Factors influencing delayed clearance of high dose methotrexate (HDMTX) in pediatric, adolescent, and young adult oncology patients.

Predictors of Delayed Clearance and Toxicities from High Dose Methotrexate in Patients Receiving Hypercvad Regimen for Treatment of Lymphoid Malignancies

Ketamine is an NMDA-receptor antagonist with analgesic and opioid-sparing properties. Although well studied in adults, more robust evidence supporting ketamine's use for pediatric pain management is needed. This retrospective study evaluates ketamine's opioid-sparing effectiveness in pediatric and young adult oncology and hematology patients. Continuous ketamine infusions administered for pain management between 2010-2020 were reviewed. Data including demographic characteristics, oncology/hematology and pain diagnoses, concurrent pain medications, and ketamine infusions' dose and duration were collected. Opioid consumption data based on delivery via patient-controlled analgesia were collected 1 day before (D1), all days during (cumulatively named D2), and 1 day after (D3) ketamine infusions and calculated as morphine-equivalent doses (mg/kg/day). Data were reported for the entire study group as well as for distinct oncology and end-of-life categories, and short-term acute pain circumstances which included vaso-occlusive crises in hematology patients. Side effects were reviewed. Significantly lower daily opioid consumption was noted in the oncology group, while decreases were not significant in the end-of-life group and in the overall study population. The acute pain group did not show an opioid reduction associated with the ketamine infusions. A largely tolerable side-effect profile was observed, with no differences among each group's incidence. Ketamine infusions were associated with significantly reduced opioid consumption for oncology patients. The opioid-sparing effects of ketamine may vary according to clinical diagnoses and circumstances of use. Overall, low-dose ketamine infusions present an acceptable safety profile in pediatric and young adult patients; nevertheless, individual risks and benefits should be considered.

Targeted Screening in Pediatric and Young Adult Oncology Patients Identifies Transfusional Iron Overload

A New Journal to Improve Care for Adolescent and Young Adult Oncology Patients and Survivors.

Adolescent and young adult oncology (AYAO) patients often receive intensive medical care and experience significant symptoms at the end of life (EOL). This study aimed to describe the characteristics of AYAO patients aged 15-26 years who died as inpatients in a hospital and to compare the illness and EOL experiences of AYAO patients who did and did not receive palliative care (PC). A standardized data extraction tool was used to collect information about demographics, treatment, terminal characteristics, and symptoms during the last month of life (LMOL) for 69 AYAO patients who died while hospitalized between 2008 and 2014. AYAO patients who died in the hospital required considerable medical and psychosocial care and experienced numerous symptoms during the LMOL. Compared to those patients who received no formal PC services, patients followed by the PC team were less likely to die in the intensive care unit (ICU) (38% vs. 68%, p = 0.024) and less likely to have been on a ventilator (34% vs. 63%, p = 0.028) during the LMOL. They also received fewer invasive medical procedures during the LMOL (median, 1 vs. 3 procedures, p = 0.009) and had a do not resuscitate order in place for a longer time before death (median, 6 vs. two days, p = 0.008). Involvement of the PC team was associated with the receipt of less intensive treatments and fewer deaths in the ICU.

Venous thromboembolism (VTE) is a known complication among pediatric and adult cancer patients. Adolescent and young adult oncology (AYAO) patients have unique biological and physiological characteristics that make them distinct from other populations. Our objective was to study the VTE incidence, risk factors, and outcomes, which have been understudied in this population. A retrospective case-control study was conducted on AYAO participants with new or relapsed cancer and an imaging confirmed VTE from January 2011 to November 2016 at our institution. Eligible AYAO participants without a history of VTE were designated as controls and were randomly selected from our institution's tumor registry. Demographics, medical history, surgeries, central venous catheter (CVC) data, VTE diagnosis and treatment, relapses, and deaths were abstracted. Thirty-five VTE cases and 70 controls were included in this analysis. Eighty percent of cases had leukemia or lymphoma (vs. a solid tumor) compared to 58% of controls. The majority of VTEs (57%) were CVC associated, and more than 70% of cases had more than one CVC placed during their cancer treatment versus 34% of controls. Infection was associated with increased VTE risk (OR=6.35, 95% CI=2.30, 17.55, p<.0001). VTE cases had increased cancer relapse (23% vs. 10%) and mortality rates (29% vs. 16%) than controls. AYAO participants with a VTE were more likely to have leukemia or lymphoma, more than one CVC or infection. Further studies are needed to identify patients who would benefit from modifiable prevention measures, such as limiting to one CVC, preventing infections, or considering prophylactic anticoagulation for those with a liquid tumor.

Adolescent and young adult oncology (AYAO) patients and caregivers may experience significant psychosocial dysfunction and financial toxicity. Understanding early risk factors is critical to improving survivorship trajectories. The authors conducted a cross-sectional study of baseline survey data from a prospective cohort of AYAO patient-caregiver dyads enrolled within 1month of medical oncology treatment initiation. Posttraumatic stress symptoms (PTSS) were measured by the Impacts of Events Scale-Revised, and financial toxicity was measured with the Comprehensive Score (COst). The authors fit models of linear association between PTSS, financial toxicity, and other end points and pairwise associations of PTSS and financial toxicity within dyads. The analytic cohort contained 41 patients, 37 caregivers, and 34 complete dyads. Clinically-concerning PTSS were observed among patients (44%) and caregivers (52%). The median COst scores were 20.0 for patients (quartiles, 12.5-29.5) and 22.0 for caregivers (quartiles, 12.8-26.0), which were consistent with high financial toxicity (patients, 46%; caregivers, 44%). PTSS were positively associated with financial toxicity (P=.013 for patients, P=.039 for caregivers), subjective distress (P<.001 for all), depressive (P<.001 for all) and anxiety symptoms (P=.005 for patients, P=.024 for caregivers), and poorer quality of life (P<.001 for patients, P=.003 for caregivers). A significant paired association was not found in PTSS (Pearson correlation coefficient [PCC], 0.23; 95% confidence interval [CI], -0.15 to 0.56). Financial toxicity was positively associated within dyads (PCC, 0.65; 95% CI, 0.36-0.83). At diagnosis, AYAO patients and caregivers exhibit substantial PTSS, which are associated with greater financial toxicity and other psychosocial distress.

High-dose methotrexate (doses ≥1 g/m(2)) is a key component of several chemotherapy regimens used to treat patients with leukemia or lymphoma. Despite appropriate precautions with hydration, urine alkalinization, and leucovorin, nephrotoxicity remains a risk which can lead to significant morbidity and mortality. Current reports of risk factors for nephrotoxicity focus on patients with nephrotoxicity with a lack of comparison to those without toxicity. This study aimed to describe the incidence of high-dose methotrexate-induced nephrotoxicity at our institution and determined risk factors for high-dose methotrexate-induced nephrotoxicity by examining characteristics of patients with and without nephrotoxicity. This was a retrospective, single-center, chart review. Adult patients with a diagnosis of leukemia or lymphoma who received high-dose methotrexate were included. Serum creatinine values were used to evaluate nephrotoxicity according to Common Terminology Criteria for Adverse Events criteria v4.03. Data related to the following proposed risk factors were collected: age, sex, body mass index, methotrexate dose, number of high-dose methotrexate exposures, leucovorin administration route, baseline renal function, albumin, hydration status, Clostridium difficile infection, urine pH, and concomitant interacting and nephrotoxic medications. The primary endpoint was evaluated with exact binomial methods and risk factors were identified using multivariable random-effects logistic regression. Final analyses included 140 patients with 432 high-dose methotrexate exposures. There were no differences in baseline demographical characteristics. Fifty-four patients (38.6%) experienced nephrotoxicity of any grade: 27.9% with grade 1, 5.7% with grade 2, 3.6% grade 3, 0% with grade 4, and 1.4% with grade 5 toxicity. More patients in the toxicity group received doses of methotrexate ≥3 g/m(2) (58.3% versus 57.2%, p < 0.001), had an albumin level <3 g/dL (31.9% versus 15.9%, p = 0.04), and received an interacting medication during high-dose methotrexate clearance (44.4% versus 24.7%, p = 0.003). Male gender (OR 2.3, 95% CI: 1.27-4.18, p = 0.006), albumin (OR 0.44, 95% CI: 0.26-0.75, p = 0.002), number of drug interactions (OR 1.60, 95% CI: 1.15-2.21, p = 0.005), and use of furosemide (OR 2.56, 95% CI 1.46-4.48, p = 0.001) were all independent risk factors for the development of nephrotoxicity. Nephrotoxicity is a possible complication of therapy with high-dose methotrexate with most instances comprising grade 1-2 toxicity. Male gender, low albumin, and administration of interacting drugs or furosemide during high-dose methotrexate clearance may predispose patients to nephrotoxicity.

Diffuse alveolar hemorrhage (DAH) is a devastating disease process with 50-100% mortality in oncology and hematopoietic cell transplant (HCT) recipients. High concentrations of tissue factors have been demonstrated in the alveolar wall in acute respiratory distress syndrome and DAH, along with elevated levels of tissue factor pathway inhibitors. Activated recombinant factor VII (rFVIIa) activates the tissue factor pathway, successfully overcoming the tissue factor pathway inhibitor (TFPI) inhibition of activation of Factor X. Intrapulmonary administration (IP) of rFVIIa in DAH is described in small case series with successful hemostasis and minimal complications. We completed a single center retrospective descriptive study of treatment with rFVIIa and outcomes in pediatric oncology and HCT patients with pulmonary hemorrhage at a quaternary hematology/oncology hospital between 2011 and 2019. We aimed to assess the safety and survival of patients with pulmonary hemorrhage who received of IP rFVIIa. We identified 31 patients with pulmonary hemorrhage requiring ICU care. Thirteen patients received intrapulmonary rFVIIa, while eighteen patients did not. Overall, 13 of 31 patients (41.9%) survived ICU discharge. ICU survival (n=6) amongst those in the IP rFVIIa group was 46.2% compared to 38.9% (n=7) in those who did not receive IP therapy (p=0.69). Hospital survival was 46.2% in the IP group and 27.8% in the non-IP group (p=0.45). There were no adverse events noted from use of IP FVIIa. Intrapulmonary rFVIIa can be safely administered in pediatric oncology patients with pulmonary hemorrhage and should be considered a viable treatment option for these patients.

ObjectivesHigh-dose methotrexate (HDMTX) is an important chemotherapeutic agent in the treatment of many cancers. Identification of the predictors of poor clearance during HDMTX infusions could advance the introduction of improved supportive care to prevent toxicities and reduce hospital length of stay. The purpose of this study was to identify relationships between patient physical characteristics and HDMTX clearance in the treatment of pediatric acute lymphoblastic leukemia (ALL). At our hospital, patients who have delayed methotrexate (MTX) clearance during a cycle of HDMTX receive an increased rate of hydration with subsequent cycles. This increase in hydration rate was examined for its potential to mitigate predictors of poor clearance and to prevent nephrotoxicity.MethodsThis study retrospectively examined the treatment records of 87 pediatric patients diagnosed with ALL who were treated on or according to Children’s Oncology Group (COG) protocols AALL0232, AALL0434, AALL1131, and AALL1231. Each patient received four cycles of HDMTX (5 g/m2 over 24 hours) at two-week intervals. Patients received either 125 ml/m2/hour (standard) or 200 ml/m2/hour (delayed clearance protocol) hydration before, with, and after each infusion. MTX levels taken at 24-, 42-, and 48-hour time points were used as an indirect measure of drug clearance. Two-tailed inference for ordinary least squares regression and both heteroskedastic and paired two-tailed t-tests were performed to identify physical characteristics associated with delayed MTX clearance and the effects of hydration rate on MTX clearance, respectively.ResultsPatient age and body surface area (BSA) were found to have statistically significant (p<0.05) positive associations with the serum MTX levels at 24, 42, and 48 hours in cycle 1. Age and BSA were significant only at the 24-hour time point in cycles 2 and 4. Weight alone was not associated with delayed MTX clearance. For patients who had delayed MTX clearance once and thus received the delayed clearance protocol in subsequent cycles, increasing the hydration rate from 125 to 200 ml/m2/hour was associated with a statistically significant decrease in average MTX levels as well as serum creatinine levels at the 24-, 42-, and 48-hour time points. Once patients with delayed clearance received the 200 ml/m2/hour rate of hydration, the history of prior poor clearance lost its predictive value for serum MTX levels and delayed clearance.ConclusionsThese results suggest that patient age and BSA are significant predictors of MTX clearance if all patients receive the same rate of hydration. Age and BSA affect the distribution phase of MTX kinetics, with downstream effects in the elimination phase. Increased hydration mitigates the effects of these physical characteristics on the elimination phase kinetics by improving renal elimination of MTX, causing a loss of significance of age and BSA as predictors of MTX levels in subsequent cycles at the 42- and 48-hour time points, but with less effect at 24 hours. Thus, hyperhydration regimens prior to cycle 1 of HDMTX could be considered for patients presenting with risk factors of advanced age or high BSA to avoid delayed clearance.

Phlebotomy for Pediatric and Young Adult Oncology Patients Treats Transfusional Iron Overload

Over the past 30 years, there has been a dramatic increase in the survival rates of younger pediatric cancer patients in contrast to adolescent and young adult (AYA) oncology patients. The reasons for this discrepancy are multifactorial, but it is clear that clinical trial enrollment correlates with better outcomes. We examined the rate of clinical trial accrual of AYA oncology patients (aged 15 to 22 y) treated at affiliated pediatric and adult cancer centers, the Children's Hospital of Pittsburgh and the University of Pittsburgh Cancer Institute. We retrospectively analyzed all new cancer diagnoses and clinical trial enrollment status between 2003 and 2006 for AYA patients at both institutions. There were 91 new AYA cancer diagnoses at Children's Hospital of Pittsburgh, of which 24 (26%) were enrolled on a clinical trial. During the same time period, only 5 of 121 new AYA cancer patients (4%) at University of Pittsburgh Cancer Institute were enrolled on a clinical trial, which was significantly lower (P<0.001). Our data demonstrate that clinical trial enrollment was superior when AYA patients were treated at a pediatric cancer center. As most AYA patients are not treated at pediatric centers, this may partly explain why their cure rates have not improved as significantly as younger pediatric oncology patients.

There are established and well-followed guidelines for pediatric oncology patients who have neutropenic fever. However, there are no explicit criteria for this patient group, and over 50% of pediatric oncology patients with fever do not present with neutropenia. In this scoping review, we have explored the outcomes of non-neutropenic fever in pediatric, adolescent, and young adult patients with cancer-directed treatment. The results of this scoping review should assist in the creation of a guideline for the management of non-neutropenic fever in this group of patients. Multiple electronic databases and reference lists were searched (PubMed, MEDLINE CENTRAL, and Google (first 100 results only)). Included are retrospective and prospective cohort studies on the management and outcome of pediatric oncology patients with non-neutropenic fever that have been published after the year 2000. Seventeen studies with a total of 10.845 fever episodes were included, that address the treatment and outcome of patients with non-neutropenic fever. The rate of bacteremia was 1.6 - 14.4% (mean 5.8%). The mortality rate was low due to non-bacterial causes. Across different studies, proposed risk factors for bacteremia were higher temperature, prolonged fever over 72 hours, ill-appearing patients, chills, hypotension, leukocytosis, infancy, and the presence of a Broivac/ Hickman catheter. Limitations to this study are the risk of bias, and potential incomplete identification of relevant studies pertinent to the research questions asked. Due to significant heterogeneity, the published data so far are not sufficient to propose evidence-based guidelines for pediatric oncology patients with non-neutropenic fever. Prospective, multicenter registries based on uniform definitions are needed. No funding was received for this manuscript.

BackgroundAdolescents and young adults with cancer require dedicated and tailored management that bridges adult and pediatric oncology services. At the National Cancer Centre Singapore, 40% of newly diagnosed adolescents and young adults report significant distress due to uncertainty about prognosis, treatment, and disruption of life milestones. A major unmet need is access to reliable, age-appropriate information. Prior studies demonstrate that digital technology can effectively deliver such support.ObjectiveThis study describes the protocol for evaluating AYABytes (Adolescent and Young Adult Building Youths, a Technology for Education and Sharing), a mobile app cocreated by patients and health care professionals to improve health-related quality of life for adolescent and young adult oncology patients. An iterative information-gathering process was conducted, including semistructured interviews with 2 clinicians, 3 cancer survivors, and 3 care partners to cocreate this mobile app. AYABytes is an interactive, phone-based intervention designed to engage adolescent and young adult oncology patients with personalized education, mood, and symptom self-management resources with an inbuilt algorithm that responds to patient-reported questionnaires.MethodsThe app will be evaluated in 2 phases—a pilot test and an implementation test. In the pilot test, the app will be launched to a test group of 20 adolescent and young adult oncology patients aged between 16 and 45 years, selected for representation among the age group and their malignancies. Patients will be allowed to use the app for 1 month. Feasibility and acceptability were assessed via a semistructured survey. In the implementation stage, 200 patients will be allowed to use the app over 6 months and will complete an EQ-5D-5L questionnaire at baseline and at the 1- and 6-month marks. Evaluation of the mobile app was performed via the mHealth App Usability Questionnaire at similar intervals.ResultsFunding for the development and trial of AYABytes was awarded in October 2020 through a National Cancer Centre Singapore research grant. Pilot testing was completed in May 2024. The implementation phase began in June 2024 and is currently ongoing.ConclusionsWe believe that AYABytes, a novel eHealth mobile app, will be both beneficial and easily used by adolescent and young adult oncology patients. Evaluating the app and its quantifiable impact on improving the quality of life of adolescent and young adult oncology patients will help enrich the evidence for mobile health interventions. It will also validate new digital approaches to help adolescent and young adult oncology patients reduce their distress and address unmet needs and concerns.International Registered Report Identifier (IRRID)DERR1-10.2196/69453

BackgroundHigh-dose methotrexate (HD-MTX) is widely used as a standard chemotherapeutic agent in pediatric cancers. Most research studies have confirmed the therapeutic efficacy of HD-MTX; however, strategies to prevent side effects vary among institutions, especially in developing countries, with limited monitoring of plasma methotrexate level.ObjectiveTo evaluate the effect of intravenous hydration during HD-MTX administration on plasma methotrexate clearance in pediatric oncology patients.Materials and methodsThis study retrospectively reviewed 165 courses of HD-MTX administered to children with acute lymphoblastic leukemia (ALL), non-Hodgkin’s lymphoma (NHL), or osteosarcoma. Demographic data of patients were collected. Adverse complications related to HD-MTX and 72-hour plasma methotrexate level were analyzed between patients receiving intravenous hydration ≥3,000 mL/m2/day and those receiving hydration <3,000 mL/m2/day.ResultsAmong 56 HD-MTX (1.5 g/m2) courses in ALL, delayed methotrexate clearance was only found in one course administered with hydration <3,000 mL/m2/day. However, no correlation was observed between adverse complications and methotrexate levels. Of 34 HD-MTX (1.5–3 g/m2) courses in NHL, no significant correlation was observed between methotrexate levels and intravenous hydration. However, increased adverse complications were found in the course with delayed methotrexate clearance. Interestingly, among 75 HD-MTX (10–12 g/m2) courses in osteosarcoma, normal methotrexate clearance was successfully achieved in all courses administered with hydration ≥3,000 mL/m2/day compared with those administered with hydration <3,000 mL/m2/day (P=0.007). Furthermore, the courses administered with hydration <3,000 mL/m2/day and had delayed methotrexate clearance were more likely to develop adverse complications.ConclusionIntravenous hydration of ≥3,000 mL/m2/day during HD-MTX administration is essentially required in osteosarcoma and can be considered as optional in ALL with HD-MTX <1.5 g/m2, especially in developing countries with limited monitoring of plasma methotrexate level.