Invasive infections are a common source of morbidity and mortality in children with cancer. The risk for infectious complications during therapy for cancer is inversely related to age: children with cancer are more commonly affected by infection compared with adult oncology patients, and infants are more vulnerable to infection than older children. This is due to both environmental exposures that occur in childhood and the chemotherapy regimens used to treat pediatric cancer; the latter are more intensive in children than in adults with analogous malignancies.
Among pediatric oncology patients, children with acute leukemia are the group at highest risk for infectious complications. Fifty percent of pediatric patients with hematologic malignancies will have an infection at some point during therapy. Children with acute lymphoblastic leukemia (ALL) have an infection-related mortality of nearly 5%, and among children with acute myelogenous leukemia (AML), infectious diseases are the cause of death in 5% to 10% of patients. , Mortality associated with invasive fungal disease in pediatric oncology patients is approximately 30%.
Survival rates for childhood cancer are approaching 80%, which is vastly improved from prior decades. This is due in part to the refinement of chemotherapy protocols and the incorporation of novel, targeted therapeutic agents that have limited toxicity and extended survival. Additionally, supportive care regimens that optimize prevention and treatment of infectious diseases have substantially contributed to improved survival in pediatric oncology patients. However, with the improvement in overall survival come new infection-related complications that arise secondary to profound immunosuppression in the context of relapsed and refractory malignancy, unclear infectious risks of novel chemotherapeutics, and emergence of resistant organisms driven by increased use of anti-infective agents in this vulnerable pediatric population.
This chapter provides a paradigm for the assessment of infectious risk factors encountered by pediatric cancer patients based on specific cancer treatment regimens. Tailored supportive care recommendations are given for patients in the context of specific malignancies and chemotherapy regimens. Finally, risk factors and infectious pathogens common to specific pediatric oncology subpopulations are highlighted.
Infectious risk assessment in oncology patients
Not all pediatric oncology patients have the same risk for acquiring infectious diseases. Risk assessment can be evaluated at several levels, but the most superficial level is separation of hematologic (leukemia or lymphoma) from nonhematologic (solid) tumors. The treatment for hematologic malignancies requires therapy directed at the malignant and normal components of the immune system, leading to prolonged and profound immune deficits. In contrast, therapy for solid tumors largely consists of intermittent cytotoxic and myelosuppressive chemotherapy that only briefly disrupts immune function, predominantly by decreasing neutrophil quantity.
In general, the approach to infection prevention, diagnosis, and management in a pediatric oncology patient should incorporate the the intensity of chemotherapy that a child will receive ( Table 3.1 ). Chemotherapy is the mainstay of cancer treatment in pediatric patients, and more intensive regimens are used for higher-risk malignancies. Increased intensity of chemotherapy results in more significant side effects, including bone marrow suppression, mucositis resulting in poor mucosal barrier integrity, and nutritional deficiency, all of which can contribute to an increased risk of opportunistic infection.
| Malignancy | Typical Therapeutic Agents | Typical Regimen Duration | Location of Treatment | Expected Duration of Severe Neutropenia | Need for CVC Access? | Mucositis Risk | Additional Infection Risk Factors | Overall Risk of Infection |
|---|---|---|---|---|---|---|---|---|
| Leukemia | ||||||||
| ALL | Conventional chemotherapy: Steroids, anthracycline, asparaginase, vincristine, methotrexate, cyclophosphamide, cytarabine, Mercaptopurine-targeted chemotherapy: + Ph+ ALL: Imatinib, dasatinib Varied, usually in relapse protocols | 6-9 months intensive followed by 2-2.5 years of low-intensity maintenance therapy | Initial therapy: Inpatient Maintenance: Ambulatory setting | Varied with each cycle, 7-28 days | Yes | Moderate (varies with each cycle) | High | |
| AML | Conventional chemotherapy: Anthracycline, etoposide, cytarabine Targeted chemotherapy: Varied, usually in relapse protocols HSCT: For high-risk and relapsed patients | 6-9 months of intensive chemotherapy | Primarily inpatient | 14-21 days for each cycle | Yes | Moderate | High | |
| CML | Targeted chemotherapy: Tyrosine kinase inhibitors | Lifelong | Ambulatory | None | No | None | Low | |
| Lymphoma | ||||||||
| Hodgkin | Conventional chemotherapy: Steroids, varied cytotoxic and myelosuppressive agents Targeted chemotherapy: ± Brentuximab HSCT: Auto for relapsed disease XRT: ± Involved field | ∼6 months | Primarily ambulatory | <7 days per cycle | Sometimes | Minimal | Low-moderate | |
| Non-Hodgkin | Conventional chemotherapy: Varied cytotoxic and myelosuppressive agents | ∼6 months | Mixed inpatient/outpatient | <7 days per cycle | Sometimes | Moderate | Moderate | |
| CNS Tumors | ||||||||
| Embryonal | Surgery Conventional chemotherapy: Varied cytotoxic and myelosuppressive agents HSCT: Autologuous in some protocols XRT: axis | ∼1 year | Mixed inpatient/outpatient | <7 days per cycle | Yes | Moderate | CSF diversion catheters, surgical site infection | Moderate-high |
| Nonembryonal | Surgery Targeted chemotherapy: Various agents dependent on tumor type XRT: Craniospinal axis | Varied | Primarily ambulatory | Minimal | Rarely | Minimal | CSF diversion catheters, Surgical site infection | Moderate |
| Solid Tumors | ||||||||
| Sarcoma | Conventional chemotherapy: Alkylating agents, anthracyclines, platinums, dactinomycin, vincristine, etoposide Surgery: Resection of primary tumor and/or XRT: Tumor bed | 6-9 months | Mixed inpatient/outpatient | <7 days per cycle | Yes | High | Poor nutrition, deconditioning, surgical site infection, endoprosthetic infection | Moderate |
| High-risk neuroblastoma | Conventional chemotherapy : Anthracycline, alkylating agents, vincristine, etoposide Targeted chemotherapy: Anti-GD2 antibody Surgery: Resection of primary tumor and XRT: Involved field and HSCT: Auto | 1.5 years | Mixed inpatient/outpatient | ∼7 days per cycle | Yes | High | High |
Myelosuppression leading to neutropenia is the most common hematologic toxicity of nearly all chemotherapy regimens. The majority of infectious complications, in particular bacterial infections and invasive fungal disease, occur in children with severe, prolonged neutropenia. , Life-threatening bloodstream infections (BSIs) are more likely to develop in patients with an absolute neutrophil count below 100 cells/μL. Additional hematologic toxicities occur in children with lymphoid malignancies who experience prolonged periods of decreased lymphocyte count and function, and are therefore at risk for hypogammaglobulinemia. Patients with hypogammaglobulinemia are further predisposed to infections caused by viruses and encapsulated bacteria.
Advances in prophylactic and empiric anti-infective therapy regimens have improved outcomes for high-risk pediatric oncology patients, particularly those with prolonged neutropenia. Details regarding specific recommendations for prophylactic and empiric treatment approaches during neutropenic periods are provided in Chapter 8 : Management Principles for Neutropenic Patients. These approaches are aimed at reducing the risk of opportunistic bacterial and fungal infections during periods of neutropenia. However, the resulting burden of exposure to anti-infective agents can result in selective pressures leading to drug-resistant pathogens. This is compounded in children with cancer by the risk of acquiring drug-resistant pathogens from the health care environment by virtue of frequent and prolonged hospitalizations. Understanding the prior anti-infective use and health care exposures for each patient is important for anticipation of infection or colonization with drug-resistant pathogens and may alter empiric treatment choices.
Several other factors pertinent to pediatric oncology patients result in immune compromise beyond neutropenia or lymphopenia. Therapy for most childhood cancers requires a central venous catheter (CVC) for administration of vesicant chemotherapy and frequent intravenous supportive care including total parenteral nutrition. The presence of a CVC compromises the innate immunity of the skin barrier and is an independent risk factor for BSI; this risk persists even after neutrophil count recovery. Approximately 25% of children with cancer have a BSI that is directly attributed to the CVC. The type of CVC can determine risk for infections; there is a higher rate of BSI and specifically gram-negative rod infection with percutaneous CVCs compared with implanted access ports. ,
Additional disruption of skin and mucosal barrier integrity can result from certain chemotherapeutic agents ( Table 3.2 ), radiation therapy (XRT), and/or surgical procedures. Mucositis, or inflammation and ulceration of the mucosal lining of the gastrointestinal tract, can be caused by chemotherapy or XRT. Breaches in the mucosal lining of the mouth and intestines enable translocation of commensal organisms into the bloodstream. In the setting of neutropenia, translocation of organisms to the bloodstream is more likely to result in a BSI. Skin integrity is disrupted in pediatric oncology patients by surgical incisions, CVCs, gastrostomy tubes, and XRT-induced burns. Any breach in skin integrity serves as a nidus for skin and soft tissue infection, especially in patients undergoing myelosuppressive therapy. Surgical site infections are exacerbated in neutropenic patients by neutropenia-associated poor wound healing and can become sites of chronic or recurrent infection in children who require repeated treatment with chemotherapy.
| Chemotherapy Category | Chemotherapy Agent | Mechanism of Action | Immunosuppressive Effects | Drug-Specific Adverse Effects | Class-Specific Adverse Effects |
|---|---|---|---|---|---|
| Alkylating agents | Cyclophosphamide Ifosfamide | Nitrogen mustard: Cross-linking DNA strands | Neutropenia Lymphopenia | Hemorrhagic cystitis Mucositis (dose related) Infertility CNS toxicity (ifosfamide) | Alopecia Anemia Nausea/vomiting Thrombocytopenia |
| Procarbazine | DNA alkylation; Inhibit protein synthesis by transmethylation of methionine into transfer RNA | Neutropenia Lymphopenia | Secondary malignancy (highly carcinogenic) Male infertility Disulfiram reaction | ||
| Temozolomide | DNA alkylation via methylating metabolite MTIC | Neutropenia Lymphopenia | Hepatotoxicity | ||
| Carmustine Lomustine | Nitrosourea: alkylates DNA and RNA | Neutropenia (delayed onset at 4-6 weeks after administration) | Secondary malignancy | ||
| Platinum analogs | Cisplatin, carboplatin, oxaliplatin | Forms DNA cross-links; binds to DNA bases and disrupts DNA function | Neutropenia (dose dependent) | Cisplatin: Nephrotoxicity Ototoxcity Electrolyte disturbances Carboplatin: Thrombocytopenia Oxaliplatin: Peripheral neuropathy | Anemia Nausea/vomiting |
| Antimetabolites | Clofarabine | Antimetabolite: Purine nucleoside analog | Prolonged neutropenia | Capillary leak syndrome Mucositis | Anemia Nausea / vomiting Thrombocytopenia |
| Cytarabine | Antimetabolite: Pyrimidine analog | Neutropenia High-dose cytarabine: increased risk of alpha hemolytic streptococcal infection during intensive treatment of AML | Diarrhea Neurotoxicity Rash / desquamation | ||
| Gemcitabine | Antimetabolite: Pyrimidine analog | Neutropenia | Flu-like symptoms Liver function abnormality | ||
| Mercaptopurine | Antimetabolite: Purine analog | Neutropenia in patients with homozygous mutation for TPMT activity | Hepatotoxicity | ||
| Methotrexate | Folate antimetabolite; inhibits dihydrofolate reductase | Neutropenia with delayed clearance or inappropriate supportive care | Hepatotoxicity Mucositis Nephrotoxicity | ||
| Nelarabine | Antimetabolite: Purine analog; ara-GTP accumulates at a higher level in T cells | Neutropenia | Liver function abnormality Neurotoxicity Peripheral neuropathy | ||
| Natural product | Anthracyclines: daunorubicin, doxorubicin, idarubicin Anthracenedione: mitoxantrone | Topoisomerase II inhibitor Inhibit DNA and RNA synthesis by intercalation | Neutropenia Lymphopenia | Alopecia Cardiotoxicity Mucositis (doxorubicin >> daunorubicin) | Anemia Nausea / vomiting Thrombocytopenia (except Vinca Alkaloids) |
| Dactinomycin | Intercalates guanine–cytosine base pairs in DNA | Neutropenia | Diarrhea | ||
| Etoposide | Topoisomerase II inhibitor | Neutropenia | Mucositis Nausea / vomiting Secondary malignancy (1-3 years after treatment) | ||
| Irinotecan | Topoisomerase I inhibitor | Neutropenia | Diarrhea mediated by toxic metabolite unconjugated SN-38 | ||
| Topotecan | Topoisomerase I inhibitor | Neutropenia | Mucositis | ||
| Vinca Alkaloids: Vincristine Vinblastine Vinorelbine | Microtubule inhibitors | Neutropenia (vinorelbine >> vinblastine >> vincristine) | Peripheral neuropathy (vincristine >> vinblastine >> vinorelbine) |
Nutritional deficiency is common during chemotherapy administration in children and can further compromise a patient’s immune function. Malnutrition impairs immunity as the result of decreased production of complement, cytokines, and immunoglobulins. Not surprisingly, underweight patients receiving chemotherapy have a higher incidence of febrile neutropenia than their peers.
A less commonly recognized immune dysfunction in this patient population is functional asplenia that can result from irradiation to the spleen. Patients with abdominal tumors or Hodgkin lymphoma (HL) may receive targeted or indirect XRT to the spleen. Splenic dysfunction results in an increased risk for infection with encapsulated organisms. The Infectious Diseases Society of America and American College of Immunization Practices recommend that asplenic patients, including those with functional asplenia, be immunized with pneumococcal polysaccharide and meningococcal vaccines.
Finally, there is a recommendation that children currently receiving cancer therapy not receive routine immunizations with the exception of the annual influenza vaccine. Although the influenza vaccine should be administered to pediatric oncology patients, it may not be effective in the setting of chemotherapy. Thus many children are unvaccinated or undervaccinated while they are undergoing cancer therapy, leaving them at risk for vaccine-preventable infections.
Disease-specific infectious risks
Hematologic malignancies
Leukemia is the most common cancer diagnosis in children and constitutes approximately 35% of all childhood cancers. ALL accounts for 75% of leukemia diagnoses in patients younger than 20 years of age and occurs most frequently in children 1 to 4 years. AML accounts for 18% of childhood leukemia and occurs bimodally with equal frequency in patients 1 to 4 years and 15 to 19 years. The remainder of leukemia diagnosed in children is made up of chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML), and biphenotypic leukemia or mixed phenotype acute leukemia (MPAL).
The survival rate of patients with ALL is significantly better than that of those with AML; children with ALL have a 5-year survival of more than 85%, whereas children with AML have an estimated 65% overall survival at 5 years. Survival rates for subtypes of ALL and AML differ, and predicted survival can be used to roughly estimate the intensity of therapeutic regimen. Efforts toward tailored therapy have focused on decreasing the use of cytotoxic and myelosuppressive chemotherapy to avoid short- and long-term toxicities without diminishing survival benefit. A dramatic example of subgroup survival difference is that of acute promyelocytic leukemia (APML), which has an overall survival approaching 95% largely due to the incorporation of targeted agents such as arsenic trioxide and retinoic acid. Hence, patients with APML incur significantly fewer infectious complications of therapy than children with other subtypes of AML.
Conversely, children with relapsed or refractory leukemia are treated with very high-intensity chemotherapy and ultimately may receive an allogeneic hematopoietic stem cell transplantation (SCT); thus these patients are at highest risk for infectious complications. Infection accounts for the majority of treatment-related deaths in children with relapsed and refractory hematologic malignancies.
Although ALL and AML are treated differently, the first phase of chemotherapy for all acute leukemia is called “induction,” and the goal is to achieve a complete disease remission. For all children with leukemia, the induction phase is a high-risk period owing to the adverse effects from neutropenia compounded by other complications, such as tumor lysis syndrome, thrombosis, and bleeding. Although there has been a decrease in mortality associated with improvements in supportive care, infections still account for up to 30% of induction deaths in pediatric patients with leukemia.
Acute lymphoblastic leukemia.
Patients with ALL are risk-stratified by criteria set forth by the National Cancer Institute into low-risk, standard risk, high-risk, or very high-risk disease groups. Determinants of risk include age, white blood cell count at presentation, cytogenetics, immunologic subtype (B cell, T cell, or MPAL), and response to induction therapy. Patients with ALL are risk-stratified based on predicted survival, and risk assessments are used to guide the intensity of therapy. In general, patients with ALL receive 6 to 9 months of intensive chemotherapy followed by 2 to 2.5 years of low-intensity maintenance chemotherapy. Risk of infection is concentrated during the first 6 to 9 months of treatment and increases with intensity of treatment regimen. The addition of anthracyclines (e.g., daunorubicin) to induction regimens in high-risk and very high-risk patients contributes to neutropenia and mucositis, both significant risk factors for infection. Thus patients treated for high- and very high-risk ALL have more infectious complications than their lower-risk counterparts. Intensive portions of therapy are most commonly delivered via an implantable venous access port, which further increases the risk for infection. To mitigate risk, implanted ports are often removed when a patient begins the maintenance portion of therapy.
ALL is most frequently diagnosed in children 1 to 4 years of age; thus pathogens common to this age group predominantly cause the infectious complications seen in young children with ALL, including upper respiratory infection, otitis media, and gastroenteritis. BSI is common during periods of neutropenia, and the frequency of BSI is correlated with duration of neutropenia. Because duration of neutropenia becomes more prolonged in later phases of chemotherapy, BSI and fungal infections occur with increased frequency in the latter portion of intensive chemotherapy for ALL, especially in higher-risk patients.
T-cell ALL, which is a small fraction of childhood ALL, historically had a worse prognosis than B-cell ALL and was thus treated with more intensive chemotherapy regimens. As the biology of T-cell ALL has been elucidated in recent years and treatment protocols have been refined, outcomes for T-cell and B-cell ALL have become increasingly similar. A notable distinction of T-cell ALL is the predilection for recalcitrant central nervous system (CNS) disease, necessitating CNS-directed therapy. The most recent treatment protocols use dexamethasone rather than prednisone for T-ALL, which provides increased potency and CNS penetration, though it is associated with significantly more infectious complications.
Acute myelogenous leukemia.
Therapy for AML requires repeated cycles of myelosuppressive chemotherapy leading to periods of severe neutropenia averaging approximately 2 to 4 weeks. Thus patients with AML have a high risk of bacterial and fungal infection. Children with AML have a 5–10% infection-related mortality and 20–50% incidence of bacterial infection. Notable exceptions to this treatment regimen are children with APML and those with Down syndrome–associated acute megakaryoblastic leukemia, both of which have excellent prognoses and require far less intensive therapy. Children with AML usually have a CVC in place for the duration of treatment to accommodate their significant supportive care needs during periods of prolonged myelosuppression.
The most common serious infections in pediatric patients with AML are caused by gram-negative bacteria, viridans group streptococci, and fungi. Viridans-group streptococcal bacteremia occurs in nearly 1 in 4 children treated for AML and accounts for approximately 15% of all infection-related deaths in pediatric patients with AML. The incidence of gram-negative bacteria infection in children treated for AML has decreased in recent years, likely as the result of widespread use of quinolone prophylaxis during periods of neutropenia, as well as improved infection control measures relating to the care of CVCs and maintenance of the hospital environment. The most common gram-negative organisms isolated are Pseudomonas aeruginosa , Klebsiella spp., and Escherichia coli. , Fungal infections occur in approximately 3% of patients undergoing therapy for de novo AML, although this incidence increases in patients with relapsed and refractory disease. ,
Chronic myeloid leukemia.
Pediatric patients with CML are treated similarly to adults, and the mainstay of treatment is aimed at inhibition of the ABL tyrosine kinase, driven by the BCR-ABL fusion protein that results from the chromosomal translocation (9;22). The BCR-ABL translocation, named the Philadelphia chromosome, results in constitutive activation of the ABL1 kinase that drives cellular proliferation. CML has become a chronic disease through the use of ABL -class tyrosine kinase inhibitors (TKIs), which keep the disease controlled even when used as monotherapy. TKIs used for pediatric CML include imatinib, dasatinib, and less commonly nilotinib. All are available as oral preparations; thus treatment does not require central venous access. Infectious complications of CML therapy are rarely reported. Although ABL -class TKIs have the potential to cause neutropenia or lymphopenia, largely because of their off-target effects, these laboratory abnormalities are rarely seen in pediatric patients. Children who experience dose-limiting hematologic toxicity of TKIs are managed by adjustment of dose or by switching to an alternative TKI. Adult patients treated with imatinib have an increased risk of hepatitis B reactivation, although this has not been reported in pediatric patients.
Down syndrome.
Children with Down syndrome (DS) have an increased risk of developing hematologic malignancies, most commonly acute leukemia. DS-associated leukemia tends to have a favorable prognosis, although treatment has historically been complicated by significant infection-related morbidity. Children with DS have much higher rates of infectious and other treatment-related complications than children without DS. Recent efforts aimed at decreasing the intensity of therapy have resulted in improved survival rates for children with DS-associated leukemia owing to fewer therapy-related complications. Importantly, a comparison of two sequential clinical trials for therapy of DS-AML published in 2004 and 2016 demonstrated infection-related mortality rates of 20% and 4.9%, respectively. Although the incidence of infection has not significantly decreased, the profile of infectious diseases in children with DS has shifted to an increased proportion of viral infections compared with bacterial and fungal infections. Viral pneumonia and viral gastroenteritis are the most common infections documented in children with DS during leukemia therapy. Importantly, children with DS may have atypical presentations of infection including without fever, and during lower-intensity treatment phases. Supportive care practices specific to children with DS require vigilance regarding skin hygiene and a high index of suspicion for infection despite atypical presentation.
Infant leukemia.
Infant leukemia, defined as acute myeloid or lymphoblastic leukemia in a child younger than 12 months, is a rare cancer and occurs in fewer than 200 children in the United States annually. The prognosis for infants with leukemia is poor, and treatment is challenging given the excess toxicity observed in this young age group. Induction mortality is much higher for infants with acute leukemia compared with older children, and much of the therapy-related mortality observed in infants is due to infectious complications. The majority of infections are caused by gram-positive organisms, followed by gram-negative bacteria and fungi. Efforts to de-intensify therapy are more challenging than in other pediatric oncology populations because infant leukemia is very difficult to treat. However, similar to patients with DS, infants require maximal supportive care, including efforts to prevent infection, close monitoring, and a high index of suspicion for infectious complications.
Lymphoma.
Lymphoma is classically categorized as either Hodgkin (HL) or non-Hodgkin (NHL) disease. HL occurs with a bimodal distribution with the first peak during adolescence and young adulthood (15 to 24 years), which makes it a common pediatric malignancy. HL is indolent and very sensitive to chemotherapy and radiation; survival rates exceed 90% in all age groups. Treatment involves several cycles of chemotherapy, typically administered over a period of less than 2 years. Each cycle can result in episodes of neutropenia generally lasting less than 7 days, and involved-field XRT for some patients. Infection rates are low among children and adolescents treated for HL owing to low treatment intensity, although some specific infectious risks arise during treatment for HL: (1) patients with splenic involvement may receive radiation to the spleen, resulting in splenic dysfunction and a higher risk of infection with encapsulated organisms; and (2) radiation is a common treatment modality for patients with HL and brings with it infectious risks factors beyond myelosuppression, including disruption of skin and mucous membrane barrier integrity.
NHL occurs with higher incidence than HL in all ages and, for the purposes of this chapter, should be conceptualized by prognosis/intensity of therapy rather than cell of origin. Lymphoblastic lymphoma (LL) arises from either T or B cells and pathologically appears identical to ALL, although it is categorized as lymphoma because of a low burden of bone marrow disease (<25%). LL is treated similarly to ALL with 6 to 9 months of intensive therapy followed by several years of maintenance chemotherapy, and thus it has infectious risks similar to those of patients treated for ALL. Mature B-cell lymphomas include Burkitt, diffuse large B-cell lymphoma, and primary mediastinal B-cell lymphoma. These high-grade mature B-cell malignancies are treated with repeated cycles of intensive chemotherapy that often result in severe mucositis, malnutrition, and brief (<7 days) but profound myelosuppression. Anaplastic large cell lymphoma is a T-cell malignancy that occurs in adolescents and young adults, and is treated with chemotherapy regimens similar to those used for mature B-cell NHL. In general, infectious complications in pediatric patients with NHL are infrequent, although common risk factors of myelosuppression, central venous catheters, and mucositis occur with increased frequency in late-stage NHL that requires higher intensity treatment.
Solid tumors
Solid tumors can be categorized as either intracranial or extracranial and portend different infectious risks based on anatomic location. Solid tumors are risk-stratified by stage at diagnosis, and in general high-stage disease requires more intensive treatment. Solid tumors are treated with a combination of chemotherapy, radiation, and surgery; each treatment modality brings with it specific infectious risks. Indwelling foreign materials are common to treatment of solid tumors, including central venous catheters, intraventricular catheters, and surgical material including long-term endoprostheses.
Central nervous system tumors.
Brain and spinal cord tumors are the most common type of pediatric solid tumor and account for up to 20% of all childhood malignancies. CNS tumors are an exception to the paradigm that chemotherapy intensity is increased in higher-risk malignancies. Children with CNS tumors are rarely treated with intensive chemotherapy, even those with very poor prognoses. The mainstays of treatment for CNS tumors are surgery and XRT and, although adjuvant chemotherapy is used, it is infrequently given at doses or combinations that cause significant myelosuppression. Thus infectious complications of CNS tumors and their treatment relate to surgical complications, the presence of indwelling catheters and other foreign material, and neurologic dysfunction.
Infectious risks specific to children with brain tumors include surgical site infections, ventriculitis/meningitis related to CSF diversion catheters, and infectious complications of neurologic dysfunction. Few studies have focused on infectious complications in children with brain tumors but have shown that the short-term postoperative infection rate is approximately 20% and consists primarily of wound infections and CSF catheter infections. This infection rate is consistent with neurosurgical infection rates in patients without brain tumors. CSF catheter infections are most often introduced at the time of surgical placement or revision, although, less commonly, they can arise as a retrograde infection from the distal end of the shunt. The latter scenario can occur from bowel contamination of a ventriculoperitoneal shunt or hematogenous seeding of a ventriculoatrial shunt. CNS tumors or resection efforts result in neurologic dysfunction to varying degrees. Infections arise in patients with neurologic dysfunction for many reasons; some examples include aspiration events leading to pneumonia, bladder stasis leading to urinary tract infections, and decubitus ulcer infections.
Of note, there are CNS tumors of embryonal origin—medulloblastoma, atypical teratoid rhabdoid tumors, and primitive neuroectodermal tumors—that tend to occur in younger children and are treated with myelosuppressive chemotherapy, often followed by autologous stem cell rescue. In addition to the infectious risks noted earlier for other CNS tumors, these patients are also at risk for bacteremia, typhlitis, and additional opportunistic infections common to children undergoing periods of profound neutropenia.
Neuroblastoma.
Neuroblastoma is the most common extracranial solid tumor in children. It arises from embryonal neural crest tissue and may present as a localized, low-grade tumor or as high-grade, widely metastatic disease. Staging is determined by histology, genetic aberrations, and metastasis. High-risk neuroblastoma (HR NBL) has poor outcomes and is treated with multimodality therapy, including cytotoxic and myelosuppressive chemotherapy, surgery, XRT, autologous SCT, and immunotherapy. Infectious risks vary throughout the treatment course, which lasts 1.5 to 2 years, and more than 50% of children treated for HR NBL have a bacterial or fungal infection at some point during therapy. Most infections occur during neutropenic periods resulting from myelosuppressive chemotherapy. Current treatment protocols include four or five cycles of neoadjuvant chemotherapy that result in neutropenic periods averaging 5 to 7 days. Postoperatively, children undergo myeloablative chemotherapy followed by autologous SCT with a longer expected duration of neutropenia (7 to 14 days). However, neuroblastoma therapy is one of the most rapidly evolving fields in pediatric oncology, with a current emphasis on decreased dosing of conventional chemotherapy to limit late-onset toxicity, and a movement toward targeted therapies. As this shift occurs, the infectious risks associated with therapy for HR NBL will also change.
Sarcoma.
The majority of sarcomas arise during childhood and adolescence. The most common types of sarcoma are osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma, although a variety of other bone and soft tissue sarcomas occur in the pediatric age group. Treatment for sarcomas includes repeated cycles of chemotherapy leading to brief (∼7 days) but profound neutropenia, and local control of the tumor, which may involve surgical resection or XRT. Advances in surgical techniques have led to increased use of endoprosthetic reconstruction rather than amputation of affected limbs. Although this approach preserves anatomy and some function, the risk of infection associated with allograft or prosthetic placement is high and constitutes the primary mode of reconstructive failure for pediatric patients. Soft tissue infections occur in up to 50% of limb salvage procedures, and infection of the prosthesis occurs in 8% to 18% depending on prosthetic material, location, and immunologic and nutritional status of the patient. Treatment of an endoprosthetic infection is complex and often requires a combination of surgical debridement and prolonged antimicrobial therapy. In rare cases, amputation is required to definitively manage endoprosthetic infections.
Children with bone and soft tissue sarcomas are treated with highly emetogenic chemotherapy which, combined with disability related to tumor location, frequently results in malnutrition and prolonged deconditioning. These factors increase the risk for and complicate infections that occur in patients with sarcoma. Supportive care in the form of nutritional support and physical therapy are paramount to infection prevention.
Wilms tumor.
Wilms tumor is the most common renal tumor of childhood. Staging is based on histology, location, metastasis, and surgical outcomes, and treatment intensity increases with higher-stage disease. Treatment consists of low-intensity chemotherapy that rarely causes profound neutropenia, surgery, and occasionally XRT. Infectious complications in children with Wilms tumor are rare.
Hepatoblastoma.
Hepatoblastoma is a liver tumor that arises in infancy and early childhood. It is a chemotherapy-sensitive tumor with very good survival rates. Children are treated with a combination of surgical resection and adjuvant chemotherapy. If the primary tumor is unresectable, patients may undergo liver transplantation, which occurs in approximately 20% of cases. For these children, infectious risks are largely those affected by solid organ transplantation (see Chapter 1 ). Infectious complications are uncommon in cases of hepatoblastoma without liver transplant.
Infectious risks associated with anticancer therapies
Children with cancer who are treated with conventional cytotoxic and myelosuppressive chemotherapy are at an increased risk of febrile neutropenia, invasive infections, and infection-related mortality. The goal of conventional chemotherapy during the induction or neoadjuvant phase in many pediatric cancers is to rapidly eradicate tumor cells to a clinically undetectable state termed remission. Optimization of chemotherapy dose intensity has resulted in improved cure rates and survival; however, the side effects of conventional chemotherapy occur as a result of lack of specificity for cancer cells and an unavoidable impact on rapidly dividing healthy cells. Thus the design of chemotherapy doses and treatment schedules requires a balance between destroying cancer cells and sparing healthy cells to avoid significant morbidity and mortality. Common side effects of conventional chemotherapy include myelosuppression and damage to mucosal barrier integrity, both of which significantly predispose patients to infection and associated morbidity and mortality.
Bone marrow suppression constitutes a dose-limiting toxicity of conventional chemotherapy consisting of neutropenia, thrombocytopenia, and anemia. Neutropenia is a driving factor for the development of opportunistic bacterial and fungal infections, and patients with febrile neutropenia require prompt evaluation and treatment with antibiotics. Combination chemotherapy consisting of multiple myelotoxic drugs results in profound, and sometimes prolonged, neutropenia and thereby increases risk of infectious complications. Growth factor support has become the standard of care after chemotherapy administration in children with solid tumors as it significantly decreases the duration of severe neutropenia and incidence of febrile neutropenia. , Growth factor use can similarly reduce the duration of neutropenia after chemotherapy for acute leukemia. However, growth factor support has the potential to introduce abnormalities in bone marrow progenitor populations, which can skew disease evaluations and possibly potentiate hematologic malignancy. Thus growth factor agents are not often used in children with leukemia. The next section reviews chemotherapeutic agents commonly used to treat pediatric cancers.
Conventional chemotherapeutic agents
The mechanisms of action of common chemotherapy drugs used to treat pediatric cancer are outlined in Table 3.2 . The cytotoxic and myelosuppressive effects of these conventional agents result from DNA damage or inhibition of DNA replication, subsequently leading to the death of rapidly dividing cells. The major toxicity of all conventional chemotherapeutic agents is that tumor cells are not specifically targeted, and thus both malignant and healthy cells are destroyed. The main categories of conventional chemotherapy drugs include alkylating agents, platinum analogs, antimetabolites, and natural products. A combination of chemotherapy from different pharmacologic classes results in optimal therapeutic endpoints, but comes with a wide range of adverse events. In addition to myelosuppression and mucositis, some of the common and significant toxic effects of these drugs are provided in Table 3.2 .
Alkylating agents.
Alkylating agents are integral to the treatment of many pediatric cancers, including ALL, HL, NBL, sarcomas, and brain tumors. These drugs work by forming reactive intermediates that attach an alkyl group to DNA base pairs which interfere with DNA replication. Myelosuppression is a common dose-limiting toxicity of alkylating agents. The nadir for absolute neutrophil count occurs 6 to 10 days after administration of alkylators, with recovery after 14 to 21 days. Delayed and prolonged myelosuppression occurs with nitrosoureas, such as carmustine and lomustine, where the nadir in platelets and neutrophils starts 4 to 6 weeks after treatment with a slow recovery thereafter.
Platinum analogs.
Platinum analogs are a backbone of many pediatric solid and brain tumors given their antineoplastic activity resulting from covalent binding of platinum to nucleophilic sites on DNA, leading to intrastrand and interstrand cross-links and DNA breaks. Besides myelosuppression, nephrotoxicity and ototoxicity are common side effects. Platinum analogs are also highly emetogenic, necessitating nutritional monitoring and support. Appropriate hydration is necessary for prevention of renal damage, and dose adjustments may be necessary to mitigate excessive or prolonged nephrotoxicity.
Antimetabolites.
The antimetabolite class consists of analogs of folic acid, pyrimidines, and purines that ultimately inhibit DNA synthesis and replication. Methotrexate is the quintessential folic acid analog and is used in high doses (>1000 mg/m ) for ALL, lymphoma, and osteosarcoma. Methotrexate inhibits dihydrofolate reductase, an enzyme required for reduction of folic acid to tetrahydrofolate or folinic acid. This inhibition leads to a reduced capacity for methylation reactions necessary for the synthesis of DNA bases. High-dose methotrexate can have significant adverse effects, including bone marrow suppression and mucositis. To alleviate these side effects, intravenous hydration necessary for drug clearance and pharmacologic rescue with reduced folate or leucovorin is administered after high-dose methotrexate in pediatric patients.
Pyrimidine and purine analogs include various drugs that inhibit synthesis of essential DNA precursors (e.g., mercaptopurine) or are converted intracellularly to nucleoside analogs and incorporated into DNA, leading to cell-cycle arrest and apoptosis. Nucleoside analogs such as mercaptopurine and cytarabine are specifically used in hematologic malignancies. Clofarabine, a pyrimidine analog, is approved for relapsed/refractory ALL, although it comes with significant toxicities and is usually not well tolerated. Nelarabine is a purine analog and has resulted in improved outcomes for patients with T-cell ALL but causes myelosuppression and peripheral neuropathy.
Natural products.
Chemotherapy derived from natural products can be divided into vinca alkaloids (e.g., vincristine), camptothecin analogs (e.g., irinotecan and topotecan), antibiotics (e.g., anthracyclines or dactinomycin), and epipodophyllotoxin derivatives (e.g., etoposide). These agents affect cell cycle progression or cause double-stranded DNA breaks, resulting in rapid death of dividing cells. Vinca alkaloids are frequently used to treat pediatric cancers and block the cell cycle during mitosis by disrupting microtubule formation. Vincristine, the most common vinca alkaloid, is not myelosuppressive, unlike many other conventional chemotherapeutics. Camptothecin analogs inhibit topoisomerase I, thus promoting genotoxic double-stranded DNA breaks and can cause dose-limiting neutropenia. Anthracyclines/anthracenediones are a major subset of antibiotic chemotherapy agents that are highly active for ALL, AML, lymphoma, and many solid tumor treatment regimens. Finally, epipodophyllotoxin derivatives like etoposide directly inhibit topoisomerase II, which results in double-stranded DNA breaks. Etoposide, which is widely used in pediatric cancer, has a dose-limiting toxicity of neutropenia. Most natural product chemotherapeutics result in neutrophil nadir at 10 to 14 days with recovery by 21 days.
Autologous stem cell transplant
Hematopoietic SCT may be allogeneic, in which the donor and recipient are two different subjects, or autologous, in which stem cells are harvested from a patient and reinfused into that same patient. The purpose of autologous hematopoietic SCT (auto-SCT), also called stem cell rescue, in patients with cancer is to enable delivery of high-dose cytotoxic and myelosuppressive chemotherapy that, without a replacement of the bone marrow, would lead to prolonged or indefinite bone marrow aplasia. Although this treatment approach is not effective for acute leukemia, the indications for auto-SCT in children have expanded over the last several decades and now include refractory lymphoma, high-risk neuroblastoma, and medulloblastoma. A variety of other solid tumors have been treated experimentally with auto-SCT with varying outcomes.
The conditioning regimens, or chemotherapeutic agents administered before SCT, are tailored to each patient’s disease process. The goal of conditioning is to use high-dose chemotherapy and/or XRT to kill cancer cells. A nearly universal side effect of the agents and doses used for conditioning is the destruction of bone marrow stem cells, thus the requirement for auto-SCT. Once autologous stem cells are infused, the time to neutrophil engraftment ranges from 1 to 3 weeks. During this period of profound neutropenia, termed the pre-engraftment period, the majority of infectious complications occur. In addition to profound, prolonged neutropenia, auto-SCT recipients have additional risk factors for serious infection, including central venous access, mucositis, and poor nutrition. There do not seem to be significant differences in infection risk attributable to underlying oncologic disease or conditioning regimen.
Most infectious complications arise in the pre-engraftment period of auto-SCT. Infections occur in 21% to 34% of patients before neutrophil engraftment. , Bacterial infections are most common, followed by viral infections. Invasive fungal diseases are rare but occur with more prolonged periods of neutropenia. Bacteremia and Clostridium difficile colitis are the most common bacterial infections in the pre-engraftment period, and gram-positive bacteremia is slightly more common than gram-negative bacteremia. Viral infections are largely due to herpesviruses. Stomatitis and other manifestations of Herpes Simplex Virus are the most common viral infections to complicate pediatric auto-SCT, although the incidence has decreased with routine use of acyclovir prophylaxis in patients who are known to have positive Herpes Simplex Virus serologic testing. Varicella zoster virus (VZV) reactivation is much more common in adult transplant patients than in the pediatric population and is reported to occur at a rate of 1% to 2% in children undergoing auto-SCT. Based on the profile of infections that have historically occurred in pediatric auto-SCT recipients, preventative measures are now used to decrease infectious risk. Data regarding the effectiveness of specific prophylactic approaches are discussed in the following pathogen-focused chapters.
Novel chemotherapeutics
Systematic assessment of combination chemotherapy regimens through clinical trials has significantly improved survival rates in pediatric oncology. However, pediatric cancer continues to be the second leading cause of death in children, largely because of relapsed and refractory malignancies, which still have dismal outcomes. Recent approaches to improve therapy for relapsed and refractory pediatric cancer have focused on targeted treatments using biologic agents for immunotherapy, cellular-based immunotherapy, and small-molecule inhibitors. Novel chemotherapeutics are increasingly used in the field of pediatric oncology and have aided in the quest to achieve cure while limiting short- and long-term toxicity.
The development of targeted treatments relies on the discovery of molecular changes that drive the malignant progression of cancer. Growth factor receptors, kinases and downstream signaling molecules, and immune surveillance mechanisms are the targets of most novel anticancer drugs. In this section, we review targeted therapeutics currently used in pediatric oncology, their mechanisms of action, and common side effects, including specific risk factors for infectious complications. The specific mechanisms of action and toxicity profiles for novel agents are summarized in Tables 3.3 and 3.4.
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