Cost-Effectiveness of the International Late Effects of Childhood Cancer Guideline Harmonization Group Screening Guidelines to Prevent Heart Failure in Survivors of Childhood Cancer.

PURPOSE: Survivors of childhood cancer treated with anthracyclines and/or chest-directed radiation are at increased risk for heart failure (HF). The International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) recommends risk-based screening echocardiograms, but evidence supporting its frequency and cost-effectiveness is limited. PATIENTS AND METHODS: Using the Childhood Cancer Survivor Study and St Jude Lifetime Cohort, we developed a microsimulation model of the clinical course of HF. We estimated long-term health outcomes and economic impact of screening according to IGHG-defined risk groups (low [doxorubicin-equivalent anthracycline dose of 1-99 mg/m2 and/or radiotherapy < 15 Gy], moderate [100 to < 250 mg/m2 or 15 to < 35 Gy], or high [≥ 250 mg/m2 or ≥ 35 Gy or both ≥ 100 mg/m2 and ≥ 15 Gy]). We compared 1-, 2-, 5-, and 10-year interval-based screening with no screening. Screening performance and treatment effectiveness were estimated based on published studies. Costs and quality-of-life weights were based on national averages and published reports. Outcomes included lifetime HF risk, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs). Strategies with ICERs < $100,000 per QALY gained were considered cost-effective. RESULTS: Among the IGHG risk groups, cumulative lifetime risks of HF without screening were 36.7% (high risk), 24.7% (moderate risk), and 16.9% (low risk). Routine screening reduced this risk by 4% to 11%, depending on frequency. Screening every 2, 5, and 10 years was cost-effective for high-risk survivors, and every 5 and 10 years for moderate-risk survivors. In contrast, ICERs were > $175,000 per QALY gained for all strategies for low-risk survivors, representing approximately 40% of those for whom screening is currently recommended. CONCLUSION: Our findings suggest that refinement of recommended screening strategies for IGHG high- and low-risk survivors is needed, including careful reconsideration of discontinuing asymptomatic left ventricular dysfunction and HF screening in low-risk survivors.

Implementing a stepwise educational approach for bridging the gap between specialty and primary care for childhood cancer survivors.

PURPOSE: To create a community of learning involving primary care providers and subspecialist to enhance providers' knowledge regarding care of adult childhood cancer survivors (CCS). METHODS: A stepwise approach was used to develop educational opportunities for providers. This process started with a local/regional in-person conference, which informed a webinar series, and resulted in the development of enduring material using a dynamic learning management system. RESULTS: Participants in all three learning platforms had an increase in knowledge from baseline regarding care for adult CCS. Majority of participants at the in-person conference and webinar series were oncology or other specialty providers. The enduring dynamic learning management system successfully reached a variety of providers and other allied health providers across the country. There was a slightly higher rate of participation on this platform by primary care providers of 12.5%. CONCLUSIONS: Care providers' knowledge of survivorship needs of adult CCS can be increased by multiple forms of instruction. However, the dynamic learning management system was most successful at reaching a broad audience. Advertisement through local and national organizations was not as successful as anticipated. Additional strategies are needed to successfully engage providers, specifically primary care providers (PCPs). IMPLICATIONS FOR CANCER SURVIVORS: The professional development needs of primary care providers regarding care of adult CCS is well recognized. A dynamic learning management system may represent the most convenient and accessible way to provide education, but new strategies for increasing providers' awareness and engagement are required. The goal of improving care of adult CCS requires increased providers knowledge.

Desensitization to pegaspargase in children with acute lymphoblastic leukemia and lymphoblastic lymphoma.

Hypersensitivity to pegaspargase is associated with inferior survival in pediatric patients with acute lymphoblastic leukemia and lymphoblastic lymphoma. In the past year, drug-supply shortages have led to the lack of an available alternative to pegaspargase. Rather than omit asparaginase from the treatment of acute lymphoblastic leukemia or lymphoblastic lymphoma patients with hypersensitivity to pegaspargase, we continued pegaspargase treatments for nine pediatric patients, utilizing a rapid desensitization protocol. There were no adverse events related to the pegaspargase during desensitization, and all patients who were checked had asparaginase serum levels above the threshold of 0.1 IU/mL at 7 to 14 days after pegaspargase therapy.

Utility of pediatric female fertility preservation discussions following pelvic radiation.

INTRODUCTION: While many childhood cancers are curable with therapy, adverse consequences in fertility exist. We sought to assess the number of female patients with pelvic tumors receiving radiation therapy, and the proportion that undergo measures for fertility preservation (FP). METHODS: A total of 53 female patients treated with pelvic tumors from 2000 to 2016 were retrospectively identified. RESULTS: 19 (34%) of these patients underwent pelvic radiation therapy (pXRT). Three of the patients received pXRT for palliative treatment. Of the 19 female patients receiving pXRT, six (31%) were prepubertal and 13 (68%) were postpubertal. Three patients (16%) had documentation of a discussion of FP measures prior to pXRT. One was prepubertal and the others were post-pubertal. Six patients (32%) were evaluated by endocrinology after radiation therapy, diagnosed with ovarian failure, and placed on hormone therapy. Current guidelines recommend discussion of FP in pre-and postpubertal patients with cancer. This 16-year retrospective review of female patients that underwent pXRT for pelvic tumors demonstrated < 17% of patients have documentation of a discussion of FP measures. CONCLUSION: Female pediatric patients who underwent chemotherapy and pXRT suffer a high rate of premature ovarian failure, high morbidity and mortality as well as low rates of documented FP discussions. Based on these findings we have established a multi-disciplinary fertility preservation team available for consultation and a protocol for discussing and documenting the impact of pXRT, along with other treatments, on fertility. LEVEL OF EVIDENCE: III.

Comparative oncology approach to drug repurposing in osteosarcoma.

BACKGROUND: Osteosarcoma is an orphan disease for which little improvement in survival has been made since the late 1980s. New drug discovery for orphan diseases is limited by the cost and time it takes to develop new drugs. Repurposing already approved FDA-drugs can help overcome this limitation. Another limitation of cancer drug discovery is the lack of preclinical models that accurately recapitulate what occurs in humans. For OS using dogs as a model can minimize this limitation as OS in canines develops spontaneously, is locally invasive and metastasizes to the lungs as it does in humans. METHODS: In our present work we used high-throughput screens to identify drugs from a library of 2,286 FDA-approved drugs that demonstrated selective growth inhibition against both human and canine OS cell lines. The identified lead compound was then tested for synergy with 7 other drugs that have demonstrated activity against OS. These results were confirmed with in vitro assays and an in vivo murine model of OS. RESULTS: We identified 13 drugs that demonstrated selective growth inhibition against both human and canine OS cell lines. Auranofin was selected for further in vitro combination drug screens. Auranofin showed synergistic effects with vorinostat and rapamycin on OS viability and apoptosis induction. Auranofin demonstrated single-agent growth inhibition in both human and canine OS xenografts, and cooperative growth inhibition was observed in combination with rapamycin or vorinostat. There was a significant decrease in Ki67-positive cells and an increase in cleaved caspase-3 levels in tumor tissues treated with a combination of auranofin and vorinostat or rapamycin. CONCLUSIONS: Auranofin, alone or in combination with rapamycin or vorinostat, may be useful new treatment strategies for OS. Future studies may evaluate the efficacy of auranofin in dogs with OS as a prelude to human clinical evaluation.

Cardiomyopathy in Childhood Cancer Survivors: Lessons from the Past and Challenges for the Future.

Childhood cancer survivors are at substantial risk for cancer treatment-related cardiomyopathy. Identification of those at highest risk has presented a longstanding challenge for survivorship researchers. To date, risk stratification approaches to screening and subsequent intervention have largely been driven by demographic and treatment-related exposures, possibly missing an opportunity for a more personalized approach. A growing body of literature suggests associations between cardiomyopathy and a number of genetic and acquired risk factors, supporting a need to incorporate these data into existing surveillance and intervention approaches. Efforts to reduce or eliminate modifiable cardiovascular risk factors are needed; however, the impact of these modifications remains to be seen. Moreover, challenges surrounding identification of effective cardiomyopathy treatment strategies in cancer survivors are ongoing. Despite these uncertainties, more accurate identification of those at highest risk and implementation of early and effective interventions for those with disease will lead to improved outcomes for childhood cancer survivors.

A Case of Immune Thrombocytopenic Purpura After Rabies Vaccination.

We describe a case of immune thrombocytopenic purpura (ITP) occurring 15 days after the first dose of a 4-dose rabies vaccination series. ITP is thought to be an immune-mediated process triggered by an infection or toxin. There is little evidence in the literature beyond case reports of an association of ITP with vaccines other than with the measles, mumps, and rubella vaccine. This is the third reported case of ITP associated with rabies vaccination. Because of the rare occurrence of this adverse event relative to the severity of rabies infection, the benefits of rabies vaccination, when indicated, outweigh the low and possible risk of ITP.

A Collaborative Step-Wise Process to Implementing an Innovative Clinic for Adult Survivors of Childhood Cancer.

With a 5 year survival rate of approximately 80%, there is an increasing number of childhood cancer survivors in the United States. Childhood cancer survivors are at an increased risk for physical and psychosocial health problems many years after treatment. Long-term follow-up care should include education, development of individualized follow up plans and screening for health problems in accordance with the Children's Oncology Group survivor guidelines. Due to survivor, provider and healthcare system related barriers, adult survivors of childhood cancer (ASCC) infrequently are receiving care in accordance to these guidelines. In this paper we describe the stepwise process and collaboration between a children's hospital and an adult academic medical center that was implemented to develop the Survivorship Transition Clinic and address the needs of ASCC in our region. In the clinic model that we designed ASCC follow-up with a primary care physician in the adult setting who is knowledgeable about late effects of childhood cancer treatment and are provided transition support and education by a transition nurse navigator.

Childhood cancer for the primary care physician.

Childhood cancer is rare among childhood diseases and requires a high index of suspicion by the primary care physician to entertain the possibility of cancer when managing common childhood diseases. This article presents an overview of common pediatric cancers, their presentations, and how the primary care physician can work up patients whom they suspect have a malignancy. The goal is to help primary care doctors in early recognition and appropriate referral of patients, in order for patients to receive required specialized care in a timely manner.

Late effects of childhood leukemia therapy.

As survival rates for children treated for childhood cancers become significantly better, the focus is increasingly on determining the late effects of treatments and the best ways to monitor for them and prevent their occurrence. This review focuses on recent literature discussing the late effects of treatment in patients treated for acute myeloid leukemia and acute lymphoblastic leukemia during childhood. The late effects of therapy for childhood leukemia include secondary malignancy, cardiotoxicity, obesity, endocrine abnormalities, reproductive changes, neurocognitive deficits, and psychosocial effects. As clinicians have become more aware of the late effects of therapy, treatment regimens have been changed to decrease late effects, but patients still require long-term follow-up for their prevention and treatment.

Review of cardiotoxicity in pediatric cancer patients: during and after therapy.

With the improvement in survival from childhood cancer, late effects of therapy are becoming more apparent. Cardiac disease, one of these late effects, has a significant impact on the life of survivors of childhood cancers. Most survivors are followed by primary care doctors and adult subspecialists after they have graduated from pediatric centers. Since much of the cardiac toxicity of therapy occurs years off of therapy, it is important for these physicians to be aware of how to monitor survivors for the development of cardiac toxicities. In this paper we will discuss the incidence of cardiac disease during treatment and in survivors, what treatment modalities contribute to its development and modalities utilized to screen for cardiac disease. Recommendations for posttherapy monitoring will be emphasized.

Can anthracycline therapy for pediatric malignancies be less cardiotoxic?

Anthracyclines have a central role in the treatment of cancer in pediatric patients but confer an increased risk of cardiac dysfunction. Several strategies have been employed to help reduce anthracycline-induced cardiotoxicity, including pretreating the patient with the iron chelator dexrazoxane and infusing the dose of anthracycline over a longer period. Much focus has also been placed on the development of methods that decrease the toxicity of parent compounds, specifically through the use of drug carriers such as liposomes, and on the development of new, potentially less toxic anthracycline derivatives, such as amrubicin and pixantrone. We provide a review of these strategies, focusing on studies in pediatric patients when available, and support the idea that anthracycline therapy can be less cardiotoxic in pediatric patients.