Background
The impact of a child's cancer diagnosis on subsequent maternal physical health is unclear.
Methods
We identified all Ontario children diagnosed less than 18 years with cancer between 1992 ...and 2017. Linkage to administrative databases identified mothers who were matched to population controls. We identified physical health conditions, acute healthcare use, and preventive healthcare use through validated algorithms using healthcare data, and compared them between exposed (child with cancer) and unexposed mothers. Predictors of health outcomes were assessed among exposed mothers.
Results
We identified 5311 exposed mothers and 19,516 matched unexposed mothers. For exposed mothers, median age at last follow‐up was 48 years, (interquartile range: 42–53). Exposed mothers had an increased risk of cancer (hazard ratio HR 1.2, 95% confidence interval 95% CI: 1.0–1.5, p = .03), but not of any other adverse physical outcomes or of increased acute healthcare use. Exposed mothers were more likely to receive influenza vaccinations (odds ratio 1.4, 95% CI: 1.3–1.5, p < .0001), and underwent cancer screening at the same rate as unexposed mothers. Among exposed mothers, bereavement was associated with a subsequent increased risk of cancer (HR 1.7, 95% CI: 1.2–2.5, p = .004) and death (HR 2.2, 95% CI: 1.2–4.1, p = .01).
Conclusion
Mothers of children with cancer are at increased risk of developing cancer, but not of other adverse physical health outcomes, and were equally or more likely to be adherent to preventive healthcare practices. Bereaved mothers were at increased risk of subsequent cancer and death. Interventions targeting specific subpopulations of mothers of children with cancer or focused on screening for specific cancers may be warranted.
Female survivors treated with thoracic radiation therapy (RT) for childhood cancer experience increased risks of breast cancer (BC). There are currently no data quantifying the potential mortality ...gains of early BC screening among such survivors.
A mathematical model of BC development was used to evaluate the marginal benefit of early-initiated screening of female survivors of adolescent Hodgkin's lymphoma (HL) starting at age 25 years on BC mortality compared with screening initiated at age 40 years. Sensitivity analyses were performed to evaluate the robustness of the estimates over a plausible range of conditions.
For survivors treated at age 15 years, the absolute risk of BC mortality by age 75 years was predicted to decrease from 16.65% with no early screening to 16.28% (annual mammography), 15.40% (annual MRI), 15.38% (same-day annual mammography and MRI), and 15.37% (alternating mammography and MRI every six months). Approximately 80 patients would need to be invited to MRI-based screening to prevent one BC death. In sensitivity analyses, the number needed to invite to MRI-based screening to prevent one BC death ranged from 71 to 333. Combinations of MRI plus mammography were predicted to produce 99.52 false positives per 1000 screenings done between age 25 to 39 years.
These findings are the first to indicate that early MRI-based screening should reduce BC mortality among women treated with RT for adolescent HL. The magnitude of this benefit is superior to that described for other accepted screening indications although MRI can produce a substantial rate of false-positive results.
Summary Background Dabrafenib plus trametinib treatment provides significant benefits over BRAF-inhibitor monotherapy in patients with BRAFV600E -mutant or BRAFV600K -mutant advanced melanoma; ...however, in many patients the disease progresses, leading to death. With many treatment options available, understanding clinical factors that predict long-term response and survival for treatments is important for optimisation of patient management. We aimed to identify clinical factors associated with long-term response and survival using pooled data from randomised trials of dabrafenib plus trametinib in patients with metastatic BRAF -mutant melanoma. Methods We did a retrospective individual data analysis based on all published randomised trials that included treatment-naive patients with BRAFV600E -mutant or BRAFV600K -mutant metastatic melanoma who received the approved dose of dabrafenib 150 mg twice daily plus trametinib 2 mg once daily. Data were pooled from patients in the BRF113220 (part C; March 26, 2010, to Jan 15, 2015), COMBI-d (May 4, 2012, to Jan 12, 2015), and COMBI-v (June 4, 2012, to March 13, 2015) randomised trials. Patients with untreated brain metastases were not permitted to enrol in these trials. Baseline factors, identified a priori based on known melanoma clinical or prognostic characteristics, were analysed for association with progression-free survival and overall survival using univariate and multivariate analyses and assessed for hierarchical effect on outcomes using regression tree analyses. We also analysed factors identified after baseline, on treatment, and at progression, for associations with survival after progression. The trials included in this analysis are registered with ClinicalTrials.gov : BRF113220, number NCT01072175 ; COMBI-d, number NCT01584648 ; COMBI-v, number NCT01597908. Findings 617 patients were included in this analysis with a median follow-up of 20·0 months (range 0−48·0, IQR 10·1−24·8); 396 patients had progression events (ie, disease progression or death) and 290 patients had died. Median progression-free survival (11·1 months 95% CI 9·7−12·9), median overall survival (25·6 months 23·1−34·3), 1-year progression-free survival (48% 44–52) and overall survival (74% 71–78), and 2-year progression-free survival (30% 26–34) and overall survival (53% 49–57) were consistent with those in the individual trials. Patients with normal lactate dehydrogenase (LDH) concentration and fewer than three organ sites containing metastases (n=237) had the longest 1-year progression-free survival (68% 95% CI 62–74) and overall survival (90% 87–94) and 2-year progression-free survival (46% 40–54) and overall survival (75% 70–81), whereas patients with LDH concentration at least two times the upper limit of normal (n=70) had the shortest 1-year progression-free survival (8% 3–19) and overall survival (40% 29–55) and 2-year progression-free survival (2% 0–13) and overall survival (7% 3–19). Of patients with disease progression (n=379), survival after progression was longest in those with progression in baseline or new non-CNS lesions (n=205; median 10·0 months 95% CI 7·9−12·0) and shortest in those with new CNS lesions or concurrent progression in baseline and new lesions (n=171; median 4·0 months 3·5−4·9). Interpretation Several patient and clinical characteristics at and after baseline are associated with outcomes with dabrafenib plus trametinib, and durable benefit is possible with targeted treatment in defined patient subsets. Funding Novartis.
Summary Background In the phase 3 CheckMate 025 study, previously treated patients with advanced renal cell carcinoma who were randomly assigned to nivolumab had an overall survival benefit compared ...with those assigned to everolimus. We aimed to compare health-related quality of life (HRQoL) between treatment groups in this trial. Methods CheckMate 025 was an open-label study done at 146 oncology centres in 24 countries. Patients were randomly assigned to treatment between Oct 22, 2012, and March 11, 2014. Patients with advanced renal cell carcinoma were randomly assigned (1:1, block size of four) to receive nivolumab every 2 weeks or everolimus once per day. The study was stopped early at the planned interim analysis in July, 2015, because the study met its primary endpoint. A protocol amendment permitted patients in the everolimus group to cross over to nivolumab treatment. All patients not on active study therapy are being followed up for survival. At the interim analysis, HRQoL was assessed with the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) and European Quality of Life (EuroQol)-5 Dimensions (EQ-5D) questionnaires. Prespecified endpoints were to assess, in each treatment group, disease-related symptom progression rate based on the FKSI-DRS and changes in reported global health outcomes based on the EQ-5D. Other endpoints were post hoc. We calculated the proportion of FKSI-DRS questionnaires completed using the number of patients with non-missing data at baseline and at least one post-baseline visit. We defined FKSI-DRS completion as completion of five or more of the nine items in the questionnaire; otherwise data were treated as missing. FKSI-DRS symptom index score was prorated for missing items. We made no adjustments for missing EQ-5D data. We used descriptive statistics and multivariate analyses, including mixed-effects model repeated-measures, for between group comparisons. Analyses were powered according to the original study protocol, and we analysed FKSI-DRS and EQ-5D data for all patients who underwent randomisation and had a baseline assessment and at least one post-baseline assessment. CheckMate 025 is registered with ClinicalTrials.gov , number NCT01668784. Findings HRQoL data were collected at baseline for 362 (88%) of 410 patients in the nivolumab group and 344 (84%) of 411 patients in the everolimus group. The mean difference in FKSI-DRS scores between the nivolumab and everolimus groups was 1·6 (95% CI 1·4–1·9; p<0·0001) with descriptive statistics and 1·7 (1·2–2·1; p<0·0001) with mixed-effects model repeated-measures analysis. In terms of FKSI-DRS score, more patients had a clinically meaningful (ie, an increase of at least 2 points from baseline) HRQoL improvement with nivolumab (200 55% of 361 patients) versus everolimus (126 37% of 343 patients; p<0·0001). Median time to HRQoL improvement was shorter in patients given nivolumab (4·7 months, 95% CI 3·7–7·5) than in patients given everolimus (median not reached, NE–NE). Interpretation Nivolumab was associated with HRQoL improvement compared with everolimus in previously treated patients with advanced renal cell carcinoma. Funding Bristol-Myers Squibb.
Background
Pain in adolescents with cancer (12–18 years) is common and negatively impacts health‐related quality of life (HRQL). The Pain Squad+ smartphone app, which provides adolescents with ...real‐time pain self‐management support, was developed to address this issue. This study evaluated the implementation of the app to inform a future randomized controlled trial (RCT) and obtain treatment effect estimates for pain intensity, pain interference, HRQL, and self‐efficacy.
Procedure
A one‐group baseline/poststudy design with 40 adolescents recruited from two pediatric tertiary care centers was used. Baseline questionnaires were completed and adolescents used the app at least twice daily for 28 days, receiving algorithm‐informed self‐management advice depending on their reported pain. A nurse received alerts in response to sustained pain and contacted adolescents to assist in pain care. Poststudy questionnaires were completed. Descriptive analyses, with exploratory inferential testing conducted on health outcome data, were used to address study aims.
Results
Most (40/52; 77%) eligible adolescents participated. Two participants withdrew participation. Intervention fidelity was impacted by technical difficulties (occurring for 15% of participants) and a prolonged time for nurse contact in the event of sustained pain. Adherence to pain reporting was 68.8 ± 38.1%. Outcome measure completion rates were high and the intervention was acceptable to participants. Trends in improvements in pain intensity, pain interference, and HRQL were significant, with effect sizes of 0.23–0.67.
Conclusions
Implementation of Pain Squad+ is feasible and the app appears to improve pain‐related outcomes for adolescents with cancer. A multicenter RCT will be undertaken to examine app effectiveness.
Cardiovascular disease (CVD), which includes cardiomyopathy/heart failure, coronary artery disease, stroke, pericardial disease, arrhythmias, and valvular and vascular dysfunction, is a major concern ...for long-term survivors of childhood cancer. There is clear evidence of increased risk of CVD largely attributable to treatment exposures at a young age, most notably anthracycline chemotherapy and chest-directed radiation therapy, and compounded by traditional cardiovascular risk factors accrued during decades after treatment exposure. Preclinical studies are limited; thus, it is a high priority to understand the pathophysiology of CVD as a result of anticancer treatments, taking into consideration the growing and developing heart. Recently developed personalized risk prediction models can provide decision support before initiation of anticancer therapy or facilitate implementation of screening strategies in at-risk survivors of cancer. Although consensus-based screening guidelines exist for the application of blood and imaging biomarkers of CVD, the most appropriate timing and frequency of these measures in survivors of childhood cancer are not yet fully elucidated. Longitudinal studies are needed to characterize the prognostic importance of subclinical markers of cardiovascular injury on long-term CVD risk. A number of prevention trials across the survivorship spectrum are under way, which include primary prevention (before or during cancer treatment), secondary prevention (after completion of treatment), and integrated approaches to manage modifiable cardiovascular risk factors. Ongoing multidisciplinary collaborations between the oncology, cardiology, primary care, and other subspecialty communities are essential to reduce therapeutic exposures and improve surveillance, prevention, and treatment of CVD in this high-risk population.
Immune and targeted therapies achieve long-term survival in metastatic melanoma; however, new treatment strategies are needed to improve patients' outcomes
. We report on the efficacy, safety and ...biomarker analysis from the single-arm safety run-in (part 1; n = 9) and biomarker (part 2; n = 27) cohorts of the randomized, placebo-controlled, phase 3 COMBI-i trial (NCT02967692) of the anti-PD-1 antibody spartalizumab, in combination with the BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Patients (n = 36) had previously untreated BRAF V600-mutant unresectable or metastatic melanoma. In part 1, the recommended phase 3 regimen was identified based on the incidence of dose-limiting toxicities (DLTs; primary endpoint): 400 mg of spartalizumab every 4 weeks plus 150 mg of dabrafenib twice daily plus 2 mg of trametinib once daily. Part 2 characterized changes in PD-L1 levels and CD8
cells following treatment (primary endpoint), and analyzed additional biomarkers. Assessments of efficacy and safety were key secondary endpoints (median follow-up, 24.3 months). Spartalizumab plus dabrafenib and trametinib led to an objective response rate (ORR) of 78%, including 44% complete responses (CRs). Grade ≥3 treatment-related adverse events (TRAEs) were experienced by 72% of patients. All patients had temporary dose modifications, and 17% permanently discontinued all three study drugs due to TRAEs. Early progression-free survival (PFS) events were associated with low tumor mutational burden/T cell-inflamed gene expression signature (GES) or high immunosuppressive tumor microenvironment (TME) GES levels at baseline; an immunosuppressive TME may also preclude CR. Overall, the efficacy, safety and on-treatment biomarker modulations associated with spartalizumab plus dabrafenib and trametinib are promising, and biomarkers that may predict long-term benefit were identified.
Abstract Over 80% of children and 60% of adults with cancer will become long-term survivors, emphasizing the importance of late effects of cancer therapy. Cardiotoxicity due to chemotherapy and ...radiation is a frequent cause of serious morbidity and premature mortality in survivors. Anthracyclines, a core component of many treatment regimens, have been implicated as a principal cause of irreversible cardiomyopathy. Approximately 60% of anthracycline-treated children will develop echocardiographic evidence of cardiac dysfunction, and 10% of those treated with high-dose anthracyclines will develop congestive heart failure within the 20 years after therapy. Adults treated with trastuzumab are at risk for a cardiomyopathy which is usually reversible. As many as 12% of adults treated with trastuzumab and 20% of those who have also received an anthracycline will develop cardiotoxicity within 5 years. Risk factors for cardiomyopathy include patient (e.g. age, sex, genetic predisposition) and treatment characteristics (e.g. cumulative anthracycline dose). Radiotherapy to a field involving the heart increases the risk for cardiomyopathy, coronary artery disease, valvular dysfunction, arrhythmias and pericardial disease. Surveillance guidelines are available to guide long-term cardiac follow-up of childhood cancer survivors, but not for survivors of adult cancers; however, periodic follow-up to detect cardiac dysfunction may be reasonable. Modifiable cardiac risk factors like hypertension, smoking and dyslipidemia interact with cancer therapies to increase the risk of cardiac disease, emphasizing the importance of risk-factor control. Coordination of care between oncologists and cardiologists would optimize care for those individuals at high risk of cardiotoxicity who would benefit from appropriate surveillance and treatment strategies.
Background
Approximately 70% of children diagnosed with a medulloblastoma will become long‐term survivors. Medulloblastoma therapy frequently causes long‐term morbidities in survivors, which places a ...considerable burden on parental caregivers. We aimed to explore the experience of parental caregivers caring for medulloblastoma survivors.
Methods
We conducted a qualitative study using grounded theory thematic analysis. We used semi‐structured parental caregiver interviews to explore family experiences, social circumstances, and family‐reported impact within families of children who had survived medulloblastoma. Parental caregivers were recruited from specialized survivor clinics at two large quaternary centers in Toronto, Canada.
Results
Sixteen of 22 eligible families participated, and 20 parental caregiver interviews were completed. Survivors were a median age of 6 years (range: 1–9 years) at diagnosis, and were 9.5 years (range: 5–12 years) from treatment at the time of the interview. Three major themes and associated subthemes emerged: (i) parental caregivers described significant long‐term challenges associated with their child's survivorship. Subthemes included medical treatment sequelae, school issues and behavioral concerns, and surveillance and access to care. (ii) Parental caregivers recognized the impact that their child's quality of life (QOL) had on both their personal and family QOL. Subthemes included parental QOL, parental mental health and coping, spousal relationships, and effects on the family unit as a whole. (iii) Parental caregivers reported experiencing conflicting emotions related to their child's survivorship status and long‐term effects. Subthemes included feeling happiness with concurrent worry, fear, and stress, as well as concerns about the future.
Conclusions
Parental caregivers of medulloblastoma survivors experience long‐term challenges, with personal and family impacts. Further work is needed to improve care models and support systems for families with a child who has survived medulloblastoma.
Pain is one of the most common and distressing symptoms reported by adolescents with cancer. Despite advancements in pain assessment and management research, pain due to cancer and/or its treatments ...continues to be poorly managed. Our research group has developed a native iPhone application (app) called Pain Squad to tackle the problem of poorly managed pain in the adolescent with cancer group. The app functions as an electronic pain diary and is unique in its ability to collect data on pain intensity, duration, location, and the impact pain has on an adolescent's life (ie, relationships, school work, sleep, mood). It also evaluates medications and other physical and psychological pain management strategies used. Users are prompted twice daily at configurable times to complete 20 questions characterizing their pain and the app transmits results to a database for aggregate reporting through a Web interface. Each diary entry represents a pain case filed by an adolescent with cancer and a reward system (ie, moving up through law-enforcement team ranks, built-in videotaped acknowledgements from fictitious officers) encourages consistent use of the diary.
Our objective was to design, develop, and test the usability, feasibility, compliance, and satisfaction of a game-based smartphone pain assessment tool for adolescents with cancer.
We used both low- and high-fidelity qualitative usability testing with qualitative semi-structured, audio-taped interviews and iterative cycles to design and refine the iPhone based Pain Squad app. Qualitative thematic analysis of interviews using constant comparative methodology captured emergent themes related to app usability. Content validity was assessed using question importance-rating surveys completed by participants. Compliance and satisfaction data were collected following a 2-week feasibility trial where users were alarmed to record their pain twice daily on the app.
Thematic analysis of usability interviews showed the app to be appealing overall to adolescents. Analyses of both low- and high-fidelity testing resulted in minor revisions to the app to refine the theme and improve its usability. Adolescents resoundingly endorsed the game-based nature of the app and its virtual reward system. The importance of app pain diary questions was established by content validity analysis. Compliance with the app, assessed during feasibility testing, was high (mean 81%, SD 22%) and adolescents from this phase of the study found the app likeable, easy to use, and not bothersome to complete.
A multifaceted usability approach demonstrated how the Pain Squad app could be made more appealing to children and adolescents with cancer. The game-based nature and built-in reward system of the app was appealing to adolescents and may have resulted in the high compliance rates and satisfaction ratings observed during clinical feasibility testing.
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