Chapter 46: Oncologic Emergencies

Etiology

Work-up

Treatment Strategies

1. Supportive care

   • Pain frequently is resistant to standard analgesics. Pain control with opioids as clinically indicated

   • Steroids to lessen pain, reduce vasogenic cord edema, and avoid radiation-induced spinal edema

      

     Dexamethasone 96 mg; administer intravenously over 15–30 min, followed by:

     Dexamethasone 24 mg/dose; administer orally for 4 doses per day (approximately every 6 hours) for 3 days. Gradually decrease doses and increase administration intervals (taper) to discontinue use after 10 days

     Note: This regimen was used in a randomized controlled trial in which high-dose dexamethasone was compared to no therapy in 57 patients with metastatic SCC treated with RT alone. Eighty-one percent of the participants in the intervention arm were ambulatory after treatment compared with 63% in the control group. Significant side effects were reported in 11% of those who received high-dose dexamethasone

      

     Sørensen PS et al. Eur J Cancer 1994;30A:22–27

     or

     Dexamethasone 10 mg; administer as a short intravenous infusion over 10–20 minutes, followed 6 hours later by:

     Dexamethasone 4 mg; administer orally every 6 hours. Taper to discontinue use within 2 weeks

     Note: Used because of an increased incidence in side effects observed with higher doses

      

     Heimdal K et al. J Neurooncol 1992;12:141–144

     Vecht CJ et al. Neurology 1989;39:1255–1257

      

2. Radiation therapy

   1. Preferred treatment for most patients with metastatic SCC

   2. If surgery is contraindicated, external beam radiotherapy with corticosteroids remains first-line therapy

   3. Indications for postoperative radiation are not clear: Treatment of tumor relapses versus combining radiotherapy with surgery to improve local control (Lutz et al. 2011); however, RT may increase the risk of pathologic fracture in cases of spinal instability

   4. Important variables:

      (1) Early diagnosis

      (2) Favorable histology

A prospective analysis of 209 patients treated with radiation and steroids

• Among patients who were ambulatory, nonambulatory, or paraplegic before treatment, 98%, 60%, and 11%, respectively, were able to ambulate

• Early diagnosis was the most important predictor of success, so a majority of patients able to walk and with good bladder function maintained these capacities

• When diagnosis was late, tumors with favorable histologies (ie, multiple myeloma, and breast and prostate carcinomas) responded best to radiation therapy

• Duration of response was also influenced by histology. A favorable histology was associated with high median response durations: for multiple myeloma, and breast and prostate carcinomas, 16, 12, and 10 months, respectively

• Median survival time was 6 months, with a 28% probability of survival at 1 year

• There was a correlation between patient survival and duration of response, with systemic relapse of disease generally being the cause of death

Notes:

• Transient myelopathy can develop 2–6 months after radiation therapy secondary to transient demyelination of the posterior columns

• The symptoms of transient myelopathy often resolve spontaneously within a year in most cases

• Chronic progressive myelitis is a late delayed complication of radiation

Conventional radiation:

• Efficacy of conventional radiotherapy is well established with complete or partial responses observed in 65–86% of patients

• There is no difference in efficacy and tolerance between different radiation schema but a short schema (8 Gy in 1 fraction) may be preferred in patients with long bone metastases or an estimated life expectancy ≤3 months

Stereotactic radiosurgery (also called stereotactic body radiation therapy [SBRT])

• A growing body of literature supports its efficacy in treating spine lesions

• Used to deliver a high dose of RT to the target volume while protecting organs at risk, usually with a single fraction

• Advocates claim it can partially overcome intrinsic tumor resistance to ionizing radiation, but solid data supporting the strategy is not available

• May be applied to any part of the body with stereotactic techniques such as Volumetric-Modulated Arc Therapy (VMAT) or CyberKnife

• For a single lesion, 8–24 Gy may be given depending on the distance to the spinal cord

• More protracted regimens can deliver 20–30 Gy in 2–6 fractions

• The best candidates include: (a) solitary lesion or oligometastatic disease; (b) ≥5 mm between lesion and spinal cord; (c) good general health status; (d) no spinal cord compression; and (e) life expectancy ≥6 months (Chawla S et al. Bone 2009;45:817–821)

• Exclusion criteria: Canal narrowing >25%, instability requiring surgical treatment, and a life expectancy =3 months (Lutz S et al. Int J Radiat Oncol Biol Phys 2011;79:965–976)

• May be valuable when considering treatment of a recurrence after RT such as spinal tumors where retreatment is limited by tolerance of the spinal cord

Intensity modulated radiotherapy (IMRT)

• Can significantly reduce the incidence and severity of iatrogenic complications by improving radiation conformation around the target volumes, with more accurate dose distributions using intensity modulation of multiple-beam irradiation (Veldeman L et al. Lancet Oncol 2008;9:367–375)

• Because IMRT requires precise repositioning devices and correction of setup errors (particularly for spinal or paraspinal lesions), it must be associated with repositioning techniques guided by imaging (IGRT) (Guckenberger M et al. Radiother Oncol 2007;84:56–63)

• IMRT can deliver high doses of radiation within a few fractions, mimicking stereotactic radiosurgery

• Single-fraction image-guided IMRT may also be used

• A retrospective analysis of 62 patients reported fracture progression in 39% of patients treated with IMRT. Risk factors for fracture were: (a) Lesions located between T10 and sacrum; (b) lytic features; and (c) percent involvement of a vertebral body. Local tumor progression occurred in only 7 patients (Rose PS et al. J Clin Oncol 2009;27:5075–5079)

3. Surgery ± Radiation

Surgery should be considered in patients with:

• Spinal instability

• Paraplegia at diagnosis

• Retropulsion of bones within the vertebral canal

• Radioresistant tumors

• Deterioration during RT

• Prior radiation therapy in the same areas

• No tissue diagnosis

Note:

(Patchell R et al. Proc Am Soc Clin Oncol 2003;22:1 [abstract 2])

The first phase III randomized trial in which the efficacy of direct decompressive surgery was evaluated in patients with metastatic SCC compared the standard 30 Gy in 3-Gy, uninterrupted, daily fractions with decompressive and stabilization surgery within 24 hours after diagnosis followed by the same radiotherapy started within 2 weeks. The trial was terminated early at interim analysis when early stopping rules were met regarding the primary end points of ambulatory rate and time ambulatory after treatment. Regarding the primary end point of ambulation, the combined treatment had a median ambulation time of 126 days, compared with 35 days for radiation alone (P = 0.006). Furthermore, baseline ambulatory and nonambulatory patients who had surgery and radiation had one-half the likelihood of being nonambulatory compared with those who had radiation alone. For nonambulatory patients, the combined-treatment patients had a significantly higher chance of regaining the ability to walk after therapy (56% vs. 19%; P = 0.03). Although the study included only 101 patients the results of this study challenges the accepted status quo of radiation alone in the management of metastatic SCC

Note:

(Shehadi JA et al. Eur Spine J 2007;16:1179–1192)

One-hundred twenty-five interventions in 87 patients with vertebral metastases in a population of 479 patients with breast cancer. Indications for spinal surgery (in patients able to tolerate it, and a life expectancy ≥3 months):

• Spinal deformity with major pain

• Spinal cord compression

• Previous irradiation of the site concerned

• Uncontrollable pain

Results:

• Of 76 patients who were ambulatory before surgery, 98% were also ambulatory after surgery

• 6/10 with pain before spinal surgery reduced to 2/10 with pain control for ≥12 months (p <0.001, significant compared to the population of patients without intervention)

• Median follow-up of 13 months

• Median survival after the first spinal surgery was 21 months (95% CI, 16–27 months)

• 39% of patients had complications; 26% considered significant

4. Chemotherapy ± Radiation

Chemotherapy can be used in combination with radiotherapy for treatment of SCC or alone for chemosensitive tumors including neuroblastoma, Ewing sarcoma, osteogenic sarcoma, germ cell tumors, and lymphomas in patients who are not candidates for surgery or radiation

5. Vertebroplasty (injecting cement percutaneously to treat a spinal metastasis with a risk of fracture [Anselmetti GC et al. Cardiovasc Intervent Radiol 2007;30:441–447; Bròdano GB et al. Eur Rev Med Pharmacol Sci 2007;11:91–100])

• Effective at relieving pain

• Increases spinal stability

• Can help prevent the risk of fracture

• Allows for radiotherapy to be delivered within a few days

6. Balloon kyphoplasty

 (Berenson J et al. Lancet Oncol 2011;12:225–235)

• For painful vertebral compression fractures, can provide rapid pain relief

• Can improve neurological function when compared with a nonsurgical strategy

• Allows for radiotherapy to be delivered within a few days

Etiology

Work-up

Treatment Strategies

General Principles

• Treatment should be selected according to the histologic disorder and stage of the primary process

• Goals of treatment are to relieve symptoms and attempt the cure of the primary malignant process

• Deferring therapy until a full diagnostic work-up has been completed does not pose a hazard for most patients, provided the evaluation completed expeditiously and the patient is clinically stable

• Treatment recommendations should be determined by a multidisciplinary team to include a radiation oncologist, medical oncologist, radiologist, and a surgeon or pulmonologist, when appropriate

• Prognosis and life expectancy are related to the histologic type and stage of the underlying malignancy at presentation

• Despite the favorable outcomes with stents, chemotherapy and/or radiotherapy comprise the basis of treatment for obstruction of the SVC

• Chemotherapy and radiotherapy are effective in relieving obstruction of the SVC in a variable proportion of patients, depending on tumor histology

• Stents can relieve symptoms rapidly in 80–95% of patients; however, severe bleeding, cardiopulmonary complications, and stent migration remain significant problems. Use of thrombolytics following stent insertion increase morbidity

• Recurrence of obstruction following stent placement occurs in 4–45% of cases

• Stents are useful in patients with diseases that respond less well to chemotherapy or radiotherapy such as mesothelioma

• Optimal timing of stent insertion—whether at diagnosis or following failure of other modalities—is currently uncertain, although they are most frequently used after chemotherapy and/or radiotherapy

• No study has described the effectiveness of steroids in SVC obstruction; their value remains uncertain but use is widespread

A Cochrane Database analysis (Rowell NP, Gleeson FV. Cochrane Database Syst Rev 2001;CD001316) reported the results of 2 randomized and 44 nonrandomized controlled trials. Studies examined enrolled patients with carcinoma of the bronchus and a diagnosis of SVC obstruction who had been treated with any combination of the following treatment modalities: (a) steroids, (b) chemotherapy, (c) radiotherapy, or (d) insertion of an expandable metal stent

Small cell lung cancer (SCLC):

• SVC obstruction is present at diagnosis in 10% of patients

• One randomized trial: The rate of recurrence of SVC obstruction was not significantly reduced by giving radiotherapy after completion of chemotherapy

• Chemotherapy and/or radiotherapy relieved SVC obstruction in 77%; 17% of those treated had a recurrence of SVC obstruction

• Data support the use of stenting when obstruction of the SVC recurs or when it persists following initial chemotherapy and radiotherapy

Non–small cell lung cancer (NSCLC):

• SVC obstruction is present at diagnosis in 1.7% of patients

• One randomized trial: Addition of induction chemotherapy to synchronous chemoradiotherapy did not increase the rates of relief of SVC obstruction

• 60% had relief of SVC obstruction following chemotherapy and/or radiotherapy; in 19% of those treated, obstruction of the SVC recurred

• Data support both stenting as part of initial therapy, and stenting when SVC obstruction recurs or persists after initial chemotherapy and/or radiotherapy

1. Radiation Therapy

   1. Most often chosen as the initial modality of treatment

   2. Provides quick relief of symptoms, often within 72 hours

   3. 70–90% of patients are free of symptoms by 2 weeks

   4. Complications:

      • Esophagitis

      • Nausea and vomiting

      • Skin irritation

      • Possible worsening of symptoms secondary to edema

   5. Recurrence of SVC syndrome is reported in 10–19% of patients treated with RT; causes include:

      • Tumor recurrence

      • Radiation fibrosis

      • Thrombosis

   6. The optimal total dose fraction has not been established and dosage must be individualized to a patient and the underlying malignancy

2. Chemotherapy

   1. An acceptable alternative. Choice of therapy is guided by evaluation

   Radiotherapy vs. Chemotherapy

   (Rowell NP, Gleeson FV. Clin Oncol [R Coll Radiol] 2002;14:338–351)

   • A systematic review of 2 randomized and 44 nonrandomized studies to determine the effectiveness of different treatment modalities for SVC obstruction in patients with carcinoma of the bronchus

   • Small cell lung cancer: Chemotherapy and/or radiotherapy relieved SVC obstruction in 77%; 17% had a recurrence of obstruction

   • Non–small cell lung cancer: Chemotherapy and/or radiotherapy relieved SVC obstruction in 60%; 16% had a recurrence of obstruction

   • Conclusions: It is reasonable to choose between RT and chemotherapy treatment on the basis of stage and performance status. Effectiveness was not clearly related to any particular radiotherapy fractionation schedule or chemotherapy regimen

3. Endovascular therapies: expandable wire stents

   1. Successfully used to open and maintain the patency of SVC obstruction resulting from malignant causes

   2. Complete resolution of SVC syndrome occurs in 68–100% of patients treated with a metallic stent

   3. Prompt resolution is achieved regardless of the stent type

      • Several investigators reported immediate relief of disabling headaches caused by SVC syndrome

      • Facial cyanosis and facial edema usually resolve within 1–2 days

      • Truncal and upper extremity edema usually resolve within 2–3 days, but may take up to 1 week

   4. Recurrence rates range from 4–45%; secondary to:

      • Tumor in-growth through the interstices of the stent

      • Tumor growth around the ends of the stent leading to thrombosis

   5. Recurrence can be treated with anticoagulation, angioplasty of the stented area, or repeated stenting

   6. Thrombolysis is often an integral part of the endovascular management of SVCs, because thrombosis is frequently a critical component of the obstruction and lysis is necessary to allow the passage of the wire. Using these techniques, technical success can be achieved in 90–100% of cases

   7. Indications:

      • Patients with reduced life expectancy

      • SVC obstruction recurring after first-line therapy

      • Patients with symptoms that are acute and so severe that immediate treatment is needed

      Note: Thrombus or complete SVC obstruction are not contraindications for stent placement although in one study thrombosis of the superior vena cava was the only independent factor for failure of the endovascular prosthesis

      (Fagedet D et al. Cardiovasc Intervent Radiol 2013;36:140–149)

   8. Complication (rates) of endovascular therapy:

      • Stent misplacement (10%)

      • Stent migration (5%)

      • Stent occlusion (10%)

      • Cardiac arrhythmias (rare)

   9. There is no consensus for anticoagulation use (warfarin/aspirin) after stent placement

   Notes:

   • Used especially in patients with the presence of a thrombus visualized on venography

   • Autopsy studies: 30–50% of patients with SVC syndrome have evidence of thrombosis

   • Suspect an obstructing thrombus if symptoms do not improve within the first week after starting radiotherapy or chemotherapy

   • Many patients have large, necrotic, friable tumor masses, and the area of tumor is under increased pressure. For these patients, anticoagulant or fibrinolytic therapy poses a considerable risk of bleeding

Etiology

Work-up

• It is essential to maintain a high index of suspicion to identify patients at risk of developing TLS

• Patients at high risk should receive preventive measures and proactive interventions

Treatment Strategies

1. Hydration and diuresis: mainstays of therapy

   1. Hydration with 3000 mL/m² per day unless a patient presents with signs of acute renal dysfunction and oliguria

      • Maintain urine specific gravity ≤1.010

      • Do not add potassium, calcium, or phosphorus to fluids so as to avoid hyperkalemia, hyperphosphatemia, and calcium phosphate precipitation

   2. Diuresis with furosemide 20–40 mg/dose; administer intravenously

      • To maintain a urine output ≥100 mL/m² per hour if there is no evidence of acute obstructive uropathy and/or hypovolemia

2. Correction of hyperkalemia

   • Hyperkalemia may develop within 12–24 hours following initiation of chemotherapy

   • Emergent treatment is indicated if cardiac toxicity or muscular paralysis is present, or if hyperkalemia is severe (serum potassium >6.5–7 mEq/L [>6.5–7 mmol/L]), even in the absence of electrocardiographic changes

     1. Glucose and insulin

        • 50% glucose, 25 g (or 1 g/kg); administer intravenously, plus

        • Regular insulin 5–10 units (or 0.1 unit/kg); administer by intravenous injection

          • Effective therapy usually leads to a 0.5- to 1.5-mEq/L decrease in plasma potassium concentrations, an effect that begins within 15 minutes, peaks at 60 minutes, and lasts for 4–6 hours

     2. Sodium bicarbonate

        • Sodium bicarbonate (NaHCO₃), 44–88 mEq (3.7–7.4 g); administer intravenously

          • Onset of action within 15–30 minutes with a duration of action of 1–2 hours

          • Sodium bicarbonate-containing solutions may or may not be compatible with solutions containing calcium salts depending on the concentrations of the additives

     3. Calcium infusions

        • Calcium gluconate 10%, 5–30 mL (or 50–200 mg/kg); administer intravenously at a rate not greater than 0.7–1.8 mEq/min, or

        • Calcium chloride 5%, 5–30 mL; administer intravenously at a rate not greater than 0.7–1.8 mEq/min

          • Indicated when it is potentially dangerous to wait for 30–60 minutes for a response to insulin and glucose or sodium bicarbonate

          • May be repeated after 5 minutes if ECG does not improve

          • The protective effect of calcium begins within minutes, but is relatively short-lived (<60 minutes)

     4. Nebulizer therapy

        • Nebulized albuterol 10–20 mg in 4 mL 0.9% sodium chloride injection; administer by inhalation over 10–15 minutes

     5. Potassium-binding cation exchange resins

        • Sodium polystyrene sulfonate 15–50 g (or 1000 mg/kg); administer orally or rectally mixed in 50–70% sorbitol solution. May be repeated every 6 hours until serum potassium is within normal limits

     6. Dialysis

        • Definitive therapy for patients with severe hyperkalemia

        • May be indicated if pharmacologic measures are ineffective, and in patients with renal failure and other metabolic derangements

3. Correction of hyperphosphatemia (and hypocalcemia)

   • Hyperphosphatemia develops within 24–48 hours following the initiation of chemotherapy

   • Hyperphosphatemia may result in precipitation of calcium phosphate in tissues resulting in hypocalcemia, intrarenal calcifications, nephrocalcinosis, and acute obstructive uropathy

     Note: Treatment of hyperphosphatemia will usually correct any related hypocalcemia; thus, calcium administration should be given only to patients with symptoms related to hypocalcemia

     1. Oral phosphate binders

        • Aluminum hydroxide 15–30 mL (or 12.5–37.5 mg/kg); administer orally every 6 hours

     2. Hemodialysis

        • The most effective therapeutic strategy

        • Consider if hyperphosphatemia is severe, especially in settings of renal failure and symptomatic hypocalcemia

        • The clearance of phosphorus is better following hemodialysis versus continuous venovenous hemofiltration versus continuous peritoneal dialysis

4. Correction of hyperuricemia

   • Hyperuricemia develops within 24–48 hours following the initiation of chemotherapy when the excretory capacity of the renal tubules is exceeded

   • In the presence of an acidic urine pH, uric acid crystals form in the renal tubules, leading to intraluminal renal tubular obstruction and the development of acute renal obstructive uropathy and renal dysfunction

     1. Xanthine oxidase inhibitor

        • Allopurinol 100 mg/m²; administer orally every 8 hours (maximum 800 mg/day), or

        • Allopurinol 3.3 mg/kg per dose; administer orally every 8 hours (maximum 800 mg/day), or

        • Allopurinol 200–400 mg/m² per day; administer intravenously as a single dose or in up to 3 divided doses (maximum 600 mg/day)

           

          Notes:

        • Patients who have no evidence of laboratory or clinical tumor lysis syndrome and a low risk for developing TLS are candidates for allopurinol

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          Allopurinol Dose Adjustments in Patients with Renal Impairment

          Creatinine Clearance	Oral Allopurinol Dose
          10–20 mL/min	200 mg/day
          3–10 mL/min	100 mg/day
          <3 mL/min	100 mg every 36–48 hours

           

        • Both allopurinol and its active metabolite, oxypurinol, inhibit xanthine oxidase, the enzyme responsible for converting hypoxanthine to xanthine and, in turn, xanthine to uric acid. Because both allopurinol and oxypurinol inhibit uric acid synthesis, but have no effect on preexisting uric acid, serum levels usually do not fall until after 48–72 hours of treatment

        • Allopurinol inhibits the metabolism of azathioprine and mercaptopurine: azathioprine and mercaptopurine doses must be decreased by 65–75% if they are used concomitantly with allopurinol

        • Side effects include rash (1.5%), nausea (1.3%), vomiting (1.2%), and renal insufficiency (1.2%)

        • The incidence of allergic reactions is increased in patients receiving amoxicillin, ampicillin, or thiazide diuretics

        • Discontinue allopurinol if allergic reactions such as skin rashes and urticaria occur

     2. Recombinant urate oxidase

        • Rasburicase (recombinant urate oxidase) appears beneficial in children with hematologic malignancies, and is cost-effective in adults with ALL, NHL, and possibly AML, although randomized controlled trials in adults have been less convincing

        • Chemotherapy should be initiated within 4–24 hours after the first rasburicase dose

           

          Notes:

        • Because urate oxidase degrades uric acid rather than preventing its synthesis as does allopurinol, rapid reduction in uric acid occurs following its administration without precursor accumulation

        • The manufacturer recommends a rasburicase dose 0.2 mg/kg for up to 5 days. However, except in rare patients with very high serum levels of uric acid, much less is usually sufficient and can confer substantial cost savings. A recommended strategy is as follows:

          (1) Evaluate patients for their TLS risk

          (2) Administer rasburicase to patients at high risk for TLS or with clinical manifestations of TLS

          (3) Begin by initially administering a single 3-mg dose of rasburicase

          (4) Follow uric acid levels and administer additional rasburicase doses only if uric acid levels remain greater than an arbitrarily selected serum uric acid concentration such as 5 mg/dL 24 hours after a rasburicase dose. The half-life of rasburicase in serum is approximately 18–21 hours, so that about one-half of the administered dose is still present 24 hours after administration

        • Rasburicase does not require dosage or schedule adjustment for patients with decreased creatinine clearance

        • Side effects include skin rash, nausea and vomiting, and, rarely, hypersensitivity reactions, including anaphylaxis. Antibodies against rasburicase or its epitopes occur in approximately 6–18% of patients

        • Commercial product labeling stipulates only a single course of rasburicase, and use not exceeding 5 days to prevent developing an allergic reaction on repeated exposure

        • Rasburicase is contraindicated in patients with G6PD deficiency and/or methemoglobinemia

          • Screen patients who are at high risk for G6PD deficiency before administering rasburicase, particularly persons with African or Mediterranean ancestry, because hydrogen peroxide, a byproduct of the urate oxidase reaction, can lead to hemolysis

          • Onset of severe hemolytic reactions is within 2–4 days after administering rasburicase

          • Permanently discontinue rasburicase in any patient who develops hemolysis and implement appropriate monitoring and supportive interventions (eg, transfusion)

        • Important: Rasburicase enzymatically degrades uric acid in blood samples left at room temperature. To monitor serum/plasma uric acid concentrations after rasburicase treatment:

          (1) Collect blood samples in pre-chilled tubes containing heparin,

          (2) Immediately immerse and maintain samples in an ice water bath, and

          (3) Assay uric acid in plasma samples within 4 hours after collection

5. Alkalinization of the urine

   1. Sodium bicarbonate administered intravenously continuously (preferred) or intermittently, every 4–6 hours

      • The amount of sodium bicarbonate added to intravenously administered fluids should produce a solution with sodium content not greater than the concentration of sodium in 0.9% sodium chloride injection (≤154 mEq/L)

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        Sodium Bicarbonate Is Added to a Solution to Maintain Urine pH 6.5 to ≤7.0

        Base Solution Sodium Content	Sodium Bicarbonate Additive	Total Sodium Content
        0.45% Sodium Chloride Injection (0.45% NS)
        77 mEq/L	50–75 mEq	127–152 mEq/L
        0.2% Sodium Chloride Injection (0.2% NS)
        34 mEq/L	100–125 mEq	134–159 mEq/L
        5% Dextrose Injection (D5W)
        0	125–150 mEq	125–150 mEq/L
        D5W/0.45% NS
        77 mEq/L	50–75 mEq	127–152 mEq/L
        D5W/0.2% NS
        34 mEq/L	100–125 mEq	134–159 mEq/L

         

        Notes:

      • Administration of as little as 100 mEq sodium bicarbonate will maintain urine pH above 7.5, a pH that is needed not because of uric acid, which has a pKa of 5.4, but because of its diprotic oxypurine precursors, xanthine (pKa = 7.74 and 11.86) and hypoxanthine (pKa 8.94 and 12.1). Thus alkalinization is not a means to avoid uric acid crystallization, as at pH 6.4 more than 90% already exists as soluble urate, but as a means to avoid xanthine and hypoxanthine crystallization

      • Discontinue sodium bicarbonate administration (while continuing hydration) if serum bicarbonate concentration is >30 mEq/L (>30 mmol/L) or urine pH >7.5

      • However, urinary alkalinization is not uniformly recommended and in a majority of cases should be avoided because:

        (1) It favors precipitation of calcium/phosphate complexes in renal tubules, a concern in patients with concomitant hyperphosphatemia

        (2) A metabolic alkalemia may result from bicarbonate administration, which can worsen the neurologic manifestations of hypocalcemia

Syndrome Of Inappropriate Secretion of Antidiuretic Hormone (SIADH) Etiology

• Of patients with cancer, 1–2% develop SIADH^{69,70,71,72,73}

• Hyponatremia is initially mediated by ADH-induced water retention

• The ensuing volume expansion activates secondary natriuretic mechanisms resulting in sodium and water loss and the restoration of near euvolemia

• The combination of water retention caused by inappropriate ADH secretion and secondary solute loss (sodium and potassium) accounts for a decrease in plasma sodium concentration

• Thus, patients with SIADH have normal volume status, hyponatremia with hypoosmolality, increased renal excretion of sodium (>40 mEq/L [>40 mmol/L]), and urine osmolality in excess of plasma osmolality

Work-up

1. Careful history with attention to excluding other possible causes, including:

   • Diuretic administration

   • Preexisting renal disease

   • Adrenal insufficiency

   • Hypothyroidism

2. Review of recent chemotherapy agents and ancillary medications used in looking for a causative agent (see above)

3. Search for pulmonary or CNS disease if clinically indicated

4. Serum sodium as part of serum electrolytes, including BUN and creatinine

5. Urine sodium, urine osmolality, plasma osmolality

6. Thyroid function tests

7. Morning serum cortisol and ACTH, if clinically indicated

Treatment Strategies

General Principles

• The first step focuses on deciding whether sodium depletion secondary to either reduced intake, gastrointestinal losses, or renal losses is present. After excluding these 3 causes, physicians often proceed with a presumptive diagnosis of SIADH

• Correction of hyponatremia is guided by the severity of the clinical presentation and the pace with which hyponatremia developed. If hyponatremia developed slowly, correct over several days

• The rate of correction should not exceed an 8- to 10-mmol/L change in serum sodium on any day of treatment. The initial rate of correction can be 1–2 mmol/L per hour for several hours in patients with severe symptoms

  1. Water restriction: the mainstay in asymptomatic hyponatremia: 500–1000 mL/24 hours

     • The associated negative water balance raises the plasma sodium concentration toward normal. It can also lead to volume depletion due to unmasking of the sodium deficit

  2. Salt (sodium) administration:

     • Severe symptomatic or resistant hyponatremia often requires the administration of salt. Whereas both sodium and water are retained in hypovolemia, sodium handling is intact in patients with SIADH. Thus, when isotonic saline is administered, the sodium will be excreted in the urine while some of the water may be retained, leading to the possible worsening of hyponatremia. Consequently, in order to elevate the plasma sodium in patients with SIADH, hypertonic saline may need to be administered

     • Measure the serum sodium concentration every 4 hours during fluids administration

     Formula used to estimate the effect of 1 L of any infusate on serum Na⁺

      

     

      

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     Infusate	Na+ Content in mmol/L
     5% Sodium chloride, hypertonic (in water)	855
     3% Sodium chloride, hypertonic (in water)	513
     0.9% Sodium chloride injection	154
     Ringer lactate injection	130
     0.45% Sodium chloride injection✫	77
     5% Dextrose injection✫	0
     ✫Should never be used in management of hyponatremia
     Estimated Total Body Water (in Liters)✫
     Patient	Fraction of Body Weight
     Nonelderly men	0.6
     Nonelderly women	0.5
     Elderly men	0.5
     Elderly women	0.45
     ✫Calculated as a fraction of body weight

      

     Notes: The initial goal is to increase the serum sodium concentration by 4–5 mmol/L over the first 12 hours. One liter of 3% sodium chloride injection will increase the serum sodium concentration by 10.9 mmol/L. To increase serum sodium concentration by 5 mmol/L, only 0.46 L are required, thus:

      

     

      

     Therefore, 460 mL 3% sodium chloride, hypertonic solution is administered intravenously over the first 12 hours (at a rate of 38 mL/hour). Twelve hours after starting the 3% sodium chloride administration, the patient's clinical condition improved and his serum sodium increased to 114 mmol/L. Consequently, the hypertonic sodium chloride infusion was stopped, but fluid restriction continued

  3. Salt plus loop diuretics

     • The effect of hypertonic saline can be enhanced by being given with a loop diuretic. This lowers the urine osmolality and increases water excretion by impairing the renal responsiveness to ADH

       1. Furosemide 20–40 mg; administer by intravenous injection

       Note: If saline and furosemide prove inadequate and hyponatremia fails to improve or worsens after 72–96 hours of fluid restriction, plasma levels of arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) should be measured to discriminate between SIADH (SIAVP) and SIANP, especially in patients with SCLC. Unlike patients with SIADH and hyponatremia, patients whose tumors produce ANP experience a persistent decline in serum sodium following fluid restriction, especially if sodium intake is not concomitantly increased. If plasma levels of AVP support the diagnosis of SIADH, consider the use of demeclocycline, or an aquaretic agent (AVP-receptor antagonist)

  4. Demeclocycline

     • Use if the above measures fail to induce nephrogenic diabetes insipidus

       1. Demeclocycline 600–1200 mg/day; administer orally

       Notes:

     • Monitoring of renal function is required because demeclocycline has nephrotoxic effects

     • Side effects: nausea, vomiting, diarrhea, glossitis, dysphagia, hepatotoxicity, nephrotoxicity

     • Contraindications: hypersensitivity to tetracyclines

  5. Aquaretic agents, arginine vasopressin (AVP)-receptor antagonists

     • Have demonstrated efficacy and safety in clinical trials and represent additional options for managing hyponatremia

     • Indicated to raise serum sodium in hospitalized patients with clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L) or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction

     • Ensure frequent monitoring of serum sodium and volume status

     • Beware an overly rapid rise in serum sodium (>12 mEq/L [>12 mmol/L] per 24 hours) as this may result in serious neurologic sequelae. In the event of an undesirably rapid rate of rise of serum sodium, discontinue treatment and monitor carefully

       Note: Additional studies are needed to determine benefits in terms of disease outcome and length of hospital stays to justify their use

       1. Conivaptan HCl: Nonselective AVP antagonist available for intravenous use in hospitalized patients only

          • Administer through large veins and change the infusion site every 24 hours to minimize the risk of vascular irritation

          • Administration:

            • Loading dose: Conivaptan HCl 20 mg; administer intravenously over 30 minutes

            • Initial dose: Conivaptan HCl 20 mg; administer by continuous intravenous infusion over 24 hours

            • Additional dosing: Conivaptan HCl 20 mg/day; administer by continuous intravenous infusion over 24 hours for an additional 1–3 days

            Notes:

          • If serum sodium is not rising at the desired rate, conivaptan HCl may be titrated upward to a dose of 40 mg daily, administered in a continuous intravenous infusion

          • The total duration of infusion for conivaptan HCl after a loading dose should not exceed 4 days

          • The maximum daily dose of conivaptan HCl after a loading dose is 40 mg/day

          • Conivaptan HCl is a sensitive substrate of CYP3A subfamily enzymes and should not be coadministered with potent CYP3A inhibitors

          • Conivaptan HCl is a potent mechanism-based inhibitor of CYP3A subfamily enzymes, and can alter the pharmacokinetics of other CYP3A substrates

          • Coadministration of digoxin 0.5 mg, a substrate for the transport protein, P-glycoprotein (P-gp, MDR1, ABCB1) with conivaptan 40 mg twice daily resulted in a 30% reduction in digoxin clearance and 79% and 43% increases in maximum digoxin plasma concentration and exposure (area under the plasma concentration vs. time curve), respectively

             

            Vaprisol (conivaptan hydrochloride) injection, for intravenous use, product label 02/2012. Marketed by Astellas Pharma US, Inc., Deerfield, IL; manufactured by Baxter Healthcare Corporation, Deerfield, IL

       2. Tolvaptan: Selective vasopressin (V₂) receptor antagonist available as 15- and 30-mg tablets for oral use

          • Usual starting dose: Tolvaptan 15 mg; administer orally once daily without regard to meals

          • Titration as needed:

            • At least 24 hours after initiating treatment: The daily dose may be increased to tolvaptan 30 mg; administer orally once daily without regard to meals

            • The daily dose may be increased to a maximum of tolvaptan 60 mg; administer orally once daily without regard to meals, as needed to achieve a desired level of serum sodium

Notes:

• During initiation and titration, frequently monitor for changes in serum electrolytes and volume

• Avoid fluid restriction during the first 24 hours of therapy

• Advise patients receiving tolvaptan to continue ingestion of fluid in response to thirst

• Tolvaptan treatment is associated with an acute reduction of the extracellular fluid volume that could result in increased serum potassium. Serum potassium concentration should be monitored serially after initiating tolvaptan treatment in patients with a serum potassium >5 mEq/L (>5 mmol/L) and persons who are using drugs known to increase serum potassium concentrations

• In clinical trials, tolvaptan has been continued for ≥6 months

• Tolvaptan is metabolized by CYP3A subfamily enzymes, and use with strong CYP3A inhibitors causes a marked (5-fold) increase in exposure. Avoid coadministration of tolvaptan with potent and moderate CYP3A subfamily enzyme inhibitors

• Coadministration of tolvaptan with potent CYP3A subfamily enzyme inducers (eg, rifampin) reduces tolvaptan plasma concentrations by 85%

Samsca (tolvaptan) tablets for oral use, product label 02/2012. Otsuka America Pharmaceutical, Inc., Rockville, MD

Hypercalcemia Associated with Cancer Etiology

• Hypercalcemia is the most common metabolic complication of malignancy, overall occurring in 10–30% of persons with cancer^{74,75,76,77,78,79,80,81,82,83,84}

• Hypercalcemia of malignancy is a grave complication with median survival rates between 6 and 10 weeks

Work-up

The tumors in a patient with hypercalcemia associated with malignant disease are generally large and readily apparent. However, a further evaluation should consider not only mechanisms potentially related to a cancer but also causes of calcium elevation that are unrelated to cancer

Evaluate:

1. Serum calcium as part of serum electrolyte, mineral, and hepatic panels that include serum albumin

2. Ionized calcium (see Notes below)

3. Levels of intact PTH should be measured routinely

4. PTHrP only in selected cases

(Although most patients with typical humoral hypercalcemia of malignancy have increased levels of circulating PTHrP, the diagnosis is usually obvious on clinical grounds. Therefore, PTHrP should only be measured in occasional cases in which the diagnosis of humoral hypercalcemia of malignancy cannot be made on clinical grounds or when the cause of hypercalcemia is obscure)

Notes: Approximately 55% of total serum calcium is bound to serum proteins (primarily albumin) and is biologically inert; approximately 45% is in the active ionized form. In general, the portion of unbound calcium varies inversely with changes in the plasma albumin concentration. Because of the high prevalence of low protein levels in persons with cancer, direct measurement of ionized serum calcium is preferred because it avoids the uncertainty about how much calcium is metabolically available as a result of variability in serum protein concentrations. However, if ionized calcium measurement is not available, serum total calcium can be estimated for decreases in serum albumin by the formulas:

1. Corrected total calcium (mg/dL) = Measured total calcium (mg/dL) + 0.8 × [4 – measured albumin (g/dL)]

   • Correction assumes each 1 g/dL decrease of albumin will decrease measured serum Ca 0.8 mg/dL and thus 0.8 must be added to the measured calcium to get a corrected calcium value

2. Corrected total calcium (mmol/L) = Measured total calcium (mmol/L) + 0.2 × [4 – measured albumin (g/dL)]

   • Correction assumes each 1 g/dL decrease of albumin will decrease measured serum Ca 0.2 mmol/L and thus 0.2 must be added to the measured calcium to get a corrected calcium value

3. Corrected total calcium (mEq/L) = Measured total calcium + 0.4 × [4 – measured albumin (g/dL)]

   • Correction assumes each 1 g/dL decrease of albumin will decrease measured serum Ca 0.4 mEq/L and thus 0.4 must be added to the measured calcium to get a corrected calcium value

Treatment Strategies

General Principles

• Therapeutic interventions depend on the presentation. Asymptomatic patients with a serum calcium level of 3.25 mmol/L (13 mg/dL) or less can be managed conservatively, whereas symptomatic patients or those with a serum calcium level above 3.25 mmol/L (>13 mg/dL) require immediate aggressive measures

• Several agents commonly used before the introduction of bisphosphonates are now used infrequently, usually when bisphosphonates are ineffective or contraindicated

1. Hydration

   • Extracellular volume deficits exist in all patients with symptomatic hypercalcemia of malignancy. Therefore, the first intervention should be intravenous hydration with isotonic saline

   • The volume deficit, and, therefore, volume needed for replacement, depends on assessment of a patient's baseline level of dehydration, renal function, cardiovascular status, degree of mental impairment, and severity of hypercalcemia

     1. Hydration with 1000–2000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously over 2–4 hours

        Note: This will result at most in a decrease in serum calcium levels of 0.5 mmol/L (1–2 mg/dL)

2. Diuretics

   1. Furosemide 20–40 mg; administer by intravenous injection

      Notes:

      • The use of diuretics should be avoided until the volume deficit has been fully corrected. Loop diuretics (such as furosemide) cause calciuresis and may be effective in acutely decreasing calcium levels after volume repletion

      • Thiazide diuretics decrease renal calcium excretion and should be avoided

3. Bisphosphonates (first-line therapy; see Chapter 44 for more information about bisphosphonates)

   • Bisphosphonates should be initiated as soon as hypercalcemia is diagnosed

   • Initiate treatment only after (a) adequate hydration with 0.9% NS; (b) adequate urine output; and (c) with doses appropriate for a patient's creatinine clearance (CrCl) or measured serum creatinine

   • Encourage ambulatory patients to maintain hydration orally

   • If hypercalcemia persists or recurs, there should be ≥7 days between consecutive treatments

   See Chapter 44 for more information about bisphosphonates utilization

   Table Graphic Jump Location

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   Hypocalcemic Effects of Bisphosphonates

   Adapted from Riccardi A et al. Tumori 2003;89:223–236, and Body J-J. Semin Oncol 2001;28(4 Suppl 11):49–53

   Bisphosphonate	Median Time to Normocalcemia	Duration of Normocalcemia	% Achieving Normocalcemia
   Pamidronate disodium81,82	4 days	28 days	70–100%
   Zoledronic acid83	4 days	32 days	87%
   Clodronate disodium81	3 days	14 days	80%
   Alendronate sodium84	4 days	15 days	74%

   1. Pamidronate disodium 90 mg; administer intravenously in 250–1000 mL 0.9% NS, 0.45% NS, or D5W, over 2–24 hours, every 3–4 weeks

      • Durations of administration >2 hours may decrease the risk for renal toxicity, particularly in patients with preexisting renal impairment

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        Dose Modifications for Renal Impairment for Doses After the First Dose

        Baseline	Retreatment	Action
        Normal SCr	SCr increased ≥0.5 mg/dL (≥44 μmol/L)	Hold until SCr is within 10% of baseline
        Abnormal SCr	SCr increased ≥1 mg/dL (≥88 μmol/L)

   2. Zoledronic acid: 4–8 mg; administer intravenously in 100 mL 0.9% NS or D5W over at least 15 minutes, every 3–4 weeks

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      Dose Adjustments for Patients with Baseline CrCl ≤ 60 mL/min

      Baseline CrCl	Recommended Doses✫
      50–60 mL/min (0.83–1 mL/s)	3.5 mg
      40–49 mL/min (0.66–0.81 mL/s)	3.3 mg
      30–39 mL/min (0.5–0.65 mL/s)	3 mg
      ✫Doses are calculated to produce an AUC (0.6 mg · hours/L) similar to that achieved in patients with CrCl = 75 mL/min

   3. Clodronate disodium 300 mg/day; administer intravenously in 500 mL 0.9% NS or D5W over at least 2 hours for up to 5 days (treatment with intravenous clodronate may continue for >5 days but should be limited to not more than 10 days for a single hypercalcemic episode), or

      Clodronate disodium 1500 mg single dose; administer intravenously in 500 mL 0.9% NS or D5W over 4 hours

      Clodronate disodium has not received FDA approval for use outside clinical trials and is not commercially available in the United States

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      Dose Modifications for Renal Impairment for Doses After the First Dose

      CrCL	Dose Reduction
      50–80 mL/min (0.83–1.33 mL/s)	25%
      12–50 mL/min (0.2–0.83 mL/s)	25–50%
      <12 mL/min (<0.2 mL/s)	50%

   4. Alendronate sodium 5, 10, or 15 mg; administer intravenously over 2 hours

      Note: A parenteral formulation is not commercially available in the United States

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      Treatment Modification for Renal Impairment

      Elderly patients	No adjustments
      CrCl ≥35 mL/min (≥0.58 mL/s)	No adjustments
      CrCl <35 mL/min (<0.58 mL/s)	Do not administer drug

4. Calcitonin-Salmon (first-line therapy)

   1. Calcitonin 4 units/kg; administer intramuscularly or by subcutaneous injection every 12 hours. If ineffective or effectiveness begins to wane (developing tachyphylaxis):

   2. Calcitonin 8 units/kg; administer intramuscularly or by subcutaneous injection every 12 hours. If ineffective or effectiveness begins to wane (developing tachyphylaxis):

   3. Calcitonin 8 units/kg; administer intramuscularly or by subcutaneous injection every 6 hours. Discontinue if ineffective or effectiveness begins to wane, and seek an alternative intervention

   Notes:

   • Calcitonin's value is the rapid onset of its hypocalcemic effect, typically within 2–6 hours after administration. The need for frequent administration and the occurrence of tachyphylaxis within a few days after instituting therapy limits its utility to the acute setting where it should be used in combination with longer-acting agents

   • Calcitonin may be used concomitantly with bisphosphonates to augment and compensate for the slower onset of hypocalcemic effect characteristic of bisphosphonate compounds

   • Adverse effects: Flushing, nausea, vomiting, local inflammatory reaction at the site of injection

5. Gallium nitrate (second-line therapy)

   Gallium nitrate 100–200 mg/m² per day; administer intravenously in 1000 mL 0.9% NS or D5W over 24 hours, daily for 5 consecutive days

   Notes:

   • Results in a gradual reduction of serum calcium over the 5-day infusion. If the serum calcium levels are lowered into normal range before 5 days of gallium nitrate administration are completed, treatment may be discontinued

   • Hydration must be maintained throughout the period of gallium nitrate administration

   • The 5-day schedule of administration is more cumbersome than single-day administration associated with bisphosphonates such as zoledronic acid and pamidronate disodium

   • Contraindications: Renal impairment (serum creatinine >2.5 mg/dL; >221 μmol/L)

   • Adverse effects: Renal failure, hypophosphatemia, hypocalcemia, respiratory alkalosis, vomiting, hypotension, tachycardia, nausea, vomiting, diarrhea, acute optic neuritis

6. Glucocorticoids (second-line therapy, with limited applications)

   • May be useful in patients with steroid-sensitive cancers such as lymphomas or multiple myeloma by decreasing the 1,25-dihydroxycholecalciferol levels

     1. Prednisone 60 mg; administer orally, daily for 7–10 days (or equivalent steroid dose)

        Note: Steroids have a slow onset of action (7 days) and short duration of action (3–4 days)

7. Plicamycin (third-line therapy)

   1. Plicamycin 25 mcg/kg; administer intravenously in 1000 mL 0.9% NS or D5W over 4–6 hours

      • Plicamycin is a highly toxic antibiotic antineoplastic with hypocalcemic activity that acts by blocking RNA synthesis in osteoclasts. Plicamycin is not available in the United States outside the context of a clinical trial

      • Plicamycin lowers serum calcium levels within 12 hours, with a maximum effect at about 48 hours, therefore:

      • Repeated doses should not be given more frequently than every 48 hours to prevent excessive iatrogenic decreases in serum calcium

        Notes:

      • Although widely used in the past, the occurrence of side effects, including thrombocytopenia, myelosuppression, hepatotoxicity, nephrotoxicity, coagulopathy including hemorrhagic diathesis, nausea, and vomiting, the availability of other effective less-toxic agents, and limited availability worldwide, currently limit plicamycin use

      • Contraindications: Bone marrow suppression, thrombocytopenia, coagulation disorder, bleeding

8. Phosphorus

   1. Neutral phosphate salts 500–1500 mg/day of elemental phosphorus; administer orally in 2–4 divided doses

      Caution: Intravenous phosphorus administration in a setting of hypercalcemia may result in deposition of calcium phosphate in renal tubules and soft tissues

      Notes:

      • Hypophosphatemia develops in most patients with hypercalcemia associated with cancer, and the presence of hypophosphatemia increases the difficulty of treating hypercalcemia

      • Phosphorus should be replaced orally or administered through a nasogastric tube

      • Avoid intravenous phosphorus administration except in the presence of severe hypophosphatemia (serum phosphorus <1.5 mg/dL [<0.48 mmol/L]) and when oral phosphorus cannot be administered

      • Intravenously administered phosphorus should be used with extreme caution and with continual serial observation of serum phosphorus and creatinine concentrations

9. Denosumab

   • Denosumab, a fully human monoclonal antibody with a high affinity and specificity for RANK ligand (RANKL)

   • Two Denosumab products have received U.S. Food and Drug Administration (FDA) approval for different indications:

     • Proprietary name, Xgeva, denosumab is approved for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors (Xgeva [denosumab] injection, for subcutaneous use, product label 11/2010. Amgen Manufacturing Limited, a subsidiary of Amgen Inc., Thousand Oaks, CA)

     • Proprietary name, Prolia, denosumab is approved for (a) use in patients who are at high risk for fracture, including patients receiving androgen-deprivation therapy (ADT) for nonmetastatic prostate cancer, (b) treatment of bone loss in women receiving adjuvant aromatase inhibitor (AI) therapy for breast cancer to increase bone mass, and (c) for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture (Prolia [denosumab] injection, for subcutaneous use, product label 09/2010. Amgen Manufacturing Limited, a subsidiary of Amgen Inc., Thousand Oaks, CA)

       Notes: Denosumab is not indicated for the prevention of SREs in patients with multiple myeloma

     • Although denosumab may garner FDA approval for hypercalcemia associated with malignancy, it is likely that delineation of optimal doses and schedules will evolve over time as has happened with the bisphosphonates. Its use in acute hypercalcemia must be demonstrated in clinical trials before it can be recommended. A single-arm, open-label, proof-of-concept study, evaluated patients with hypercalcemia of malignancy with albumin-corrected serum calcium (CSC) levels ≥12.5 mg/dL despite recent intravenous bisphosphonate treatment. They received subcutaneous denosumab on days 1, 8, 15, and 29, and then every 4 weeks. By day 10, 12/15 patients (80%; 95% confidence interval [CI] = 52–96%) had achieved a CSC ≤11.5 mg/dL, the primary endpoint. However, the median response duration was only 26 days

        

       Hu et al. J Natl Cancer Inst 2013; 105:1417–1420

     • Administration:

       Denosumab 120 mg; administer by subcutaneous injection in the upper arm, upper thigh, or abdomen every 4 weeks

       Ancillary medicines: Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia

       Caution: The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance of less than 30 mL/min (<0.5 mL/s) or in persons receiving dialysis

     • Adverse effects: Hypocalcemia and osteonecrosis of the jaw (ONJ)

     • In a recent statistical analysis comparing the rates of skeletal-related events (SREs) "observed with denosumab to those with placebo based on the results of the registrational studies of zoledronic acid and pamidronate, denosumab reduced the risk of developing a first skeletal related event (SRE) by 48%". The number needed to treat (NNT) "with denosumab compared with placebo was 4 patient-years, indicating that, on average, treatment of 4 patients with denosumab for one year is expected to prevent one additional first SRE compared with no treatment"

        

       Martin et al. Clin Cancer Res 2012;18:4841–4849

Anaphylaxis Etiology

• An acute hypersensitivity reaction is an unpredictable and potentially catastrophic complication of treatment with chemotherapeutic agents and can occur at any time during the administration of therapy^{85,86,87,88,89}

• Almost all the antineoplastic drugs have been reported to cause hypersensitivity reactions

• Certain classes of chemotherapeutic agents commonly associated with hypersensitivity reactions include the taxanes, platinum compounds, asparaginases, and epipodophyllotoxins (etoposide, teniposide)

• Despite prophylactic measures with steroids or antihistamines to reduce the incidence of hypersensitivity reactions, hypersensitivity reactions still occur and severe reactions may require immediate medical management with the drugs listed below

Work-up

1. Focused physical examination

2. Establishment of a stable airway

3. Establishment of intravenous access

4. Administration of epinephrine

Note: Parenteral epinephrine is the cornerstone of management

Treatment Strategies