Impact of undernutrition on the pharmacokinetics of chemotherapy in children with cancer: A systematic review

Objectives

This systematic review provides an overview of the effect of undernutrition on the pharmacokinetics of chemotherapy in children with cancer.

Methods

PubMed, Embase, and Cochrane were searched to identify eligible studies. This study uses the definition for undernutrition from the World Health Organization and the Gomez classification.

Results

Four studies with a total of 668 children with cancer were included and n = 121 (18%) were undernourished. Significant decreased clearance rates were found for vincristine in undernourished children compared to children with a normal nutritional status.

Conclusion

Presenting outcomes only show significant changes in the pharmacokinetics of vincristine in undernourished children with cancer. However, data are scarce, groups were small, and none of the studies included severely undernourished children. In order to improve outcomes for (severely) undernourished children with cancer, more pharmacokinetic research is needed. The ultimate goal would be to develop subgroups, and ultimately individualized drug dosing in order to improve outcomes for children with cancer worldwide.     

Failure of granulocyte-macrophage colony-stimulating factor to reduce febrile neutropenia in children with recurrent solid tumors treated with ifosfamide,carboplatin, and etoposide chemotherapy

Ifosfamide, carboplatin, and etoposide (ICE) chemotherapy has promising activity against various solid tumors but produces significant myelotoxicity that might be ameliorated by hematopoietic growth factors. Twelve patients with relapsed solid tumors were treated with ICE chemotherapy. Carboplatin was given on day 1 at a targeted area under the concentration-time curve (AUC) of 8 mg/mL × min (adjusted for each patient's glomerular filtration rate), followed by ifosfamide 2 g/m² and etoposide 100 mg/m² on days 2 through 4. Granulocyte-macrophage colony-stimulating factor (GM-CSF), 1,000 μg/m²/day, was started 24 hours after each course and given for 17 days or until the absolute neutrophil count (ANC) reached 10 × 10⁹/L. Myelotoxicity and responses in these patients were compared to those of eight patients who received the same therapy without GM-CSF. Patients received a median of three courses (range, 1–8). All 20 patients developed grade 4 neutropenia and grade 3 or 4 thrombocytopenia. The median duration of neutropenia was significantly shorter in patients who received GM-CSF (16.75 vs. 10 days, P = 0.005). However, the two groups did not differ in the proportion of courses associated with hospitalization for febrile neutropenia, the duration of hospitalization, or the median duration of thrombocytopenia. There were two complete, four partial, and three objective responses in the 12 patients treated with ICE plus GM-CSF, and two partial and three objective responses in the 8 patients treated with ICE only. GM-CSF did not reduce the occurrence of febrile neutropenia or the duration of thrombocytopenia associated with ICE chemotherapy. Studies of other hematopoietic growth factors in conjunction with this promising combination are merited. © 1994 Wiley-Liss, Inc.     

Atypical mycobacterial infections in children with cancer

Atypical mycobacteria are seen more frequently as a cause of serious infection in children with cancer. Thirteen pediatric cancer patients with blood or tissue cultures positive for atypical mycobacteria were identified by review of records over a 5-year period at one center. All had central venous catheters and were lymphopenic at the time of infection. Eleven children had rapidly growing mycobacteria and two children had M. avium-intracellulare. Nine patients had positive blood cultures. Three were treated with catheter removal as sole therapy, five had catheter removal plus antibiotics, and one had antibiotics alone. Two patients with pulmonary M. avium-intracellulare infection received antibiotic therapy alone. It is concluded that infection with rapidly growing mycobacteria in children with cancer is associated with presence of a central venous catheter and lymphopenia. Some children with uncomplicated catheter-associated infection with rapidly growing mycobacteria may be sufficiently treated with removal of the catheter alone.     

Late orthopedic effects in children with Wilms' tumor treated with abdominal irradiation

Between 1970 and 1984, 31 children with biopsy-proven Wilms' tumor received nephrectomy, chemotherapy, and abdominal irradiation and were followed beyond skeletal maturity. Three patients (10%) developed late orthopedic abnormalities requiring intervention. Ten children received orthovoltage irradiation, and all cases requiring orthopedic intervention or developing a scoliotic curve of >20d? were confined to this group, for a complication frequency of 50%. Those children who developed a significant late orthopedic abnormality (SLOA) as defined were treated to a higher median dose (2,890 cGy) and a larger field size (150 cm²) than those who did not (2,580 cGy and 120 cm²). Age at irradiation, sex, and initial stage of disease did not appear to influence the risk of developing an SLOA. No child who received megavoltage irradiation developed an SLOA despite treatment up to 4,000 cGy or to field sizes of 400 cm². We conclude that modern radiotherapy techniques rarely lead to significant late orthopedic abnormalities previously associated with abdominal irradiation in children with Wilms' tumor.     

Infections with viridans group streptococci in children with cancer

Infection with viridans group streptococci (VGS) causes morbidity and mortality in children with cancer. Incidence of these infections has increased over time. Neutropenic patients with acute myeloid leukemia and those receiving high-dose cytarabine or undergoing stem cell transplantation are at highest risk. One-third of infected patients develop a shock syndrome despite prompt antibiotic therapy. Host defense mechanisms contribute substantially to colonization and tissue damage, but the origin of the shock syndrome is not well understood. VGS infection may be accompanied by neurological complications, myocarditis, and acute respiratory distress syndrome. Routine systemic antimicrobial prophylaxis against VGS infection has not been proven effective. Current recommendations include appropriate antibiotic therapy and intensive supportive care.     

Right atrial thrombosis associated with central venous catheters in children with cancer

Right atrial thrombosis (RAT) is infrequently diagnosed in children with cancer. Once RAT is documented, medical fibrinolysis or surgical thrombectomy is recommended. A RAT was documented in a child with lymphoma and was successfully lysed with recombinant tissue-type plasminogen activator. The case is presented and therapeutic options reviewed.     

Advanced small cell carcinoma of the ovary in a seventeen-year-old female, successfully treated with surgery and multi-agent chemotherapy

Advanced small cell carcinoma of the ovary (FIGO stage III or IV) is a rare and usually lethal tumor seen in adolescents and young women. In pediatric patients with advanced disease, there have been only two case reports of successful therapy, we report a third patient, diagnosed at 17 years of age, with an abdominal mass and metastatic disease to regional and distant lymph nodes, who was successfully treated with surgery and intensive multi-agent chemotherapy. Imatinib, thalidomide, and celecoxib were also administered for up to 24 months following initial chemotherapy. She remains in remission 3 years from diagnosis.     

Posttraumatic stress disorder and risk factors in parents of children with a cancer diagnosis

The purpose of this study was to determine the prevalence of posttraumatic stress disorder (PTSD) in parents of children with cancer. Five questionnaires were administered to 104 parents, including a sociodemographic questionnaire, a traumatic events check list, the Structured Clinical Interview for DSM-IV PTSD and Major Depressive Disorder modules, and the self-rating instrument General Health Questionnaire-12. The prevalence of PTSD was 34.6%. The statistically significant tendency to develop PTSD were found in the female gender, better educational status, death of a loved one, previous history of psychiatric disorder, having a child with poorer prognosis, and the presence of radiotherapy in child's treatment. The vulnerable parents must receive psychosocial support.     

Prognostic variables in patients with advanced colorectal cancer treated with fluorouracil and leucovorin-based chemotherapy

Possible prognostic variables for tumor response, time to progression (TTP), and survival in 141 patients with advanced colorectal cancer treated with fluorouracil and leucovorin-based chemotherapy were analyzed. None of the variables examined for their possible influence on tumor response attained significance in the stepwise logistic regression. In the univariate analysis, variables found to be strongly associated with TTP were performance status (PS) (P = 0.0301), liver involvement (P = 0.030), and the initial values of WBC (P = 0.0319), lactic dehydrogenase (LDH; P = 0.0053), γ-glutamyl-transpeptidase (γ-GT; P = 0.0013), alkaline phosphatase (ALP; P = 0.0186), albumin (P = 0.0004), and carcinoembryonic antigen (CEA; P = 0.0014). In the Cox analysis, liver involvement (P = 0.0553), albumin (P = 0.0181), PS (P = 0.0484), and ALP (P = 0.0553) were retained as independently significant variables. When only patients with liver metastases were included in the analysis, then only albumin (P < 0.001) demonstrated a prognostic significance. Also, in the univariate analysis, variables predicting survival were PS (P = 0.0230), grade (P = 0.0060), liver involvement (P = 0.0002), LDH (P = 0.0001), γ-GT (P < 0.001), ALP (P = 0.0006), albumin (P = 0.0309), and CEA (P = 0.0005). With the multivariate analysis, γ-GT (P = 0.004), albumin (P = 0.0634), and CEA (P = 0.0804) were selected as significant. In those patients who presented with liver involvement, variables predicted survival were γ-GT (P = 0.0041), albumin (P = 0.0442), and the percentage of involved liver parenchyma (P = 0.0690). These results could be helpful for the stratification of future trials in advanced colorectal cancer. © 1996 Wiley-Liss, Inc.     

Medical and non-medical barriers to outpatient treatment of fever and neutropenia in children with cancer

BACKGROUND: A number of clinical trials have employed clinical criteria that can identify pediatric patients at low-risk for complicated episodes of fever and neutropenia (F&N) and have successfully treated low-risk patients in the outpatient setting. Despite this, inpatient management remains the standard of care. This trial tested the hypothesis that a strategy of initial hospitalization followed by continuation of therapy in the outpatient setting could be practically implemented in the majority of episodes. PROCEDURE: Patients presenting with F&N were initially evaluated to determine if they had high-risk clinical criteria that would exclude them from this approach. Eligible patients were then hospitalized and treated with iv antibiotics. On subsequent days the attending physician determined whether the patient had exhibited improvement and could continue therapy in the outpatient setting with oral antibiotics. Outpatients were seen three times weekly and continued antibiotics until recovery from F&N. RESULTS: Outpatient oral antibiotic therapy was practically implemented in less than one-quarter of episodes of pediatric F&N. Forty-nine percent of episodes were excluded from study by medical and social protocol exclusion criteria. One hundred five episodes were enrolled and among these 59 episodes included outpatient management. Common barriers to outpatient care included serious medical comorbidities, non-medical barriers including language and distance of residence from the medical center, and lack of interest. The average duration of outpatient care was 3.6 days following an average of 3.5 days of hospitalization. Ninety percent did not require rehospitalization. They experienced no complications. CONCLUSIONS: In only a minority of episodes can outpatient antibiotic management be implemented. Medical comorbidities and social barriers can make the transition to outpatient care difficult. However, initial hospitalization followed by oral antibiotic outpatient management appears safe and effective for low-risk patients who exhibit good responses to initial antibiotic therapy in hospital.     

Diminished ovarian reserve in adolescent cancer survivors treated with heavy metal chemotherapy

The extent to which heavy metal chemotherapy results in treatment-related ovarian damage is controversial. Anti-Mullerian hormone (AMH) levels measured more than 1 year after cancer therapy completion were abstracted from the medical records of 39 female survivors of childhood cancer aged 11 years and older, whose only gonadotoxic exposure was heavy metal chemotherapy. One-fifth of survivors who received cisplatin had AMH levels indicative of diminished ovarian reserve at last measurement. There was an observed clustering of low AMH in patients diagnosed in the peripubertal age range (i.e., 10–12 years). These findings may support a small, but present, risk of gonadal damage after heavy metal chemotherapy.