Due to the relatively low incidence (approximately 400 per year) of childhood osteosarcoma in the US1
, conducting a large comprehensive study of osteosarcoma survivors at any one institution is very difficult. However, the CCSS with its large multi-institutional cohort enables comprehensive assessments of various sequelae of a large number of 5-year+ osteosarcoma survivors. This is an important subset of patients to examine in detail as these patients receive very invasive surgeries and multimodal chemotherapy with known significant toxicities.
Mortality estimates in this cohort of 5-year survivors of osteosarcoma were elevated when compared to the US population with a 20-year survival probability of 88.6%which is similar to the reported overall CCSS mortality25
. Females had a slight survival advantage compared to males (90.0% vs. 87.3%), however, females had a higher SMR compared to males, because of the lower mortality rates of females (compared to males) in the US population coupled with the increased risk of an SMN in females. The development of an SMN or recurrent disease were predictive of death, as was the use of radiation and exposure to cisplatinum which may be a marker for extent or aggressiveness of disease. In data not shown, it is noted that radiation therapy was predominately given to older cohorts when survival was likely poorer and systemic therapy was limited. When cisplatinum exposure was further examined, higher cumulative exposure was associated with deaths attributed to recurrences, SMNs, and cardiac toxicity. However, cumulative cisplatinum exposure is correlated with other exposures such as higher cumulative dose of anthracycline. Thus, the exact contribution of cisplatinum to the observed increase in risk of death is not clear, and it is possibly a surrogate for more aggressive disease or disease recurrence necessitating more chemotherapy exposure.
When comparing our survival rates of 5-year survivors with those reported in other studies, caution must be used as the majority of the survivorship studies report survival from diagnosis as compared to survival of those alive 5 years from diagnosis. In one large study of 1,702 patients with newly diagnosed osteosarcoma between 1980 and 1998 from the German Cooperative Osteosarcoma Study Group, the overall survival at five years from diagnosis was 65.3%. Survival rates continued to decline with 10 and 15 years survival rates of 59.8% and 57.3%. These rates would approximate this study’s survival rates of 5 year survivors at 10 and 15 years from diagnosis.2
The cumulative incidence of recurrences in our study was relatively stable after 5 years (24.5% at 5 years and 28.1% at 25 years) with only 24 subjects experiencing a recurrence more than 5 years after diagnosis. This is comparable to a large study of 576 patients with relapsed osteosarcoma where only 5.7% of the relapses occurred after 5 years.26
In contrast to the recurrences, the majority of SMNs occurred ten or more years from diagnosis. A prior report from CCSS showed that bone tumor survivors had a cumulative incidence of 3.3% at 20 years 9
. The current report extends these data and focuses on osteosarcoma patients. The SIR for all SMNs was 4.8 with a cumulative incidence of 1.0% at 10 years and 5.4% at 25 years, which was consistent with a 10-year cumulative incidence reported by Goldsby et al27
. Several other studies have reported on the incidence of SMNs with rates ranging from 2 to 5% at 10 years28-31
The literature reports that the incidence and magnitude of hearing loss increases with increasing cumulative cisplatinum doses with a threshold between 240-400 mg/m2
with younger age associated with greater risk.32, 33
In the current study, we confirmed increased hearing loss and increased prevalence of vertigo with increasing cumulative cisplatinum dose. However, younger age at diagnosis was not predictive of this late sequelae, which may be due to the small numbers of children who were diagnosed at a very young age among the osteosarcoma group (12 survivors under the age of 4 years at diagnosis) in this cohort.
Although anthracyclines are known to have cardiac toxicity, they are an integral part of osteosarcoma therapy and the majority of patients with osteosarcoma now receive close to what is considered the maximum cumulative dosing (450 mg/m2
). Recent studies34
have demonstrated a cumulative incidence of 10% at 20 years for acute congestive heart failure for those who received over 300 mg/m2
, but even those with lower cumulative anthracyclines doses may be at risk.35
In our study, 19 who reported having congestive heart failure with 13 of the 19 having received greater than 360 mg/m2
of anthracyclines. Reports of congestive heart failure are important to note in this cohort, as nearly 86% received anthracyclines with 58.2% receiving greater than 210 mg/m2
of anthracyclines. Congestive heart failure tended to be more common in patients farther from treatment. In addition to congestive heart failure 11 reported having cardiovascular disease. One limitation of this data is that this relies on self reporting which is an underestimation and also it is unknown how well surveillance imaging and follow-up was performed in this group of survivors.
As previously identified, bone sarcoma survivors were more likely than the siblings to have chronic and adverse health conditions.15, 16
Since survivors of osteosarcoma in the current study had a large number of Grade 3 or 4 chronic health conditions due to the high number of amputations (72%) performed in this treatment era (1970-1986), we adjusted for amputations when comparing against siblings and other survivors. This is reflected in decreased relative risks when compared to Oeffinger et al. paper.15
Interestingly osteosarcoma survivors had more Grade 3-4 conditions (even after adjusting for amputation) compared to other survivors, likely reflecting the effects of extensive surgery and chemotherapy received by this group of survivors.
When general health status was examined, osteosarcoma survivors were more likely than the sibling cohort to report adverse health status. When osteosarcoma survivors were compared to survivors of other tumors, general health, mental health and anxiety were not different, but functional status, activity limitations and pain were more likely to be a problem. Given the use of amputation and surgeries in this osteosarcoma cohort compared to other survivors, this would be expected. However, with 72% of the CCSS osteosarcoma survivors having an amputation, one would expect a greater number reporting impaired functional status (15%) or activity limitation (29%). This is remarkable and is likely due to adaptation to their limitations. The increased incidence of chronic conditions and limitations and pain seen in osteosarcoma survivors is especially concerning, given the relative lack of health insurance of this osteosarcoma cohort (25.9%). Survivors of osteosarcoma also seemed to compare reasonably in terms of marital status, employment, and education, despite the impact therapy had on the development of chronic illnesses and general health. However, differences exist when compared to siblings and additional support services may allow for improved integration.
When interpreting the results of this study, there are some limitations that must be considered. The majority of the outcomes were based upon self-report and thus may be subject to over- or under-reporting. Exceptions to the self-report included the occurrence of second malignancies, where pathology reports were obtained to verify and classify cases. Causes of death were determined using death certificate information. Assessments of chronic health conditions were restricted to individuals over the age 18 years at the time of enrollment in CCSS. While the vast majority of osteosarcoma patients were over 18, our results can not be applied to younger survivors. Lastly, we used the CCSS sibling cohort to compare with the osteosarcoma survivors for a number of outcomes. Since siblings of pediatric cancer survivors may experience a variety of stressors resulting from the psychosocial and familial impact of having a sibling with cancer, the magnitude of risk observed may be an underestimate. Although this group of survivors was treated differently in terms of surgery (more amputations), more varied chemotherapy regimens and supportive care compared to current osteosarcoma patients, this serves as a baseline for future comparisons.
Overall, the childhood osteosarcoma survivors in this cohort did relatively well considering their extensive treatment: however, they are an at-risk population and warrant life-long follow-up for SMNs, adverse medical conditions and issues related to general health and disability/function and pain. Prospective evaluation of current patients with osteosarcoma will be important to assess both acute and long term effects of current osteosarcoma therapy and their impact on survivorship.