Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Cancer and antineoplastic therapies and the risk of infection in the pediatric cancer patient
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.
TABLE 3.1
Infectious Risk Assessment by Oncologic Diagnosis
| 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 |
ALL , acute lymphoblastic leukemia; AML , acute myelogenous leukemia; CNS , central nervous system; CSF , cerebrospinal fluid; CVC , central venous catheter; GD2 , glycolipid disialoganglioside; HSCT , hematopoietic stem cell transplantation; Ph+ , Philadelphia chromosome positive; XRT , radiation therapy.
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.
TABLE 3.2
Conventional Chemotherapeutics
| 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) |
AML , acute myelogenous leukemia; Ara-GTP , araguanosine-5′-triphosphate; MTIC; 3-methyl-(triazen-1-yl)imidazole-4-carboxamide; RNA , ribonucleic acid; SN-38 , 7-ethyl-10-hydroxy-camptothecin; TMPT , tumor molecular targeting peptide.
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.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here