Pleuroparenchymal fibroelastosis as a late complication of childhood cancer therapy: A case series.

Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial pneumonia with distinct clinicopathologic features. It has been associated with exposure to hematopoietic stem cell transplantation (HSCT) and classical alkylating agents. Here, we highlight PPFE as a late complication of childhood cancer therapy by describing the cases of four survivors of childhood cancer with a diagnosis of treatment-related PPFE. All patients received high-dose alkylating agents. PPFE should be considered in the differential diagnosis of restrictive lung disease in patients with history of exposure to alkylating agents or HSCT. Development of PPFE-specific, noninvasive diagnostic tools and disease-modifying therapies will clinically benefit these patients.

Using Real-World Data to Explore the Impact of One-Time Financial Grants Among Young Adult Cancer Survivors.

Young adult (YA) cancer survivors experience worse financial outcomes than older survivors. This analysis used data from Expect Miracles Foundation to explore the impact of one-time financial grants on financial well-being and access to health care. Among 300 respondents, the average grant was $1526 (standard deviation = $587; range $300-$3000). Respondents reported improved ability to pay expenses (t = 4.45, p < 0.001), increased financial decision-making power (t = 2.79, p = 0.06), decreased medical debt impact (t = 2.1, p = 0.04), improved transportation access (t = 2.38, p = 0.02), and fewer challenges in accessing care (t = 3.0, p = 0.005) 6 months after receiving a financial grant. Financial assistance offers YAs an opportunity to meet medical and nonmedical expenses.

Do discussions of financial burdens decrease long-term financial toxicity in adolescent and young adult cancer survivors?

PURPOSE: This study aims to evaluate the associations between patient-provider cost discussions with patient-reported out-of-pocket (OOP) spending and long-term financial toxicity (FT) among adolescent and young adult (AYA; 15-39 years old) cancer survivors. METHODS: Using a cross-sectional survey, we assessed the themes and quality of patient discussions with providers about financial needs and general survivorship preparation, quantified patients' levels of FT, and evaluated patient-reported OOP spending. We determined the association between cancer treatment cost discussion and FT using multivariable analysis. In a subset of survivors (n = 18), we conducted qualitative interviews and used thematic analysis to characterize responses. RESULTS: Two hundred forty-seven AYA survivors completed the survey at a mean of 7 years post treatment and with a median COST score of 13. 70% of AYA survivors did not recall having any cost discussion about their cancer treatment with a provider. Having any cost discussion with a provider was associated with decreased FT (ß = 3.00; p = 0.02) but not associated with reduced OOP spending (χ2 = 3.77; p = 0.44). In a second adjusted model, with OOP spending included as a covariate, OOP spending was a significant predictor of FT (ß = - 1.40; p = 0.002). Key qualitative themes included survivors' frustration about the lack of communication related to financial issues throughout treatment and in survivorship, feeling unprepared, and reluctance to seek help. CONCLUSION: AYA patients are not fully informed about the costs of cancer care and FT; the dearth of cost discussions between patients and providers may represent a missed opportunity to reduce costs.

The long-term financial experiences of adolescent and young adult cancer survivors.

BACKGROUND: Cancer-related financial hardship can negatively impact financial well-being and may prevent adolescent and young adult (AYA) cancer survivors (ages 15-39) from gaining financial independence. This analysis explored the financial experiences following diagnosis with cancer among AYA survivors. METHODS: We conducted a cross-sectional, anonymous survey of a national sample of AYAs recruited online. The Comprehensive Score for Financial Toxicity (COST) and InCharge Financial Distress/Financial Well-Being Scale (IFDFW) assessed financial hardship (cancer-related and general, respectively), and respondents reported related financial consequences and financial coping behaviors (both medical and non-medical). RESULTS: Two hundred sixty-seven AYA survivors completed the survey (mean 8.3 years from diagnosis). Financial hardship was high: mean COST score was 13.7 (moderate-to-severe financial toxicity); mean IFDFW score was 4.3 (high financial stress). Financial consequences included post-cancer credit score decrease (44%), debt collection contact (39%), spending more than 10% of income on medical expenses (39%), and lacking money for basic necessities (23%). Financial coping behaviors included taking money from savings (55%), taking on credit card debt (45%), putting off major purchases (45%), and borrowing money (42%). In logistic regression models, general financial distress was associated with increased odds of experiencing financial consequences and engaging in both medical- and non-medical-related financial coping behaviors. DISCUSSION: AYA survivors face long-term financial hardship after cancer treatment, which impacts multiple domains, including their use of healthcare and their personal finances. Interventions are needed to provide AYAs with tools to navigate financial aspects of the healthcare system; connect them with resources; and create systems-level solutions to address healthcare affordability. IMPLICATIONS FOR CANCER SURVIVORS: Survivorship care providers, particularly those who interact with AYA survivors, must be attuned to the unique risk for financial hardships facing this population and make efforts to increase access available interventions.

Germline Genetic and Treatment-Related Risk Factors for Diabetes Mellitus in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study and St Jude Lifetime Cohorts.

PURPOSE: To characterize germline genetic risk factors of diabetes mellitus among long-term survivors of childhood cancer. METHODS: Adult survivors of childhood cancer from the Childhood Cancer Survivor Study (CCSS) Original Cohort (n = 5,083; 383 with diabetes) were used to conduct a discovery genome-wide association study. Replication was performed using the CCSS Expansion (n = 2,588; 40 with diabetes) and the St Jude Lifetime (SJLIFE; n = 3,351; 208 with diabetes) cohorts. Risk prediction models, stratified on exposure to abdominal radiation, were calculated using logistic regression including attained age, sex and body mass index, diagnosis, alkylating chemotherapy, age at cancer diagnosis, and a polygenic risk score (PRS) on the basis of 395 diabetes variants from the general population. Area under the receiver operating characteristic curve (AUC) was calculated for models on the basis of traditional risk factors, clinical risk factors, and PRS. RESULTS: There was a genome-wide significant association of rs55849673-A with diabetes among survivors (odds ratio, 2.9; 95% CI, 2.0 to 4.2; P = 3.7 × 10-8), which is related to expression of ERCC6L2 in the Genotype-Tissue Expression project. The association of rs55849673-A was observed largely among survivors not exposed to abdominal radiation (odds ratio = 3.5, P = 1.1 × 10-7) and the frequency of rs55849673-A was consistently higher among diabetic survivors in the CCSS Expansion and SJLIFE cohorts. Risk prediction models including traditional diabetes risk factors, clinical risk factors and PRS had an optimism-corrected AUC of 0.801, with an AUC of 0.751 in survivors treated with abdominal radiation versus 0.813 in survivors who did not receive abdominal radiation. CONCLUSION: There is evidence for a novel locus of diabetes among survivors not exposed to abdominal radiation. Further refinement and validation of clinic-based risk prediction models for diabetes among long-term survivors of childhood cancer is warranted.

Second cancer risk in childhood cancer survivors treated with intensity-modulated radiation therapy: An updated analysis of more than 10 years of follow-up.

BACKGROUND: It is unclear how intensity-modulated radiation therapy (IMRT) impacts long-term risk of second malignant neoplasms (SMNs) in childhood cancer patients. PROCEDURE: Patients aged ≤21 years treated with IMRT between 1998 and 2009 and who survived ≥5 years after IMRT were included. SMN site in relation to isodose level (IDL) of IMRT was evaluated. Standardized incidence ratios (SIR) and excess absolute risks (EAR) were calculated. Cumulative incidences were estimated with death as a competing risk. RESULTS: Three-hundred twenty-five patients were included with median follow-up of 11.2 years from IMRT (interquartile range: 9.4-14.0) among patients alive at the end of follow-up. Two hundred (62%) patients had ≥10 years of follow-up and 284 (87%) patients were alive at the time of analysis. Fifteen patients developed SMNs (11 solid, four hematologic). Median time from IMRT to solid SMN was 11.0 years (range: 6.8-19.2) with 10- and 15-year cumulative incidences 1.8% (95% CI: 0.7-3.9) and 3.5% (95% CI: 1.4-7.5), respectively; SIR was 13.7 (95% CI: 6.9-24.6) and EAR was 2.8 per 1000 person-years (95% CI: 1.0-4.6). Eight solid SMNs developed within the IMRT field (100% IDL [n = 5], 80% IDL [n = 1], 50% IDL [n = 1], 40% IDL [n = 1]), one within the 70%-80% IDL of a conventional field, one was out-of-field, and one could not be determined. CONCLUSIONS: With median follow-up of >10 years, many solid SMNs after IMRT in childhood cancer survivors develop in the high-dose region. These data serve as a foundation for comparison with other modalities of radiation treatment (e.g., proton therapy).

Biochemical measures of ovarian function in female survivors of retinoblastoma treated with intra-arterial melphalan: an initial report.

Since 2006, ophthalmic artery chemosurgery (OAC) has been used for ocular-sparing treatment of retinoblastoma. Systemic exposure to melphalan is known to cause ovarian dysfunction, but the effect of melphalan-based OAC has not yet been determined. Here, we assess biochemical and symptomatic measures of ovarian function in a cohort of pubertal female survivors of retinoblastoma treated with melphalan-based OAC. These 13 patients all had normal gonadotropins at a median age of 11.1 years, 9.6 years from the completion of therapy. None had symptoms of ovarian dysfunction. This study provides initial evidence that ovarian function remains intact after melphalan-based OAC.

Economic distress, financial toxicity, and medical cost-coping in young adult cancer survivors during the COVID-19 pandemic: Findings from an online sample.

BACKGROUND: Young adult (YA) cancer survivors are at risk for financial toxicity during and after cancer treatment. Financial toxicity has been associated with medical-related cost-coping behaviors such as skipping or delaying treatment. The coronavirus disease 2019 (COVID-19) pandemic has resulted in dire economic consequences that may worsen financial hardship among young survivors. METHODS: This was a cross-sectional survey; data collection occurred online. A convenience sample was recruited through YA cancer advocacy groups and social media. Negative economic events associated with the COVID-19 pandemic (eg, income loss, increased debt, and decreased job security) and medical-related cost-coping were documented. A validated measure assessed cancer-related financial toxicity. RESULTS: Participants (N = 212) had a mean age of 35.3 years at survey completion and a mean age of 27.4 years at diagnosis. Financial toxicity (mean, 14.0; SD, 9.33) was high. Two-thirds of the sample experienced at least 1 negative economic event during COVID-19, and 71% engaged in at least 1 medical cost-coping behavior. Cost-coping and pandemic-related negative economic events were significantly correlated with cancer-related financial toxicity. In multivariable analyses, pandemic-related negative economic events and financial toxicity were associated with cost-coping. CONCLUSIONS: Acute negative economic events associated with the COVID-19 pandemic may exacerbate cancer-related financial toxicity and overall financial hardship among YAs and lead to cost-coping behaviors that can compromise survivorship care and health outcomes. Multilevel, systematic interventions are needed to address the financial needs of YA survivors after the global pandemic.

Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors.

The spectrum of germline predisposition in pediatric cancer continues to be realized. Here we report 751 solid tumor patients who underwent prospective matched tumor-normal DNA sequencing and downstream clinical use (clinicaltrials.gov NCT01775072). Germline pathogenic and likely pathogenic (P/LP) variants were reported. One or more P/LP variants were found in 18% (138/751) of individuals when including variants in low, moderate, and high penetrance dominant or recessive genes, or 13% (99/751) in moderate and high penetrance dominant genes. 34% of high or moderate penetrance variants were unexpected based on the patient's diagnosis and previous history. 76% of patients with positive results completed a clinical genetics visit, and 21% had at least one relative undergo cascade testing as a result of this testing. Clinical actionability additionally included screening, risk reduction in relatives, reproductive use, and use of targeted therapies. Germline testing should be considered for all children with cancer.

Updated Breast Cancer Surveillance Recommendations for Female Survivors of Childhood, Adolescent, and Young Adult Cancer From the International Guideline Harmonization Group.

PURPOSE: As new evidence is available, the International Late Effects of Childhood Cancer Guideline Harmonization Group has updated breast cancer surveillance recommendations for female survivors of childhood, adolescent, and young adult cancer. METHODS: We used evidence-based methods to apply new knowledge in refining the international harmonized recommendations developed in 2013. The guideline panel updated the systematic literature review, developed evidence summaries, appraised the evidence, and updated recommendations on the basis of evidence, clinical judgement, and consideration of benefits versus the harms of the surveillance interventions while attaining flexibility in implementation across different health care systems. The GRADE Evidence-to-Decision framework was used to translate evidence to recommendations. A survivor information form was developed to counsel survivors about the potential harms and benefits of surveillance. RESULTS: The literature update identified new study findings related to the effects of prescribed moderate-dose chest radiation (10 to 19 Gy), radiation dose-volume, anthracyclines and alkylating agents in non-chest irradiated survivors, and the effects of ovarian function on breast cancer risk. Moreover, new data from prospective investigations were available regarding the performance metrics of mammography and magnetic resonance imaging among survivors of Hodgkin lymphoma. Modified recommendations include the performance of mammography and breast magnetic resonance imaging for survivors treated with 10 Gy or greater chest radiation (strong recommendation) and upper abdominal radiation exposing breast tissue at a young age (moderate recommendation) at least annually up to age 60 years. As a result of inconsistent evidence, no recommendation could be formulated for routine breast cancer surveillance for survivors treated with any type of anthracyclines in the absence of chest radiation. CONCLUSION: The newly identified evidence prompted significant change to the recommendations formulated in 2013 related to moderate-dose chest radiation and anthracycline exposure as well as breast cancer surveillance modality.

Magnetic Resonance Imaging Screening for Trilateral Retinoblastoma: The Memorial Sloan Kettering Cancer Center Experience 2006-2016.

PURPOSE: Magnetic resonance imaging (MRI) has been used for baseline brain imaging and afterward as a screening tool for trilateral retinoblastoma (TRB), but there is no consensus on timing or frequency of screening worldwide. In this study, a cohort of hereditary retinoblastoma patients at increased risk for TRB was identified and the usefulness of aggressive neuroimaging was examined. DESIGN: Retrospective review of the medical records and MRI reports of patients with retinoblastoma treated at Memorial Sloan Kettering Cancer Center between January 1, 2006, and December 31, 2016. PARTICIPANTS: Three hundred forty-nine total patients with retinoblastoma, including 215 hereditary retinoblastoma patients in the screening group. METHODS: We reviewed 804 MRI studies of the orbit or brain. Patient and disease characteristics, including laterality, family history, and gene mutation status were analyzed. The impression of every MRI was coded 1 to 5, each value representing a different abnormality. MAIN OUTCOME MEASURES: We calculated the incidence of TRB in patients with germline disease as well as the incidence of screening MRI scans showing TRB. RESULTS: Among our hereditary retinoblastoma screening cohort (n=215) 4 patients with TRB were identified on screening MRI. All 4 patients showed bilateral disease, pineal gland tumors, and a latency period of at least 1 year. Three of the 4 were deceased by the end of the study. The incidence of TRB diagnosis was 1.9% (95% confidence interval [CI], 0.7%-4.9%). Of the 804 screening MRI scans performed on the screening cohort, 691 (86%) were unremarkable and 4 reported a lesion suspicious for TRB. The overall incidence of detecting TRB on screening MRI in the at-risk cohort was 0.5% (95% CI, 0.2%-1.3%) with a number needed to treat of 202. CONCLUSIONS: All cases of TRB in our center during the study period developed before the patient was 3 years of age and after a total of only 4 lifetime MRIs. Overall survival from TRB was not improved as a result of screening, and many false-positive results required additional, subsequent MRI scans with anesthesia.

Late Infection-Related Mortality in Asplenic Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study.

Purpose Infection-related outcomes associated with asplenia or impaired splenic function in survivors of childhood cancer remains understudied. Methods Late infection-related mortality was evaluated in 20,026 5-year survivors of childhood cancer (diagnosed < 21 years of age from 1970 to 1999; median age at diagnosis, 7.0 years [range, 0 to 20 years]; median follow-up, 26 years [range, 5 to 44 years]) using cumulative incidence and piecewise-exponential regression models to estimate adjusted relative rates (RRs). Splenic radiation was approximated using average dose (direct and/or indirect) to the left upper quadrant of the abdomen (hereafter, referred to as splenic radiation). Results Within 5 years of diagnosis, 1,354 survivors (6.8%) had a splenectomy and 9,442 (46%) had splenic radiation without splenectomy. With 62 deaths, the cumulative incidence of infection-related late mortality was 1.5% (95% CI, 0.7% to 2.2%) at 35 years after splenectomy and 0.6% (95% CI, 0.4% to 0.8%) after splenic radiation. Splenectomy (RR, 7.7; 95% CI, 3.1 to 19.1) was independently associated with late infection-related mortality. Splenic radiation was associated with increasing risk for late infection-related mortality in a dose-response relationship (0.1 to 9.9 Gy: RR, 2.0; 95% CI, 0.9 to 4.5; 10 to 19.9 Gy: RR, 5.5; 95% CI, 1.9 to 15.4; ≥ 20 Gy: RR, 6.0; 95% CI, 1.8 to 20.2). High-dose alkylator chemotherapy exposure was also independently associated with an increased risk of infection-related mortality (RR, 1.9; 95% CI, 1.1 to 3.4). Conclusion Splenectomy and splenic radiation significantly increase risk for late infection-related mortality. Even low- to intermediate-dose radiation exposure confers increased risk, suggesting that the spleen is highly radiosensitive. These findings should inform long-term follow-up guidelines for survivors of childhood cancer and should lead clinicians to avoid or reduce radiation exposure involving the spleen whenever possible.

Fertility information needs and concerns post-treatment contribute to lowered quality of life among young adult female cancer survivors.

BACKGROUND: Cancer treatment may lead to premature menopause and infertility. Young adult female cancer survivors (YAFCS) are often concerned about their fertility and future family-building options, but research is limited on how concerns may affect more general quality of life (QOL) domains. This study examined how fertility factors relate to QOL among YAFCS who received gonadotoxic therapy. METHOD: A national sample of YAFCS completed an online, anonymous survey. The survey included investigator-designed questions about perceived fertility information needs (five items; Cronbach's α = .83) and general QOL (four items; α = .89), the Reproductive Concerns after Cancer Scale (RCACS) and Decisional Conflict Scale (DCS). Analyses included Pearson's correlation, t tests, and stepwise regression. RESULTS: Participants (N = 314) were an average of 30 years old (SD = 4.1) and 5 years (SD = 5.4) post-treatment; 31% reported being infertile and 19% had undergone fertility preservation (FP). Overall, QOL was relatively high (M = 7.3, SD = 1.9, range 0-10) and did not vary by fertility status (t[272] = .743, p = .46), prior FP (t[273] = .53, p = .55) or sociodemographic/clinical factors (p's > .05) except socioeconomic indicators (p's < .05).In separate models, greater unmet fertility information needs (ß = - .19, p = .004) and, among fertile women, greater reproductive concerns (ß = - .26, p = .001) related to lower QOL. Among fertile women without prior FP, greater decisional distress about future FP related to lower QOL (ß = - .19, p = .03). CONCLUSIONS: These preliminary findings suggest that unaddressed fertility information needs, concerns, and decision distress may affect general QOL among post-treatment YAFCS who hope to have children in the future. Future work should identify ways to optimally incorporate fertility counseling and support resources into survivorship care programs, including referrals to reproductive specialists as appropriate.

Osteochondroma in long-term survivors of high-risk neuroblastoma.

BACKGROUND: Osteochondromas are benign bony protrusions that can be spontaneous or associated with radiotherapy (RT). Current treatment of high-risk neuroblastoma includes dose-intensive chemotherapy, local RT, an anti-GD2 monoclonal antibody (MoAb), and isotretinoin. Late effects are emerging. METHODS: The authors examined osteochondromas in 362 patients who were aged <10 years when diagnosed with neuroblastoma, had received a MoAb plus isotretinoin since 2000, and had survived >24 months from the time of the first dose of the MoAb. The incidence rate of osteochondroma was determined using the competing risks approach, in which the primary event was osteochondroma calculated from the date of neuroblastoma diagnosis and the competing event was death without osteochondroma. RESULTS: A total of 21 osteochondroma cases were found among 14 patients who were aged 5.7 to 15.3 years (median, 10.4 years) and 3.1 to 11.2 years (median, 8.2 years) from the time of neuroblastoma diagnosis. The cumulative incidence rate was 0.6% at 5 years and 4.9% at 10 years from the neuroblastoma diagnosis. Nine osteochondromas were revealed incidentally during assessments of neuroblastoma disease status or bone age. Thirteen osteochondromas were detected outside RT portals and had characteristics of spontaneous forms. Complications were limited to pain necessitating surgical resection in 3 patients, but follow-up was short at 0.3 to 7.7 years (median, 3.5 years). CONCLUSIONS: Osteochondromas in long-term survivors of neuroblastoma should be expected because these benign growths can be related to RT and these patients undergo radiologic studies over years, are monitored for late toxicities through and beyond adolescence, and receive special attention (because of concerns about disease recurrence) if they develop a bony protuberance. A pathogenic role for chemotherapy, anti-GD2 MoAbs, or isotretinoin remains speculative.

Second cancer risk in childhood cancer survivors treated with intensity-modulated radiation therapy (IMRT).

BACKGROUND: Treatment with radiotherapy (RT) is associated with an increased risk of second malignant neoplasms (SMNs) in childhood cancer survivors; it is unclear how treatment with intensity-modulated radiation therapy (IMRT) impacts this risk. We provide the first report of SMN risk in a cohort of childhood cancer survivors treated with IMRT. PROCEDURE: Retrospective review of patients ≤21 years of age treated with IMRT at Memorial Sloan Kettering Cancer Center between December 1998 and February 2009. Eligible patients survived at least 5 years from IMRT initiation. The risk of SMN was assessed via standardized incidence ratios (SIRs) and excess absolute risk (EAR). The cumulative incidence was estimated using methods for competing risks. RESULTS: Among 242 patients, six developed SMNs: four developed second solid cancers (all within the radiation field), and two developed myelodysplastic syndrome. Median time from IMRT initiation to a second solid cancer was 7.2 years (range, 6.8-9.5), with a 10-year cumulative incidence of 3.3% (95% confidence interval [CI], 1.0-7.8%), SIR of 11.4 (95% CI, 3.1-29.2) and EAR of 1.8 per 1,000 person-years (95% CI, -0.1 to 3.8). CONCLUSIONS: Longer follow-up is required to determine how the risk of SMN after IMRT compares to other modalities of radiation treatment, such as proton therapy. This study provides a preliminary report, which will serve as a baseline for future longitudinal analyses of SMN risk after IMRT. Pediatr Blood Cancer 2015;62:311-316. © 2014 Wiley Periodicals, Inc.