Supportive care of patients with cancer

Febrile neutropenia

Febrile neutropenia (FN) is defined by the following criteria:

• A single oral temperature ≥38.3°C (101.0°F) or an oral temperature ≥38.0°C (100.4°F) sustained for >1 hour or that occurs twice within a 24-hour period.

• An ANC<0.5×10 ⁹ /L or ANC<1.0×10 ⁹ /L expected to decrease to <0.5×10 ⁹ /L over the subsequent 48 hours.

Families should be advised against taking rectal temperatures. Recent consumption of hot or cold beverages should not alter management if the patient has had a documented oral temperature taken. Alternate routes for fever measurement, including axillary, otic, and temporal, should be discouraged but all should be managed in the same manner if there is a documented fever.

Initial FN evaluation should include the following:

• Complete blood count (CBC) with differential.

• Complete metabolic panel.

• Blood cultures from each lumen of the CVC or peripheral cultures if without a CVC (≥1 mL of blood).

• Clean-catch bacterial urine cultures (urine catheterization should not be done, especially in the neutropenic patient).

• Gram stain and culture from suspicious skin, oropharyngeal, or CVC sites.

• Additional measures that may be considered but are not routinely recommended include:

  • Blood cultures via venipuncture, in addition to cultures from central venous lines, can be considered a means to determine bacteremia versus CVC infection based on the differential time to positivity, although the impact of this measure on treatment decision-making in FN is unclear.

  • Coagulation studies in the patient with bleeding.

  • Chest radiography (CXR) is not routinely recommended and should only be done in the patient with respiratory compromise, symptoms of pulmonary infection, or auscultatory signs.

  • Patients with sinus tenderness should have computed tomography (CT) of the sinuses.

  • Patients with esophagitis should be considered for endogastroduodenoscopy with biopsy and culture to rule out viral and fungal causes.

  • Patients with diarrhea should have a stool sample sent for culture, rotavirus, and Clostridium difficile testing.

  • Viral studies can also be considered, especially with seasonal viruses such as RSV, influenza, and enterovirus and for herpes simplex virus (HSV) in those with mucocutaneous lesions. In light of the recent pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing is required for all febrile patients and appropriate contact droplet precautions must be undertaken.

  • Lumbar puncture is rarely indicated but if the patient has central nervous system (CNS) signs a head CT should be performed first to rule out mass lesions or hemorrhagic stroke that may lead to increased intracranial pressure.

  • Shunt fluid examination from implanted devices such as VP shunts or Ommaya reservoirs is rarely indicated but should be considered in patients with altered mental status and performed in patients with any meningeal signs or symptoms.

Management of FN

The initial management of pediatric FN includes rapid assessment of the patient, recognition of those exhibiting signs and symptoms of sepsis, rapid initiation of broad-spectrum antibiotics and other necessary supportive care measures, and subsequent admission to the hospital. Although multiple risk stratification models have been published, none have been validated across varied pediatric oncology cohorts. However, the current consensus guidelines recommend consideration for initial outpatient or step-down management in pediatric patients with “low-risk” FN. Adult Infectious Diseases Society of America (IDSA) guidelines define low-risk broadly for those patients with minimal or no comorbidities and neutropenia expected to last ≤7 days. Given that “low-risk” is not uniformly defined in pediatric oncology, outpatient management or early discharge should be done under carefully determined institutional guidelines while guaranteeing close patient monitoring and, possibly, administration of an oral fluoroquinolone while neutropenic. See Fig. 32.1 for an algorithmic approach to initial management of FN.

Antibiotic selection should be based on microbial prevalence and sensitivity patterns at individual institutions. Due to the acute risk of Gram-negative sepsis, empiric coverage must include these organisms, including Pseudomonas . Multiple empiric regimens are acceptable, although, in general, monotherapy has supplanted dual therapy as the regimen of choice:

• Monotherapy

  • Fourth-generation antipseudomonal β-lactam cephalosporin; cefepime 150 mg/kg per day intravenous (IV) divided q8h (max 2 g/day).

  • Carbapenems

    • –

      Imipenem/cilastatin 60- to 100-mg/kg per day (imipenem component) IV divided q6h (max 4 g/day).

    • –

      Meropenem 60 mg/kg per day IV divided q8h (max 3 g/day) (can be increased to 120 mg/kg per day IV divided q8h with max 6 g/day in severe infection).

  • Piperacillin/tazobactam (Zosyn) 240 to 300 mg/kg per day (piperacillin component) IV divided q8h (max 16 g/day).

• Dual therapy (antipseudomonal β-lactam plus an aminoglycoside)

  • Ceftazidime 150 mg/kg per day IV divided q8h (max 6 g/day) plus tobramycin 7.5 mg/kg per day IV divided q8h or 7–9-mg/kg per dose IV daily.

Multiple metaanalyses have shown that monotherapy with broad-spectrum, antipseudomonal β-lactams are noninferior to dual therapy. The empiric utilization of anti–Gram-positive antibiotics without a documented infection does not improve outcomes. Patients on aminoglycosides or vancomycin should have trough levels monitored weekly due to risks of nephrotoxicity and ototoxicity with frequent monitoring of renal function. Vancomycin trough levels are also utilized to determine antibiotic efficacy with a documented Gram-positive infection. Although not well studied, daily dosing of aminoglycosides may improve efficacy and decrease nephrotoxicity as compared to divided dosing throughout the day. Trough levels can similarly be monitored with daily dosing, although this methodology requires further validation. Patients with underlying renal dysfunction should receive renal dosing with more frequent trough monitoring. Dual therapy can be considered in the following clinical scenarios:

• Patient instability (e.g., hypotension, altered mental status, oliguria, moderate-to-severe respiratory distress).

• Concern for resistant pathogens (e.g., extended-spectrum β-lactamase-producing Serratia, Pseudomonas, Acinetobacter, Citrobacter, Enterobacter, Klebsiella spp.).

• Need for synergism for specific pathogens (e.g., Enterococcus, Mycobacterium spp., methicillin-resistant Staphylococcus aureus ).

• Need for synergism with specific infections (e.g., endocarditis, cryptococcal meningitis).

Vancomycin should be considered in the following situations at a dose of 60-mg/kg per day IV divided q8h (max 4 g/day):

• Patients with AML receiving high-dose cytarabine due to risk for Streptococcus viridans infection with associated septic shock and acute respiratory distress syndrome.

• Presentation with hypotension or other evidence of shock.

• Mucositis.

• Prior history of alpha-hemolytic Streptococcus infection.

• Skin breakdown or catheter site infection.

• Colonization with resistant organisms treated only with vancomycin.

• Vegetations on echocardiogram.

• Severe pneumonia.

Anaerobic organisms are treated with carbapenems, piperacillin/tazobactam, or metronidazole 30-mg/kg per day IV divided q8h (max 1.5 g/day) and should be considered in the following situations:

• Typhlitis (neutropenic colitis).

• Significant mucosal breakdown.

• Perianal skin breakdown.

• Peritoneal signs or other abdominal pathology.

• Sinusitis not responding to initial treatment.

Clindamycin is used less frequently due to the risk of C. difficile infection that ideally should be treated with oral metronidazole or oral vancomycin 40 mg/kg per day divided q6–8h though IV metronidazole may also be utilized in the patient unable to tolerate oral intake.

Patients should be monitored closely for signs of sepsis and treated accordingly with fluid resuscitation, vasopressor support, and management in an intensive care setting, as required. Post-HSCT patients are at risk for particular infections based on the time point after transplant as summarized in Table 32.2 .

Table 32.2

Common infections seen at different time points following hematopoietic stem cell transplantation.

From Hastings, C.H., Torkildson, J.C., Agrawal, A.K., 2021, Pediatric Hematology/Oncology Handbook. Children’s Hospital and Research Center Oakland, third ed. Wiley Blackwell, Hoboken, NJ. Used with permission.

First 30 days	Bacterial	Gram-negative aerobes and anaerobes
		Staphylococcus epidermidis
	Fungal	Aspergillus sp.
		Candida sp.
	Viral	Herpes simplex type I reactivation
30–120 days	Fungal	Candida albicans and Candida tropicalis
		Aspergillus sp.
		Other Candida sp., Trichosporon sp., Fusarium sp.
		Pneumocystis jirovecii
	Viral	Cytomegalovirus
		Adenovirus
		Epstein–Barr virus
		Human herpesvirus 6
	Protozoal	Toxoplasma sp.

Alterations in initial FN management

Modifications to the initial empiric regimen should be made based on the patient’s clinical course, any positive cultures, and total time of FN. Patients who are initially treated with dual antibiotic therapy or have had vancomycin added can have these secondary agents discontinued 24–72 hours after initial presentation if they have no new clinical signs and all cultures for susceptible organisms are negative. It is unclear if pediatric patients with continued fevers should have daily blood cultures from each CVC lumen beyond the first 48 hours of persistent fevers unless there is a clinical change. Adult IDSA guidelines recommend against daily cultures and the most recent pediatric consensus guidelines do not address this question. Single-institution studies have shown limited yield (though not zero) beyond this initial 48-hour period. A daily CBC with differential should be performed to monitor for count recovery with continuation of empiric antibiotics. Resolution of neutropenia occurs once the ANC is ≥0.5×10 ⁹ /L. An ANC ≥0.2×10 ⁹ /L and rising on two consecutive days is a sign of impeding count recovery as well as bacterial protection. The absolute phagocyte count (neutrophils plus monocytes) can also be utilized as a measure of sufficient immune recovery. Once the patient has defervesced with negative cultures and neutrophil recovery, all antibiotics can be discontinued and the patient discharged. Based on institutional guidelines, “low-risk” patients without ANC recovery who are afebrile for 24 hours with negative blood cultures for 48 hours can be discharged assuming close follow-up and, possibly, on oral levofloxacin until ANC≥0.5×10 ⁹ /L. Patients with positive cultures require continuation of antibiotics to complete an appropriate course, generally 7–10 days for Gram-positive organisms and 10–14 days for Gram-negative organisms, assuming the infection can be cleared after the initiation of antibiotics appropriate for the organism sensitivity (see the section “Management of CVCs” for further information).

Fungal infection

Patients with prolonged (i.e., >7–10 days) and profound (i.e., ANC<0.1×10 ⁹ /L) neutropenia are at the highest risk for developing an invasive fungal infection (IFI). Patients, especially those with hematologic malignancy and those not anticipated to have prompt neutrophil recovery, should have the addition of an empiric antifungal approximately 3–5 days after presentation for FN, generally with an echinocandin (i.e., micafungin, caspofungin, and anidulafungin) or extended-spectrum azole (i.e., voriconazole and posaconazole). Possible drug interactions with azole agents must be considered. Once empiric antifungal agents have been initiated, chest CT and abdominal ultrasound should be considered to rule out occult fungal infection once the patient has experienced neutrophil recovery if with persistent or recrudescent fever. CT of the sinuses can be considered in the patient with sinus symptoms. CT of the abdomen and pelvis is generally not indicated unless the patient has localizing signs and a negative abdominal ultrasound. See Fig. 32.2 for an algorithmic approach to the continued management of FN.

Biomarkers of IFI have been utilized in adult patients and may also be beneficial in pediatric patients. Galactomannan is a cell wall component of growing hyphae and can be detected from serum, urine, or bronchoalveolar lavage (BAL) fluid. Galactomannan can be a useful marker for aspergillosis although false-positive results can occur; serial repetition in conjunction with corroborative clinical and radiographic findings makes the test most useful. Testing of serum β- d -glucan, a cell wall component of most fungi, as well as polymerase chain reaction (PCR), may improve detection of IFI although data are lacking in pediatric patients and these tests are not currently routinely recommended.

Risk factors for fungal disease include the following:

• Recrudescence of fever after the recovery of neutrophils.

• Persistent fevers.

• Active graft-versus-host disease.

• Prolonged recent corticosteroid usage.

• Development of lower respiratory symptoms (cough, chest pain, hemoptysis, dyspnea).

• Development of new, focal papulonodular skin rash or eschar.

• Upper respiratory symptoms (nasal discharge), nasal eschar, periorbital swelling, and perforation of hard palate.

• Sinus tenderness with concomitant findings on CT sinuses (i.e., erosion of sinus walls, skull base destruction).

• Findings on CT chest imaging (i.e., nodules, infiltrates, halo or crescent sign, cavitation).

• Shoulder pain.

• Focal neurologic findings with concomitant finding of mass lesion, mastoiditis, or empyema on CT head.

• Galactomannan positivity (serum, BAL).

• Positive fungal culture (blood, urine).

Invasive aspergillosis (especially Aspergillus fumigatus ) is being seen with increasing frequency and is often found as isolated pulmonary disease. CT chest findings most often show nodules and cavitation with the halo and crescent signs being much less common as compared with adults. Patients with concern for invasive candidiasis (often through blood or urine culture positivity) should have CT imaging of the head, chest, abdomen, and pelvis and ophthalmic evaluation to rule out potential sites of disseminated disease. Patients with sinus disease are at increased risk of zygomycosis, especially mucormycosis (i.e., Mucor, Rhizomucor, Rhizopus ).

Treatment of IFI includes the following:

• Invasive aspergillosis

  • IV voriconazole

    • –

      2 to <12 years: loading 7 mg/kg per dose q12h×2 doses (max 400 mg/dose) followed by 7 mg/kg per dose q12h (max 200 mg/dose).

    • –

      ≥12 years: loading 6 mg/kg per dose q12h×2 doses followed by 4 mg/kg per dose q12h.

  • PO voriconazole

    • –

      2 to <12 years: loading 8 mg/kg per dose (max 400 mg/dose) BID×2 doses followed by 7 mg/kg per dose (max 200 mg/dose) BID.

    • –

      ≥12 years:

      • o

        <40 kg: 100 mg BID (max dose 150 mg).

      • o

        ≥40 kg: 200 mg BID (max dose 300 mg).

  • Posaconazole

    • –

      For children >13 years of age, 300 mg delayed-release tablet BID on the first day followed by 300 mg daily or 200 mg suspension TID (with meals).

  • Micafungin

    • –

      4 mg/kg (max 150 mg) IV q24h.

    • –

      Can be given in conjunction with an extended-spectrum azole although data on treatment synergy are lacking.

  • Caspofungin

    • –

      70 mg/m ² IV loading dose (max 70 mg/dose) followed by 50 mg/m ² IV q24h (max 70 mg/dose).

    • –

      Can be given in conjunction with an extended-spectrum azole although data on treatment synergy are lacking.

• Mucormycosis

  • Liposomal amphotericin B (Ambisome).

    • –

      5 mg/kg per dose IV q24h.

  • Combination therapy has not shown benefit.

  • Surgical resection with soft tissue and rhino-orbito-cerebral disease.

• Invasive candidiasis

  • Treatment based on sensitivities, often sensitive to fluconazole.

  • Fluconazole 12 mg/kg IV loading dose followed by 6 to 12 mg/kg IV q24h (max 400 mg/dose).

  • Echinocandins have been found to be at least noninferior to fluconazole.

Fever in the nonneutropenic oncology patient

The nonneutropenic oncology patient remains susceptible to infection secondary to the presence of a CVC as well as immune dysfunction secondary to chemotherapy effect or effect of the underlying malignancy. Evaluation of the nonneutropenic patient should mirror that of the neutropenic patient with a careful history and physical as well as blood culture and CBC. Patients without concerning findings can be managed in the outpatient setting as long as close follow-up can be ensured. Patients should receive ceftriaxone while awaiting results of the initial blood cultures. Patients in whom close follow-up or rapid return to hospital is unreliable, those with concerning findings on examination and those with dropping blood counts with the potential for severe neutropenia in the subsequent 48 hours should be admitted.

Infection prophylaxis

Strategies to prevent infection are not as well established as treatment of infection, especially in pediatric patients. Ongoing studies are determining whether antibiotic and antifungal prophylaxis are beneficial and whether certain agents are superior. Risk stratification to determine which pediatric populations should receive prophylaxis has shown that those with the longest periods of chemotherapy-related neutropenia and therefore those receiving the most intensive myelosuppressive regimens, namely, AML and relapsed acute lymphoblastic leukemia (ALL), are at the highest risk.

Hospital infection control practices

Multiple hospital-based infection control practices are vital to protect immunocompromised patients from nosocomial infection. Important interventions include the following:

• Hand hygiene.

• Mandatory vaccination of health-care workers.

• Isolation of immunocompromised patients.

• Isolation of patients with communicable diseases.

• Visitor screening.

• Healthcare work restriction.

Healthcare workers are a significant potential reservoir of infection for patients and healthcare workers have been shown to not restrict themselves from work, especially those with a viral upper respiratory infection. Therefore institutional standards must be in place to enforce restriction of healthcare workers from attending to high-risk patients if they develop upper respiratory symptoms.

Anticipatory guidance

Patients undergoing chemotherapy and HSCT and their families must be advised as to the potential sources of infection outside of the hospital setting. As a means to prevent infection, patients should be advised to avoid crowded places such as movie theaters, shopping malls, and grocery stores where they may be exposed to viral pathogens. Similarly, families should employ screening at home to ensure that visitors are free of respiratory symptoms. It is often best to avoid exposure to young children who may be reservoirs of viral disease.

Household contacts should receive yearly inactivated influenza vaccine and young, susceptible contacts should be immunized against varicella. Those who develop a postvaccination rash are recommended to be separated from susceptible individuals until the lesions have crusted over due to the theoretical risk of transmission even though no case of transmission of vaccine strain varicella to the immunocompromised has been reported. Additional live-virus vaccines such as measles–mumps–rubella (MMR) and rotavirus have been deemed safe. Oral poliovirus is contraindicated and LAIV is relatively contraindicated.

Antiemetic agents

Effective antiemetic agents provide control of vomiting by blocking neurochemical receptors and thus inhibiting stimulation of the CTZ. Those agents with proven antiemetic activity in children include the following:

• 5-HT ₃ receptor antagonists —ondansetron is the most widely utilized 5-HT ₃ receptor antagonist although granisetron, dolasetron, and palonosetron are available in the United States, with tropisetron available internationally but not approved by the US Food and Drug Administration (FDA). Ondansetron is dosed as 0.15 mg/kg q8h to a maximum of 8 mg, although it is equally effective when given as a single daily dose of 0.45 mg/kg or 16 mg/m ² to a maximum of 24 mg. Granisetron has clinically been shown to be equally efficacious and safe and is dosed as a single daily 40 µg/kg IV dose. Palonosetron has a higher binding affinity to the 5-HT ₃ receptor and 5–10 times longer half-life than first-generation agents and may have benefit for delayed CINV. Palonosetron is dosed at 0.02 mg/kg (max 1.5 mg) for children 1 month to <17 years and 0.25 mg IV or 0.5 mg PO for patients ≥17 years. Further research is required in pediatric oncology patients to determine the optimal dose, cost-effectiveness, and relative efficacy of palonosetron as compared to first-generation agents although it has been shown to be noninferior. Olanzapine is an antipsychotic with 5-HT ₃ receptor antagonism that should be considered in patients with refractory CINV.

• Neurokinin-1 receptor (substance P) antagonists (aprepitant, fosaprepitant, rolapitant) are used in combination with a 5-HT ₃ receptor antagonist and dexamethasone to prevent acute and delayed CINV in patients receiving highly emetogenic chemotherapy. Pediatric patients ≥12 years of age utilize adult dosing for aprepitant (125 mg on day 1, 80 mg on days 2 and 3) while those <12 years of age should receive 3 mg/kg on day 1, followed by 2 mg/kg on days 2 and 3 to the above maximum doses (i.e., if <12 years and >40 kg). Aprepitant is a moderate inhibitor of CYP3A4 and thus drug interactions are an important consideration, especially in patients receiving etoposide, ifosfamide, imatinib, irinotecan, paclitaxel, and vinca alkaloids (in addition to steroids). The antiemetic dose of dexamethasone should be halved when given with aprepitant. Rolapitant has not been studied extensively in pediatric patients.

• Corticosteroids are effective through unclear mechanisms but are most beneficial when initiated prior to the onset of chemotherapy in regimens that do not utilize steroids as part of treatment. Steroids should also be avoided in patients with CNS malignancy due to concern for dexamethasone decreasing influx of chemotherapeutic agents into the brain by altered permeability of the blood–brain barrier.

• Dopamine receptor antagonists —these have been replaced by 5-HT ₃ receptor antagonists as the primary antiemetic of choice. Metoclopramide has generally gone out of favor due to potential for dystonic reaction and extrapyramidal side effects with given at high dose (i.e., 1 mg/kg) necessitating concomitant utilization of diphenhydramine though may have benefit at lower doses without this risk.

• Cannabinoids —those approved for CINV include dronabinol and nabilone and are thought to work by targeting cannabinoid-1 (CB-1) and CB-2 receptors in the brain. These agents have demonstrated modest efficacy for CINV in children, although side effects, including euphoria, dizziness, and hallucinations, must be considered.

Antihistamines, such as diphenhydramine, affect histaminergic receptors in the CTZ and are empirically effective but have not been systematically studied. Similarly, benzodiazepines (i.e., lorazepam) and anticholinergics (i.e., scopolamine) are widely utilized and empirically beneficial but not well studied. Benzodiazepines are useful adjuncts especially in the patient with anticipatory CINV. See Table 32.3 for a description of agents, proposed mechanism of action and suggested dosage.

Alternative therapies, including ginger, acupressure/acupuncture, hypnosis, and other behavior modification techniques, may be beneficial but have not been studied systematically, especially in pediatric patients.

Although patient factors are important when considering the risk of CINV, chemotherapy agents have direct emetogenic risk as described in Table 32.4 . When patients are undergoing therapy with multiple agents, the emetogenicity of the regimen is determined based on the agent with the highest risk. Management of CINV should follow these guidelines:

• Moderate–high to high emetogenic risk

  • 5-HT ₃ receptor antagonist.

  • Aprepitant.

  • Dexamethasone (if allowed).

    • –

      If dexamethasone not allowed, use additional breakthrough agent(s) and consider utilization of palonosetron as the specific 5-HT ₃ receptor antagonist.

• Moderate emetogenic risk

  • 5-HT ₃ receptor antagonist.

  • Dexamethasone (if allowed).

    • –

      If dexamethasone not allowed, use aprepitant.

• Moderate–low emetogenic risk

  • 5-HT ₃ receptor antagonist.

• Minimal emetogenic risk

  • No routine prophylaxis.

Prevention and treatment of oral mucositis

Evidence-based interventions that are effective in the prevention and treatment of oral mucositis, especially in pediatric patients, are extremely limited. Palifermin, a recombinant keratinocyte growth factor-1, has been shown to increase cellular proliferation and mediate epithelial cell repair with a decrease in duration and severity of oral mucositis in adult patients undergoing HSCT. Extremely limited pediatric data have shown unclear benefit in HSCT at an IV dose of 60 μg/kg per day daily for 3 days prior to the start of the preparative regimen and for 3 days after completion. A single IV dose of 180 μg/kg given 3 days prior to chemotherapy start has been utilized with similar efficacy as the standard dosing in non-HSCT patients. Low-level laser therapy, or photobiomodulation (local application of a monochromatic, narrowband, coherent light source), has shown potential benefit in the prevention and treatment of oral mucositis though pediatric data are limited. Other preventative and treatment modalities that have shown inconsistent and limited pediatric evidence include glutamine and cryotherapy. Additional treatment modalities that are vital include pain control as well as continued oral care with saline rinses at a minimum. Oral hygiene, including gentle brushing and flossing, should ideally be continued if tolerable.

Developmental issues in pediatric pain management

Undertreatment of pain in young children is known to have short-term physiologic effects and may influence later pain behaviors, including those children with newly diagnosed cancer. A child’s development stage must be considered in the assessment of pain; children under 3 years of age and those with developmental delay must have pain intensity measured by behavioral observation scales while older children (i.e., >8 years) can utilize adult scales. Physiologic aspects can affect the pharmacokinetics and pharmacodynamics of analgesic drug delivery including increased potential for sedatory hypoventilation in infants and increased drug clearance in young children as compared to adults due to a proportionally larger liver mass.