Late Effects Of Cancer Therapy Research Articles

Barriers to Receiving Follow-up Care Among Childhood Cancer Survivors.

Little is known on why adherence to follow-up care in childhood cancer survivors (CCS) is lacking. This study characterized barriers to adherence to follow-up care among CCS, identified sociodemographic correlates of barriers, and examined whether barriers to follow-up care relate to health-related quality of life. Adult CCS (N=84) were anonymously surveyed via REDCap using the Barriers to Care Questionnaire (BCQ) and the Quality of Life Scale-Cancer Survivor (QOL-CS). Both descriptive and correlation analyses were conducted. The median BCQ total score was 88.5 (interquartile ranges:78.4 to 95.7), with the greatest barriers reported in the Skills (eg, ease of navigating the healthcare system) and Pragmatism subscales (eg, cost). There was a statistically significant correlation between the BCQ total score and the QOL-CS total score (rs=0.47, P <0.0001) and the physical, psychological, and social QOL-CS subscales (all P 's<0.05). The results found that barriers to follow-up care for CCS are mostly related to cost and appointment logistics, and that more barriers to care is associated with lower health-related quality of life among CCS. Identifying barriers to follow-up care is the first step in improving adherence, which would allow for earlier detection of late effects of cancer therapy and thereby result in reductions in morbidity and mortality.

OUTC-04. SUBSEQUENT CNS MALIGNANCY AMONG SURVIVORS OF CHILDHOOD CANCER: A REPORT FROM THE CHILDHOOD CANCER SURVIVOR STUDY (CCSS)

Abstract Subsequent malignant neoplasms (SMNs) of the central nervous system (CNS) following childhood cancer are a frequently fatal late effect of cancer therapy. We used the CCSS (5-year childhood cancer survivors, diagnosed 1970-1999) to assess whether temporal changes in therapy have reduced CNS SMN risk. Twenty-year cumulative incidence rates (95% confidence interval) were estimated, and standardized incidence ratios (SIR, 95% CI) were calculated comparing observed to expected rates from SEER. Multivariable models assessed demographic and treatment-related risk factors for CNS SMN. Among survivors diagnosed between 1970-1979 (N=6223), 1980-1989 (N=9680), and 1990–1999 (N=8999) with median follow-up of 40.5, 32.2, and 22.6 years, respectively, 157 CNS SMNs (1970s, 52; 1980s, 63; 1990s, 42) were identified, excluding meningiomas. Malignant gliomas (N=131) were the most common SMNs. Cranial radiotherapy (CRT) exposure decreased by treatment decade, with the proportion of survivors receiving no CRT increasing from 23.0% (1970s), to 45.7% (1980s), and 66% (1990s). Decreases in &amp;gt;0–10Gy exposure (39.0% to 14.1%) and 20.1–30Gy (19.2% to 2.4%) were observed while those receiving &amp;gt;30Gy CRT has not substantially changed (12%, 11.1%, and 8.8%, respectively). Twenty-year cumulative incidence and SIR for development of SMN were 0.32% (0.18-0.46%) and 6.6 (5.0–8.7); 0.55% (0.41-0.70%) and 8.3 (6.6-10.4); and 0.43% (0.31-0.55%) and 9.2 (7.0–12.0), respectively, with no statistically significant differences between treatment eras, including when stratified by attained age. Multivariate analysis showed increased risk for all CRT dose levels &amp;gt;10Gy and for primary diagnoses of medulloblastoma/PNET (HR 3.6, 2.0-6.6) and astrocytoma (HR 2.4, 1.4-3.9). Three-year cumulative incidences of death after SMN, by treatment decade, were 70%, 73%, and 69%, respectively. In conclusion, CNS SMN incidence has not decreased despite fewer survivors being treated with CRT, and CNS SMNs remain a significant source of mortality for affected patients.

Cost-Effectiveness of Blinatumomab in Pediatric Patients with High-Risk First-Relapse B-Cell Precursor Acute Lymphoblastic Leukemia in France.

Based on the results of the phase III randomized 20120215 trial, the European Medicines Agency granted the approval of blinatumomab for the treatment of pediatric patients with high-risk first-relapsed Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (ALL). In France, blinatumomab received reimbursement for this indication in May 2022. This analysis assessed the cost effectiveness of blinatumomab compared with high-risk consolidation chemotherapy (HC3) in this indication from a French healthcare and societal perspective. A partitioned survival model with three health states (event-free, post-event and death) was developed to estimate life-years (LYs), quality-adjusted life-years (QALYs) and costs over a lifetime horizon. Patients who were alive after 5 years were considered to be cured. An excess mortality rate was applied to capture the late effects of cancer therapy. Utility values were based on the TOWER trial using French tariffs, and cost input data were identified from French national public health sources. The model was validated by clinical experts. Treatment with blinatumomab over HC3 was estimated to provide gains of 8.39 LYs and 7.16 QALYs. Total healthcare costs for blinatumomab and HC3 were estimated to be €154,326 and €102,028, respectively, resulting in an increment of €52,298. The incremental cost-effectiveness ratio was estimated to be €7308 per QALY gained from a healthcare perspective. Results were robust to sensitivity analyses, including analysis from the societal perspective. Blinatumomab administered as part of consolidation therapy in pediatric patients with high-risk first-relapsed ALL is cost effective compared with HC3 from the French healthcare and societal perspective.

Specific causes of excess late mortality and association with modifiable risk factors among survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort

5-year survival after childhood cancer does not fully describe life-years lost due to childhood cancer because there are a large number of deaths occurring beyond 5-years (late mortality) related to cancer and cancer treatment. Specific causes of health-related (non-recurrence, non-external) late mortality and risk reduction through modifiable lifestyle and cardiovascular risk factors are not well described. Through using a well-characterised cohort of 5-year survivors of the most common childhood cancers, we evaluated specific health-related causes of late mortality and excess deaths compared with the general US population and identified targets to reduce future risk. In this multi-institutional, hospital-based, retrospective cohort study, late mortality (death ≥5 years from diagnosis) and specific causes of death were evaluated in 34 230 5-year survivors of childhood cancer diagnosed at an age younger than 21 years from 1970 to 1999 at 31 institutions in the USA and Canada; median follow-up from diagnosis was 29 years (range 5-48) in the Childhood Cancer Survivor Study. Demographic, self-reported modifiable lifestyle (ie, smoking, alcohol, physical activity, and BMI) and cardiovascular risk factors (ie, hypertension, diabetes, and dyslipidaemia) associated with health-related mortality (which excludes death from primary cancer and external causes and includes death from late effects of cancer therapy) were evaluated. 40-year cumulative all-cause mortality was 23·3% (95% CI 22·7-24·0), with 3061 (51·2%) of 5916 deaths from health-related causes. Survivors 40 years or more from diagnosis experienced 131 excess health-related deaths per 10 000 person-years (95% CI 111-163), including those due to the top three causes of health-related death in the general population: cancer (absolute excess risk per 10 000 person-years 54, 95% CI 41-68), heart disease (27, 18-38), and cerebrovascular disease (10, 5-17). Healthy lifestyle and absence of hypertension and diabetes were each associated with a 20-30% reduction in health-related mortality independent of other factors (all p values ≤0·002). Survivors of childhood cancer are at excess risk of late mortality even 40 years from diagnosis, due to many of the leading causes of death in the US population. Modifiable lifestyle and cardiovascular risk factors associated with reduced risk for late mortality should be part of future interventions. US National Cancer Institute and the American Lebanese Syrian Associated Charities.

A Pediatric Case of Treatment-related Myelodysplastic Syndrome While on Therapy for Pre-B Acute Lymphoblastic Leukemia.

Treatment-related myelodysplastic syndrome (t-MDS) is a rare late effect of cancer therapy. After alkylating agents, this typically occurs years after completion of therapy. Treatment of t-MDS in pediatrics is an allogeneic stem cell transplant, however, the prognosis remains poor. This case demonstrates t-MDS developing in a patient receiving treatment for pre-B acute lymphoblastic leukemia. This patient was treated with a combination of hematopoietic stem cell transplant and hypomethylating agents. These agents should be considered for use in patients with t-MDS, before transplant to limit additional chemotherapy and as maintenance therapy post-transplant to reduce the risk of relapse.

Standardization of Fertility Preservation Discussion Among Pediatric Oncology and Bone Marrow Transplant Patients: A Single Institution Experience.

Purpose: Infertility is an impactful late effect of cancer therapy. Options for fertility preservation exist, however, barriers remain. Within our division, we lacked a standard approach to discussing fertility preservation. Methods: During the time period of 2014-2020, a fertility preservation program was developed with program improvements implemented over time and provider comfort with fertility identified and addressed through educational intervention. To evaluate how our improvements affected frequency of documented reproductive health discussions, 474 pubertal pediatric patients with new oncological diagnoses were reviewed. Descriptive analysis of sociodemographic determinants was performed. Results: One hundred seventy-five patients met inclusion criteria. Racial/ethnic composition was similar in those receiving and not receiving a fertility consult. Although 19.3% of Caucasians pursued fertility preservation, none of the eight African Americans or five Hispanic females did. Division feedback identified a lack of knowledge regarding available fertility preservation options and diagnoses that should prompt this conversation as barriers to the consulting fertility preservation team. Pre- and posteducation assessments demonstrated increased comfort in discussing fertility preservation and knowledge regarding diagnoses at higher risk of infertility. Integration of a standardized fertility preservation process and addressing barriers identified led to a 33.6% increase in fertility discussions. Conclusion: The establishment of a fertility preservation process and team and division-wide education has led to improvement in rates of fertility discussion in pediatric and adolescent and young adult cancer patients. Similar to young adult data, our data suggest that some racial health disparities may exist in the utilization of fertility preservation in the pediatric oncology population.

Late side effects of cancer treatment in childhood cancer survivors.

Childhood cancers are usually treated with chemotherapy and radiation. Therefore, understanding the late side effects of such treatments is important to improve the quality of life in childhood cancer survivors. The present study aimed to investigate the late complications of treatments in childhood cancer survivors. This study is a retrospective descriptive study. A total number of 93 cases were enrolled in this study. These cases had a history of childhood cancer documented in their medical records at the Shafa Hospital, Ahvaz, Iran. The age range was 5.9-21.3 years and included 62 males and 31 female patients. Many of the patients at this hospital with childhood cancer had experienced chemotherapy side effects as well as late effects of cancer therapy. Hypothyroidism is a late complication of therapy in thoracic cancers and head/neck tumors with relative frequencies of 23.1% and 12.5%, respectively. Scoliosis was observed in the patients undergoing the ABVD + COPP and 8/1 regimens with relative frequencies of 4% and 50%, respectively. Lower growth percentiles were also late side effects of cancer therapy. The highest relative frequency of growth retardation was observed in the <5 age group (46.7%). Restrictive lung changes had an overall relative frequency of 6.5% in male patients with all types of tumors. Sensorineural hearing loss was observed in patients with leukemia and Hodgkin lymphoma with relative frequencies of 8.7% and 24.0, respectively. The occurrence of most side effects could be decreased through early diagnosis, dose adjustment of some drugs, and preventative measures.

Advanced glycation end products and their related signaling cascades in adult survivors of childhood Hodgkin lymphoma: A possible role in the onset of late complications

Hodgkin lymphoma (HL) is today one of the most curable pediatric cancers. Despite survival rates now exceeding 90%, survivors of pediatric HL are still at higher risk to develop late effects of cancer therapy. Premature aging has been proposed as a paradigm to explain the onset of long-term complications in these subjects. High levels of advanced glycation end products (AGEs), together with chronic inflammation and oxidative unbalance, have been shown to be among the main factors contributing to aging. The present study aims to evaluate glycoxydation, inflammatory status, and oxidative stress in plasma and peripheral blood mononuclear cells (PBMC) obtained from 20 adult survivors of pediatric HL and 40 age- and sex-matched healthy controls. After the isolation of PBMC and the collection of plasma, we performed the analyses of gene expression by qRT-PCR and measured inflammatory and oxidative-stress markers. AGEs plasma levels, expressed as Nϵ-carboxymethyl-lysine and methylglyoxal hydroimidazolone, were markedly higher in HL survivors than in healthy subjects. HL survivors also showed a condition of higher oxidative stress, as demonstrated by an increased expression of NADPH oxidase on PBMC. Antioxidant defenses, evaluated in terms of alpha-tocopherol, GSSG/GSH ratio and catalase plasma levels, were strongly impaired in survivors. This pro-oxidative condition led to the over-expression of both NLRP3 and NFkB genes in PBMC and, consequently, to increased plasma levels of interleukin(IL)-1β and IL-6. Finally, the expression of the receptors for AGEs in PBMC confirmed the dysregulated AGE pathways. Data show AGEs accumulation in survivors of pediatric HL. The consequent activation of the receptor for AGEs leads to the persistent activation of intracellular signaling toward inflammation. These results suggest that the co-existence of AGEs accumulation, unbalanced oxidative status, and inflammation could play a role in the onset of late complications in HL survivors.

Possible Mechanisms of Subsequent Neoplasia Development in Childhood Cancer Survivors: A Review.

Simple SummaryDue to improvements in the treatment of childhood cancer, around 80% of children are cured. However, childhood cancer survivors are at risk of developing late effects, including subsequent malignant neoplasm; these are defined as histologically different cancers, which appear after treatment for primary cancer. The risk of subsequent malignant neoplasm formation is influenced mainly by previous anticancer therapy (chemotherapy, radiotherapy, immunotherapy, and targeted therapy), genetic factors, and the length of survival. For these reasons, at present, for the treatment of tumors with a good prognosis, it is important to consider the possible risk of late side effects e.g. use of radiotherapy in Hodgkin’s lymphoma only if chemotherapy does not induce complete remission or in nephroblastoma only in locally advanced stages. Therefore, we study risk factors for the development of subsequent malignant neoplasm. In the review, we present possible risk factors for the development of subsequent neoplasm. Advances in medicine have improved outcomes in children diagnosed with cancer, with overall 5-year survival rates for these children now exceeding 80%. Two-thirds of childhood cancer survivors have at least one late effect of cancer therapy, with one-third having serious or even life-threatening effects. One of the most serious late effects is a development of subsequent malignant neoplasms (histologically different cancers, which appear after the treatment for primary cancer), which occur in about 3–10% of survivors and are associated with high mortality. In cancers with a very good prognosis, subsequent malignant neoplasms significantly affect long-term survival. Therefore, there is an effort to reduce particularly hazardous treatments. This review discusses the importance of individual factors (gender, genetic factors, cytostatic drugs, radiotherapy) in the development of subsequent malignant neoplasms and the possibilities of their prediction and prevention in the future.

Patient preferences for cancer survivorship care: Results of an online survey.

12064 Background: Nearly 17 million cancer survivors live in the United States. Workforce shortages are projected to diminish the number of available medical oncologists (MOs) to care for newly diagnosed patients with cancer and for the growing number of cancer survivors. Models of survivorship care include oncologist-led, primary care-led, and shared care approaches. Recent proposals recommend a risk-stratified approach to care, guided by individual and cancer-specific factors, but there is little evidence regarding patient preferences for non-oncologist survivorship care. Methods: We developed a survey in partnership with patient advocates. The primary endpoints were patient-reported comfort with survivorship care by a primary care provider (PCP) or in a dedicated survivorship clinic. We distributed the survey to online, cancer-specific patient communities from June to August 2020. Logistic regression analyses were adjusted for patient age, race and ethnicity, insurance, and cancer type and stage. Results: Of 1166 responses, 975 surveys were complete and available for analysis. Respondents were primarily women (91%), white (92%), and US residents (73%); 78% had a college or graduate degree. Two-thirds had private insurance. Thirty-six different cancer types were reported; 61% of respondents had breast cancer, and 25% were treated for more than one type of cancer. Most respondents (83%) had nonmetastatic disease, 74% reported experiencing late effects of cancer therapy, and almost all (93%) had a PCP. Only 21% of respondents were comfortable seeing a PCP (versus MO) for survivorship care, including cancer follow-up, side effect management, and monitoring for recurrence or progression. About half (55%) were comfortable with follow-up in a survivorship clinic instead of with their MO. Multivariable analyses showed no significant associations between age, race or ethnicity, insurance, cancer type, or stage at diagnosis and comfort with follow-up care from a PCP or in a survivorship clinic. In analyses restricted to the 439 respondents with a history of early-stage breast cancer, the 239 (54%) who were within 1 to 5 years of diagnosis were less comfortable with PCP versus MO follow-up, compared with the 52 (12%) who were &gt; 15 years from diagnosis (OR 0.40; 95% CI 0.20–0.75; p= 0.004). In this sub-analysis, time from diagnosis was not associated with comfort being seen in a survivorship clinic. Conclusions: In our study, most patients with a history of cancer were not comfortable receiving follow-up care from their PCP. It is often recommended that survivors of early-stage breast cancer transition to primary care for follow-up and surveillance, but our study revealed comfort with this approach only many years after diagnosis. While both PCP survivorship training and patient confidence in PCP follow up is needed, preferences of cancer survivors should be considered in designing new models of survivorship care.

Late effects of radiation therapy in pediatric patients and survivorship.

Advances in multimodality therapy have led to childhood cancer cure rates over 80%. However, surgery, chemotherapy, and radiotherapy may lead to debilitating or even fatal long-term effects among childhood survivors beyond those inflicted by the primary disease process. It is critical to understand, mitigate, and prevent these late effects of cancer therapy to improve the quality of life of childhood cancer survivors. This review summarizes the various late effects of radiotherapy and acknowledges the Pediatric Normal Tissue Effects in the Clinic (PENTEC), an international collaboration that is systematically analyzing the association between radiation treatment dose/volume and consequential organ toxicities, in developing children as a basis to formulate recommendations for clinical practice of pediatric radiation oncology. We also summarize initiatives for survivorship and surveillance of late normal tissue effects related to radiation therapy among long-term survivors of childhood cancer treated in the past.

Reduced Morbidity and Mortality in Survivors of Childhood Acute Lymphoblastic Leukemia: A Report From the Childhood Cancer Survivor Study.

Risk-stratified therapy, which modifies treatment on the basis of clinical and biologic features, has improved 5-year overall survival of childhood acute lymphoblastic leukemia (ALL) to 90%, but its impact on long-term toxicity remains unknown. We assessed all-cause and health-related late mortality (including late effects of cancer therapy), subsequent malignant neoplasms (SMNs), chronic health conditions, and neurocognitive outcomes among 6,148 survivors of childhood ALL (median age, 27.9 years; range, 5.9-61.9 years) diagnosed between 1970 and 1999. Therapy combinations and treatment intensity defined 6 groups: 1970s-like (70s), standard- or high-risk 1980s-like (80sSR, 80sHR) and 1990s-like (90sSR, 90sHR), and relapse/transplantation (R/BMT). Cumulative incidence, standardized mortality ratios, and standardized incidence ratios were compared between treatment groups and with the US population. Overall, 20-year all-cause late mortality was 6.6% (95% CI, 6.0 to 7.1). Compared with 70s, 90sSR and 90sHR experienced lower health-related late mortality (rate ratio [95% CI]: 90sSR, 0.2 [0.1 to 0.4]; 90sHR, 0.3 [0.1 to 0.7]), comparable to the US population (standardized mortality ratio [95% CI]: 90sSR, 1.3 [0.8 to 2.0]; 90sHR, 1.7 [0.7 to 3.5]). Compared with 70s, 90sSR had a lower rate of SMN (rate ratio [95% CI], 0.3 [0.1 to 0.6]) that was not different from that of the US population (standardized incidence ratio [95% CI], 1.0 [0.6 to 1.6]). The 90sSR group had fewer severe chronic health conditions than the 70s (20-year cumulative incidence [95% CI], 11.0% [9.7% to 12.3%] v 22.5% [19.4% to 25.5%]) and a lower prevalence of impaired memory (prevalence ratio [95% CI], 0.7 [0.6 to 0.9]) and task efficiency (0.5 [0.4 to 0.7]). Risk-stratified therapy has reduced late morbidity and mortality among contemporary survivors of standard-risk ALL, represented by 90sSR. Health-related late mortality and SMN risks among 5-year survivors of contemporary, standard-risk childhood ALL are comparable to the general population.

Late mortality and chronic health conditions in long-term survivors of early-adolescent and young adult cancers: a retrospective cohort analysis from the Childhood Cancer Survivor Study.

Treatment outcomes among survivors of cancer diagnosed during adolescence and early young adulthood have not been characterised independently of survivors of cancers diagnosed during childhood. We aimed to describe chronic health conditions and all-cause and cause-specific mortality among survivors of early-adolescent and young adult cancer. The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort study with longitudinal follow-up of 5-year survivors diagnosed with cancer before the age of 21 years at 27 academic institutions in the USA and Canada between 1970 and 1999. We evaluated outcomes among survivors of early-adolescent and young adult cancer (aged 15-20 years at diagnosis) and survivors diagnosed at age younger than 15 years (matched on primary cancer diagnosis, including leukaemia, lymphoma, CNS tumours, neuroblastoma, Wilms tumour, soft-tissue sarcomas, and bone cancer) by comparing both groups to siblings of the same age. Mortality was ascertained with the National Death Index. Chronic health conditions were classified with the Common Terminology Criteria for Adverse Events. Standardised mortality ratios (SMRs) were estimated with age-specific, sex-specific, and calendar year-specific US rates. Cox proportional hazard models estimated hazard ratios (HRs) for chronic health conditions and 95% CIs. Among 5804 early-adolescent and young adult survivors (median age 42 years, IQR 34-50) the SMR compared to the general population for all-cause mortality was 5·9 (95% CI 5·5-6·2) and among 5804 childhood cancer survivors (median age 34 years; 27-42), it was 6·2 (5·8-6·6). Early-adolescent and young adult survivors had lower SMRs for death from health-related causes (ie, conditions that exclude recurrence or progression of the primary cancer and external causes, but include the late effects of cancer therapy) than did childhood cancer survivors (SMR 4·8 [95% CI 4·4-5·1] vs 6·8 [6·2-7·4]), which was primarily evident more than 20 years after cancer diagnosis. Early-adolescent and young adult cancer survivors and childhood cancer survivors were both at greater risk of developing severe and disabling, life-threatening, or fatal (grade 3-5) health conditions than siblings of the same age (HR 4·2 [95% CI 3·7-4·8] for early adolescent and young adult cancer survivors and 5·6 [4·9-6·3] for childhood cancer survivors), and at increased risk of developing grade 3-5 cardiac (4·3 [3·5-5·4] and 5·6 [4·5-7·1]), endocrine (3·9 [2·9-5·1] and 6·4 [5·1-8·0]), and musculoskeletal conditions (6·5 [3·9-11·1] and 8·0 [4·6-14·0]) when compared with siblings of the same age, although all these risks were lower for early-adolescent and young adult survivors than for childhood cancer survivors. Early-adolescent and young adult cancer survivors had higher risks of mortality and severe and life threatening chronic health conditions than the general population. However, early-adolescent and young adult cancer survivors had lower non-recurrent, health-related SMRs and relative risks of developing grade 3-5 chronic health conditions than childhood cancer survivors, by comparison with siblings of the same age, which were most notable more than 20 years after their original cancer. These results highlight the need for long-term screening of both childhood and early-adolescent and young adult cancer survivors. National Cancer Institute and American Lebanese-Syrian Associated Charities.

Diabetes risk in childhood cancer survivors: A population-based study

Abstract Objective With continued improvements in survival following childhood cancer, the long-term health consequences of cancer treatments are receiving greater focus. Diabetes is emerging as a potential late effect of cancer therapy; however, the magnitude of risk has not been well established. The goal of our study was to evaluate the risk for diabetes in childhood cancer survivors in Ontario using validated population-based databases. Methods We used provincial administrative health databases to compare the rate of diabetes in childhood cancer survivors and controls from the general population. Diabetes was measured using a validated algorithm. We used a cause-specific hazard regression model in which death and development of another cancer were treated as competing risks. Results We identified 10,438 1-year survivors of childhood cancer that were diagnosed before age 21 between January 1, 1990, and December 31, 2010. The mean follow up was 11.2 years (standard deviation, 6.9). Cancer survivors had a 55% increased rate of developing diabetes compared with matched controls (HR 1.51, 95% CI 1.28 to 1.78) in models adjusted for rurality and income. Individuals treated for cancer between ages 6 and 10 had the highest increased rates of diabetes (HR 3.89, CI 2.26 to 6.68). Among cancer types, leukemia and lymphoma were associated with the greatest increased risk for diabetes. Conclusions Our study supports evidence of an increased risk for diabetes in survivors of childhood cancer. Future research is warranted for better identification of treatment-related risk factors for diabetes in this population.

Aspirin ameliorates the long-term adverse effects of doxorubicin through suppression of cellular senescence.

A number of childhood cancer survivors develop adverse, late onset side effects of earlier cancer treatments, known as the late effects of cancer therapy. As the number of survivors continues to increase, this growing population is at increased risk for a number of health‐related problems. In the present study, we have examined the effect of aspirin on the late effects of chemotherapy by treating juvenile mice with doxorubicin (DOX). This novel mouse model produced various long‐term adverse effects, some of which resemble premature aging phenotypes. DOX also resulted in the tissue accumulation of senescent cells and up‐regulation of cyclooxygenase‐2 (COX2) expression. However, treatment with aspirin following juvenile exposure to DOX improved body weight gain, ameliorated the long‐term adverse effects, and reduced the levels of senescence markers. Moreover, aspirin reduced p53 and p21 accumulation in DOX‐treated human and mouse fibroblasts. However, the suppressive effect of aspirin on DOX‐induced p53 accumulation was significantly decreased in COX2 knockout mouse embryonic fibroblasts. Additionally, treatment of senescent fibroblasts with aspirin or celecoxib, a COX2 specific inhibitor, reduced cell viability and decreased the levels of Bcl‐xL protein. Taken together, these studies suggest that aspirin may be able to reduce the late effects of chemotherapy through the suppression of cellular senescence.

Radiation-Induced Neuropathy - a Late Effect of Cancer Therapy (P3.6-001)

Radiation-Induced Neuropathy - a Late Effect of Cancer Therapy (P3.6-001)

Diabetes Risk in Childhood Cancer Survivors: A Population-Based Study.

With continued improvements in survival following childhood cancer, the long-term health consequences of cancer treatments are receiving greater focus. Diabetes is emerging as a potential late effect of cancer therapy; however, the magnitude of risk has not been well established. The goal of our study was to evaluate the risk for diabetes in childhood cancer survivors in Ontario using validated population-based databases. We used provincial administrative health databases to compare the rate of diabetes in childhood cancer survivors and controls from the general population. Diabetes was measured using a validated algorithm. We used a cause-specific hazard regression model in which death and development of another cancer were treated as competing risks. We identified 10,438 1-year survivors of childhood cancer that were diagnosed before age 21 between January 1, 1990, and December 31, 2010. The mean follow up was 11.2 years (standard deviation, 6.9). Cancer survivors had a 55% increased rate of developing diabetes compared with matched controls (HR 1.51, 95% CI 1.28 to 1.78) in models adjusted for rurality and income. Individuals treated for cancer between ages 6 and 10 had the highest increased rates of diabetes (HR 3.89, CI 2.26 to 6.68). Among cancer types, leukemia and lymphoma were associated with the greatest increased risk for diabetes. Our study supports evidence of an increased risk for diabetes in survivors of childhood cancer. Future research is warranted for better identification of treatment-related risk factors for diabetes in this population.

Late effects of treatment in survivors of childhood cancers: A single-centre experience.

Background & objectives:With improved survival of childhood cancer patients, the number of long-term cancer survivors is increasing. Some studies have assessed the long-term morbidity after childhood cancer treatment in the developing countries. This study was conducted to assess the spectrum of late effects of cancer treatment in paediatric cancer survivors.Methods:Evaluation of the first 300 patients who completed five years of follow up in the after treatment completion clinic was done. Details of primary diagnosis, treatment received and current clinical status were noted. The spectrum of late effects was ascertained by appropriate investigations.Results:Haematological malignancies comprised 25 per cent of total cases. Most common primary diagnosis comprised acute lymphoblastic leukaemia, retinoblastoma and Hodgkin's lymphoma. The median age at evaluation and follow up was 14 and 8.5 yr, respectively. Twenty three per cent (69) of the survivors had a minimal disability (growth retardation or underweight), 13 per cent (39) had moderate disabilities needing medical attention (hepatitis B surface antigen positive, myocardial dysfunction, azoospermia and hypothyroidism), while two per cent had major/life-threatening disabilities (mental retardation, liver disease and mortality). Eleven patients relapsed on follow up, of those five patients expired. Two second malignancies were recorded during the period of follow up.Interpretation & conclusions:Late effects were of concern; however, severe disability (Grade 3-5) was seen in only two per cent survivors. Lifelong follow up of childhood cancer survivors is required to assess cancer-related morbidity, occurrence of a secondary neoplasm, to facilitate timely diagnosis and to implement remedial or preventive interventions to optimize health outcomes. Awareness towards the existence of late effects of cancer therapy is required among parents, patients and health professionals.

Perspectives on the role of bystander effect and genomic instability on therapy-induced secondary malignancy

Deviation from the orchestra of regulated cell division into unregulated and then result into the formation of tumor is known as carcinogenesis. While causes and hallmarks of many cancer types are well established, newer concepts on tumor cell response to treatment, challenges established therapeutic regime and drives into alternative toward the better management. The phenomena of therapeutics induced bystander response, and genomic instability on late effects of cancer therapy is emerging as a newer challenge. Bystander response is defined as the manifestation of radiation/chemotherapy drug signatures on the unexposed cells which are in the closer vicinity of the directly exposed; on the other hand, genomic instability is defined as the expression of radiation/chemotherapy drug signatures in the progeny of exposed cells. Unequivocally, existence of those phenomena has been demonstrated with many cell types (both in vitro and in vivo) followed by radiation and widely used chemotherapeutic drugs. Nevertheless, it is also revealed that the effects are variable and depend on dose, type of radiation/chemicals agents, experimental model, type of donor and recipient cells, and biomarkers adopted; moreover, to observe those effects, reactive oxygen species has been reported as leading mediators of those responses when compared to other molecules such as interleukins, cytokines, and inflammatory markers. Available data on those phenomena and our findings suggest that a role of therapeutic drugs induced bystander effects, and genomic instability on the development of secondary malignancy cannot be ruled out completely.

Smoking, Binge Drinking, and Drug Use Among Childhood Cancer Survivors: A Meta-Analysis.

Childhood cancer survivors are at risk for late effects of therapy, some of which may be exacerbated by smoking, alcohol, or drug use. We undertook a meta-analysis of the literature to determine whether survivors engage in risk-taking behaviors at rates different from their peers/siblings. Studies comparing current engagement in risk-taking behaviors between cancer survivors and siblings or matched peers were identified in MEDLINE (1946-), EMBASE (1947-), PsychINFO (1806-), and the Cochrane Controlled Trials Register. Two reviewers assessed publications for inclusion and extracted data independently. Studies were combined using inverse variance weighting to determine odds ratios (OR) and prevalence rates of risk-taking behaviors in survivors compared to controls. Fourteen of 1,713 studies satisfied inclusion criteria. Twelve assessed smoking, six binge drinking, and seven drug use. Among survivors, 22% (95% confidence interval 0.19, 0.26) smoked, 20% (0.08, 0.51) were binge drinkers, and 15% (0.10, 0.23) used drugs. Survivors were less likely than siblings to smoke (OR 0.68 [0.49, 0.96]) or binge drink (OR 0.77 [0.68, 0.88]), but similarly likely to use drugs (OR 0.33 [0.03, 3.28]). Survivors were less likely than matched peers to smoke (OR 0.54 [0.42, 0.70]) or use drugs (OR 0.57 [0.40, 0.82]), but equally likely to binge drink (OR 0.97 [0.38, 2.49]). Childhood cancer survivors engage in similar or lower rates of risk taking than their siblings/peers. Future studies should identify survivors most likely to benefit from focused interventions, and determine the impact of risk-taking behaviors on the risk for late effects of cancer therapy.