5-year Survivors Of Childhood Cancer Research Articles

Late and very late mortality in 5‐year survivors of childhood cancer: Changing pattern over four decades—Experience from the Nordic countries

Long-term survivors of childhood cancer suffer from a higher mortality than the general population. Here we evaluate late and very late mortality, and patterns of causes of death, in 5-year survivors after childhood and adolescent cancer in cases diagnosed during four decades in the five Nordic countries. The study is population-based and uses data of the nationwide cancer registries and the cause of death registers. There were in all 37,515 incident cases, diagnosed with cancer before the age of 20 years, between 1960 and 1999. The 5-year survivor cohort used in the mortality analyses consisted of 21,984 patients who were followed up for vital status until December 31, 2005 (Norway, Sweden) or 2006 (Denmark, Finland, Iceland). At the latest follow-up, 2,324 patients were dead. The overall standardized mortality ratio was 8.3 and the absolute excess risk was 6.2 per 1,000 person-years. The pattern of causes of death varied markedly between different groups of primary cancer diagnosis, and was highly dependent on time passed since diagnosis. With shorter follow-up the mortality was mainly due to primary cancer, while with longer follow-up, mortality due to second cancer and noncancer causes became more prominent. Mortality between 5 and 10 years after diagnosis continued to decrease in patients treated during the most recent period of time, 1990-1999, compared to previous periods, while mortality after 10 years changed very little with time period. We conclude that improvement of definite survival demands not only reducing early but also late and very late mortality.

Childhood cancer survivors at increased risk for subsequent gastrointestinal and genitourinary neoplasms

Reulen RC, Frobisher C, Winter DL, Kelly J, Lancashire ER, Stiller CA, et al. Long-term Risks of Subsequent Primary Neoplasms Among Survivors of Childhood Cancer. JAMA 2011;305:2311-9. Among survivors of childhood cancer, what is the long-term risk of developing subsequent primary neoplasms? Population-based cohort study. Great Britain. 17 981 5-year survivors of childhood cancer diagnosed with cancer at younger than 15 years between 1940 and 1991 who are participating in the British Childhood Cancer Survivor Study. Median follow-up time was 24.3 years through December 2006. Subsequent primary neoplasms were identified through the National Health Service Central Registers. Standardized incidence ratios (SIRs), absolute excess risks (AERs), and cumulative incidence of subsequent primary neoplasms. Among this cohort, 1354 subsequent primary neoplasms were ascertained; the most frequently observed being central nervous system (n=344), nonmelanoma skin cancer (n=278), digestive (n=105), genitourinary (n=100), breast (n=97), and bone (n=94). The overall SIR was 4 times more than expected (SIR, 3.9; 95% CI, 3.6-4.2; AER, 16.8 per 10 000 person-years). The AER at older than 40 years was highest for digestive and genitourinary subsequent primary neoplasms (AER, 5.9 [95% CI, 2.5-9.3]; and AER, 6.0 [95%CI, 2.3-9.6] per 10 000 person-years, respectively); 36% of the total AER was attributable to these 2 subsequent primary neoplasm sites. The cumulative incidence of colorectal cancer for survivors treated with direct abdominopelvic irradiation was 1.4% (95% CI, 0.7%-2.6%) by age 50 years, comparable with the 1.2% risk in individuals with at least 2 first-degree relatives affected by colorectal cancer. Among a cohort of British childhood cancer survivors, the greatest excess risk associated with subsequent primary neoplasms at older than 40 years was for digestive and genitourinary neoplasms.

Occurrence of Multiple Subsequent Neoplasms in Long-Term Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study

Childhood cancer survivors experience an increased incidence of subsequent neoplasms (SNs). Those surviving the first SN (SN1) remain at risk to develop multiple SNs. Because SNs are a common cause of late morbidity and mortality, characterization of rates of multiple SNs is needed. In a total of 14,358 5-year survivors of childhood cancer diagnosed between 1970 and 1986, analyses were carried out among 1,382 survivors with an SN1. Cumulative incidence of second subsequent neoplasm (SN2), either malignant or benign, was calculated. A total of 1,382 survivors (9.6%) developed SN1, of whom 386 (27.9%) developed SN2. Of those with SN2, 153 (39.6%) developed more than two SNs. Cumulative incidence of SN2 was 46.9% (95% CI, 41.6% to 52.2%) at 20 years after SN1. The cumulative incidence of SN2 among radiation-exposed survivors was 41.3% (95% CI, 37.2% to 45.4%) at 15 years compared with 25.7% (95% CI, 16.5% to 34.9%) for those not treated with radiation. Radiation-exposed survivors who developed an SN1 of nonmelanoma skin cancer (NMSC) had a cumulative incidence of subsequent malignant neoplasm (SMN; ie, malignancies excluding NMSC) of 20.3% (95% CI, 13.0% to 27.6%) at 15 years compared with only 10.7% (95% CI, 7.2% to 14.2%) for those who were exposed to radiation and whose SN1 was an invasive SMN (excluding NMSC). Multiple SNs are common among aging survivors of childhood cancer. SN1 of NMSC identifies a population at high risk for invasive SMN. Survivors not exposed to radiation who develop multiple SNs represent a population of interest for studying genetic susceptibility to neoplasia.

Long-term Risks of Subsequent Primary Neoplasms Among Survivors of Childhood Cancer

Survivors of childhood cancer are at excess risk of developing subsequent primary neoplasms but the long-term risks are uncertain. To investigate long-term risks of subsequent primary neoplasms in survivors of childhood cancer, to identify the types that contribute most to long-term excess risk, and to identify subgroups of survivors at substantially increased risk of particular subsequent primary neoplasms that may require specific interventions. British Childhood Cancer Survivor Study--a population-based cohort of 17,981 5-year survivors of childhood cancer diagnosed with cancer at younger than 15 years between 1940 and 1991 in Great Britain, followed up through December 2006. Standardized incidence ratios (SIRs), absolute excess risks (AERs), and cumulative incidence of subsequent primary neoplasms. After a median follow-up time of 24.3 years (mean = 25.6 years), 1354 subsequent primary neoplasms were ascertained; the most frequently observed being central nervous system (n = 344), nonmelanoma skin cancer (n = 278), digestive (n = 105), genitourinary (n = 100), breast (n = 97), and bone (n = 94). The overall SIR was 4 times more than expected (SIR, 3.9; 95% confidence interval [CI], 3.6-4.2; AER, 16.8 per 10,000 person-years). The AER at older than 40 years was highest for digestive and genitourinary subsequent primary neoplasms (AER, 5.9 [95% CI, 2.5-9.3]; and AER, 6.0 [95%CI, 2.3-9.6] per 10,000 person-years, respectively); 36% of the total AER was attributable to these 2 subsequent primary neoplasm sites. The cumulative incidence of colorectal cancer for survivors treated with direct abdominopelvic irradiation was 1.4% (95% CI, 0.7%-2.6%) by age 50 years, comparable with the 1.2% risk in individuals with at least 2 first-degree relatives affected by colorectal cancer. Among a cohort of British childhood cancer survivors, the greatest excess risk associated with subsequent primary neoplasms at older than 40 years was for digestive and genitourinary neoplasms.

Secondary leukemia 15 years or more after treatment for childhood cancer: A report from the Childhood Cancer Survivor Study.

9577 Background: Previous evaluations of survivors of childhood cancer suggest that the cumulative incidence of secondary leukemia plateaus at ~2% 10-15 years after primary cancer therapy. Risk beyond 15 years has not been comprehensively assessed, in part because of the lack of comprehensive long-term follow-up of previous cohorts beyond this time period. Methods: The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort study of 5-year survivors of childhood cancer treated between 1970 and 1986. Self-reported secondary leukemias >5 years from primary diagnosis were confirmed by pathology report or medical records. Diagnostic bone marrow samples were acquired and centrally reviewed. The standardized incidence ratio (SIR) was derived using age, gender, and calendar year specific rates from surveillance epidemiology and end results data. Results: Of 14,358 5-year survivors, 43 developed subsequent leukemia >5 years from primary diagnosis with 13 cases of leukemia occurring ≥ 15 years from diagnosis. Five were AML (2 with confirmed preceding MDS), 4 ALL (2 pre-B lineage, 1 T-cell, 1 unknown), 2 were APL with t(15;17). Two AML cases had 7q- deletion. One ALL had a complex karyotype including t(9;22) and another a p53 mutation. The mean age at diagnosis of leukemia was 31.6 years (range 18 to51), and occurred after a latency of 21.6 years from diagnosis. Sarcomas (n=5) and Hodgkin lymphoma (n=4) were the most common primary diagnoses. Six of the 13 patients received radiation therapy, while only 5 received alkylating agents, and none received epipodophyllotoxins. The SIR for leukemias occurring ≥ 15 years from diagnosis was 3.5 (95% CI 1.9 - 6.0). Eight of 13 are deceased with a median survival of 2 years after diagnosis of leukemia. Conclusions: This is the first description of increased risk of secondary leukemia ≥ 15 years from primary malignancy, demonstrating a 3.5-fold increased risk above that of the general population. Radiation was the most common treatment exposure. These findings indicate a high level of suspicion should be maintained for subjects who received radiation or alkylators and develop pancytopenia to facilitate early detection and intervention.

Melanoma as a subsequent neoplasm in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

9510 Background: Survivors of childhood cancer are at increased risk of developing subsequent neoplasms. The incidence and clinical characteristics of subsequent melanoma has not been well described in survivors of childhood cancer. Methods: Analysis included 14,358 5-year survivors of childhood cancer diagnosed between 1970-1986. Cumulative incidence (CIN) of first occurrence of subsequent melanoma (invasive, ocular, or in situ) was estimated. The association of potential risk factors and CIN of melanoma were tested using cause specific hazards models with age as the time scale and censoring at time of death. Risks for subsequent malignant melanoma as compared to SEER data base (excluding in situ and ocular melanomas) were calculated using standardized incidence ratios (SIR) and excess absolute risk (EAR) per 1000 person years. Results: 55 survivors reported 61 malignant melanomas (invasive 50, in situ 9, and ocular 2). Median time to tumor development was 20.7 yrs (range 5.6-35.4yrs). Median age at diagnosis of first subsequent melanoma was 32yrs (10.9 – 49.0 yrs) and 28 were male. Initial diagnoses included leukemia (16), lymphoma (15), soft tissue and bone sarcoma (n=15), brain tumor (5), Wilms’ tumor (3), and neuroblastoma (1). At last contact, 82% of patients were alive. The CIN of first subsequent melanoma (excluding in-situ and ocular) at 36 yrs from initial cancer was 0.72% (95% CI 0.37-1.07). CIN point estimates by diagnosis ranged from 0.23% for brain tumors to 1.3% for soft tissue and bone sarcoma survivors. The SIR was 2.95 (95% CI 2.19 – 3.89), and EAR was 0.12 (95% CI 0.07 – 0.18) per 1000 person years. Occurrence of melanoma was not associated with age at primary cancer diagnosis, sex, race or family history of cancer. Conclusions: Although the incidence is low, survivors of childhood cancer are at increased risk for developing malignant melanoma. Continued surveillance and awareness of this risk is critical for early detection and treatment of this disease.

Relationship between the brain radiation dose for the treatment of childhood cancer and the risk of long-term cerebrovascular mortality

To date, very little is known about the long-term risk of death from cerebrovascular sequelae following childhood cancer treatment. The purpose of this study was to assess the role of treatment in very long-term cerebrovascular mortality following childhood cancer. We studied 4227 5-year survivors of a childhood cancer. Information on chemotherapy was collected and the radiation dose delivered to 11 anatomical sites in the brain was estimated. The main outcome that was considered was death due to cerebrovascular disease occurring before 1 January 2008. After a median follow-up of 29 years, 23 deaths due to cerebrovascular diseases had occurred. In the brain, the radiation dose delivered to the prepontine cistern seemed to play a greater role than the average radiation dose received throughout the brain or the dose to any other specific anatomical site in the brain. The risk of death from cerebrovascular disease increased linearly with the local radiation dose to the prepontine cistern. Each unit of absorbed radiation (Gray) delivered to this area increased the risk by 22% (95% confidence interval: 1-44%). Compared with patients who had not received radiotherapy or who had received <0.1 Gray in the prepontine cistern area, those who had received >50 Gray had a 17.8-fold (4.4-73.0) higher hazard ratio of death from cerebrovascular disease. In conclusion, among 5-year survivors of childhood cancer, the radiation dose to the brain during radiotherapy was significantly associated with long-term cerebrovascular mortality.

Reproductive status in adult male long-term survivors of childhood cancer

This study assessed the long-term effects of cancer therapies on reproductive status in adult male childhood cancer survivors, evaluated the treatment-related risk factors for hypergonadotropic hypogonadism and assessed the association between the FSH levels and the later need for assisted reproductive techniques (ART). The study cohort included adult male 5-year survivors of childhood cancer who were treated in our institution between 1966 and 2003. Data concerning patient and treatment characteristics, FSH, LH and testosterone levels and pregnancy outcome were collected. Multivariate regression analyses were performed to evaluate the treatment-related risk factors for disturbances in reproductive endocrine status. The diagnostic and predictive values of FSH and later need for ART were evaluated. Data on reproductive endocrine status were available for 488 survivors (86.4%) of the 565 male survivors who visited the outpatient clinic in adulthood. The median follow-up time from initiation of treatment to first visit to the outpatient clinic in adulthood was 15 years. The prevalence rates of elevated FSH levels and decreased testosterone levels were 33 and 12%, respectively. The use of procarbazine, cyclophosphamide, vinca-alkaloids, other alkylating agents, pelvic/abdominal irradiation, total body irradiation and testicular surgery were identified as treatment-related risk factors for elevated FSH levels. During the follow-up period, 73 men reported 120 conceptions, which resulted in 103 live births. Of these men, 56 (77%) were able to achieve conception naturally. All men whose partners conceived by assisted reproductive techniques (n = 13) had elevated FSH levels at their first visit after their 18th birthday (sensitivity: 100%; 95% CI: 71-100%) and all male survivors with a normal FSH level did not need assisted reproductive techniques (negative predictive value: 100%; 95% CI: 89-100%). One-third of young adult male survivors of childhood cancer has elevated FSH levels. FSH appears to be a very sensitive marker for the need of assisted reproductive techniques in male childhood cancer survivors.

Cardiac Function in 5-Year Survivors of Childhood Cancer

Cardiac Function in 5-Year Survivors of Childhood Cancer

Cardiac Function in 5-Year Survivors of Childhood Cancer—Reply

Cardiac Function in 5-Year Survivors of Childhood Cancer—Reply

Cardiac Function in 5-Year Survivors of Childhood Cancer

Childhood cancer survivors (CCSs) have an increased risk of morbidity and mortality. We evaluated the prevalence and determinants of left ventricular (LV) dysfunction in a large cohort of long-term CCSs treated with different potentially cardiotoxic therapies. The study cohort consisted of all adult 5-year CCSs who were treated with potentially cardiotoxic therapies and who visited our late effects outpatient clinic. Echocardiography was performed in patients who had received anthracyclines, cardiac irradiation, high-dose cyclophosphamide, or high-dose ifosfamide. Detailed treatment data were registered. Both multivariate linear and logistic regression analyses were performed. Of 601 eligible CCSs, 525 (87%) had an echocardiogram performed, of which 514 were evaluable for assessment of the LV shortening fraction (LVSF). The median overall LVSF in the whole group of CCSs was 33.1% (range, 13.0%-56.0%). Subclinical cardiac dysfunction (LVSF <30%) was identified in 139 patients (27%). In a multivariate linear regression model, LVSF was reduced with younger age at diagnosis, higher cumulative anthracycline dose, and radiation to the thorax. High-dose cyclophosphamide and ifosfamide were not associated with a reduction of LVSF. Vincristine sulfate was associated with a nonsignificant decrease of cardiac function (P = .07). Epirubicin hydrochloride was as cardiotoxic as doxorubicin when corrected for tumor efficacy, and daunorubicin hydrochloride seemed less cardiotoxic. A high percentage (27%) of young adult CCSs have an abnormal cardiac function. The strongest predictors of subclinical cardiac dysfunction are anthracycline dose, cardiac irradiation, and younger age at diagnosis. There is a suggestion that daunorubicin is less cardiotoxic than other anthracyclines.

Long-term Cause-Specific Mortality Among Survivors of Childhood Cancer

Survivors of childhood cancer are at increased risk of premature mortality compared with the general population, but little is known about the long-term risks of specific causes of death, particularly beyond 25 years from diagnosis at ages when background mortality in the general population starts to increase substantially. To investigate long-term cause-specific mortality among 5-year survivors of childhood cancer in a large-scale population-based cohort. British Childhood Cancer Survivor Study, a population-based cohort of 17,981 5-year survivors of childhood cancer diagnosed with cancer before age 15 years between 1940 and 1991 in Britain and followed up until the end of 2006. Cause-specific standardized mortality ratios (SMRs) and absolute excess risks (AERs). Overall, 3049 deaths were observed, which was 11 times the number expected (SMR, 10.7; 95% confidence interval [CI], 10.3-11.1). The SMR declined with follow-up but was still 3-fold higher than expected (95% CI, 2.5-3.9) 45 years from diagnosis. The AER for deaths from recurrence declined from 97 extra deaths (95% CI, 92-101) per 10,000 person-years at 5 to 14 years from diagnosis, to 8 extra deaths (95% CI, 3-22) beyond 45 years from diagnosis. In contrast, during the same periods of follow-up, the AER for deaths from second primary cancers and circulatory causes increased from 8 extra deaths (95% CI, 7-10) and 2 extra deaths (95% CI, 2-3) to 58 extra deaths (95% CI, 38-90) and 29 extra deaths (95% CI, 16-56), respectively. Beyond 45 years from diagnosis, recurrence accounted for 7% of the excess number of deaths observed while second primary cancers and circulatory deaths together accounted for 77%. Among a cohort of British survivors of childhood cancer, excess mortality from second primary cancers and circulatory diseases continued to occur beyond 25 years from diagnosis.

Subsequent Neoplasms in 5-Year Survivors of Childhood Cancer: The Childhood Cancer Survivor Study

The occurrence of subsequent neoplasms has direct impact on the quantity and quality of life in cancer survivors. We have expanded our analysis of these events in the Childhood Cancer Survivor Study (CCSS) to better understand the occurrence of these events as the survivor population ages. The incidence of and risk for subsequent neoplasms occurring 5 years or more after the childhood cancer diagnosis were determined among 14,359 5-year survivors in the CCSS who were treated from 1970 through 1986 and who were at a median age of 30 years (range = 5-56 years) for this analysis. At 30 years after childhood cancer diagnosis, we calculated cumulative incidence at 30 years of subsequent neoplasms and calculated standardized incidence ratios (SIRs), excess absolute risks (EARs) for invasive second malignant neoplasms, and relative risks for subsequent neoplasms by use of multivariable Poisson regression. Among 14,359 5-year survivors, 1402 subsequently developed 2703 neoplasms. Cumulative incidence at 30 years after the childhood cancer diagnosis was 20.5% (95% confidence interval [CI] = 19.1% to 21.8%) for all subsequent neoplasms, 7.9% (95% CI = 7.2% to 8.5%) for second malignant neoplasms (excluding nonmelanoma skin cancer), 9.1% (95% CI = 8.1% to 10.1%) for nonmelanoma skin cancer, and 3.1% (95% CI = 2.5% to 3.8%) for meningioma. Excess risk was evident for all primary diagnoses (EAR = 2.6 per 1000 person-years, 95% CI = 2.4 to 2.9 per 1000 person-years; SIR = 6.0, 95% CI = 5.5 to 6.4), with the highest being for Hodgkin lymphoma (SIR = 8.7, 95% CI = 7.7 to 9.8) and Ewing sarcoma (SIR = 8.5, 95% CI = 6.2 to 11.7). In the Poisson multivariable analysis, female sex, older age at diagnosis, earlier treatment era, diagnosis of Hodgkin lymphoma, and treatment with radiation therapy were associated with increased risk of subsequent neoplasm. As childhood cancer survivors progress through adulthood, risk of subsequent neoplasms increases. Patients surviving Hodgkin lymphoma are at greatest risk. There is no evidence of risk reduction with increasing duration of follow-up.

Hospitalisations 1998–2000 in a British Columbia population-based cohort of young cancer survivors: Report of the Childhood/Adolescent/Young Adult Cancer Survivors (CAYACS) Research Program

Background and objectives Because of late effects among survivors of cancer in young people, increased hospitalisations would be expected. This study determined the occurrence, frequency and days in hospital (DIH) of hospital admissions among 5-year survivors of childhood and adolescent cancer diagnosed in British Columbia (BC), compared hospitalisation risk with the general population and examined the impact of sociodemographic, health care system and clinical factors. Design This population-based study frequency matched 1157 survivors of cancer diagnosed before 20 years of age from 1970 to 1992 from the BC Cancer Registry with 11,570 randomly selected individuals from BC’s health insurance plan Client Registry. Administrative hospitalisation records from 1998 to 2000 were linked to study cohorts, and regression and trend analyses were carried out. Results From 1998 to 2000, 240 (21%) of survivors and 614 (5.3%) of the population sample were admitted to hospital at least once [adjusted OR = 4.36 (95% CI 3.68–5.16)]. Hospitalised survivors had a higher average number of admissions (2.0 versus 1.5 admissions, respectively) and longer mean DIH (10.9 versus 7.8 d, respectively) than hospitalised population controls. Female gender and older age increased the risk of hospitalisation, as did the presence of a relapse or second cancer by 5 years post-diagnosis. Conclusion Our cohort of child and adolescent cancer survivors had higher odds of hospitalisation, more admissions among those hospitalised and longer stay in hospital compared to the population sample. This has implications for health care system resources and appropriate management of late effects of survivors.

Gastrointestinal malignancies as a subsequent malignant neoplasm in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

9520 Background: There is emerging evidence that childhood cancer survivors (CCS) develop gastrointestinal (GI) malignancies more frequently and earlier than the general population. We determined the risk of GI subsequent malignant neoplasms (SMN) and described factors associated with their development to inform surveillance recommendations. Methods: We assessed the risk of GI SMN in a cohort of 14,372 5-year CCS and compared that to population-based data from the Surveillance, Epidemiology and End Results (SEER) program. Multivariate Cox regression models identified associations between key risk factors and GI SMN development. Results: 45 CCS developed GI SMN at a median age of 33.5 years (range: 9.7-44.8) and a median of 22.8 years (range: 5.5-30.2) from their original diagnoses. The 30-year cumulative incidence of a GI SMN was 0.64% (95% confidence interval [CI]: 0.43-0.86). The most frequent SMN locations were colorectal (n=24; 53%), stomach (n=7; 16%), and hepatobiliary system (n=4, 9%). CCS with a GI SMN were more likely to be deceased than those without (51.1 vs. 13.8%, p<0.05). 60.9% of deceased died of their GI SMN. The risk of GI SMN was almost 5-fold higher in CCS than the general population (standardized incidence ratio [SIR]=4.6, 95% CI: 3.5-6.1) with absolute excess risk (AER) of 14 per 100,000 person-years (py). Colorectal SMN SIR was 4.19 (95% CI: 2.78-6.30), EAR was 7/100,000 py. Survivors of Wilms' tumor, Hodgkin's lymphoma and bone tumors were at highest risk. The multivariate model revealed abdominal radiation (RR=5.32, 95% CI: 2.74-10.32), alkylating agents (RR=2.60, 95% CI: 1.06-6.37) and platinum drugs (RR=4.73, 95% CI: 1.49-15.14) increased the risk of GI SMN. Conclusions: While the overall incidence is low, CCS are at increased risk for developing a GI SMN with an associated elevated risk of mortality. Surveillance in at-risk survivors should commence at a younger age than is recommended for the general population. No significant financial relationships to disclose.

Survey of childhood cancer survivors who stopped follow‐up physician visits

Childhood cancer cure rates have increased remarkably; however, survivors face an increased risk of morbidity and mortality. Survivors may benefit from anticipatory guidance and periodic surveillance to minimize morbidity and mortality. Subjects included 114 5-year survivors of childhood cancer who were diagnosed and treated in three hospitals in Nagoya between 1975 and 2001 and who stopped follow-up physician visits during the preceding 2 years. We conducted a survey of their socioeconomic status, knowledge about their diagnosis and late effects of treatment received, and current hospital attendance patterns. Eighty-eight of 114 subjects replied. Sixty-six survivors knew about their disease, but only 26 knew about possible late effects of cancer treatment. Although 78 respondents indicated they were healthy and had no trouble in their daily lives, 46 had at least one chronic condition. In response to the question regarding why they did not visit the hospital regularly, many subjects responded that the physician-in-charge told them they did not need to visit the hospital anymore; others thought it was unnecessary to consult a physician because they were in good health. Some cancer survivors who stop follow-up physician visits may still be suffering from cancer-related illnesses. Both survivor-related and physician-related barriers contribute to cancer survivors stopping follow-up physician visits. To ensure that survivors undergo appropriate follow-up visits, it is necessary to educate survivors, their families, and medical staff about the late effects of cancer and its treatment and the importance of long-term follow up.

Long-term Mortality from Second Malignant Neoplasms in 5-Year Survivors of Solid Childhood Tumors: Temporal Pattern of Risk according to Type of Treatment

The temporal pattern in mortality from late second malignant neoplasms in solid childhood cancer survivors, according to the type of treatment, has not been investigated in detail. We studied 4,230 5-year survivors of solid childhood cancer diagnosed between 1942 and 1986 in France and the United Kingdom. Complete clinical, chemotherapy, and radiotherapy data were recorded and the integral radiation dose was estimated for 2,701 of the 2,948 patients who had received radiotherapy. After a median follow-up of 28 years, 134 fatal events were due to second malignancies, compared with the 13.3 expected from the general France-UK population rates. The standardized mortality ratio was of a similar magnitude after radiotherapy alone and chemotherapy alone and higher after both treatments. The standardized mortality ratio decreased with follow-up, whereas the absolute excess risk increased significantly over a period of at least 25 years after the first cancer. This temporal pattern was similar after chemotherapy alone, radiotherapy alone, or both treatments. We observed a similar long-term temporal pattern among survivors who had died of a second malignant neoplasm of the gastrointestinal tract and breast. Survivors who had received a higher integral radiation dose during radiotherapy were at a particularly high risk, as well as those who had received alkylating agents and epipodophyllotoxins. Five-year survivors of childhood cancer run a high long-term mortality risk for all types of second malignant neoplasms whatever the treatment received and require careful long-term screening well beyond 25 years after the diagnosis.

Temporal Trends in Cause-Specific Late Mortality Among 5-Year Survivors of Childhood Cancer

Five-year survival rates for childhood cancer have improved over the past four decades. However, it is unknown whether changes in primary cancer therapy have improved rates of long-term (> 5 years from diagnosis) durable remissions and reduced treatment-related deaths. We investigated changes in patterns of late mortality over time and cause-specific attribution of late-mortality among 5-year survivors. Using data from the Surveillance, Epidemiology and End Results (SEER) population-based registry, we assessed all-cause and cause-specific (recurrence/progression of primary disease, external cause, and nonrecurrence/nonexternal cause) late mortality during four consecutive time periods from 1974 through 2000 among 26,643 5-year survivors of childhood cancer. All-cause late mortality improved during more recent eras, dropping from 7.1% (95% CI, 6.4% to 7.8%) among children diagnosed during 1974 to 1980 to 3.9% (95% CI, 3.3% to 4.4%) among children diagnosed during 1995 to 2000 (P < .001), largely because of reduced mortality from recurrence or progression. While there was no significant reduction in mortality attributable to other health conditions (including treatment-related health conditions), analysis controlling for demographic characteristics identified a trend toward reduced risk during more recent eras (P = .007). Disparity by race/ethnicity was identified, with higher mortality among non-Hispanic blacks than among non-Hispanic whites for all-cause and nonrecurrence/nonexternal -cause late mortality. While overall patterns of mortality from other health conditions do not differ over time, adjustment for demographic characteristics provides evidence that risk of treatment-related mortality may be lower in more recent eras. Disparities in health care utilization among survivors should be explored.

Temporal Trends in Cause-Specific Late Mortality Among 5-Year Survivors of Childhood Cancer

Temporal Trends in Cause-Specific Late Mortality Among 5-Year Survivors of Childhood Cancer

Late-Occurring Neurologic Sequelae in Adult Survivors of Childhood Acute Lymphoblastic Leukemia: A Report From the Childhood Cancer Survivor Study

Children with acute lymphoblastic leukemia (ALL) are often cured, but the therapies they receive may be neurotoxic. Little is known about the incidence and severity of late-occurring neurologic sequelae in ALL survivors. Data were analyzed to determine the incidence of adverse long-term neurologic outcomes and treatment-related risk factors. We analyzed adverse neurologic outcomes that occurred after diagnosis in 4,151 adult survivors of childhood ALL who participated in the Childhood Cancer Survivor Study (CCSS), a retrospective cohort of 5-year survivors of childhood cancer diagnosed between 1970 and 1986. A randomly selected cohort of the survivors' siblings served as a comparison group. Self-reported auditory-vestibular-visual sensory deficits, focal neurologic dysfunction, seizures, and serious headaches were assessed. The median age at outcome assessment was 20.2 years for survivors. The median follow-up time to death or last survey since ALL diagnosis was 14.1 years. Of the survivors, 64.5% received cranial radiation and 94% received intrathecal chemotherapy. Compared with the sibling cohort, survivors were at elevated risk for late-onset auditory-vestibular-visual sensory deficits (rate ratio [RR], 1.8; 95% CI, 1.5 to 2.2), coordination problems (RR, 4.1; 95% CI, 3.1 to 5.3), motor problems (RR, 5.0; 95% CI, 3.8 to 6.7), seizures (RR, 4.6; 95% CI, 3.4 to 6.2), and headaches (RR, 1.6; 95% CI, 1.4 to 1.7). In multivariable analysis, relapse was the most influential factor that increased risk of late neurologic complications. Children treated with regimens that include cranial radiation for ALL and those who suffer a relapse are at increased risk for late-onset neurologic sequelae.