Advances in multimodal therapy for pediatric ES have led to gradually improving 5-year survival rates, increasing from 42% in 1975–1984 to 58% in 1985–1994 to 60% in 1996–2004 (2
). With this improvement in 5-year survival, the numbers of long-term survivors of ES have gradually increased. This study provides a comprehensive description of long-term survival and key health outcomes from a relatively large and geographically diverse cohort of 5-year ES survivors treated in the 1970s and 1980s. To our knowledge, this is the first study that provides detailed information regarding survival beyond 10 years for patients diagnosed with ES. Importantly, for individuals who survived their ES at least 5 years after diagnosis, 75% remained alive at 25 years after diagnosis. Whereas 60% of late mortality (≥5 years after diagnosis) was attributable to recurrence/progression of the primary disease, it is important to note that 40% of late mortality was attributable to other causes, most notably second cancers (14%) and cardiac disease (6%). Pediatric oncologists must continue to engage in large randomized controlled therapeutic trials in an effort to improve the primary treatment of ES because 60% of the late mortality in this cohort was attributable to recurrent disease.
As noted, a major contributing factor to late mortality and to diminished health status of ES survivors was a subsequent malignant neoplasm. Previous studies with shorter follow-up reported an increased risk of secondary cancers following therapy for ES, primarily therapy-induced acute myelogenous leukemia (t-AML) or radiation-induced sarcomas (osteosarcoma and soft tissue sarcoma) (9
). To our knowledge, our sample from the CCSS cohort is the largest number, to date, of case patients with subsequent malignant neoplasms following ES (excluding nonmelanoma skin cancer: 36 malignancies among 34 survivors). By 25 years following the ES diagnosis, the cumulative incidence of a second malignant neoplasm among survivors in our cohort was 9%. It is important to understand that to be eligible for the CCSS, participants had to have survived at least 5 years from the date of their primary cancer diagnosis. Thus, patients who died from t-AML within 5 years of ES diagnosis would not have been included. The small number of patients with t-AML in our cohort (n = 2) likely reflects this eligibility criterion. Notably, breast and thyroid cancer represented 32% and 12% of the second cancers, respectively. Indeed, the highest absolute excess risk of a second cancer was for breast cancer, which confirms two previous reports (11
). In addition, to our knowledge, this study is the first to report an excess risk among both ES survivors treated with low-dose (1200–1500 cGy) whole-lung irradiation and women not treated with radiation to the chest area. With respect to the former group, the Children's Oncology Group (38
) recommends early initiation for breast cancer screening among women treated with at least 2000 cGy chest radiation. However, as noted by Inskip et al. (39
), the risk of breast cancer among women treated with therapeutic radiation during their childhood years is linearly related to the radiation dose; thus, screening among women treated with lower-dose whole-lung irradiation should be considered. Surprisingly, we also found an excess of risk among women who were not treated with radiation to the chest or breast area, suggesting a possible underlying genetic predisposition and warranting further investigation.
Few studies have focused on serious morbidities other than second cancers. The generalizability of these studies is limited by smaller cohorts of ES survivors (<100), shorter follow-up, and/or lack of a comparison population (4–8). The prevalence of chronic conditions in ES survivors in our study (70.7%) is modestly higher than the 62% reported for the entire CCSS cohort (26
). This outcome is not surprising given the routine use of moderate- to high-dose anthracyclines, alkylating agents, musculoskeletal surgeries, and radiation in the treatment of ES. For these survivors, the burden of chronic conditions remained high from diagnosis through follow-up. Although many conditions developed within 5 years of diagnosis, it is important to recognize that about half of the most serious conditions did not occur until later. In particular, arrhythmias and other cardiac conditions, pulmonary conditions, and problems with balance were approximately evenly split between the two time intervals (onset <5 and ≥5 years from diagnosis). The importance of long-term follow-up to monitor for these and other late-occurring conditions cannot be overemphasized.
Infertility was common among both male and female ES survivors. Female survivors were 35% less likely to report a pregnancy than siblings of childhood cancer survivors, even after excluding women who were surgically sterile. As reported by Green et al. (29
), infertility is associated with ovarian irradiation and high-dose alkylating agent chemotherapy. Contemporary therapy for ES includes high-dose cyclophosphamide and ifosfamide (40
), and so we can anticipate that the rate of infertility will not be much different in women treated in the CCSS era compared with women treated today. Thus, it is imperative that methods of fertility conservation be further studied (42
Musculoskeletal problems are relatively common late complications of treatment in ES survivors (5
). The ES survivors in our cohort reported substantial functional impairment. Moderate to extreme adverse mental health was more common among ES survivors in this study than among siblings but was similar to the entire CCSS cohort (16.3% of ES survivors in this study vs 17.2% of all survivors in the CCSS) (32
). This result for mental health suggests that despite having considerable functional impairment and high rates of infertility, second cancers, and serious chronic health problems, long-term survivors of ES cope remarkably well.
One of the potential limitations of this study is that the CCSS cohort is institutionally based rather than population based; because institutions may have specific referral patterns, the potential exists for enrollment of a nonrepresentative survivor population. At the time the cohort was constructed, it was estimated that the institutions selected to participate in CCSS diagnosed and treated approximately 50% of pediatric cancer patients in the United States. It is notable that results from CCSS have been remarkably consistent for outcomes, including late mortality and chronic health conditions derived from population-based series (45
). A second potential limitation of this study is that participants were treated between 1970 and 1986, so the results may not be relevant to current treatment modalities, although contemporary therapy for ES still includes the frequent use of high-dose anthracycline and alkylating agents (3
), as well as radiation or surgery for local control (47
). Although radiation is still an important modality for these patients, the use of lower doses (4500–5500 cGy rather than 6000–7000 cGy), smaller fields (1–2 cm margin rather than whole bone or muscle compartment) and conformal techniques (intensity-modulated, three-dimensional, limited area radiation therapy) will potentially decrease morbidity in currently treated patients. The CCSS is currently expanding the cohort to include patients diagnosed between 1987 and 1999. This expansion will provide important information regarding late effects of more contemporary therapeutic protocols. Nevertheless, the present results are relevant in underscoring the critical importance of long-term risk-based health care for this high-risk population of cancer survivors. A third potential limitation is that although mortality and subsequent malignant neoplasms were externally verified, most chronic health conditions and health status outcomes in this study were self-reported, introducing the possibility of reporting bias. Survivors may be more likely to be aware of asymptomatic health conditions simply because of more frequent medical checkups; however, detection bias is unlikely to account for the magnitude of difference between survivors and siblings. Radiation has been implicated as the primary treatment modality associated with late mortality. However, this observation is confounded by the use of radiation in patients with more advanced disease or when the tumor is centrally located (ie, pelvis, spine, head, and neck) and where surgery may not be a viable option for local control. Indeed, more than three-quarters of the ES survivors in this study were treated with radiation, thus limiting our subanalysis of some outcomes. Notably, whereas the incidence of second malignancies was higher among irradiated survivors vs nonirradiated survivors, mortality attributable to subsequent neoplasms and cardiac or pulmonary disease (ie, excluding progression or recurrence of ES) was similar for the two groups. Clinicians who treat ES appear to have incorporated the recommendation to use surgery for local control more frequently in clinical practice. In a recent trial conducted by the Children's Oncology Group (3
), which enrolled patients from 1995 through 1998, 65% of patients were treated with surgery alone for local control; the remainder were treated with radiotherapy alone or a combination of surgery and radiotherapy.
In summary, this retrospective cohort of ES survivors and siblings of childhood cancer provides clear evidence of long-term negative sequelae in ES survivors. In addition to increased mortality following ES, survivors are at substantially higher risk of morbidity because of second malignancies, chronic health conditions, and functional impairment, all of which require extensive clinical management. Enrollment and long-term follow-up in late effect programs is clearly indicated in this cohort.