Among patients in whom childhood cancer was diagnosed in the 1970s and 1980s, 18% of those who survived for 5 years died within the subsequent 25 years. In recent decades, cancer treatments have been ...modified with the goal of reducing life-threatening late effects.
We evaluated late mortality among 34,033 patients in the Childhood Cancer Survivor Study cohort who survived at least 5 years after childhood cancer (i.e., cancer diagnosed before the age of 21 years) for which treatment was initiated during the period from 1970 through 1999. The median follow-up was 21 years (range, 5 to 38). We evaluated demographic and disease factors that were associated with death from health-related causes (i.e., conditions that exclude recurrence or progression of the original cancer and external causes but include the late effects of cancer therapy) using cumulative incidence and piecewise exponential models to estimate relative rates and 95% confidence intervals.
Of the 3958 deaths that occurred during the study period, 1618 (41%) were attributable to health-related causes, including 746 deaths from subsequent neoplasms, 241 from cardiac causes, 137 from pulmonary causes, and 494 from other causes. A reduction in 15-year mortality was observed for death from any cause (from 12.4% in the early 1970s to 6.0% in the 1990s, P<0.001 for trend) and from health-related causes (from 3.5% to 2.1%, P<0.001 for trend). These reductions were attributable to decreases in the rates of death from subsequent neoplasm (P<0.001), cardiac causes (P<0.001), and pulmonary causes (P=0.04). Changes in therapy according to decade included reduced rates of cranial radiotherapy for acute lymphoblastic leukemia (85% in the 1970s, 51% in the 1980s, and 19% in the 1990s), of abdominal radiotherapy for Wilms' tumor (78%, 53%, and 43%, respectively), of chest radiotherapy for Hodgkin's lymphoma (87%, 79%, and 61%, respectively), and of anthracycline exposure. Reduction in treatment exposure was associated with reduced late mortality among survivors of acute lymphoblastic leukemia and Wilms' tumor.
The strategy of lowering therapeutic exposure has contributed to an observed decline in late mortality among 5-year survivors of childhood cancer. (Funded by the National Cancer Institute and the American Lebanese-Syrian Associated Charities.).
The American Cancer Society (ACS) recommends that individuals with a cervix initiate cervical cancer screening at age 25 years and undergo primary human papillomavirus (HPV) testing every 5 years ...through age 65 years (preferred); if primary HPV testing is not available, then individuals aged 25 to 65 years should be screened with cotesting (HPV testing in combination with cytology) every 5 years or cytology alone every 3 years (acceptable) (strong recommendation). The ACS recommends that individuals aged >65 years who have no history of cervical intraepithelial neoplasia grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening (qualified recommendation). These new screening recommendations differ in 4 important respects compared with the 2012 recommendations: 1) The preferred screening strategy is primary HPV testing every 5 years, with cotesting and cytology alone acceptable where access to US Food and Drug Administration‐approved primary HPV testing is not yet available; 2) the recommended age to start screening is 25 years rather than 21 years; 3) primary HPV testing, as well as cotesting or cytology alone when primary testing is not available, is recommended starting at age 25 years rather than age 30 years; and 4) the guideline is transitional, ie, options for screening with cotesting or cytology alone are provided but should be phased out once full access to primary HPV testing for cervical cancer screening is available without barriers. Evidence related to other relevant issues was reviewed, and no changes were made to recommendations for screening intervals, age or criteria for screening cessation, screening based on vaccination status, or screening after hysterectomy. Follow‐up for individuals who screen positive for HPV and/or cytology should be in accordance with the 2019 American Society for Colposcopy and Cervical Pathology risk‐based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors.
No studies have estimated the population-level burden of morbidity in individuals diagnosed with cancer as children (ages 0-19 years). We updated prevalence estimates of childhood cancer survivors as ...of 2011 and burden of morbidity in this population reflected by chronic conditions, neurocognitive dysfunction, compromised health-related quality of life, and health status (general health, mental health, functional impairment, functional limitations, pain, and fear/anxiety).
Surveillance, Epidemiology, and End Results (SEER) Program data from 1975 to 2011 were used to update the prevalence of survivors of childhood cancers in the United States. Childhood Cancer Survivor Study data were used to obtain estimates of morbidity burden indicators, which were then extrapolated to SEER data to obtain population-level estimates.
There were an estimated 388,501 survivors of childhood cancer in the United States as of January 1, 2011, of whom 83.5% are ≥5 years after diagnosis. The prevalence of any chronic condition among ≥5-year survivors ranged from 66% (ages 5-19) to 88% (ages 40-49). Estimates for specific morbidities ranged from 12% (pain) to 35% (neurocognitive dysfunction). Generally, morbidities increased by age. However, mental health and anxiety remained fairly stable, and neurocognitive dysfunction exhibited initial decline and then remained stable by time since diagnosis.
The estimated prevalence of survivors of childhood cancer is increasing, as is the estimated prevalence of morbidity in those ≥5 years after diagnosis.
Efforts to understand how to effectively decrease morbidity burden and incorporate effective care coordination and rehabilitation models to optimize longevity and well-being in this population should be a priority.
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.
Summary Background The effect of many contemporary chemotherapeutic drugs on pregnancy and livebirth is not well established. We aimed to establish the effects of these drugs on pregnancy in male and ...female survivors of childhood cancer not exposed to pelvic or cranial radiotherapy. Methods We used data from a subset of the Childhood Cancer Survivor Study cohort, which followed 5-year survivors of the most common types of childhood cancer who were diagnosed before age 21 years and treated at 27 institutions in the USA and Canada between 1970 and 1999. We extracted doses of 14 alkylating and similar DNA interstrand crosslinking drugs from medical records. We used sex-specific Cox models to establish the independent effects of each drug and the cumulative cyclophosphamide equivalent dose of all drugs in relation to pregnancies and livebirths occurring between ages 15 years and 44 years. We included siblings of survivors as a comparison group. Findings We included 10 938 survivors and 3949 siblings. After a median follow-up of 8 years (IQR 4–12) from cohort entry or at age 15 years, whichever was later, 4149 (38%) survivors reported having or siring a pregnancy, of whom 3453 (83%) individuals reported at least one livebirth. After a median follow-up of 10 years (IQR 6–15), 2445 (62%) siblings reported having or siring a pregnancy, of whom 2201 (90%) individuals reported at least one livebirth. In multivariable analysis, survivors had a decreased likelihood of siring or having a pregnancy versus siblings (male survivors: hazard ratio HR 0·63, 95% CI 0·58–0·68; p<0·0001; female survivors: 0·87, 0·81–0·94; p<0·0001) or of having a livebirth (male survivors: 0·63, 0·58–0·69; p<0·0001; female survivors: 0·82, 0·76–0·89; p<0·0001). In male survivors, reduced likelihood of pregnancy was associated with upper tertile doses of cyclophosphamide (HR 0·60, 95% CI 0·51–0·71; p<0·0001), ifosfamide (0·42, 0·23–0·79; p=0·0069), procarbazine (0·30, 0·20–0·46; p<0·0001) and cisplatin (0·56, 0·39–0·82; p=0·0023). Cyclophosphamide equivalent dose in male survivors was significantly associated with a decreased likelihood of siring a pregnancy (per 5000 mg/m2 increments: HR 0·82, 95% CI 0·79–0·86; p<0·0001). However, in female survivors, only busulfan (<450 mg/m2 HR 0·22, 95% CI 0·06–0·79; p=0·020; ≥450 mg/m2 0·14, 0·03–0·55; p=0·0051) and doses of lomustine equal to or greater than 411 mg/m2 (0·41, 0·17–0·98; p=0·046) were significantly associated with reduced pregnancy; cyclophosphamide equivalent dose was associated with risk only at the highest doses in analyses categorised by quartile (upper quartile vs no exposure: HR 0·85, 95% CI 0·74–0·98; p=0·023). Results for livebirth were similar to those for pregnancy. Interpretation Greater doses of contemporary alkylating drugs and cisplatin were associated with a decreased likelihood of siring a pregnancy in male survivors of childhood cancer. However, our findings should provide reassurance to most female survivors treated with chemotherapy without radiotherapy to the pelvis or brain, given that chemotherapy-specific effects on pregnancy were generally few. Nevertheless, consideration of fertility preservation before cancer treatment remains important to maximise the reproductive potential of all adolescents newly diagnosed with cancer. Funding National Cancer Institute, National Institutes of Health, and the American Lebanese–Syrian Associated Charities.
The first generation of childhood cancer survivors is now aging into their fourth and fifth decades of life, yet health risks across the aging spectrum are not well established.
Analyses included ...14,359 5-year survivors from the Childhood Cancer Survivor Study, who were first diagnosed when they were younger than 21 years old and who received follow-up for a median of 24.5 years after diagnosis (range, 5.0 to 39.3 years) along with 4,301 of their siblings. Among the survivors, 5,604 were at least 35 years old (range, 35 to 62 years) at last follow-up. Severe, disabling, life-threatening, and fatal health conditions more than 5 years from diagnosis were classified using the Common Terminology Criteria for Adverse Events, grades 3 to 5 (National Cancer Institute).
The cumulative incidence of a severe, disabling, life-threatening, or fatal health condition was greater among survivors than siblings (53.6%; 95% CI, 51.5 to 55.6; v 19.8%; 95% CI, 17.0 to 22.7) by age 50 years. When comparing survivors with siblings, hazard ratios (HR) were significantly increased within the age group of 5 to 19 years (HR, 6.8; 95% CI, 5.5 to 8.3), age group of 20 to 34 years (HR, 3.8; 95% CI, 3.2 to 4.5), and the ≥ 35 years group (HR, 5.0; 95% CI, 4.1 to 6.1), with the HR significantly higher among those ≥ 35 years versus those 20 to 34 years old (P = .03). Among survivors who reached age 35 years without a previous grade 3 or 4 condition, 25.9% experienced a subsequent grade 3 to 5 condition within 10 years, compared with 6.0% of siblings (P < .001).
Elevated risk for morbidity and mortality among survivors increases further beyond the fourth decade of life, which affects the future clinical demands of this population relative to ongoing surveillance and interventions.
Cardiovascular disease is a competing cause of death in patients with cancer with early-stage disease. This elevated cardiovascular disease risk is thought to derive from both the direct effects of ...cancer therapies and the accumulation of risk factors such as hypertension, weight gain, cigarette smoking, and loss of cardiorespiratory fitness. Effective and viable strategies are needed to mitigate cardiovascular disease risk in this population; a multimodal model such as cardiac rehabilitation may be a potential solution. This statement from the American Heart Association provides an overview of the existing knowledge and rationale for the use of cardiac rehabilitation to provide structured exercise and ancillary services to cancer patients and survivors. This document introduces the concept of cardio-oncology rehabilitation, which includes identification of patients with cancer at high risk for cardiac dysfunction and a description of the cardiac rehabilitation infrastructure needed to address the unique exposures and complications related to cancer care. In this statement, we also discuss the need for future research to fully implement a multimodal model of cardiac rehabilitation for patients with cancer and to determine whether reimbursement of these services is clinically warranted.
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