Chronic diseases in long-term childhood cancer survivors can involve multiple organ systems and have a wide spectrum of severity. One way to capture the burden of morbidity in survivors is to ask for a self-assessment of overall general health and then compare the grouped responses with that of grouped sibling responses. Self-assessment of overall health was ascertained as part of the baseline questionnaire (complete baseline questionnaire is available at www.stjude.org/ccss
). Hudson et al analyzed the health status of 9,535 adult survivors (≥ 18 years of age) in the cohort, using 2,916 randomly selected siblings from the families of the cancer survivors as a comparison group.1
Survivors and siblings in the two cohorts were asked at baseline “Would you say that your health is excellent, very good, good, fair or poor?” Self-reported fair or poor health was observed in 10.9% of survivors compared with 4.9% of siblings. Specific demographic factors associated with this self-report of reduced general health included female sex, lower income and educational attainment, and older age at interview. Cancer-related risk factors for self-reported poor health included a primary diagnosis of bone tumor, CNS tumor, and Hodgkin's disease (HD).1
Understanding the contributing factors to this self-described detriment in health was the goal of further analyses.
To systematically analyze the prevalence and severity of the self-reported chronic medical conditions reported by cohort members, Oeffinger et al adapted a well-accepted toxicity scoring system utilized most frequently for new drug evaluations in cancer clinical trials (the National Cancer Institute's Common Toxicity Criteria for Adverse Events [CTCAE] version 3.0).6
Questionnaire-based data from the baseline questionnaire were mapped to organ-specific toxicities listed in the CTCAE using a 5-point severity scale from mild (severity score = 1) to life-threatening or disabling (score = 4) or fatal (score = 5). In a landmark publication, Oeffinger et al reported on the prevalence, incidence, and severity of chronic disease (self-reported), analyzing 137 specific conditions in the 10,397 cohort members who were older than 18 years of age at entry into the CCSS study and compared them with a similar-aged sibling cohort enrolled in CCSS. At the time of the analysis, the mean age of both the survivor and sibling cohorts was 26.5 years with a range of 18 years to 56 years, and the interval from time of primary diagnosis of cancer to time of interview was 17.5 years with a range of 6 to 31 years. Approximately two thirds (67.4%) of the survivors were known to have had a prior exposure to RT and 62% had been exposed to chemotherapy as treatment for their primary cancer.7
Oeffinger et al7
reported that childhood cancer survivors have a high risk of development of significant chronic conditions, and that many members of the cohort suffer from more than one chronic illness. The authors reported that the prevalence of at least one severe (grade 3), or life-threatening/disabling (grade 4) chronic illness was 27.5% among survivors, compared to 5.2% in siblings. In addition, the prevalence of multiple conditions was high, with 23.8% of survivors reporting more than three conditions (compared with 5.4% of siblings).
Severe or life-threatening conditions in the survivor cohort and their associated relative risk compared to the sibling comparison group included: congestive heart failure (relative risk [RR], 15.1; 95% CI, 4.8 to 47.9); coronary artery disease (RR, 10.4; 95% CI, 4.1 to 25.9); cerebrovascular accident (RR, 9.3; 95% CI, 4.1 to 21.1); and renal failure or dialysis (RR, 8.9; 95% CI, 2.2 to 36.6). Although the percentage of survivors reporting any one of the above conditions was low (fewer than 2% of the overall cohort for each), the relative risks were substantial. Perhaps even more striking was the cumulative incidence of chronic conditions noted in the report. Overall, the cumulative incidence of a grade 3, 4, or 5 chronic condition in the cohort was 33.1% at 25 years after primary diagnosis. Of note, this published analysis included the occurrence of secondary malignancy as either a chronic grade 4 or 5 outcome.
In , cumulative incidence of organ-system toxicity in the overall CCSS cohort is presented. This analysis utilized the same CCSS data set as Oeffinger et al7
but excluded secondary malignancy as a chronic disease, given that analyses of secondary cancers in the CCSS are presented in other articles in this issue of Journal of Clinical Oncology
. Of particular interest is the slope of the cumulative incidence curves for endocrine, pulmonary, and cardiac disease, suggesting that the cohort continues to face new-onset organ system morbidity as the cohort members age and long after treatment concludes. The proportion of survivors and siblings reporting an organ-specific chronic illness, and the associated relative risks are presented in . The percentage of survivors reporting a severe, disabling, life-threatening, or fatal condition for any one chronic disease group ranges from 0.8% (renal condition) to 7.6% (endocrine condition), and the RRs compared to siblings are striking, with survivors 7.5 (95% CI, 6.4 to 8.9) times more likely to have a grade 3, 4, or 5 condition. It should also be noted that self-report may underestimate some of the chronic conditions that might be expected in this cohort, in particular gastrointestinal, renal, and musculoskeletal toxicity. Follow-up questionnaires, as well as ancillary studies that directly measure these conditions, will further refine these estimates and present a more detailed analysis of survivor health.
Cumulative incidence of chronic health conditions (grade 1 to 5 and grade 3 to 5).
Relative Risk of Chronic Health Condition by Major Organ System As Compared With Siblings
Oeffinger et al7
found that survivors of all primary cancer diagnoses had an increased relative risk of development of grade 3 or 4 chronic conditions when compared with siblings (adjusting for age, sex, and race/ethnic group); the highest RRs were associated with a primary diagnosis of bone tumors (RR, 38.9; 95% CI, 31.2 to 48.5) and CNS tumors (RR, 12.6; 95% CI, 10.3 to 15.5). Survivors exposed to any RT, any chemotherapy, and specific treatment combinations were all found to have significantly elevated RRs of severe or life-threatening conditions compared with siblings. The risk of a grade 3 or 4 chronic condition was at least 10-fold above the risk in siblings for survivors with the following exposures: abdominal or pelvic RT plus an alkylating agent (RR, 10.0; 95% CI, 8.2 to 12.1), an anthracycline plus an alkylating agent (RR, 10.9; 95% CI, 9.0 to 13.1), chest RT plus bleomycin (RR, 13.6; 95% CI, 9.8 to 18.7), chest RT plus an anthracycline (RR, 13.0; 95% CI, 10.4 to 16.3), chest RT plus abdominal or pelvic irradiation (RR, 10.9; 95% CI, 8.9 to 13.2). As shown in (left panel), RT alone, chemotherapy alone, and the combination of chemotherapy and RT are associated with an increasing cumulative incidence of chronic illness over time. Interestingly, the cumulative incidence of chronic grade 3, 4, or 5 conditions for patients treated with RT alone slopes upward at approximately 10 years after diagnosis, confirming the late onset pattern of radiation damage. Note that the incidence rates shown in the figures, and those discussed throughout this article, are left truncated at 5 years after diagnosis, reflecting the eligibility entry criteria for the cohort. Also, as mentioned previously, the data presented in exclude secondary malignancies as a chronic condition.
Fig 2. Cumulative incidence of chronic health conditions by exposure (grade 3 to 5 only). Survivors exposed to radiation in more than one anatomic site are included in each appropriate radiation curve in the right panel. RT, radiation therapy; CHEMO, chemotherapy; (more ...)
Finally, (right panel) presents the relative cumulative incidences of chronic conditions in patients treated with different radiation fields. Of note, total body radiation (TBI) results in the highest cumulative incidence of significant chronic illness, despite the relatively low radiation doses associated with this therapy. TBI is highly associated with certain underlying cancer diagnoses and other nonradiation therapies. Multivariate analyses may elucidate further the contribution of specific diagnoses and pre- and post-transplant therapies to this TBI-associated burden of chronic illness.
The availability of cohort studies outside of North America generally confirm the high burden of chronic disease in childhood cancer survivors. In the Netherlands, Geenen and colleagues reported on the health of 1,315 survivors with a median age of 24.4 years at the time of assessment.8
Their analysis benefited from nearly complete follow-up, with 94.3% of the survivors participating (compared with 81.2%9
in the CCSS), and outcomes were directly measured in a clinical setting, rather than by self-report. Compared with the CCSS, this cohort is quite homogeneous, both because primary therapy in the Netherlands is quite uniform and in terms of lack of ethnic and racial diversity. Given these differences, it is remarkable to note that the findings are quite similar: in the Dutch cohort, 70% of survivors have at least one chronic condition and 40% have at least one severe or disabling condition. The somewhat higher proportion of survivors having significant chronic disease in this report compared to the CCSS may be due to the methods used, including direct measurement of outcome rather than self-report. Similarly, the British Childhood Cancer Survivor Study, another population-based study, has reported its initial findings in a cohort of childhood cancer patients diagnosed in Britain between 1940 and 1991, and known to have survived 5 years. The strength of this cohort includes the large size, long follow-up, and the ability to link to British National Health Service data on participants.10