Oncology Group Long-Term Follow-Up Guidelines Research Articles

Sexual and Reproductive Health Care after Gonadotoxic Treatment in Females at a Tertiary Pediatric Hospital

Study ObjectivesRecommendations from the Children's Oncology Group Long-Term Follow-Up (COG-LTFU) Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer emphasize the importance of reproductive health care, yet little is known regarding adherence to these recommendations and non-fertility-related sexual and reproductive health (SRH) outcomes. MethodsFollow-up of outcomes on the basis of the COG-LTFU guidelines was assessed in female patients who underwent fertility preservation consultation before gonadotoxic therapy between 2016 and 2022 at a single institution and were at least 6 months from treatment completion. ResultsWe included 140 patients, with a mean time of 2.7 years from treatment completion. Eighty-six patients were 12 years old or older, of whom sexual activity was recorded in 59 (68.7%), and 12 of 31 (38.7%) sexually active patients underwent sexual function assessment. The 57 (66.3%) patients at high risk of premature ovarian insufficiency (POI) at diagnosis were more likely than minimal-risk counterparts (29, 33.7%) to have abnormal uterine bleeding (42.1% vs 17.2%, P = .03), to be diagnosed with POI (29.8% vs 0%, P = .01), and to have sexual activity recorded (77.2% vs 51.7%, P = .03). Of 17 patients with POI, 82.4% were on hormone replacement therapy, and 58.8% had undergone bone mineral density testing. ConclusionThis study adds to the limited literature regarding non-fertility-related SRH outcomes after gonadotoxic therapy and illustrates opportunities to improve adherence to the COG-LTFU guidelines. Increased attention to SRH guidelines may increase detection and treatment of SRH conditions, improving the health and quality of life of female cancer survivors.

FRI225 Clinical Course Of Late-onset Adrenal Insufficiency Due To Treatment Of Childhood Acute Lymphoblastic Leukemia

Abstract Disclosure: M. Iwabuchi: None. Background: Some people who were treated for cancer during childhood may develop endocrine problems as because of changes in the function of endocrine system. Acute lymphoblastic leukemia is the most common type of cancer and leukemia in children and components of ALL treatment are induction, consolidation, maintenance, and central nervous system prophylaxis. It is recommended that people who had irradiation in a dose of 40 Gy or higher to the central area of the hypothalamic-pituitary axis should have a blood test done to check the cortisol level and should be done yearly for at least 15 years since this complication can occur many years after irradiation. Clinical Case: A man in his 40s was admitted with symptoms of diarrhea, low-grade fever, and drowsiness. The serum sodium level that caused his symptoms decreased to 100 mEq/L and was adequately corrected. Endocrinological examination confirmed the diagnosis of central adrenal insufficiency. Soon after starting hormonal replacement therapy with hydrocortisone, his general conditions improved. After establishing our relationship, he confessed to having a history of ALL in childhood. According to his medical records at the time, he underwent induction therapy with vincristine-prednisone in 1977, maintenance therapy with 6-mercaptopurine, and radiation therapy to the central nervous system of 25 Gy in 1983. In 2023, 40 years have passed since radiation therapy. He was able to lead a normal life on oral hydrocortisone 20 mg/day without recurrence of adrenal insufficiency. Clinical Lesson: A 40-old male survivor of ALL developed adrenal insufficiency in 30 years after cranial irradiation during childhood. Undiagnosed adrenal insufficiency is often the cause of death. We should consider childhood cancer survivors have the risk of a central adrenal insufficiency. The Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers (COG LTFU Guidelines) are a resource for healthcare professionals who provide ongoing care to survivors of pediatric malignancies. The screening recommendations in these guidelines are appropriate for asymptomatic survivors of childhood, adolescent, or young adult cancer presenting for routine exposure-based medical follow-up. It is recommended that people who had irradiation in a dose of 40 Gy or higher to the central area of the hypothalamic-pituitary axis should have a blood test done to check the cortisol level and should be done yearly for at least 15 years since this complication can occur many years after irradiation. This case highlights the importance of long-term follow-up of cancer survivors after irradiation and the delayed presentation of adrenal insufficiency. This is the first report of the subsequent treatment course of late-onset adrenal insufficiency that developed 30 years after irradiation for childhood central nervous system ALL. Presentation: Friday, June 16, 2023

Impact of Volumetric Dosimetry on the Projected Cost of Radiation-Related Late Effects Screening After Childhood Cancer: A Real-World Cohort Analysis.

Screening guidelines for childhood cancer survivors treated with radiation currently rely on broad anatomic irradiated regions (IR) to determine risk for late effects. However, contemporary radiotherapy techniques use volumetric dosimetry (VD) to define organ-specific exposure, which supports more specific screening recommendations that could be less costly. This was a cross-sectional study of 132 patients treated with irradiation at Children's Hospital Los Angeles from 2000 to 2016. For 5 key organs (cochlea, breast, heart, lung, and colon), radiation exposure was determined retrospectively using both IR and VD methods. Under each method, Children's Oncology Group Long-Term Follow-Up Guidelines were used to identify organs flagged for screening and recommended screening tests. Projected screening costs incurred under each method were computed through age 65 using insurance claims data. Median age at the end of treatment was 10.6 years (range, 1.4-20.4). Brain tumor was the most common diagnosis (45%) and head/brain the most common irradiated region (61%). For all 5 organs, use of VD rather than IR resulted in fewer recommended screening tests. This led to average cumulative estimated savings of $3769 (P = .099), with significant savings in patients with CNS tumors (P = .012). Among patients with savings, average savings were $9620 per patient (P = .016) and significantly more likely for females than males (P = .027). Use of VD to enhance precision of guideline-based screening for radiation-related late effects permits fewer recommended screening tests and generates cost-savings.

Abstract 34: Evaluation of Potential Risk for Developing Treatment-Associated Late Effects Among Childhood Cancer Survivors in Northern Tanzania

Abstract Purpose: Global advancement in pediatric cancer treatment has significantly increased survival rates for children with cancer. Childhood cancer survivors (CCS) now represent a growing population at risk of potentially debilitating late effects of their treatment. This study evaluates the potential risk for long-term complications related to cancer therapy among childhood cancer survivors who completed treatment in Tanzania at Bugando Medical Centre (BMC), and compares the relative risk assessment of childhood cancer survivors at BMC as compared to the published British Childhood Cancer Survivor Study (BCCSS) cohort. Methods: Files of all patients age <18 yo with an oncologic diagnosis who received and completed their treatment at BMC from 2016 to 2020 were retrospectively reviewed. Extracted data included patient demographics, primary disease diagnosis and site, treatment received, and cumulative treatment doses. BCCSS risk assessment was assigned and predicted long-term follow-up surveillance needs were extrapolated from published Children’s Oncology Group Long-Term Follow-Up Guidelines. Results: 190 patients were initially identified, with 17 excluded due to missing treatment information. Among the remaining 173 patients, the mean age was 7yo, 47% were female (n=82), and the most common diagnoses were Wilms tumour (30%, n=52) and Burkitt’s Lymphoma (26%, n=45). 98% received chemotherapy (n=170), 42% (n=73) underwent tumour resection, and 8% (n=18) received radiation. Distribution of BCCSS late effect risk assessment included 6% low risk (n=10), 80% moderate risk (n=139) and 14% (n=24) high risk. This was a higher rate of moderate/severe risk (94%) compared to the published UK BCCSS cohort (84%). Based on treatment received, the late effects with highest potential risk were cardiomyopathy (57% of patients, n=98), bladder and urinary tract toxicity (50%, n=87), and ototoxicity (22%, n=38). Conclusion: Childhood cancer survivors at BMC have a higher risk of late effects as compared to published survivor cohorts in high-income countries. There is a need to develop and improve long-term follow-up care for survivors by enhancing patient and provider education to promote early detection of late effects. Based on risk assessment, survivorship programs in Tanzania should at a minimum include the capacity to perform echocardiograms, urinalysis, renal ultrasound, audiological evaluation, fundoscopic and neurological exams, and renal function test. Citation Format: Goodluck Nchasi, Gaudence Ajuaye, David Noyd, Hannah Spiegl, Erica Sanga, Heronima Joas, Kristin Schroeder. Evaluation of Potential Risk for Developing Treatment-Associated Late Effects Among Childhood Cancer Survivors in Northern Tanzania [abstract]. In: Proceedings of the 11th Annual Symposium on Global Cancer Research; Closing the Research-to-Implementation Gap; 2023 Apr 4-6. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(6_Suppl):Abstract nr 34.

Clinician perceptions of Passport for Care, a web-based clinical decision support tool for survivorship care plan delivery.

The Children's Oncology Group Long-Term Follow-Up Guidelines provide exposure-based risks and recommendations for late effects screening of survivors of childhood cancer. Passport for Care (PFC) is a web-based clinical decision support tool for generating a personalized survivorship care plan (SCP) derived from the Guidelines and user-entered exposures. We assessed PFC clinician user practices and perceptions of PFC impact on clinic workflow, guidelines application, and survivor shared decision-making. A 35-item REDCap survey was emailed to all PFC users (n=936) in 146 current and former PFC user clinics. Anonymous responses were permitted. Results were summarized and compared with a 2012 survey. Data were available from 148 respondents representing 64 out of 146 PFC user clinics (minimum clinic response rate 44%, excluding 49 anonymous responses). Generation of a personalized SCP was the most common application of PFC, followed by determination of surveillance recommendations and use as a survivor database. Twenty-five respondents (17%) felt data entry was a significant or insurmountable barrier to PFC application. Sixty-nine percent of respondents attributed PFC with a very high/high impact on guidelines adherence in their clinical practice, compared with 40% who attributed PFC with having a significant impact on adherence in 2012 (p<.001). The survey results provide valuable insights on patterns of SCP delivery and Survivor Clinic workflow. User-perceived benefits to PFC included facilitating clinician ability to follow guidelines recommendations in clinical practice. Importantly, some barriers to resource utilization were also identified, suggesting a need for user-informed adaptations to further improve uptake.

SWK-10. Survivorship: Education, Clinical Guidelines, and Transition to Adult Care

As the cure rates of patients with pediatric brain tumors increases, the long term care needs of the survivors increase as well. Survivorship includes several facets of multidisciplinary care including education, clinical care guidelines, and transition to adult medical care. The neuro-oncology program at a large tertiary care hospital has developed a team to address survivorship needs. The Children’s Oncology Group (COG) Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers was utilized as a backbone that was then customized for neuro-oncology patient education including disease type and treatment. The education was compiled into patient handouts as well as electronic medical record (EMR) statements that can easily be added to a clinic note or letter to referring providers. In addition, a diagnosis and treatment summary was placed both in the EMR as well as given to patients at various time points to ensure long term knowledge. Next, follow-up guidelines and roadmaps were developed and customized to tumor type and treatment received (surgery, radiation, chemotherapy). The roadmaps ensure patients are receiving high-quality comprehensive follow-up and screening from a large multidisciplinary team. Finally, patients will transition to adult care. With a large seven state catchment area, the adult care providers vary on local provider availability, knowledge, and medical complexity of the survivor. Each patient is evaluated based on their needs, availability of care locally, and ability to travel. The team developed relationships with the clinical team at the academic center adjacent to the pediatric hospital to support a smooth transition to adult care. The adult neuro-oncology care team can also serve as a consulting service for local adult providers. The survivorship team will continue to address the complex needs of brain tumor survivors and provide education for a smooth transition to adult care.

Informatics tools to implement late cardiovascular risk prediction modeling for population health management of high-risk childhood cancer survivors.

10048 Background: Marked improvements in outcomes for children with cancer and robust cohort studies with longitudinal follow-up inform evidence-based guidelines for survivors at risk for late cardiomyopathy. Clinical informatics tools to integrate data from multiple sources have the potential to catalyze population health management. Methods: The Oklahoma Childhood Cancer Survivor cohort was constructed from an institutional cancer registry of survivors diagnosed between 2005 and 2014 (n=382). Data elements (cumulative anthracycline, cumulative chest-directed radiotherapy, alkylator, and platinum exposures) were extracted from Passport for Care (PFC) to implement previously validated late cardiovascular risk prediction modeling from the Childhood Cancer Survivor Study (CCSS) for cardiomyopathy. Risk groups were compared to the Children’s Oncology Group (COG) Long-Term Follow-up Guidelines. Standard query language facilitated extraction of echocardiogram data from the electronic health record to determine adherence, defined as an echocardiogram within 27 months and 63 months from the last day of therapy for high and moderate risk survivors, respectively. Results: Sixty-nine percent (n=264) of survivors from the cancer registry were documented in PFC, of whom 29%, 56%, and 15% were classified as low, moderate, high risk, respectively, based on the CCSS late cardiomyopathy risk calculator. Concordance was modest for high and moderate risk groups (Kappa = 0.42 and 0.46, respectively) and good for the low risk group (Kappa = 0.77) compared to COG risk groups. There was excellent adherence to echocardiogram guidelines with 93% and 81% of moderate and high-risk survivors, respectively. There were significant differences based on risk group (p=0.02) and age at diagnosis (p&lt;0.01). Conclusions: Clinical informatics tools represent a feasible approach to leverage discrete data elements regarding key treatment exposures from PFC to successfully implement previously validated late cardiovascular risk prediction models on a population health level. PFC promotes adherence to echocardiogram surveillance and serves as a platform for future interoperability to generate real-world data to improve survivorship-focused care. [Table: see text]

Implementing a mHealth intervention to increase colorectal cancer screening among high-risk cancer survivors treated with radiotherapy in the Childhood Cancer Survivor Study (CCSS)

BackgroundCancer survivors treated with any dose of radiation to the abdomen, pelvis, spine, or total body irradiation (TBI) are at increased risk for developing colorectal cancer (CRC) compared to the general population. Since earlier detection of CRC is strongly associated with improved survival, the Children’s Oncology Group (COG) Long-Term Follow-Up Guidelines recommend that these high-risk cancer survivors begin CRC screening via a colonoscopy or a multitarget stool DNA test at the age of 30 years or 5 years following the radiation treatment (whichever occurs last). However, only 37% (95% CI 34.1–39.9%) of high-risk survivors adhere to CRC surveillance. The Activating cancer Survivors and their Primary care providers (PCP) to Increase colorectal cancer Screening (ASPIRES) study is designed to assess the efficacy of an intervention to increase the rate of CRC screening among high-risk cancer survivors through interactive, educational text-messages and resources provided to participants, and CRC screening resources provided to their PCPs.MethodsASPIRES is a three-arm, hybrid type II effectiveness and implementation study designed to simultaneously evaluate the efficacy of an intervention and assess the implementation process among participants in the Childhood Cancer Survivor Study (CCSS), a North American longitudinal cohort of childhood cancer survivors. The Control (C) arm participants receive electronic resources, participants in Treatment arm 1 receive electronic resources as well as interactive text messages, and participants in Treatment arm 2 receive electronic educational resources, interactive text messages, and their PCP’s receive faxed materials. We describe our plan to collect quantitative (questionnaires, medical records, study logs, CCSS data) and qualitative (semi-structured interviews) intervention outcome data as well as quantitative (questionnaires) and qualitative (interviews) data on the implementation process.DiscussionThere is a critical need to increase the rate of CRC screening among high-risk cancer survivors. This hybrid effectiveness-implementation study will evaluate the effectiveness and implementation of an mHealth intervention consisting of interactive text-messages, electronic tools, and primary care provider resources. Findings from this research will advance CRC prevention efforts by enhancing understanding of the effectiveness of an mHealth intervention and highlighting factors that determine the successful implementation of this intervention within the high-risk cancer survivor population.Trial registrationThis protocol was registered at clinicaltrials.gov (identifier NCT05084833) on October 20, 2021.

A review of the risks of long-term consequences associated with components of the CHOP chemotherapy regimen

A common chemotherapy regimen in post-transplant lymphoproliferative disease (PTLD) following solid organ transplants (SOT) is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). This study reviews the quantitative evidence for long-term consequences associated with components of CHOP identified from the Children’s Oncology Group Long-Term Follow-Up Guidelines. Cited references were screened using pre-specified criteria (English, systematic review, randomized controlled trial n > 100, observation study n > 100, case series n > 20). Relevant data were extracted and synthesized. Of 61 studies, 66% were retrospective cohort studies, 28% were in the US, and 95% enrolled pediatric patients. No study focused specifically on the CHOP regimen. Long-term consequences for CHOP components observed in >3 studies included cardiac toxicity (n = 14), hormone deficiencies/infertility (n = 14), secondary leukemia (n = 7), osteonecrosis (n = 6), and bladder cancer (n = 4). These effects are significant, impact a high percentage of patients, and occur as early as one year after treatment. Although none of the studies focused specifically on the CHOP regimen, 30%, 23%, and 15% evaluated alkylating agents (eg, cyclophosphamide), anthracyclines (eg, doxorubicin), and corticosteroids (eg, prednisone), respectively. All three product classes had a dose dependent risk of long-term consequences with up to 13.2-fold, 27-fold, 16-fold, 14.5-fold, and 6.2 times increase in risk of heart failure, early menopause, secondary leukemia, bladder cancer, and osteonecrosis, respectively. Lymphoma patients had significantly elevated risks of cardiac toxicity (up to 12.2-fold), ovarian failure (up to 3.8‐fold), and osteonecrosis (up to 6.7-fold). No studies were found in PTLD or SOT. Safe and effective PTLD treatments that potentially avoid these long-term consequences are urgently needed.

First Person Profile: Melissa M. Hudson, MD: The director of the Division of Cancer Survivorship at St. Jude Children's Research Hospital believes that education for survivors is vital: The director of the Division of Cancer Survivorship at St. Jude Children's Research Hospital believes that education for survivors is vital.

Dr. Hudson completed a pediatric hematology/oncology fellowship with the University of Texas MD Anderson Cancer Center. “It was very influential in my career,” she says. “It was during a time that when children were diagnosed, they would be admitted into the hospital for months at a time. It was difficult to watch the suffering, and it made me question whether pursuing this specialty was the right decision. However, a trusted mentor recognized my passion for pediatric oncology and encouraged me to stay the course, which ultimately proved to be a good decision for me.” The exposure at MD Anderson was influential in her decision to pursue a career in pediatric hematology and oncology. “While rotating through the outpatient pediatric oncology clinics at MD Anderson, I witnessed multidisciplinary care that was curing children with cancer. I was attracted to the patient population and specialty; children were surviving cancer, and I wanted to be a part of this effort,” she says. Dr. Hudson joined the St. Jude faculty in 1989 as a pediatric oncologist and has remained with the institution ever since. As co-chair of the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer and the International Late Effects of Childhood Cancer Guideline Harmonization Group, she continues to play a leadership role in developing guidance for health surveillance of childhood cancer survivors. Dr. Hudson is also currently a co-leader of the Cancer Control & Survivorship Program at St. Jude and has coauthored a vast number of journal publications. Dr. Hudson has received many honors during her career. She was the 2020 recipient of the Northwestern Mutual Award for Excellence in Childhood Cancer Survivorship by the American Society of Pediatric Hematology/Oncology.1 She is particularly proud to have been honored with 2 Team Science Awards from the American Association for Cancer Research: She received one in 2009 as part of the hematologic malignancy investigators at St. Jude, and she received the other in 2019 for the investigators' work in survivorship. “The 2019 award was the culmination of true team science, with so many folks working across disciplines to focus on survivor health,” she says. She is proud to be a longtime member of St. Jude's faculty. “It's an incredible place to practice medicine,” she says. “Even with families who may not always have happy outcomes, you always have the resources to put patients and families first. It's such a gift that our fundraising efforts not only support research to improve childhood cancer outcomes but also relieve the practical burdens experienced by families affected by childhood cancer.” Dr. Hudson's areas of research have expanded significantly over the years. During her first 10 to 15 years as a clinical investigator, Dr. Hudson's clinical efforts and research primarily focused on hematologic malignancies, specifically Hodgkin lymphoma. Today, Dr. Hudson's special research interests include the burden of disease and the quality of life after a cancer diagnosis, the development of survivorship care guidelines, the use of various data sources to direct patient care, and the development of long-term follow-up care goals. Dr. Hudson believes she has been lucky during her career. “I've had new opportunities and challenges roughly every 10 years that reinvigorated my research and my overall attitude.” The availability of curative therapy for Hodgkin lymphoma and the risk of late effects in this population led to her increasing involvement as director of the St. Jude After Completion of Therapy (ACT) Clinic. The ACT Clinic provides long-term care for survivors of childhood cancer who have been treated at St. Jude.2 “We educate survivors about their cancer history and associated health risks, health screening recommended for their specific cancer treatments, and ways to reduce health risks,” she says. “We also assist them with identifying health services and resources as they transition from pediatric oncology to primary care.” In the early years, reports from survivors about health problems during adulthood, such as serious infection after splenectomy and breast cancer after chest radiation, increased Dr. Hudson's awareness of the need to proactively counsel and surveil patients based on their specific treatments. “This understanding informed our first efforts at risk-based health surveillance in childhood cancer survivors.” “Over time, perceptions of the importance of survivor education have changed. Now everyone has the same mantra: that survivors need to understand cancer treatment–related health risks to guide their health decisions and behaviors.” —Melissa M. Hudson, MD “The big challenge for the future will be to integrate new agents into already effective regimens of cytotoxic therapy,” she continues. “Hopefully, these efforts will result in precision treatments that will reduce the risk of late toxicities as well as precision survivorship care that addresses the broad needs of survivors across the lifespan.”

Utilization of Cardiac Surveillance in Pediatric Blood Cancer Survivors Who Received Anthracycline-Based Therapy Differs By Age: A Claims-Based Analysis

Background: The Children's Oncology Group Long-Term Follow-up Guidelines recommend surveillance for late effects in pediatric cancer survivors based on therapeutic exposures. In particular, the Guidelines recommend an echocardiogram, or comparable imaging, every 2 to 5 years to evaluate cardiac function in survivors exposed to anthracycline chemotherapy. However, little is known about the real-world utilization of cardiac surveillance tests following the completion of cancer therapy.Objective: This study fills this gap by describing the proportion of anthracycline-treated survivors of pediatric cancer who received surveillance for cardiac function following the completion of their cancer therapy.Method: We developed an algorithm to identify a cohort of pediatric cancer survivors using the IBM MarketScan ® Commercial Claims and Encounters Database (a nationwide private insurance enrollment and claims database). The cohort for inclusion was enrollees who (1) received anthracycline for blood cancer (leukemia or lymphoma); (2) aged ≤21 years at cancer diagnosis; (3) completed all cancer therapy between 2009 and 2018; and (4) remained continuously insured for at least one year post-therapy. Outcomes assessed included the receipt of: (1) echocardiogram, (2) cardiac magnetic resonance imaging (MRI), (3) multiple gate acquisition (MUGA) scan, and (4) any of the aforementioned cardiac surveillance tests over the 5-year period after the completion of all cancer therapy. The Kaplan-Meier (K-M) method was used to estimate the cumulative incidence of an event post-therapy, where the event was defined as the initial healthcare claim for a cardiac surveillance test. Individuals were censored if they had not received a test by study termination or were lost to follow-up at any time during the 5 years post-therapy. Multivariate Cox proportional hazard models were estimated to identify the demographic and cancer-related factors strongly associated with the initial test receipt.Results: Among 1,914 eligible blood cancer survivors, 259 (13.5%) survivors received a hematopoietic stem cell transplantation (HSCT; Table 1). The K-M estimated probability of receiving a cardiac surveillance test by 5 years post-therapy was 61.0% (95% Confidence Interval [CI]: 57.2% to 64.7%), with the median time to the initial test being 2.6 years (95% CI: 2.2 to 3.1 years) from therapy completion. The vast majority of cardiac surveillance test users underwent an echocardiogram (n=850; versus only 10 who had a cardiac MRI, and 14 who had a MUGA scan) by the end of their follow-up period.The proportion of survivors who had an initial cardiac test increased over time but varied by age at cancer therapy completion and the receipt of HSCT. The K-M estimated probability of receiving an initial test by 5 years post-therapy was: 86.0% (95% CI: 77.3% to 91.6%) for children (ages ≤11 years), 85.0% (95% CI: 75.4% to 91.1%) for adolescents (ages 12-17 years), and 36.8% (95% CI: 32.6% to 41.0%) for young adults (ages 18-28 years; Figure 1). Multivariate Cox models showed that compared with children, adolescents were more likely to receive an initial cardiac test (Hazard Ratio [HR] = 1.3; 95% CI: 1.1 to 1.5), while young adults were less likely to receive a test (HR = 0.4; 95% CI: 0.3 to 0.5). In addition, survivors who received a HSCT were more likely than those who did not to complete an initial cardiac test (HR=1.8; 95% CI: 1.5 to 2.2).Conclusions: This nationwide, claims data-based study showed that a substantial proportion of anthracycline-exposed survivors of blood cancers had not completed a cardiac surveillance test within 5 years post-therapy. Within this high-risk population, young adults were significantly less likely to receive surveillance testing for the prevention and early detection of cardiac dysfunction. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

An Evidence Review of the Long-Term Consequences Associated with Components of the CHOP Chemotherapy Regimen in Transplant Recipients

Introduction: Epstein-Barr virus-driven post-transplant lymphoproliferative disease (EBV + PTLD) can be an aggressive, often deadly disease without any approved treatments. Current available treatments for EBV + PTLD may include cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). However, the long-term consequences of CHOP are poorly understood in immunocompromised transplant patients with cancer who may have different outcomes than immunocompetent cancer patients. This study reviewed and described the evidence for the long-term consequences associated with components of CHOP in transplant recipients.Methods: Potential long-term consequences of the components of CHOP were identified from the Children's Oncology Group Long-Term Follow-Up (COG LTFU) Guidelines. Abstracts were screened and eligibility was based on reporting data for the identified COG LTFU long-term consequences along with pre-specified criteria (English, systematic review, randomized controlled trial n>100, observation study n>100, case series n>20). Relevant studies that met the criteria were extracted and synthesized; of these, studies were selected if they evaluated patients who received any type of transplantation as part of their primary cancer treatment.Results: A total of 7 studies met the pre-specified selection criteria, all of which evaluated patients with hematopoietic stem cell transplantation (HCT) and none assessed solid organ transplant (SOT). None of the studies focused specifically on the CHOP regimen or EBV + PTLD. Long-term consequences of alkylating agents (eg, cyclophosphamide) and corticosteroids as primary treatment reported in these HCT studies included: hormone deficiencies and infertility (n=4 studies), osteonecrosis (n=2), and health status and quality of life (QoL; n=1).Results from three studies suggested that cancer survivors who received alkylating agents experienced hormone deficiencies and those with a HCT had a high risk. One quantified this by showing that, compared with cancer survivors without a history of HCT (CS), cancer survivors with a history of HCT (CS-HCT) and a history of total body irradiation had significantly impaired follicle stimulating hormone (40.42 vs 9.39 mIU/ml, P<0.001), Estradiol (15.09 vs 25.13 pg/ml, P=0.04), Inhibin B (10.61 vs 32.92 pg/ml, P=0.003), anti-Müllerian hormone (0.01 vs 1.28 ng/ml, P<0.001), antral follicle count (0.71 vs 17.78, P<0.001) and ovarian volume (1.82 vs 8.21 ml, P<0.001). In one study on the risk of osteonecrosis, the CS-HCT group had a significantly increased risk of developing osteonecrosis compared to the CS group treated with chemotherapy (6.8% vs 1.4%, respectively); cumulative incidence of osteonecrosis was 3.8% in the CS group for a steroid dose >5,835 mg/m 2 and 23.8% in the CS-HCT group for a post-transplant steroid dose >2,055 mg/m 2; and patients developed symptomatic osteonecrosis within a median of 2.4 years in the CS group with chemotherapy and 0.9 years after the first transplant in the CS-HCT group. A second study showed the rate ratio (RR) of osteonecrosis compared with a sibling comparison group was highest among the CS-HCT for acute lymphoblastic leukemia, acute myelogenous leukemia, and chronic myelogenous leukemia (RR = 26.9, 66.5, and 93.1, respectively; P<0.001 for all). One study reported that childhood acute leukemia survivors treated with HCT with preparative regimen with either busulfan-cyclophosphamide or total body irradiation/cyclophosphamide had a significantly lower QoL short-form (SF)-36 mental and physical composite scores in both treatment groups compared with norms.Conclusions: Since only a small number of studies (7) of long-term consequences in transplant recipients were identified and none were seen in patients with EBV + PTLD or in SOT recipients, more research is needed to evaluate adverse consequences of CHOP or its components in EBV + PTLD, especially in SOT patients where no studies were found. Results from this review suggest that immunocompromised HCT recipients who were cancer survivors are significantly more impaired by long-term consequences (hormone deficiencies and infertility, osteonecrosis, and QoL) of alkylating agents (eg, cyclophosphamide) and corticosteroids as primary treatment compared with other cancer survivors without HCT. DisclosuresWatson: Atara Biotherapeutics: Current Employment, Current holder of individual stocks in a privately-held company. Gadikota: Maple Health Group: Current Employment. Barlev: Atara Biotherapeutics: Current Employment. Beckerman: Maple Health Group: Current Employment.

Quantification of Long-Term Consequences Associated with Components of the CHOP Chemotherapy Regimen

Introduction: A common chemotherapy regimen for Epstein-Barr virus-driven post-transplant lymphoproliferative disease (EBV + PTLD) following solid organ transplants is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Long-term adverse consequences of CHOP, particularly the incidence, timing, and risk factors associated with these events, in any cancer survivor remain poorly understood. In this study, we review the evidence to determine how often long-term consequences associated with the components of CHOP occur.Methods: Potential long-term consequences of CHOP components were identified from the Children's Oncology Group Long-Term Follow-Up (COG LTFU) Guidelines. Abstracts were screened and eligibility was based on reporting data for the identified COG LTFU long-term consequences along with pre-specified criteria (English, systematic review, randomized controlled trial n>100, observation study n>100, case series n>20). Studies that met the inclusion criteria were extracted and synthesized. Quantification of late effects evaluated in >3 studies were reported.Results: Long-term consequences in the 45 studies that met the pre-specified criteria included cardiac toxicity, hormone deficiencies/infertility, secondary leukemia, osteonecrosis (ON), and urotoxicity/bladder cancer. Although none of the studies focused specifically on the CHOP regimen, 30%, 23%, and 15% evaluated alkylating agents (eg, cyclophosphamide), anthracyclines (eg, doxorubicin), and corticosteroids (eg, prednisone), respectively. Time to onset from treatment was as early as 1 year for cardiac toxicity, <5 for infertility, 2 for ON, 3 for secondary leukemia, and 5 for bladder cancer. Longer follow-up times were associated with higher percentages of long-term consequences. For example, cardiac toxicity and hormone deficiencies/infertility affected >20% of patients, and secondary leukemia, ON, urotoxicity/bladder malignancy affected 10-20% of patients (Table 1). A wide range in the incidence and timing of these late effects was observed, likely due to variation in the treatment regimens, follow-up time, and event definition.The synthesized evidence supports that CHOP components increased the risk of long-term consequences in a dose-dependent manner. Cardiac toxicity risk was elevated even at anthracycline doses of <150 mg/m 2 (traditionally considered a ‘safe’ dose range). Hazard ratios (HRs) for heart failure at doses of ≤300 to <400 mg/m 2 were 4.33 and 13.19 for daunorubicin and doxorubicin, respectively. Studies also reported significantly elevated risk of cardiac toxicity in patients with lymphoma treated with anthracyclines (eg, HR of up to 12.2) compared with the sibling cohort. Patients <5 years of age vs ≥5 years of age at exposure had a significantly higher risk of cardiac toxicity (HR of 1.89). Patients exposed to cumulative doses of cyclophosphamide ≥6 g/m 2 had significant reproductive risks. The risk of early menopause was shown to be dose dependent and as much as 27-fold higher in patients treated with both radiation below the diaphragm and alkylating agent chemotherapy. Patients exposed to high-dose cyclophosphamide (>7.5 g/m 2) were at statistically significantly higher risk (odds ratio of 12.0) for diminished ovarian reserve as measured by their Anti-Müllerian hormone level. One study reported 3.8- and 3.2-fold increases in risk of ovarian failure in patients who had been diagnosed with Hodgkin's lymphoma and Non-Hodgkin's lymphoma, respectively. High-doses of anthracyclines and alkylating agents were associated with up to 16-fold increases in risk of secondary leukemia. The risk of bladder cancer significantly increased with increasing dose of cyclophosphamide, with a 6- and 14.5-fold increased risk at cumulative doses of 20‒49 g and ≥50 g, respectively. Intensive corticosteroid therapy was associated with significant risk of ON, with one study showing cancer survivors had a 6.2 times higher likelihood of ON as compared to their sibling comparison group.Conclusions: Patients exposed to components of CHOP have a dose-dependent risk of cardiac toxicity, infertility, secondary leukemia, ON, and bladder cancer that are often significant, impacted a high percentage of patients, and occurred as early as 1 year after treatment. Safe and effective PTLD treatments that potentially avoid these long-term consequences are urgently needed. [Display omitted] DisclosuresWatson: Atara Biotherapeutics: Current Employment, Current holder of individual stocks in a privately-held company. Gadikota: Maple Health Group: Current Employment. Barlev: Atara Biotherapeutics: Current Employment. Beckerman: Maple Health Group: Current Employment.

Impact of using volumetric dosimetry to screen childhood cancer survivors for radiation-related late effects.

12066 Background: Late effects screening guidelines for survivors of childhood cancer treated with radiation therapy currently use irradiated regions (IR) rather than volumetric dosimetry (VD), which more precisely identifies organs-at-risk (OAR). We recently showed that VD reduced mean number of recommended screening diagnostic imaging studies and procedures by 37.0% per patient (p&lt;0.001).1 Here we have incorporated chemotherapy and refined volumetric dosimetry dose thresholds. Methods: This was a cross-sectional cohort study of patients (n=132) treated for cancer using computerized tomography-planned irradiation at Children’s Hospital Los Angeles from 2000-2016. For each patient, both VD and IR methods were used to determine radiation exposure to the cochlea, heart, lung, breast, and colon. Dose thresholds for VD were based on those supplied in the Children’s Oncology Group (COG) Long-Term Follow-Up Guidelines. Relevant chemotherapy exposures were recorded. Under each method, COG Long-Term Follow-Up Guidelines were applied to determine potential chemotherapy- and radiation-related late effects and their correlative screening practices (complete audiologic evaluation, pure tone audiometry, mammogram, breast MRI, echocardiogram, pulmonary functions test, and/or colonoscopy). Identified OAR were compared using Exact McNemar’s test. Total numbers of screening practices were computed using VD and IR and compared. Results: Median age at end of treatment was 10.6 years (range 1.4-20.4). The most frequent cancer type was brain tumor (45%), followed by bone and soft tissue tumor (39%) and leukemia/lymphoma (16%). Head/brain was the most commonly irradiated region (61%), followed by abdomen (22%). Anthracyclines were received by 25% of patients at &lt; 250 mg/m2 and by 16% at ≥ 250 mg/m2. With use of VD, fewer patients were flagged for screening for each organ of interest: cochlea (-21.3%, p&lt;0.001), heart (-22.5%, p&lt;0.001), lung (-13.8%, p=0.219), breast (-25%, p=0.625), colon (-51.9%, p&lt;0.001). Over the lifetime of this cohort, use of VD resulted in recommendations for 1,333 fewer pure tone audiometric tests (-21.5%), 9 fewer complete audiologic evaluations (-16.1%), 4 fewer pulmonary function tests (-13.8%), 112 fewer mammograms (-25.0%) and breast MRIs (-25.0%), 349 fewer echocardiograms (-16.1%), and 275 fewer colonoscopies (-51.9%). Conclusions: Use of VD rather than IR significantly reduces guideline-based screening for radiation-related late effects in long-term childhood cancer survivors. This work forms the basis for a comparative cost-effectiveness analysis of these two approaches. (1) Cohen-Cutler et al, Cancer Medicine, 2020.

Surveillance for radiation-related late effects in childhood cancer survivors: The impact of using volumetric dosimetry.

ABSTRACTBackgroundRadiation‐related screening guidelines for survivors of childhood cancer currently use irradiated regions (IR) to determine risk for late effects. However, contemporary radiotherapy techniques utilize volumetric dosimetry (VD) to determine organ‐specific exposures, which could inform need for late effect surveillance.MethodsThis cross‐sectional cohort study involved patients treated for cancer using computerized tomography‐planned irradiation at Children's Hospital Los Angeles from 2000–2016. Organs at risk were identified using both VD and IR. Under each method, Children's Oncology Group Long‐Term Follow‐Up Guidelines were applied to determine radiation‐related potential late effects and their correlative recommended screening practices. Patients served as their own controls. Mean number of potential late effects per patient and recommended screening practices per patient per decade of follow‐up were compared using paired t‐tests; comparisons were adjusted for diagnosis and gender using random effects, repeated measure linear regression.ResultsIn this cohort (n = 132), median age at end of treatment was 10.6 years (range, 1.4–20.4). Brain tumor was the most common diagnosis (45%) and head/brain the most common irradiated region (61%). Under IR and VD, the mean number of potential late effects flagged was 24.4 and 21.7, respectively (−11.3%, p < 0.001); concordance between the two methods was 6.1%. Under VD, the difference in mean number of recommended screening practices per patient was −7.4% in aggregate but as large as −37.0% for diagnostic imaging and procedures (p < 0.001 for both).ConclusionUse of VD rather than IR is feasible and enhances precision of guideline‐based screening for radiation‐related late effects in long‐term childhood cancer survivors.

Adherence to Children’s Oncology Group Long-Term Follow-up Guidelines among high-risk adolescent and young adult cancer survivors

Adherence to Children’s Oncology Group Long-Term Follow-up Guidelines among high-risk adolescent and young adult cancer survivors

"There Is No Before Cancer… There Is Only Cancer." Perceived Late Effects of Pediatric Cancer on Survivors.

Although "late effects" connotes experiencing effects later in life, they can emerge immediately after active treatment. The effects that survivors experience have been reported but rarely from the point of view of the survivors regarding their life after treatment. To examine the perceived late effects of pediatric cancer on survivors and their self-identified primary support persons in order to understand the multifaceted nature of living after a pediatric cancer diagnosis. Using a pragmatic interpretive phenomenology approach, 10 survivors of pediatric cancer (aged 21-28 years) and 9 of their support persons (aged 23-73 years) participated, completing background questionnaires and semistructured, one-on-one interviews. Interview transcripts were analyzed thematically. Both survivors and support persons acknowledged that survivors experienced negative physical and cognitive health outcomes that require follow-up care. Survivors acknowledged that their cancer experience and residual effects have changed the trajectory of their lives. Research on young adult survivors of pediatric cancer and the residual/late effects and emotional outcomes they experience is warranted. Longitudinal research can aid in understanding how effects develop or worsen over time. The findings of this study support The Children's Oncology Group Long-term Follow-up Guidelines for practitioners. As the frontline caring for these individuals and families, nurses' involvement in transitional care out of treatment is necessary. Continued involvement and understanding of long-term pediatric cancer survivorship for nurses are also imperative for continuity for survivors and families.

Adherence to Children’s Oncology Group (COG) long-term follow-up guidelines for echocardiogram screening in young adult survivors of childhood cancer.

e22513Background: Late morbidity is of increasing importance with improved survival from childhood cancer. The COG Long-term Follow-up Guidelines recommend echocardiogram screening in patients who ...

Specialized survivor clinic attendance increases adherence to cardiomyopathy screening guidelines in adult survivors of childhood cancer.

To determine if attendance at a specialized clinic for adult survivors of childhood cancer is associated with better rates of adherence to the Children's Oncology Group (COG) Long-term Follow-up (LTFU) guidelines for cardiomyopathy screening. We conducted a retrospective population-based study using administrative data in Ontario, Canada of 5-year survivors diagnosed between 1986 and 2005 at risk of therapy-related late cardiomyopathy. Patients were classified into three groups based on the recommended frequency of screening: annual, every 2years, and every 5years. Of 1811 eligible survivors followed for median 7.8years (range 0-14.0), patients were adherent to screening for only 8.6% of their period of follow-up. Survivor clinic utilization had the strongest association with increased rates of adherence: when compared to no attendance, ≥5 clinic visits/10-year period had RR of adherence of 10.6 (95% CI 5.7-19.5) in the annual group, 3.3 (95% CI 2.3-4.8) in the every 2-year group, and 2.3 (95% CI 1.6-3.2) in the every 5-year group. Additional factors associated with increased adherence after adjusting for clinic attendance included annual assessment by a general practioner, female sex, diagnosis prior to 2003, and living in a rural area. In a model of specialized survivor care, increased clinic utilization is associated with improved patient adherence to COG LTFU cardiomyopathy screening guidelines. Specialized survivor clinics may improve health outcomes in survivors through improved adherence to screening. However, rates of adherence remain suboptimal and further multifacetted strategies need to be explored to improve overall rates of screening in adult survivors of childhood cancer.

Risk factors and surveillance for reduced bone mineral density in pediatric cancer survivors.

Pediatric cancer survivors are at increased risk of developing low bone mineral density (BMD) due to cancer treatment. This study assessed the yield of screening for low BMD in pediatric-aged cancer survivors as per the Children's Oncology Group Long-Term Follow-Up (COG-LTFU) Guidelines, which recommend screening survivors who received steroids, methotrexate, or hematopoietic cell transplant (HCT). This is a retrospective cohort study of 475 pediatric blood cancer and noncentral nervous system solid tumor survivors screened for low BMD with dual-energy X-ray absorptiometry (DXA) as per the COG-LTFU Guidelines from 2003 to 2010. Risk factors for low BMD (DXA Z-score ≤-2) were evaluated by univariate and multivariate analysis. The mean DXA Z-score was -0.1 for both whole body and lumbar spine measurements. Among at-risk survivors, 8.2% (39/475) had low BMD. Multivariate analysis of survivors with low BMD showed significant association with male gender (odds ratio [OR] 3.4, 95% confidence interval [CI], 1.3-9.0), exposure to total body irradiation (TBI), cranial, or craniospinal radiation (OR 5.2, 95% CI, 1.8-14.9), and gonadal dysfunction (OR 4.3, 95% CI, 1.4-13.0). Methotrexate exposure was not significantly associated with low BMD. Survivors receiving HCT had a reduced risk of low BMD (OR 0.2, 95% CI, 0.1-0.9). The highest risk factors for low BMD were male gender, exposure to TBI, cranial, or craniospinal radiation, and gonadal dysfunction. Survivors receiving methotrexate or HCT therapy have the lowest risk for low BMD among those screened. Future studies should investigate risk of low BMD for survivors receiving HCT without radiation exposure.