Study Points

Childhood Leukemias and Lymphomas

Course #62344-

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Study Points

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  1. Discuss the prevalence and types of childhood leukemia and lymphoma.
  2. Identify the clinical signs and symptoms associated with childhood leukemia.
  3. Describe the diagnostic testing for and classification of childhood leukemias.
  4. Discuss the prognostic variables for childhood leukemias.
  5. Describe the clinical presentation, diagnosis, and prognostic variables of Hodgkin lymphoma.
  6. Discuss the signs and symptoms, diagnosis, and prognostic variables associated with non-Hodgkin lymphomas.
  7. Explain the principles of communicating a diagnosis of childhood cancer.
  8. Discuss the importance of clinical trials and the issues unique to trials involving children.
  9. Outline the treatment approaches for childhood leukemia and lymphoma.
  10. Discuss the various means of supportive care needed for children/adolescents with leukemia or lymphoma.
  11. Describe the elements of effective palliation of symptoms in the end of life for children/adolescents with cancer.
  12. Recognize the psychosocial and spiritual needs of children/adolescents with cancer and their families.
  13. Discuss coping mechanisms of children/adolescents with cancer and their effect on psychosocial adjustment.
  14. Explain the psychosocial effect of childhood cancer on family dynamics.
  15. Define the most common long-term effects of childhood leukemias and lymphomas and their treatment.
  16. Outline recommendations for necessary surveillance and long-term monitoring specific for a child's or adolescent's cancer and treatment.
  1. Of the following, the clearest risk factor for pediatric leukemia and lymphoma is

    OVERVIEW OF CHILDHOOD LEUKEMIAS AND LYMPHOMAS

    Unlike other types of cancers in adults, childhood leukemia and lymphoma are not associated with lifestyle risk factors, but the etiology is unclear. The only clear risk factor for childhood hematologic cancer is an inherited genetic syndrome, especially Down syndrome, which is associated with a 10-fold to 20-fold increased risk of leukemia [19,20,21,22]. Increased risk is associated with several other genetic syndromes as well (Table 1) [20,21,22].

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  2. The most cases of pediatric leukemia occur in which of the following age groups?

    TYPES OF LEUKEMIA

    Acute leukemia occurs in approximately 4,920 children and adolescents each year, with most cases occurring in children 1 to 4 years of age. The median age at diagnosis is 6 years of age [1,15]. The incidence is higher for male than female children/adolescents for all races/ethnicities (5.4 per 100,000 vs. 4.4 per 100,000, respectively) [15]. Among racial/ethnic populations of children/adolescents, the incidence of leukemia (all types) is highest for the Asian/Pacific Islander population and lowest for the non-Hispanic Black population (Table 2) [1,15].

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  3. The incidence of leukemia is highest for which of the following racial/ethnic populations?

    TYPES OF LEUKEMIA

    INCIDENCE OF PEDIATRIC LEUKEMIA AND LYMPHOMA ACCORDING TO RACE/ETHNICITY

    Cancer TypeIncidence (per 1 million)
    Non-Hispanic WhiteNon-Hispanic BlackHispanicAsian/Pacific Islander
    Leukemia (all types)46326247
    Acute lymphoblastic leukemia34194732
    Acute myeloid leukemia88910
    Hodgkin lymphoma1419199
    Non-Hodgkin lymphoma19111010
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  4. Which of the following statements about Hodgkin lymphoma is TRUE?

    TYPES OF LYMPHOMA

    Hodgkin lymphoma was first described in 1832 by Thomas Hodgkin as a "peculiar enlargement" and "affection" of the lymph nodes of the neck and other areas of the body, along with enlargement of the spleen and possibly the liver; there were often deposits of firm tubercle-like nodules in the spleen and liver [27]. The malignant cells, subsequently named Reed-Sternberg cells, arise from B lymphocytes and exist with Hodgkin cells (large, mononuclear cell variants) within an immunoreactive background consisting of lymphocytes, eosinophils, neutrophils, histiocytes, plasma cells, fibroblasts, and collagen [27]. According to the WHO/REAL system, Hodgkin lymphoma may be categorized as classical and nonclassical [14]. Classical Hodgkin lymphoma is further categorized into four subtypes: lymphocyte predominant, nodular sclerosis, mixed cellularity, and lymphocyte depleted [14,48,49]. Two of the four subtypes of classical Hodgkin lymphoma account for most cases in children. Lymphocyte-predominant Hodgkin lymphoma and lymphocyte-depleted Hodgkin lymphoma are both rare in children.

    In the United States, the incidence of Hodgkin lymphoma is much lower for children up to 4 years of age than for older children and adolescents [47]. In children younger than 10 years of age, the incidence of Hodgkin lymphoma is twofold to threefold higher in boys than in girls. In children 10 to 14 years of age, the incidence is approximately 1.2-fold higher in boys than in girls. In adolescents 15 to 19 years of age, the incidence is similar for males and females [47]. Hodgkin lymphoma is the most curable childhood cancer, with a five-year survival rate of 98% in 2013–2019, an increase from 88% in 1975–1983 [1].

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  5. Which of the following statements about the distinction between acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) is TRUE?

    DIAGNOSIS OF LEUKEMIAS

    CLINICAL MANIFESTATIONS OF ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) AND ACUTE MYELOGENOUS LEUKEMIA (AML)

    Clinical Sign/SymptomALLAML
    Involvement of central nervous systemYes (20% to 25%)Yes (5% to 30%)
    History
    Low-grade fever; fatigue/weaknessMost common symptomYes
    Anorexia or weight lossYesYes
    Discomfort in bones and/or jointsYesYes
    Easy bruising or increased bleedingYes (33%)Uncommon
    InfectionNoOften first presenting symptom
    Physical Examination
    PallorYesYes
    LymphadenopathyYesYes
    Splenomegaly/hepatomegalyYes (60%)Yes (<50%)
    Mediastinal massYes (10% to 18%)Rare
    Ecchymoses of skin or mucous membranesYesNo
    PetechiaeYesNo
    Inflammation/bleeding of gumsNoYes
    Cutaneous rashNoYes
    Laboratory Values (Median)
    Hemoglobin8 g/dL8 g/dL
    White blood cell count12 x 109/L20 x 109/L
    Platelet count53 x 109/L70 x 109/L
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  6. The most common symptom associated with ALL is

    DIAGNOSIS OF LEUKEMIAS

    A low-grade fever of unknown etiology is the most common symptom associated with ALL [41]. If fever has persisted for more than two weeks, further evaluation for leukemia is warranted. Findings on physical examination that should prompt diagnostic testing for leukemia include pallor, petechiae, ecchymoses of the skin or mucous membranes, or lymphadenopathy (enlargement of more than 2 centimeters). Splenomegaly or hepatomegaly is evident at the time of diagnosis in approximately 60% of children with ALL and in less than half of children with AML [41].

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  7. Which of the following statements about the cytogenetics of leukemia is TRUE?

    DIAGNOSIS OF LEUKEMIAS

    In infant leukemia (both ALL and AML), abnormality of the mixed-lineage leukemia (MLL) gene at 11q23 is found in nearly 80% of cases [34]. Across all pediatric age groups, the most common structural abnormality in ALL, occurring in approximately 20% to 25% of cases of B-cell ALL, is reciprocal translocation of t(12;21)(p13;q22), which results in fusion of the TEL and AML1 genes. However, TEL-AML1 fusion is rare in T-cell ALL [68]. Several other common abnormalities occur frequently in ALL (Table 7) [60].

    Structural abnormalities are found in approximately 60% of pediatric AML cases and are usually linked to specific subtypes. The most common translocations are t(8;21), which is associated primarily with the M2 subtype, and t(15;17), which is strongly linked to the M3 subtype [60,69]. Other common abnormalities associated with AML are aberrations of 11q23 and inv(16) [60].

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  8. Of the following, the best prognostic factor in AML appears to be

    DIAGNOSIS OF LEUKEMIAS

    The ability of cytogenetic findings to predict outcome has varied, but they appear to be the best prognostic factors in AML [70,116,117]. In one study, trisomy 8 was the strongest predictor of poor prognosis, and in another, abnormalities of 11q23, q3, or chromosomes 5 or 7 were associated with a high rate of treatment failure [82]. In the series of patients treated at St. Jude, the best outcome was associated with t(9;21), and a favorable outcome has also been associated with t(8;21), t(15;17), and inv(16) [22,70]. Aberrations of chromosome 16q have also been shown to be a prognostic indicator of complete remission and better overall survival [69,71]. For children with monosomy 7, AML progresses rapidly and the response to treatment is poor [60,77]. In contrast to the situation in ALL, children with Down syndrome and AML have a good response to treatment [71,116]. Advances in technology are allowing researchers to identify other factors associated with outcome, and further studies are needed to confirm the usefulness of these factors as prognostic variables [118].

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  9. On physical examination, the sign/symptom most commonly associated with Hodgkin lymphoma is

    DIAGNOSIS OF LYMPHOMA

    Children and adolescents with Hodgkin lymphoma are often asymptomatic, and the disease is frequently an incidental finding during a routine examination or evaluation of an injury. Approximately 25% to 30% of children will have one of three archetypal constitutional symptoms, known as B symptoms: unexplained, intermittent fever of 38 degrees Centigrade; drenching night sweats; or unintentional loss of more than 10% of body weight within the past six months (Table 8) [119]. The suspicion of Hodgkin lymphoma is increased when B symptoms are present with lymphadenopathy or splenomegaly. Patients may also have nonspecific systemic symptoms, such as fatigue and anorexia. In some patients, generalized pruritus may be present for months before lymphadenopathy is found, and excoriations may be evident as a result of excessive scratching [119]. On physical examination, the most common finding is a persistent, painless adenopathy, usually in the supraclavicular or cervical area [63,119]. As noted, reactive lymphadenopathy is common in children/adolescents, making it necessary to carefully evaluate patients to first rule out other infectious or inflammatory conditions. Involvement of the supraclavicular nodes should prompt earlier evaluation for Hodgkin lymphoma, as the cervical nodes are most commonly involved in infection and inflammatory conditions. Infectious mononucleosis can be distinguished from Hodgkin lymphoma by the presence of symmetrical cervical lymphadenopathy with pharyngitis. A tuberculin test may be helpful to rule out tuberculosis, which also may have similar clinical characteristics.

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  10. Hodgkin lymphoma with involvement of a single lymph node region is considered

    DIAGNOSIS OF LYMPHOMA

    LUGANO SYSTEM FOR STAGING OF HODGKIN LYMPHOMA

    StageCriteria
    I (limited stage)Involvement of a single lymph node region or single extranodal site
    II (limited stage)Involvement of two or more lymph node regions (number to be stated) on the same side of the diaphragm, and may include limited contiguous extranodal involvement
    III (advanced stage)Involvement of lymph node regions in the spleen or on both sides of the diaphragm
    IV (advanced stage)Noncontiguous involvement of one or more extralymphatic organs or tissues with or without associated lymph node involvement
    Subclassifications
    AAsymptomatic
    BDisplaying specific symptoms of unexplained loss of more than 10% of body weight in the six months before diagnosis, unexplained fever with temperatures greater than 38 degrees Centigrade for more than three days, or drenching night sweats
    ESingle extranodal site involvement in stage I or limited contiguous extranodal involvement in stage II. Involvement of noncontiguous extranodal sites is considered stage IV.
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  11. The most significant prognostic variable in Hodgkin lymphoma is

    DIAGNOSIS OF LYMPHOMA

    Prognostic variables have less importance in Hodgkin lymphoma because of advances in treatment, but some variables are helpful in predicting outcome. The most significant prognostic indicator is stage of disease. The outcome associated with stage I, II, or III disease is better than that for stage IV disease [47,123,131]. Studies in which prognostic factors were evaluated in multivariate analysis have demonstrated the following factors to be of import [131,132]:

    Presence of B symptoms

    Mediastinal disease bulk

    Results of laboratory studies

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  12. Which of the following statements about prognostic factors in non-Hodgkin lymphoma is TRUE?

    DIAGNOSIS OF LYMPHOMA

    For B-cell lymphomas, the most important prognostic factor is tumor burden, as determined by either stage of disease or the serum lactate dehydrogenase level [120]. The tumor burden is high for patients with extensive bone marrow involvement (more than 25%) [120]. Serum lactate dehydrogenase level is a well-recognized risk factor that correlates with tumor burden, and a level of more than 1,000 IU/L has been associated with a poor prognosis [52,151,152].

    Age and sex have also been evaluated as prognostic factors in B-cell lymphoma; many studies have not found them to be predictive of outcome [120]. In one study involving children/adolescents with diffuse large B-cell lymphoma, the event-free survival was significantly better for male patients than for female patients and the outcome was better for younger girls than for adolescent girls [139]. Again, the universal applicability of these findings is not established.

    In an analysis of pooled data from three multicenter studies of prognostic variables in anaplastic large-cell lymphoma, multivariate analysis demonstrated that the following factors were significantly associated with a risk for treatment failure [120,144,152,153,154,155]:

    Presence of a mediastinal mass

    Involvement of the lung

    Focal lesions of the liver or spleen (and/or hepatomegaly or splenomegaly)

    Skin involvement

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  13. Which of the following statements about interpreters is TRUE?

    COMMUNICATION WITH THE PATIENT AND FAMILY

    Studies have demonstrated that the use of professional interpreters rather than "ad hoc" interpreters (family members, bilingual staff, etc.) leads to better outcomes [165,166,167]. In addition, individuals with limited English language skills have indicated a preference for professional interpreters rather than family members [168]. Despite this clear benefit and preference, a survey of more than 900 pediatricians showed that professional interpreters were the third most commonly used resource; bilingual family members were used most often [169]. According to one study, this practice has only modestly improved since 2004 [170]. Professional interpreters have recommended that clinicians can further enhance the quality of care by meeting with interpreters before discussions of bad news and by explicitly discussing with the interpreter whether strict interpretation or cultural brokering is expected [171].

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  14. Which age has the National Commission for Protection of Human Subjects of Biomedical and Behavioral Research set as the threshold for a child to participate in a discussion about assent for a clinical trial?

    TREATMENT APPROACHES

    Clearly, more children/adolescents should participate in clinical trials to provide the maximum opportunity for cure and long-term survival. Healthcare professionals should encourage parents to seek care at a pediatric cancer center and to ask about clinical trials if the issue is not raised. This is particularly important for older children and adolescents [202]. Assent for clinical trial participation in the pediatric setting differs from its counterpart in the adult setting (informed consent) in many ways and is a complicated issue. The obvious and primary difference between the two settings is the patient's capacity for decision making. It is generally believed that children/adolescents should be involved in the discussion and decision making about medical treatment (including participation in a clinical trial) if the discussion is developmentally appropriate [188,203,204]. Various ages have been suggested as the threshold for sufficient capacity to reason and understand a discussion about a clinical trial and make a decision to participate. The National Commission for Protection of Human Subjects of Biomedical and Behavioral Research, the California legislature, and the AAP have set the threshold for participating in the assent discussion at 7 years of age [203,204]. However, others have argued that a child at this age cannot understand all aspects of a research trial, and the ages of 9 years, 11 years, and 14 years have all been suggested as thresholds [204,205,206]. The age range of 9 to 14 years has been noted as the "transition period," or the ages at which there is the most variability in the capacities of individual children [204]. Studies involving focus groups of healthy adolescents have shown that research concepts such as placebo and randomization are difficult to understand even for teenagers [207]. Clearly, age is but one of several factors that should be considered when determining the appropriateness of engaging a child in the decision-making process; other factors include level of maturity, physiologic and psychological state, and the child's reasons for his or her preferences [206,208].

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  15. Which of the following statements about the treatment of ALL is TRUE?

    TREATMENT APPROACHES

    The goals of remission induction therapy are to induce complete remission (defined as eradication of 99% of the initial burden of leukemia cells), to restore normal hematopoiesis, and to regain a normal performance status [41,220]. This phase of treatment typically lasts four weeks [220]. The rate of complete remission after induction therapy is high, ranging from 96% to 99% [74,220]. Of the patients in whom complete remission is not achieved within the first four weeks of treatment, approximately 50% will experience a toxic death during induction (usually due to infection) and the remaining 50% will have resistant disease [94,156,220,226,227]. The protocols for children with high-risk or very-high-risk ALL and all adolescents with ALL involve treatment with at least four chemotherapeutic agents. These agents most often include a corticosteroid (prednisone or dexamethasone), vincristine, and asparaginase and/or an anthracycline (doxorubicin or daunorubicin) [220,228]. The COG protocols reserve the use of a four-drug induction for patients with high-risk B-cell ALL and T-cell ALL and do not include administration of anthracycline during induction to patients with standard-risk ALL [220,228]. Patients treated by three other study groups receive an induction regimen with four or more drugs regardless of presenting features [220]. A meta-analysis of studies comparing the use of dexamethasone or prednisone showed that dexamethasone was more efficacious, with lower rates of events (death from any cause, refractory or relapsed leukemia, second malignancy, and CNS relapse) but no difference in bone marrow relapse or overall mortality [229]. Dexamethasone was associated with higher rates of toxicity, however, and it is not clear whether the short-term benefits found will translate to better overall survival [229]. A randomized trial comparing doxorubicin and daunorubicin given during induction found no difference in efficacy between the agents in early response measures [230]. In June 2021, the U.S. Food and Drug Administration (FDA) approved Rylaze (Erwinia asparaginase [recombinant]) as a component of the multi-agent chemotherapy regimen to treat ALL (and lymphoblastic lymphoma) in adult and pediatric patients (one month and older) who have developed hypersensitivity to Escheria coli-derived asparaginase products [231]. Rylaze was found to maintain a clinically meaningful level of asparaginase activity throughout the entire duration of treatment [231]. In 2022, the FDA approved a new dosing regimen for Rylaze in adult and pediatric patients with ALL who are 1 month of age or older and who have developed hypersensitivity to E. coli-derived asparaginase [232].

    The emergence of targeted therapies for treatment of Philadelphia chrome-positive (Ph+) disorders with tyrosine kinase inhibitors (TKIs) represents an important advancement in ALL therapy. Imatinib mesylate and dasatinib are inhibitors of BCR-ABL tyrosine kinase and approved by the FDA for treatment-naïve patients with pediatric Ph+ ALL [228]. In one study of early response to TKIs during remission induction in children with Ph+ ALL, TKIs (imatinib and dasatinib) produced a marked drop in minimal residual disease levels. At the end of remission induction, 9 of 11 patients who received imatinib or dasatinib and conventional induction chemotherapy had remission, compared with two of 16 patients who received chemotherapy alone. The five-year event-free survival rate was 68.6% for the 11 patients who received TKIs compared with 31.6% for the 19 patients who did not [233].

    Consolidation/intensification therapy begins after normal hematopoiesis has been restored. The most commonly used intensification regimen was first introduced by the Berlin-Frankfurt-Munster (BFM) clinical trials group and usually includes methotrexate with 6-mercaptopurine (6-MP) and high-dose asparaginase, followed by reinduction treatment (the same regimen given during the first few months of remission induction therapy). Maintenance typically includes 6-MP, weekly low-dose methotrexate, and sometimes administration of vincristine and a corticosteroid, as well as continued intrathecal therapy [74,220,228]. This regimen, with variations (e.g., intensification for higher-risk patients, use of escalating doses of methotrexate without leucovorin rescue, elimination or truncation of some phases for lower-risk patients), has been adopted by COG and has been associated with favorable outcomes in children with standard-risk ALL [234,235].

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  16. The American Society for Blood and Marrow Transplantation recommends hematopoietic stem cell transplantation for ALL in patients with

    TREATMENT APPROACHES

    In 2012, the American Society for Blood and Marrow Transplantation (ASBMT) published an update to its 2005 recommendation that HSCT be done after first complete remission of Ph+ ALL when a matched related donor is available [250,251]. Allogeneic HSCT is recommended for children who [251]:

    Are in their second complete remission following an early marrow relapse for B-cell ALL

    Have had failure of primary induction therapy but subsequent complete remission

    Have T-cell ALL in their second complete remission

    Have ALL in their third or greater remission

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  17. Which of the following statements about relapsed or refractory AML is TRUE?

    TREATMENT APPROACHES

    Most relapses occur during the first year, and the most common site of relapse is the bone marrow (92%) [258]. Relapse occurs in the CNS in 10% to 20% of patients and in the skin in 4%.

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  18. Low-risk Hodgkin lymphoma is most often treated with

    TREATMENT APPROACHES

    Favorable-risk (low-risk) disease is defined differently by different clinical trial groups, but for the most part it encompasses patients with localized stage I and II disease without adverse prognostic features (e.g., "B" symptoms, extranodal extension, mediastinal bulky disease). Favorable-risk disease can be treated with reduced therapy, which consists of two to four cycles of multiagent chemotherapy and low-dose (15–25 Gy), involved-field radiation [47,272,273]. The regimens used most often include etoposide, which has commonly replaced alkylating agents and anthracyclines, in an effort to reduce gonadal toxicity and enhance antineoplastic activity [47]. Intermediate-risk disease is treated with three to six cycles of compacted, dose-intensive chemotherapy and low-dose, involved-field radiation, usually as consolidation therapy. For high-risk disease, four to six compacted, dose-intensive cycles of chemotherapy in addition to low-dose (15–25 Gy) involved-field radiation therapy to involved sites of disease are recommended [272]. The dose-intensive regimen of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone led to response within four weeks in 74% of children/adolescents with stage IIB or IIIB Hodgkin lymphoma with bulk disease or stage IV disease [274]. When followed by guideline-directed consolidation therapy, the treatment led to overall survival of 97% and five-year event-free survival of 94% [274]. More recent pediatric trials conducted in North America and Europe have used procarbazine-free standard backbone regimens, which represent dose-dense therapies that use six drugs to maximize intensity without exceeding thresholds of toxicity [47]. Early response to therapy may be considered in determining the need for radiation in those who have complete remission. Advanced radiation techniques, such as intensity-modulated radiation therapy and proton therapy, may be considered depending on the clinical scenario and if an improvement is expected [272,275].

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  19. The most significant predisposing factor for infection in a child/adolescent being treated for leukemia or lymphoma is

    SUPPORTIVE CARE

    Of primary concern during treatment for leukemia or lymphoma is the risk of infection, which is the leading cause of morbidity and mortality among children with cancer [22,320]. Infection is a result of the severe immunosuppression caused by both treatment (chemotherapy and radiation therapy) and the disease process itself. Immunosuppression and associated neutropenia increase the risk for opportunistic infection with bacterial, viral, fungal, and protozoal organisms [320,321]. Most infections that occur in children during or after treatment for leukemia or lymphoma are the same as those found in healthy children [321].

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  20. Which of the following is the most appropriate course when fever develops in a child/adolescent with an indwelling central venous catheter?

    SUPPORTIVE CARE

    The risk of infection is also increased for children who have an indwelling central venous catheter. Indwelling venous catheters are used in most children/adolescents with cancer to facilitate the administration of medications, fluids, and blood products. The risk of infection related to these catheters has ranged from approximately 3% to 60%, and the risk is greater with external catheters than with implanted ones [332,333]. Care of external catheters requires strict adherence to aseptic technique, daily flushing of the catheter, and frequent changes of the sterile dressing [321]. If a fever develops, blood for cultures should be obtained through the catheter and from a peripheral site and empiric treatment with antibiotics should be started. Routine removal of the catheter is not necessary, as nearly 75% of catheter-related infections resolve with the catheter intact [334]. However, if signs of septicemia develop and bacteremia persists 48 hours after the start of antibiotic administration, the catheter should be removed [320]. The catheter should also be removed immediately if the infection is fungal.

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  21. Most pediatric oncologists consider which of the following hemoglobin levels as the threshold for the transfusion of packed red blood cells in children/adolescents with leukemia or lymphoma?

    SUPPORTIVE CARE

    Myelosuppression caused by chemotherapy may lead to anemia and thrombocytopenia. In these cases, blood products may be needed. No hemoglobin level has been established as a threshold for transfusion of blood; the need for transfusion of packed red blood cells (preferred to whole blood) is based on careful evaluation of individual patients [332]. Transfusion was once done for a hemoglobin of less than 10 g/dL, but most clinicians now consider 7–8 g/dL as the threshold due to the risks associated with transfusions [320,332]. Erythropoietin at a dose of 600 units/kg to 900 units/kg once weekly for 16 weeks has been shown to be safe for increasing the hemoglobin level and decreasing the need for transfusion among children 5 to 18 years of age who were being treated with myelosuppressive chemotherapy for nonmyeloid cancers [342].

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  22. Which of the following statements about symptoms in children/adolescents with cancer is TRUE?

    PALLIATIVE AND END-OF-LIFE CARE

    The assessment and management of symptoms represent the cornerstone of palliative care [178,359]. Symptom management is crucial not only to relieve physical and psychological suffering but also to avoid feelings of mistrust and fear [354]. In general, studies have shown that pain, fatigue, and nausea/vomiting are the most common physical symptoms in children being treated for cancer [178,354,360,361,362]. Symptoms differ, however, according to age, the type of cancer, the type of treatment, and the degree of distress they cause. For example, in one study, 35% of children/adolescents 10 to 18 years of age had clinically significant pain, lack of energy, drowsiness, nausea, cough, lack of appetite, and psychological symptoms; the most distressing symptoms were pain, insomnia, mouth sores, and difficulty swallowing [363]. A similar study of younger children, 7 to 12 years of age, demonstrated lethargy, pain, or insomnia occurring in approximately 33%, with pain, insomnia, pruritus, nausea, sadness, and worry being the most distressing symptoms [364].

    Effective management of symptoms requires careful assessment, physical examination, and functional evaluation, all of which should be repeated at regular intervals to ensure ongoing alleviation. Several tools are available to assess pain. However, such tools are lacking for other symptoms, highlighting the importance of the patient's self-report of symptoms. A symptom checklist for children can help facilitate monitoring and self-reporting of symptoms [362]. Symptom management should be timely and include both pharmacologic and nonpharmacologic strategies [178,347,354]. Because stress and anxiety can exacerbate physical symptoms, attention to psychosocial issues is essential for optimum symptom management.

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  23. Which of the following statements about the assessment of pain in children/adolescents is TRUE?

    PALLIATIVE AND END-OF-LIFE CARE

    Pain may be related to treatment, diagnostic procedures, and/or progressive disease. The patient's self-report of pain, when possible, is the most reliable indicator [57,354]. Assessment of pain must be appropriate for each child's age, developmental level, and cultural context. Pain assessment tools have been developed for several different age groups among children/adolescents, from birth to 18 years of age, and for nonverbal or cognitively impaired children (Table 16) [57,365,366,367,368,369,370,371,372,373,374]. These tools are designed to either provide a score according to a set of behavioral cues, as in the case of infants and young children, or allow the child to self-report on the intensity and location of pain. Several tools have been modified and validated for use among children/adolescents of different races/ethnicities, including Black, Hispanic, Asian, and Alaska Native populations [375,376,377,378].

    It is also helpful to evaluate behaviors to determine if a young child has pain. Indicators of pain in infants include facial expressions such as frowning, a furrowed brow, a quivering chin, crying, sucking, flexing of fingers and toes, and breath-holding. Behavioral indicators are also important for older children, as they may not admit to having pain because of fear of an injection. Indicators in older children include decreased energy level; decreased eating; lack of interest in usual activities; holding or protecting part of the body; seeking comfort or closeness; and whining or groaning [365,366,367,368,369].

    Physical examination and functional evaluation are other components of pain assessment. During the examination, the clinician should watch closely for nonverbal cues that suggest pain. These cues are especially important when examining patients who are unable to verbally communicate. To evaluate how pain may be influencing function, the clinician should watch the patient to see how pain limits movements and should ask the patient or family how the pain interferes with normal activities. Determining functional limitations can help enhance patient compliance in reporting pain and adhering to pain-relieving measures, as clinicians can discuss compliance in terms of achieving established functional goals.

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  24. Studies have shown that most children/ adolescents with cancer die in

    PALLIATIVE AND END-OF-LIFE CARE

    The high survival rates for children with leukemia and lymphoma has of course led to a decreasing number of childhood deaths. Still, 10% to 30% of patients will have relapsed disease and die. Despite the fact that these children would benefit from hospice care delivered by a multidisciplinary palliative care team, studies have shown that most children with cancer die in the hospital [391]. However, one report indicated a significant increase in the number of children/adolescents who died at home since the late 1990s, and a survey of bereaved parents and pediatric oncologists ranked home as their first choice for end-of-life pediatric cancer care [392,393]. Still, hospice care is used by only 5% to 25% of eligible children in the United States and Canada [394].

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  25. The barrier to end-of-life care that has been reported by pediatric oncologists most often is

    PALLIATIVE AND END-OF-LIFE CARE

    The potential death of a child goes against the natural order and is associated with feelings of distress and failure for parents as well as clinicians. Parents and family members continue to hope for a cure and often see the end of curative therapy as "giving up" [354,413]. In a survey of pediatric oncologists, the most frequently reported barrier to end-of-life care was unrealistic expectations of the family, noted by approximately 48% of respondents [414]. Family denial was another commonly reported barrier, noted by 36% of respondents [414]. Paradoxically, the high rates of cure and long-term survival associated with most pediatric leukemias and lymphomas foster parents' hope for cure [349,413]. Feelings of denial and hope are also factors in late hospice referrals. Most hospice referrals are made at the time of disease progression (44%), at the end of therapeutic options (26%), or at the time of imminent death (20%) [407]. Earlier hospice referral, such as at the time of disease relapse, would enhance the quality of care for children and their families, yet only 2.5% of referrals are made at that time [407]. A survey of pediatric oncologists found that they were less likely to refer patients after chemotherapy had been stopped and more likely to refer at the time of diagnosis of cancer/incurable cancer. They also preferred that "supportive care" be used in place of "palliative care," because the term was negatively perceived by their patients [404].

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  26. Among children/adolescents with cancer, most hospice referrals are made at the

    PALLIATIVE AND END-OF-LIFE CARE

    The potential death of a child goes against the natural order and is associated with feelings of distress and failure for parents as well as clinicians. Parents and family members continue to hope for a cure and often see the end of curative therapy as "giving up" [354,413]. In a survey of pediatric oncologists, the most frequently reported barrier to end-of-life care was unrealistic expectations of the family, noted by approximately 48% of respondents [414]. Family denial was another commonly reported barrier, noted by 36% of respondents [414]. Paradoxically, the high rates of cure and long-term survival associated with most pediatric leukemias and lymphomas foster parents' hope for cure [349,413]. Feelings of denial and hope are also factors in late hospice referrals. Most hospice referrals are made at the time of disease progression (44%), at the end of therapeutic options (26%), or at the time of imminent death (20%) [407]. Earlier hospice referral, such as at the time of disease relapse, would enhance the quality of care for children and their families, yet only 2.5% of referrals are made at that time [407]. A survey of pediatric oncologists found that they were less likely to refer patients after chemotherapy had been stopped and more likely to refer at the time of diagnosis of cancer/incurable cancer. They also preferred that "supportive care" be used in place of "palliative care," because the term was negatively perceived by their patients [404].

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  27. Which of the following age groups has a concept of death that involves recognition of all the components of irreversibility, universality, nonfunctionality, and causality?

    PALLIATIVE AND END-OF-LIFE CARE

    FEARS, CONCEPTS OF DEATH, AND SPIRITUAL INTERVENTIONS ACCORDING TO DEVELOPMENTAL AGE OF CHILDREN AND ADOLESCENTS

    AgePrimary FearsConcept of DeathSpiritual Interventions
    InfantSeparation; strangersUnable to differentiate death from temporary separation or abandonment
    Provide consistent caretakers
    Minimize separation from parents and significant others
    Decrease parental anxiety
    Maintain crib/nursery as "safe place" (no invasive procedures)
    Encourage parental presence
    Encourage/facilitate use of spiritual support system for the family
    ToddlerSeparation; loss of control
    Recognizes death in terms of immobility
    Often viewed as reversible, temporary, or foreign
    Minimize separation from parents and significant others
    Keep security objects at hand
    Provide simple, brief explanations
    Explain and maintain consistent limits
    Encourage participation in daily care
    Provide opportunities for play and play therapy
    Reassure the child that disease is not punishment (by God, Higher Power, or other authority figure)
    Early school-age childBodily injury and mutilation; loss of control; the unknown; the dark; being left alone
    Recognizes death in terms of immobility
    Often viewed as reversible, temporary, or foreign
    Begins to question and develop a mature concept
    Do not underestimate level of comprehension
    Provide simple, concrete explanations
    Provide advance preparation (days for major events, hours for minor events)
    Use pictures, models, actual equipment, medical play when providing explanations
    When appropriate, initiate discussion of love and caring from Higher Power to relieve anxiety and loneliness
    Show behavioral qualities of love, trust, respect, caring, and setting of firm limits and disciplining without anger
    School-age childLoss of control; bodily injury and mutilation; failure to live up to expectations of important others; deathRecognizes all the components of irreversibility, universality, nonfunctionality, and causality
    Provide choices whenever possible
    Stress contact with school or organized religious peer group
    Use diagrams, pictures, and models for explanations
    Emphasize the "normal" things the child can do
    Reassure child that he/she has done nothing wrong; hospitalization is not punishment
    Be alert to anxiety about being punished by deity
    Provide appropriate concrete explanations in response to questions regarding spiritual beliefs
    Continue spiritual rituals; if appropriate, promote prayer and relationship with child's concept of God
    Model behaviors that show forgiveness and acceptance
    AdolescentLoss of control; altered body image; separation from peer group
    Speculates on the implications and ramifications of death
    Understands effect of death on other people and society as a whole
    Future-oriented, difficult to understand reality of death as a present possibility
    Allow adolescent to be an integral part of decision making regarding care
    Give information sensitively
    Allow as many choices and as much control as possible
    Be honest about treatment and consequences
    Stress what the adolescent can do for himself or herself and the importance of cooperation and compliance
    Assist in maintaining contact with peer group
    Provide answers without bias and enable participation in discussions of illness in terms of philosophical or spiritual beliefs
    Encourage contact with friends and use of spiritual rituals if appropriate
    Observe and document verbalizations of adolescent's values and beliefs
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  28. Which of the following statements regarding psychosocial issues for childhood cancer patients is TRUE?

    PSYCHOSOCIAL ISSUES FOR THE PATIENT AND FAMILY

    Addressing psychosocial issues is an integral component of comprehensive cancer care not only to help patients and their families cope with a cancer diagnosis and the stress related to treatment, but also to help alleviate latent psychosocial distress. The diagnosis and course of a child's cancer can detrimentally affect family members' interactions with one another and their social environment. Yet, responding to childhood cancer can prompt positive growth if psychosocial issues are managed effectively. Although many families are resilient, the negative psychosocial consequences for one or more family members touched by a child's cancer can be lasting and severe. Studies have found that the psychological distress experienced by family members is often greater than that experienced by the patient [438]. For example, parents, who are already distressed by their child's illness also often struggle with conflicted feelings when their role as parent means they must manage the competing needs of various family members. The authors of one qualitative analysis sought to identify parental expectations of support from healthcare providers during a child's life-threatening illness [439]. Based on thematic analyses conducted with data from 31 semi-structured interviews of parents, the authors identified three themes and one overall expectation [439]:

    "Help us survive this."

    "Let's fight together. Please fight with me, not against me, to care for my family."

    "Guide me through the darkness. I am suffering."

    The overall expectation was for mutuality with the healthcare providers and healthcare system in order to keep fighting together for the family's survival [439].

    Clinicians in the pediatric and family medicine setting are well-positioned to monitor family members' coping abilities and psychosocial states during the trajectory of the illness. Most parents believe that psychosocial issues should be discussed with the child's physician and would find that discussion to be valuable [177]. However, less than 50% of parents raise such topics, and parents report that only 15% to 20% of physicians assess the family's psychosocial issues [177]. Clinicians may be able to provide the auxiliary emotional support and guidance the child and his or her family needs [439,440]. If necessary, they can refer at-risk family members to intervention programs/specialists to improve coping strategies and promote healthy psychological adjustment.

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  29. The two main types of coping are

    PSYCHOSOCIAL ISSUES FOR THE PATIENT AND FAMILY

    Coping has been defined as the "constantly changing cognitive and behavioral efforts to manage the specific external and/or internal demands that are appraised as taxing or exceeding the resources of the person" [441]. The two main types of coping are problem-focused and emotion-focused [441]. The goal of problem-focused coping is to change aspects of an event to relieve distress. If the individual cannot manage a stressful event, emotion-focused coping is used to regulate feelings or alter his or her interpretation of the situation. Emotion-focused coping mechanisms intended to alter interpretations are categorized into four control strategies: predictive control, vicarious control, illusory control, and interpretative control [360]. These control strategies are used commonly by children and their parents when coping with cancer [361,362]. Using combinations of problem-solving and emotion-regulating mechanisms to meet each cancer-related challenge decreases short-term distress and promotes healthy social and cognitive development and adaptation [442].

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  30. Which of the following statements about gender differences in coping is TRUE?

    PSYCHOSOCIAL ISSUES FOR THE PATIENT AND FAMILY

    Some studies have shown differences in the coping styles of male and female children/adolescents with cancer. One study found that older female children (12 to 18 years of age) use a wider repertoire of emotion-focused and problem-focused coping strategies than their male counterparts [477]. Among male participants in the study, use of emotion-focused coping was linked to a disposition to experience anger and anxiety but not depression. Emotion-focused coping in the female participants was not associated with these variables. Depressive symptoms were less likely to develop in female participants who used problem-focused strategies.

    In another study, male children 11 to 18 years of age were found to use disengagement coping strategies, such as problem avoidance, wishful thinking, social withdrawal, and self-criticism, more often than female children did [478,479]. Engagement coping strategies include problem-solving, cognitive-restructuring, social support, and expression of emotions. Male children were also found to use humor coping significantly more often than girls in a study of children 7 to 14 years of age who had ALL [455,480]. Healthy psychosocial adjustment was strongly correlated to humor coping [455].

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  31. The most commonly reported source of social support by children/adolescents with cancer is their

    PSYCHOSOCIAL ISSUES FOR THE PATIENT AND FAMILY

    Mothers are the most commonly reported source of social support by children/adolescents with cancer. As a child with cancer develops into an adult, however, his or her social support needs extend beyond the family. Socialization with peers contributes to coping abilities and psychological adjustment of children/adolescents with cancer [481,482,483]. For adolescents 12 to 14 years of age, family-independent social networks are significantly smaller than those of adolescents 15 to 18 years of age, which may contribute to less effective coping. The emotional support of peers is particularly important for continued participation in school and social activities [483]. Hospitalizations, poor physical health/appearance, academic difficulties, and poor parental coping skills can also limit the patient's development of relationships with peers [457,484].

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  32. Which of the following statements about the effect of parental factors on the psychosocial adjustment of a child/adolescent with cancer is TRUE?

    PSYCHOSOCIAL ISSUES FOR THE PATIENT AND FAMILY

    Parental factors linked to the psychological outcomes and quality of life for a child with cancer include education, communication styles, and coping strategies [457,478,485,489,490,491,492,493].

    Parental education: Children with cancer are more likely to experience poor psychological adjustment if their parents' education level does not exceed high school.

    Parental communication styles: Most healthcare professionals agree that parents should talk openly, honestly, and age-appropriately to a child about his or her illness. Open lines of communication protect children with cancer from suffering emotional distress in isolation and promote high-quality care. In addition, poor cancer-related communication is linked to children's and adolescents' noncompliance with cancer treatments.

    Parental coping strategies: Coping mechanisms of parents can be reflected by children with cancer. A correlation study demonstrated similarities in the use of disengagement coping—in particular, problem avoidance—by parents and their adolescent child. Three months after diagnosis, parental differences in information-seeking were correlated with lower quality of life for children with cancer. However, other dissimilarities in maternal and paternal coping mechanisms, such as religious or support-seeking coping styles, do not appear to affect patients' quality of life.

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  33. The most common psychological disturbance for parents of childhood cancer survivors is

    PSYCHOSOCIAL ISSUES FOR THE PATIENT AND FAMILY

    Although parental emotional distress and psychosomatic complaints are high shortly following a child's cancer diagnosis, prospective studies have shown that most survivors' parents adjust within 1 to 10 years [510,511,512]. Still, approximately 25% to 33% of parents face long-term psychological issues [365,510,512,513]. Healthcare professionals' attention to the specific needs of the family can enhance the family's resilience [514,515,516,517]. Post-traumatic stress disorder is the most common psychological disturbance for parents of childhood cancer survivors [513,518].

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  34. The rate of at least one physical or psychosocial late effect among survivors of childhood cancer is as high as

    LONG-TERM HEALTH CARE FOR CHILDHOOD CANCER SURVIVORS

    Late effects are usually defined as those occurring at least two years after completion of treatment and are chronic and sometimes progressive [56]. These late effects are primary contributors to mortality and morbidity for survivors. Among 20,483 five-year survivors in the CCSS group, mortality was 8.4 times higher for survivors than for the age-, sex-, and year-matched U.S. population [5]. The overall absolute excess risk of mortality was 7.36, which represents an additional seven deaths per 1,000 individuals who were followed up for one year [5]. The leading cause of mortality was recurrent and/or progressive disease (approximately 58%), followed by subsequent neoplasms (19%), circulatory system diseases (7%), and respiratory system diseases (3%) [5]. The cause of mortality varied by sex, with a higher proportion of deaths related to a subsequent neoplasm among female survivors and a higher proportion of cardiac deaths among male survivors [5]. The morbidity related to pediatric cancer treatment has a substantial impact on the health status and quality of life for survivors. Studies have shown that 63% to 75% of childhood cancer survivors have at least one physical or psychosocial late effect and that 28% to 40% have a severe or life-threatening condition [3,4]. However, one study found the incidence of severe or life-threatening conditions to be much higher. Researchers evaluated 14,359 five-year survivors in the CCSS cohort for risk of severe, disabling, life-threatening, and fatal events, and 4,301 siblings were included for comparison [536]. The cumulative incidence of a severe, disabling, life-threatening, or fatal health condition was greater among survivors than siblings (53.6% and 19.8%, respectively) by 50 years of age [536]. Correlation of late effects with primary diagnosis has indicated that leukemia and non-Hodgkin lymphoma are associated with lower burdens of adverse events, whereas the burden associated with Hodgkin lymphoma is often higher than the average burden (Table 21) [3,4,537].

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  35. The burden of late adverse events is highest for survivors of which type of cancer?

    LONG-TERM HEALTH CARE FOR CHILDHOOD CANCER SURVIVORS

    Late effects are usually defined as those occurring at least two years after completion of treatment and are chronic and sometimes progressive [56]. These late effects are primary contributors to mortality and morbidity for survivors. Among 20,483 five-year survivors in the CCSS group, mortality was 8.4 times higher for survivors than for the age-, sex-, and year-matched U.S. population [5]. The overall absolute excess risk of mortality was 7.36, which represents an additional seven deaths per 1,000 individuals who were followed up for one year [5]. The leading cause of mortality was recurrent and/or progressive disease (approximately 58%), followed by subsequent neoplasms (19%), circulatory system diseases (7%), and respiratory system diseases (3%) [5]. The cause of mortality varied by sex, with a higher proportion of deaths related to a subsequent neoplasm among female survivors and a higher proportion of cardiac deaths among male survivors [5]. The morbidity related to pediatric cancer treatment has a substantial impact on the health status and quality of life for survivors. Studies have shown that 63% to 75% of childhood cancer survivors have at least one physical or psychosocial late effect and that 28% to 40% have a severe or life-threatening condition [3,4]. However, one study found the incidence of severe or life-threatening conditions to be much higher. Researchers evaluated 14,359 five-year survivors in the CCSS cohort for risk of severe, disabling, life-threatening, and fatal events, and 4,301 siblings were included for comparison [536]. The cumulative incidence of a severe, disabling, life-threatening, or fatal health condition was greater among survivors than siblings (53.6% and 19.8%, respectively) by 50 years of age [536]. Correlation of late effects with primary diagnosis has indicated that leukemia and non-Hodgkin lymphoma are associated with lower burdens of adverse events, whereas the burden associated with Hodgkin lymphoma is often higher than the average burden (Table 21) [3,4,537].

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  36. Of the following, which is the greatest risk factor for the development of a subsequent neoplasm in a childhood cancer survivor?

    LONG-TERM HEALTH CARE FOR CHILDHOOD CANCER SURVIVORS

    The greatest risk factor for a subsequent neoplasm is radiation therapy (relative risk: 2.7), followed by female sex and childhood Hodgkin disease (relative risk: 1.5 for both), and older age at the time of childhood cancer diagnosis (relative risk: 1.3) [7]. It is important to note, however, that changes to treatment protocols over time (e.g., the move to limited use of radiation therapy) may affect risk among children/adolescents treated within the past decade. Overall, the most frequently occurring subsequent solid tumors among childhood cancer survivors are breast, thyroid, and CNS cancers and soft-tissue sarcoma [7,543].

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  37. Of the following, the greatest contributor to the risk for neurocognitive impairment in pediatric cancer survivors is

    LONG-TERM HEALTH CARE FOR CHILDHOOD CANCER SURVIVORS

    Neurocognitive impairment is among the most common and distressing late effect of pediatric cancer treatment [4,319,457,526,570,571,572]. In one study, the relative risk of severe cognitive dysfunction among more than 10,000 survivors was 10.5 compared with sibling controls [3]. In another study, cognitive or psychosocial disorders represented approximately 8% of all severe, life-threatening, or disabling events [4]. A cancer experience alone increases the risk for neurocognitive impairment, and the interruption of regular schooling during treatment can have serious effects on academic performance [534]. Cranial radiation is the greatest contributor to the risk for neurocognitive deficits. The highest risk is associated with cranial radiation in combination with an age of younger than 3 years at the time of treatment or female sex [534]. The intensity of treatment and the time since treatment are also factors [534]. The replacement of prophylactic cranial radiation with intrathecal chemotherapy has led to a decrease in neurocognitive toxicity, but intrathecal chemotherapy (primarily methotrexate) is associated with some level of deficit in approximately 30% of survivors [570,571,572].

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  38. The neurocognitive deficits in survivors of childhood leukemia and lymphoma are most often related to

    LONG-TERM HEALTH CARE FOR CHILDHOOD CANCER SURVIVORS

    The deficits in survivors of leukemia and lymphoma are more often related to information processing [534].

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  39. Which of the following is NOT among the basic elements of a cancer survivorship care plan?

    LONG-TERM HEALTH CARE FOR CHILDHOOD CANCER SURVIVORS

    It is imperative that every childhood cancer survivor have written documentation of his or her specific diagnosis and all diagnostic and treatment details [534]. The concept of survivorship care plans has been developed as a way to facilitate better follow-up care for all survivors [584,585]. Among the basic elements of a survivorship care plan are [534,585]:

    Diagnostic tests performed and results

    Disease characteristics (e.g., histologic type, stage, grade, site)

    Start and end dates of treatment

    Type of treatment (chemotherapy and radiation therapy regimens, including doses and schedules)

    Indicators of treatment response

    Treatment-related toxicities

    Psychosocial and other supportive services provided

    Information on possible late and long-term effects of treatment and symptoms of such effects

    Information on possible signs of recurrence

    Description of recommended cancer screening and other periodic testing and examinations, their performance schedule, and which provider should perform them

    Specific recommendations for healthy behaviors (e.g., diet, exercise, healthy weight, sunscreen use, immunizations, smoking avoidance/cessation, osteoporosis prevention)

    List of cancer-related resources and information (e.g., web-based sources and telephone listings for major cancer support organizations)

    Identifying number and title of clinical trial (if applicable)

    Full contact information on treating institutions and key individual practitioners

    Identification of a key contact and a coordinator of continuing care

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  40. Which of the following subgroups of childhood cancer survivors is in particular need of encouragement to maintain physical activity?

    LONG-TERM HEALTH CARE FOR CHILDHOOD CANCER SURVIVORS

    The health behaviors of childhood cancer survivors have not been well-studied, but overall, young cancer survivors report lifestyle behaviors that are at least as healthy as the age-matched population [56,532]. Behaviors have been shown to vary according to race/ethnicity; overall, Black survivors have reported better preventive practices and have been less likely to engage in risky behaviors such as smoking and alcohol consumption [589]. In one study, 40% of survivors reported eating a nutritious diet, 64% said they practiced sun protection, and 94% said they did not smoke [590]. In a later and much larger study, the rate of physical inactivity was high (52% to 72%), with the lowest rate for Hispanic male survivors and the highest rate for Black female survivors [589]. In that same study, the rates of smoking among Black and Hispanic survivors were lower than the rates among their peers in the general population [589].

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