky capillaries and development of noncardiogenic pulmonary edema severe enough to require mechanical ventilation. This so-called capillary leak may also result from systemic cytokine release and resultant immunologic-mediated toxicity to alveolar capillary endothelium.

Cytarabine at moderate and high doses used in leukemic patients is well known for resulting in respiratory failure via noncardiogenic pulmonary edema (NCPE). Haupt et al was the first to report “massive” and “moderate” pulmonary edema in 24% and 33%, respectively, of 181 leukemic patients on autopsy who received cytosine arabinoside.¹⁸ In a more recent report and review performed by Kopterides et al, there is an approximate incidence of NCPE resulting in respiratory failure of 11% to 28% in leukemic patients treated with either induction or consolidation chemotherapy consisting of cytarabine.¹⁹ Clinical findings typically include low-grade fever, severe dyspnea, hypoxemia, and crackles on lung examination. The onset of respiratory failure is reported anywhere from 2 to 21 days following treatment and in most cases, efforts to rule out alternate etiologies were carried out by sampling of respiratory secretions and cardiac evaluations. Histological findings reported are those showing massive alveolar edema with a highly proteinaceous, noninflammatory infiltrate suggesting increased vascular permeability as the mechanism of disease. Radiographic findings ranged from a diffuse interstitial pattern, mixed interstitial and alveolar patterns, alveolar pattern and normal. These findings were more often diffuse and bilateral than localized. Mortality due to cytarabine-induced NCPE from case reports range from 13% to 69%, though the number of total cases is limited. Corticosteroids at doses ranging 0.75 to 4 mg/kg per day have been used with good results, though there are no clinical studies to better define their efficacy or optimal dosing.¹⁹

Gemcitabine has also been associated with NCPE though much more rarely at approximately 0.1%. This entity is distinct from a transient, self-limited dyspnea that is associated with gemcitabine administration 5% to 8% of the time. The pulmonary toxicity of gemcitabine is thought to escalate with each successive dose; however, cases of NCPE have been reported on first administration.²⁰ There are less than a dozen case reports, all demonstrating significant mortality unless identified early and systemic steroids administered and gemcitabine discontinued.³⁴

Administration of IL-2 has a 3% to 20% dose-related incidence of NCPE in the context of a generalized vascular leak syndrome. Radiographic findings include bilateral infiltrates and pleural effusions. With knowledge of the mechanism of IL-2–induced pulmonary toxicity, careful attention to volume resuscitation can limit these effects. Clinical and radiographic findings typically resolve with discontinuation of the IL-2.^16,21 Other chemotherapeutic agents rarely associated with NCPE and respiratory failure includes intrathecal methotrexate, vinblastine, and mitomycin C.

Retinoic acid syndrome, or ATRA syndrome, is characterized by a collection of clinical findings including fever, weight gain, elevated WBC count, respiratory distress, interstitial infiltrates, pleural and pericardial effusions, episodic hypotension, and acute renal failure after initiation of therapy for APML. Respiratory distress and fever are represented most commonly (>80%). Initially it was associated with an incidence of 26% in patients treated with all-trans-retinoic acid (ATRA) and is highly responsive to high-dose steroids and temporary cessation of ATRA, though more recent reports indicate this may be decreasing (2%-11%). Its onset occurs at a median of 5 days based on published controlled trials and case reports with a mortality of 2%. Radiographic findings suggest pulmonary edema and can include pulmonary vascularity, peribronchial cuffing, GGOs, consolidation, nodules, air bronchograms, and pleural effusions.^22-25

Bleomycin is best known for causing a late onset, dose-dependent pulmonary fibrosis 1 to 6 months after administration in up to 10% of patients.²⁶ Bleomycin exerts its cytotoxic effect in the lungs via generation of reactive oxygen species and resultant oxidative injury to pneumocytes. The generation of ROS may be exacerbated by administration of supplemental oxygen and is felt to have contributed to the development of postoperative respiratory failure in patients previously treated with bleomycin in case reports.²⁷ A recent case report described the use of nitric oxide in a case of postop ARDS as an oxygen-sparing strategy to minimize hyperoxia-induced bleomycin toxicity. The study confirmed earlier findings by Dellinger et al of an increase in PaO2 with the addition of nitric oxide to lowest possible concentration of oxygen. The mechanism of this benefit is likely due to improved V/Q matching; however, the effects on mortality are less clear.^28,29

Pulmonary venoocclusive disease due to deposition of fibrinous material in the pulmonary veins and venules has been reported after treatment with bleomycin as well as mitomycin and BCNU. Typical of any occlusive process with in the pulmonary circulatory bed, clinical findings include pulmonary hypertension with resultant dyspnea and hypoxia. Onset is rarely acute and treatment involves discontinuation of the implicated drug and supportive therapy with mechanical ventilation. Treatment of pulmonary hypertension with prostacyclin is currently not recommended due to adverse effects in case reports.^30,31

Alveolar hemorrhage can been seen in instances of germ cell tumors with pulmonary involvement undergoing initial chemotherapeutic treatment, though this is as a result of tumor response to chemotherapy rather than the chemotherapeutic agent itself. Bevacizumab has been associated with pulmonary hemorrhage and hemoptysis in 2.3% of patients treated for NSCLC.¹⁶

Finally, innumerable chemotherapeutic agents as well as radiation therapy have been demonstrated to cause pneumonitis and interstitial lung disease. This topic will not be discussed as it lies outside of the focus of this text. For a review of the pulmonary manifestations likely to be encountered in the acute, ICU setting, please see Table 95-3.

In general, as stated earlier, the diagnosis of pulmonary-related drug toxicity is a diagnosis of exclusion. Treatment typically involves discontinuing the offending agent, supportive care with bronchodilators and mechanical ventilation, taking care to avoid high inspired oxygen concentrations in cases of bleomycin and mitomycin C toxicity, and systemic steroids ranging 0.5 to 1.0 mg/kg/day depending on severity. In instances of noncardiogenic pulmonary edema, diuretics should be utilized following cardiovascular assessment.

CARDIOTOXICITY

The cardiotoxic effects of cancer therapy range from acute and subacute, including manifestations such as pericarditis, myocarditis, acute coronary syndrome (ACS), SVTs, and QT prolongation, to chronic, insidious onset of left ventricular dysfunction resulting in cardiomyopathy and congestive heart failure (CHF).³² A critically ill patient may present acutely with chest pain following recent cancer treatment, or have a remote history of potentially cardiotoxic therapy and is admitted after a progressive decline in cardiac status. In either case, knowledge of the common cardiotoxic therapies is essential to the appropriate diagnosis and subsequent management of these patients. A summary of cardiotoxic effects of chemotherapy is presented in Table 95-4.