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J Clin Oncol. 2011 August 1; 29(22): 3056–3064.
Published online 2011 June 27. doi:  10.1200/JCO.2011.34.6585
PMCID: PMC3157966

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

Abstract

Purpose

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.

Patients and Methods

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.

Results

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).

Conclusion

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.

INTRODUCTION

The relative 5-year survival rate after a diagnosis of childhood cancer, which was less than 30% in 1960, is now 79%.1 As of 2005, there were more than 328,000 survivors of childhood cancer in the United States.2 Perhaps the most serious late complication for these survivors is the development of subsequent neoplasms (SNs), many of which are subsequent malignant neoplasms (SMNs).310 SMNs are the most common cause of treatment-related death in long-term survivors (standardized mortality ratio, 15.2; 95% CI, 13.9 to 16.6).11 Combined with the increase of the cumulative incidence of SMNs in the Childhood Cancer Survivor Study (CCSS) population over the last decade (3.2% at 20 years from diagnosis to 9.3% at 30 years),6 it is clear that the development of SMNs is a central issue for aging survivors. However, it appears that the increasing cumulative incidence of a first SN does not fully describe the risk for this population. Survivors who experience their first SN may be at risk for the development of multiple SNs. The aging population of the CCSS allows a comprehensive assessment of this question.

PATIENTS AND METHODS

Identification and Contact of the Cohort

The CCSS is a retrospective, cohort study that provides longitudinal follow-up of 5-year survivors of childhood cancer who were treated at 26 institutions in the United States and Canada. Eligibility for participation in the CCSS included diagnosis of cancer before age 21 years; initial treatment between January 1, 1970, and December 31, 1986; and survival for at least 5 years from diagnosis. Participants were recruited from survivors treated for initial diagnoses of leukemia, CNS malignancy, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Wilms tumor, neuroblastoma, soft tissue sarcoma, or bone tumors. The cohort methodology and study design have been previously described in detail.12,13 The CCSS was approved by institutional review boards at the 26 participating centers, and participants provided informed consent.

Collection of baseline data was initiated in 1994. All participants completed a questionnaire that included information on demographics, personal and family medical history, medical late effects experienced, and diagnosis of new neoplasms. Additionally, occurrence of SNs was collected in three subsequent follow-up questionnaires. Therapeutic exposures were ascertained through abstraction of medical and radiation therapy records of each participant by using a standardized protocol.13 Study questionnaires are available at http://ccss.stjude.org.

Definition and Ascertainment of Subsequent Neoplasms

SNs include new neoplasms (malignant and benign; Appendix Table A1, online only) collected from the cohort, not including recurrence of the primary childhood malignancy. SNs were initially ascertained through self- or proxy-report questionnaires and/or death certificates. Occurrences were subsequently confirmed by pathology report or, when not available, were confirmed by death certificate or other medical records reviewed by study investigators. Only SNs occurring 5 or more years after the childhood cancer diagnosis were evaluated.5,6 For this analysis, the term SN1 was defined as the first SN to occur after the primary diagnosis; SN2 represents the second SN; SN3, the third SN; and SN4, the fourth SN. Similarly, SMNs are numbered and defined.

Statistical Analysis

SNs were divided into three mutually exclusive subsets: SMNs, which included only malignant diagnoses utilized by the U.S. Surveillance Epidemiology and End Results (SEER) program with an International Classification of Diseases (ICD) –O behavior code of 3, thus excluding nonmelanoma skin cancers and nonmalignant meningiomas; nonmelanoma skin cancers (NMSCs, which included ICD-O morphology codes 8070, 8071, 8081, 8090, 8094); and all other benign neoplasms, which included meningiomas that were defined by an ICD-O behavior code of 0, 1, or 2, regardless of ICD-O site and morphology codes.

Frequency distributions of the entire cohort, those with SNs (any, ≥ 2, or ≥ 3) and SMNs (any, ≥ 2, or ≥ 3) were characterized by demographic and treatment variables. Exact information regarding location of the SN was not always available. The cumulative incidence of SN2, utilizing time from SN1 to the earliest of SN2, death, or last follow-up, was compared by using Gray's approach,14 in which death was incorporated as a competing risk event, in addition to describing the patterns of SN occurrence by each potential categoric risk factor. Cumulative incidence of SMN2 was analyzed in a similar manner from time of SMN1. Conditional cumulative incidence analyses for subsequent breast neoplasms and NMSCs after development of a first breast or NMSC SN were evaluated, with conditioning at 0, 6, 12, and 24 months of SN-free time from initial neoplasm. Five patients were excluded from cumulative incidence analyses on the basis of a missing date of SN diagnosis.

In multivariable analyses, we employed the method by Fine and Gray15 for modeling the subdistribution hazard rate of SN2 as a function of risk factors, assuming its proportionality, analogous to Cox regression. This allowed us to directly evaluate the risk factors associated with the cumulative incidence of SN2 while accounting for deaths as competing events. Analyses were adjusted for age at primary diagnosis, sex, ethnicity group, family history of cancer (in first-degree relative), education level, annual household income, smoking status, age at SN1, and time from primary cancer to SN1. In addition, other treatment and demographic factors that were significant at the .15 level in univariate analyses (Gray's test) were also included. Analyses were completed by using S-Plus CRR function (Spotfire S-Plus version 8.1; TIBCO, Seattle, WA).

In addition to the Fine and Gray15 method for estimating subdistribution hazard ratios (HRs), we employed Cox regression to estimate cause-specific HRs. Cause-specific hazards models with age as the time scale were utilized, and the outcome measure was defined as interval from age at SN1 to the minimum age at SN2, date of death, or date of last follow-up. We chose to emphasize the results of Fine and Gray analysis, because our primary interest was on covariate effects on cumulative incidence (and associated subdistribution HRs), but we also showed the cause-specific hazard analysis results (Appendix Table A2, online only), noting that the two methods gave similar conclusions for risk factors of SN2 and their effects.

RESULTS

We identified 14,358 survivors (median age at last follow-up, 31.9 years; range, 5.6 to 56.3 years), who accrued a total of 327,297 person-years of follow-up time, with a median of 23.0 years from diagnosis (range, 5.0 to 37.6 years). Within this cohort, radiation exposure was common (occurring in 67.9% of those who consented to release their medical records). Additional characteristics of the cohort are listed in Table 1 and in Appendix Table A3 (online only). Within this cohort, 1,382 people (9.6%) developed SN1, with a total of 9,387 person-years of follow-up time. Among these 1,382 SN1 occurrences, 386 (27.9%) developed an SN2. Of those with SN2, 153 (39.6%) developed greater than two SNs. In addition, 735 (5.1%) of the 14,358 members of the cohort developed SMN1, 68 (9.3%) of whom developed SMN2.

Table 1.
Characteristics of the CCSS Cohort: Entire Cohort, Survivors With Subsequent Neoplasms, and Survivors With Subsequent Malignant Neoplasms

NMSC was the most common SN (1,104 total episodes; Appendix Table A4, online only) and occurred as SN1 in 485 survivors (Fig 1A), 61 (12.6%) of whom subsequently developed an invasive SMN. Other important patterns were identified. Of 176 participants who had a breast neoplasm as SN1, 37 developed a new breast neoplasm as SN2 (Fig 1B). Multiple subsequent meningiomas were common (Fig 1C). Thyroid cancer, soft-tissue sarcomas, and CNS malignancies were frequently observed as SN1 and preceded a variety of additional SNs (Figs 1D to to11F).

Fig 1.
Survivors with multiple neoplasms after first subsequent neoplasm (SN) when SN1 is (A) nonmelanoma skin cancer (NMSC), (B) breast cancer, (C) meningioma, (D) thyroid cancer, (E) soft tissue sarcoma (STS), and (F) CNS malignancies (Malig). Gold, blue, ...

Among survivors with SN1, the cumulative incidence of SN2 was 33.4% (95% CI, 30.3% to 36.5%) at 10 years, was 38.8% (95% CI, 35.1% to 42.5%) at 15 years, and was 46.9% (95% CI, 41.6% to 52.2%) at 20 years (Fig 2A). When SN1 was an SMN, the cumulative incidence of developing SMN2 after SMN1 was 12.4% (95% CI, 9.1% to 15.6%) at 15 years (Fig 2A). The cumulative incidence of SN2 was highest among survivors of a primary Hodgkin's lymphoma (50.3% at 15 years; 95% CI, 44.1% to 56.6%) or CNS malignancy (44.5% at 15 years; 95% CI, 33.4% to 55.6%; Figs 2B and and2C).2C). Among survivors exposed to radiation as therapy for their primary cancer, the cumulative incidence of SN2 was 41.3% (95% CI, 37.2% to 45.4%) at 15 years from SN1 compared with 25.7% (95% CI, 16.5% to 34.9%) for those not treated with radiation (Appendix Table A5, online only). Similarly, among patients with SMN1 who were not exposed to radiation, the cumulative incidence of SMN2 was 22.8% at 10 years.

Fig 2.
(A) Cumulative incidence of second subsequent neoplasm (SN2) after occurrence of first SN (top line) with 95% CI and of second subsequent malignant neoplasm (SMN2; bottom line) after occurrence of first SMN (SMN1) with 95% CI; (B, C) cumulative incidence ...

Within this cohort, there were 252 breast lesions (n = 189 invasive, n = 61 in situ, and n = 2 benign). The cumulative incidence of developing a second breast SN was 20.7% (95% CI, 14.7% to 26.7%) at 10 years from the time of development of the initial breast SN (Fig 3A). Because of a significant rate of synchronous breast lesions, cumulative incidences of a second breast neoplasm conditioned on time from first breast SN of 6, 12, and 24 months were 12.6% (95% CI, 7.3% to 18.0%), 10.4% (95% CI, 5.2% to 15.7%), and 9.6% (95% CI, 4.4% t0 14.8%), respectively, at 10 years from initial breast SN. The cumulative incidence of developing a second NMSC at 10 years from the first NMSC was 49.0% (95% CI, 43.5% to 54.5%). Because multiple lesions at presentation were common, when conditioned on time from first NMSC (Fig 3B) of 6, 12, and 24 months, the cumulative incidences of a second NMSC were 40.8% (95% CI, 34.7% to 46.9%), 38.2% (95% CI, 32.0% to 44.4%), and 33.8% (95% CI, 27.3% to 40.3%), respectively, at 10 years from first NMSC.

Fig 3.
Conditional cumulative incidence of (A) second subsequent breast neoplasm after occurrence of first subsequent breast neoplasm and of (B) second subsequent nonmelanoma skin cancer (NMSC) after first subsequent NMSC, conditioned on time of 0 (gold line), ...

Among survivors who received radiation and developed an SN, 414 had NMSC as SN1, whereas 570 had an invasive SMN as SN1. The cumulative incidence of an additional invasive malignancy (ie, SMN) was 20.3% (95% CI, 13.0% to 27.6%) at 15 years after NMSC compared with 10.7% (95% CI, 7.2% to 14.2%) after SMN1 (Fig 4) and was potentially influenced by the survival estimates for those with an invasive SMN as SN1 (45.4% at 15 years; 95% CI, 37.0% to 53.8%) that were lower than for those with NMSC as SN1 (79.0% at 15 years; 95% CI, 68.4% to 89.6%).

Fig 4.
Cumulative incidence of a subsequent malignant neoplasm among radiotherapy-exposed patients after nonmelanoma skin cancer (NMSC) as first subsequent neoplasm (SN; blue line) and subsequent malignant neoplasm (SMN) as SN1 (gold line).

The limitation of incomplete information regarding treatment for SNs and SMNs is recognized. Table 2 provides multivariable models evaluating risk factors (ie, demographic, treatment exposure for primary cancer, health behaviors, family history) associated with the cumulative incidences of multiple SNs and multiple SMNs after SN1 and SMN1, respectively. Exposure to radiation for the primary cancer was associated with cumulative incidence of SN2 (subdistribution HR, 2.16; 95% CI, 1.32 to 3.55). However, radiation appeared protective from SMN2 (subdistribution HR, 0.48; 95% CI, 0.25 to 0.94; cause-specific HR, 0.41; 95% CI, 0.20 to 0.85). Note that the radiation-exposed survivors had a lower survival estimate at 10 years from SMN1 (56.1%; 95% CI, 49.8% to 62.4%) compared with those who had no radiation exposure (64.3%; 95% CI, 49.6% to 79.0%). Additionally, older age at SN1 (≥ 30 years) was associated with higher cumulative incidence of developing an SN2 compared with those younger than 30 years of age (HR, 1.9; 95% CI, 1.28 to 2.82). Women were more likely than men to develop SMN2 (HR, 2.53; 95% CI, 1.23 to 2.51). However, when breast neoplasia as SMN2 was removed from analysis, association with female sex did not reach statistical significance (HR, 1.57; 95% CI, 0.70 to 3.50). Having a first-degree relative with cancer and being a current smoker were associated with an increased cumulative incidence for multiple SMNs, but the associations were not statistically significant at the.05 level.

Table 2.
Multivariable-Adjusted Subdistribution Hazard Ratios for Development of SN2 From Time of SN1 and for SMN2 From Time of SMN1

DISCUSSION

It is well established that the cumulative incidence of SNs increases with increased time from diagnosis.7,11,16 We now describe the experience of long-term survivors of childhood cancer after SN1 and the risk for multiple occurrences of SNs, either benign or malignant. Greater than one quarter (28%) of the CCSS population with SN1 experienced an additional neoplasm, such that, within 20 years from diagnosis of SN1, the estimated cumulative incidence of SN2 was 47%. Although previous studies have identified occurrences of multiple SMNs, the number of patients reported in any one study has been too small (range, 2 to 32) to allow detailed description and analysis.6,8,1720 Although not included in the current analysis, the experience of retinoblastoma survivors would certainly suggest that underlying genetic susceptibility (eg, RB1 gene alteration in the case of certain patients with retinoblastoma) plays a role in development of multiple SNs.16,21 Considering the young age (median, 32 years) of the CCSS cohort, these survivors have yet to reach ages when sharp increases in the incidence of cancer in the general population occur. Therefore, it appears that the multiple tissue injuries accrued as a result of cancer therapy, along with the impact of genetic susceptibility of some survivors to multiple cancers, set the stage in the second decade of survival (median follow-up, 18 years) for a significant increase in the number of survivors with multiple cancers.

Certain patterns of SNs raise concern. Of 176 survivors who experienced a breast neoplasm as SN1, 37 (21%) experienced one or more subsequent primary breast neoplasms. In all, 42 women experienced multiple breast neoplasms, with a cumulative incidence of 20.7% at 10 years from diagnosis of the initial lesion. In many of these occurrences, women had bilateral (synchronous) lesions at presentation not thought to be metastatic, or occurrence of a tumor in the contralateral breast shortly after the primary diagnosis. Nonetheless, among those who were tumor free at 1 year from the initial diagnosis, 10% will still develop a subsequent breast neoplasm 10 years from the initial diagnosis. Although increased risk for breast cancer after treatment for childhood cancer has been well documented,17 this pattern for multiple cancers raises new concerns. Similarly, of 142 participants who had a nonmalignant meningioma, 126 occurred as SN1, and 12 survivors (10%) experienced multiple meningiomas. Therefore, not only is the incidence of meningioma increasing with time from treatment exposure18 but also, with time, survivors may be at increasing risk for multiple meningiomas as well.

Among radiation-exposed individuals who developed NMSC as SN1 in this analysis, one in five developed an invasive neoplasm within 15 years, an incidence almost twice that of those also exposed to radiation but who had an invasive neoplasm (SMN) as SN1. Therefore, NMSC may represent a clinical marker for early identification of a population at high risk for a future malignant neoplasm. Occurrence of NMSC as a first SN may identify survivors with genetic susceptibility to radiation injury and/or deficient DNA repair. In the general population, there is evidence for an association between a NMSC diagnosis and increased risk for subsequent cancer.19,20 Future studies regarding genetic susceptibility should include evaluation of polymorphisms in genes associated with DNA repair.22 In addition, a surprising number of patients with SMN1 who were not exposed to radiation developed SMN2 (cumulative incidence, 22.8% at 10 years). This may identify a population of patients with an underlying cancer predisposition syndrome. We note that SMN1 as SN1 may also identify a genetically susceptible population, but, because of the higher rate of mortality after SMN1 (compared with NMSC as SN1), these patients don't have the same opportunity to develop SMN2. Additionally, though many survivors had multiple NMSCs at presentation, conditional cumulative incidence analysis identifies the high risk that remains in these survivors for future additional NMSCs.

Repeated investigations have identified that female sex, young age at primary cancer diagnosis, radiation exposure, family history of cancer, as well as a primary diagnosis of sarcoma or Hodgkin's lymphoma increase risk for SMN.5,6,23 In this analysis, radiation exposure and older age at SN1 (≥ 30 years) appear to be the most important risk factors for development of multiple SNs. Although the association with radiation is plausible given the established association between radiation and SMN1, we hypothesize that older age at SN1 identifies a population of survivors who are reaching ages at which, in the general population, cancer risks increase. The appearance of a protective effect of radiation for development of SMN2 after SMN1 is likely artifactual as a result of death as a competing risk for SMN2 development. Survivors with SMN1 who had received radiation were more likely to die and, thus, less likely to have SMN2. Furthermore, because both the subdistribution HR (0.48) and cause-specific HR (0.41) for developing SMN2 after SMN1 indicated protective effects of having had radiation for the original childhood cancer, we infer that risk of death and risk of SMN2 were positively correlated, perhaps highly, after SMN1. That is, deaths after SMN1 removed survivors who were at high risk for SMN2 from risk sets disproportionately more in the radiation-exposed subgroup. Had this not been the case, the cause-specific HR would not have been in the protective direction. Although females were at increased risk for SMN2 after SMN1, patients with first-degree relatives with cancer and patients with a smoking history may also be at increased risk. However, these findings were of borderline statistical significance. Additionally, having a sarcoma or a p53 (Li-Fraumeni) –associated SMN1 was not found to be associated with developing multiple malignancies.

Limitations of this study should be considered. The majority of SNs are initially ascertained by self report, which may result in underestimation of true incidence rates. Additionally, although CCSS has collected detailed chemotherapy exposures and radiation dosimetry and volume measures relating to the primary cancer, only limited information was available regarding treatment of SNs, restricting risk factor analyses to primary cancer exposures only. Clearly, exposures resulting from treatment of subsequent neoplasms could impact subsequent cancer risk. The limitation of not having the SN treatment information to include in the risk factor analysis does not detract from the findings and clinical implications of the high cumulative incidence of multiple subsequent neoplasms. Finally, systematic and precise determination of SN occurrence as in field versus out of the radiation field was not possible in many of the occurrences, because exact information regarding location of the SN was not always available either from the respondent or as noted on the pathology report.

In conclusion, with increased follow-up time, survivors of childhood cancer are at increasing risk for multiple subsequent neoplasms. The CCSS cohort, with its large population and comprehensive follow-up over two decades, provides a unique resource for evaluation of patterns of SNs as the cohort ages. Although some of the traditional risk factors for SMNs, such as radiation exposure and female sex, are evident among those with multiple neoplasms, future studies should utilize the CCSS biospecimen collection as a resource to identify causes of genetic susceptibility in these populations. Diagnosis of a NMSC may identify those survivors with a predisposition for subsequent invasive neoplasms. Thus, in addition to annual screening dermatologic examination, compliance with additional guidelines for screening for invasive malignancy (ie, mammography, colonoscopy) is important.

Appendix

Table A1.

Benign Neoplasm Subtypes Identified Within the CCSS Cohort

Tumor GroupSpecific Histopathologic DiagnosisCount
BreastIntraductal carcinoma, noninfiltrating NOS46
Comedocarcinoma, noninfiltrating5
Noninfiltrating intraductal papillary adenocarcinoma3
Lobular carcinoma in situ3
Carcinoma in situ NOS2
Intraductal carcinoma and lobular carcinoma in situ2
Neoplasm, uncertain whether benign or malignant2
Myeloid leukemiaMyelodysplastic syndrome NOS3
Chronic myeloproliferative disease1
MelanomaMelanoma in situ7
Nonmelanoma skin*Squamous cell carcinoma in situ NOS12
Bowen's disease2
Nonmalignant meningiomaMeningioma NOS138
Meningotheliomatous meningioma8
Fibrous meningioma5
Transitional meningioma5
Meningiomatosis NOS3
RenalOxyphilic adenoma1
Soft tissue sarcomaNeurilemmoma NOS19
Fibrous histiocytoma NOS1
Hemangioblastoma1
OtherSquamous cell carcinoma in situ NOS18
Neoplasm, uncertain whether benign or malignant7
Neoplasm, benign4
Transitional cell carcinoma in situ3
Carcinoma in situ NOS2
Adenocarcinoma in situ2
Bowen's disease1
Sex cord-stromal tumor1
Granulosa cell tumor NOS1
Leydig cell tumor NOS1
Gonadoblastoma1
Teratoma NOS1
Subependymal giant cell astrocytoma1
Myxopapillary ependymoma1
Ganglioglioma1
Total314

NOTE. Subtypes are identified as International Classification of Diseases O-2 codes ending in 0, 1, or 2.

Abbreviations: CCSS, Childhood Cancer Survivor Study; NOS, not otherwise specified.

*Does not include malignant nonmelanoma skin cancers (ie, International Classification of Diseases O behavior code 3; n = 1,090).

Table A2.

Multivariable-Adjusted Hazard Ratios for Development of SN2 From Time of SN1 and, for SMN2, From Time of SMN1 With Age As the Time Scale, Using Cause-Specific Hazards Model

CharacteristicSN1 → SN2
SMN1 → SMN2
Hazard Ratio95% CIPHazard Ratio95% CIP
Age at diagnosis, years
    < 101.001.00
    ≥ 101.601.07 to 2.40.02222.170.52 to 9.13.2906
Sex
    Female0.960.76 to 1.22.76662.631.07 to 6.46.035
    Male1.001.00
Ethnicity
    Other1.100.66 to 1.83.7256NA
    Black non-Hispanic0.580.14 to 2.38.45311.370.16 to 11.54.7693
    Hispanic1.000.49 to 2.04.99781.880.53 to 6.75.3314
    White non-Hispanic1.001.00
First-degree relative with cancer
    Yes1.140.89 to 1.47.29231.750.91 to 3.36.0924
    No1.001.00
Radiation exposure
    Yes2.011.27 to 3.17.00280.410.20 to 0.85.0159
    No1.001.00
Age at SN1, years
    < 301.00
    ≥ 301.821.19 to 2.78.0059
Time from Primary to SN1
    Time from Primary to SN1 by 10 years1.461.07 to 1.98.0154
Education
    < High school1.410.87 to 2.28.1661.240.34 to 4.58.7416
    High school graduate0.930.64 to 1.34.68431.110.41 to 2.99.8426
    > High school1.001.00
Household income, $ per year
    ≥ 20,0001.390.96 to 2.01.08281.470.54 to 3.98.4538
    < 20,0001.001.00
Smoking
    Current0.870.60 to 1.25.44791.720.72 to 4.11.224
    Former0.920.66 to 1.29.63320.920.34 to 2.51.8701
    Never1.001.00
P53-associated SN1
    Yes1.460.76 to 2.80.2525
    No1.00
Primary sarcoma
    Yes1.100.52 to 2.34.8067
    No1.00
Age at SMN1
    Age at SMN1 by 10 years1.090.30 to 3.93.9002
Time from primary to SMN1
    Time from primary to SMN1 by 10 years1.060.33 to 3.40.9178

Abbrevations: NA, not applicable; SMN, subsequent malignant neoplasm; SN, subsequent neoplasm.

Table A3.

Additional Characteristics of the Childhood Cancer Survivor Study Cohort: Entire Cohort, Survivors With Subsequent Neoplasm, and Survivors With Subsequent Malignant Neoplasms

Subsequent Neoplasm
Subsequent Malignant Neoplasm
Entire Cohort
Any
Multiple
≥ 3
Any
Multiple
≥ 3
Characteristic*No.%No.%No.%No.%No.%No.%No.%
Total14,3581001,382100386100153100735100681003100
Treatment era
    1970-19797,74954.045733.19825.43623.525735.01826.5133.3
    1980-19866,60946.092566.928874.611776.547865.05073.5266.7
Education
    < High school4,79535.321616.64010.9149.612317.81116.700.0
    High school graduate2,31517.019414.95013.61913.011316.41218.2133.3
    > High school6,48547.788968.427775.511377.445565.84365.2266.7
Annual household income, $ per year
    < 20,0002,66821.021717.64011.21611.011718.169.800.0
    > 20,00010,04779.01,01582.431788.813089.053181.95590.23100
Treatment of primary diagnose
    RT only390.340.310.310.720.300.000.0
    Chemotherapy only8316.6252.051.421.4142.134.800.0
    Surgery only9137.3372.971.910.7223.346.300.0
    RT + chemotherapy1,47111.715812.54612.61611.0558.134.8133.3
    RT + surgery1,48511.826921.210428.64732.412919.11219.000.0
    RT + chemotherapy + surgery5,55144.168954.418550.87551.738857.53047.600.0
    Chemotherapy + surgery2,28418.2856.7164.432.1659.61117.5266.7
Alkylating score
    05,80550.156849.817453.26650.026644.32646.400.0
    1-24,46338.539935.09328.43728.022437.31832.12100
    3-41,31011.317415.26018.32922.011118.51221.400.0
Epipodophyllotoxin
    None11,36391.21,18294.034695.814297.963294.56095.23100
    1-1,0003562.9292.361.721.4121.800.000.0
    1,001-4,0003522.8241.951.400.0142.123.200.0
    ≥ 4,0003823.1231.841.110.7111.611.600.0
Time from primary to secondary cancer, years
    < 1541229.941229.911028.74831.429340.02942.600.0
    ≥ 1596770.196770.127371.310568.644060.03957.43100

Abbreviation: RT, radiation therapy.

*Percentages for individual characteristics were calculated on total number of participants providing information for those characteristics.

Table A4.

Total Number of Subsequent Neoplasms and Subsequent Malignant Neoplasms by Type of Neoplasm

Type of NeoplasmSubsequent Neoplasm
Subsequent Malignant Neoplasm
No.%No.%
Total2,210100806100
Bone sarcoma452.04455.58
Breast25211.4018923.45
Lymphoblastic leukemia100.45101.24
Myeloid leukemia311.40273.35
Non-Hodgkin's lymphoma210.95212.61
Hodgkin's lymphoma90.4191.12
Malignant CNS763.44769.43
Melanoma562.53496.08
Nonmelanoma skin1,10449.95
Nonmalignant meningioma1597.19
Renal210.95202.48
Soft tissue sarcoma944.25739.06
Thyroid1315.9313116.25
Other2019.1015619.35

Table A5.

Specific Neoplasm Subtypes Identified Within the CCSS Cohort As SN1 or SN2-Positive for Survivors Who Did Not Receive Radiation Therapy

Tumor GroupSN1
SN2-Positive
Specific Histopathologic DiagnosisCountSpecific Histopathologic DiagnosisCount
Bone sarcomaOsteosarcoma NOS2Osteosarcoma NOS2
BreastInfiltrating duct carcinoma11Infiltrating duct carcinoma6
Infiltrating duct and lobular carcinoma4Infiltrating duct and lobular carcinoma1
Intraductal carcinoma, noninfiltrating NOS4
Phyllodes tumor, malignant3
Infiltrating ductular carcinoma2
Mucinous adenocarcinomas1
Lobular carcinoma NOS1
Lymphoblastic leukemiaAcute lymphoblastic leukemia NOS2
Adult T-cell leukemia/lymphoma2
Myeloid leukemiaAcute promyelocytic leukemia2
Acute myeloid leukemia1
Chronic myeloproliferative disease1
Myelodysplastic syndrome NOS1
Non-Hodgkin's lymphomaMalignant lymphoma, large-cell, diffuse NOS1
Hodgkin's lymphomaHodgkin's disease, nodular sclerosis NOS2
Hodgkin's disease, lymphocytic predominance, nodular1
Malignant CNSAstrocytoma, anaplastic3Primitive neuroectodermal tumor1
Ependymoma NOS1
Astrocytoma NOS1
Fibrillary astrocytoma1
Pilocytic astrocytoma1
MelanomaOligodendroglioma NOS1
Malignant melanoma NOS8Malignant melanoma NOS3
Melanoma in situ1
Superficial spreading melanoma2
Nonmelanoma skinBasal cell carcinoma NOS30Basal cell carcinoma NOS11
Squamous cell carcinoma NOS1Squamous cell carcinoma NOS1
Squamous cell carcinoma in situ NOS1
RenalMeningioma NOS2Renal cell carcinoma2
Meningotheliomatous meningioma1
Soft tissue sarcomaFibrous histiocytoma, malignant3Fibrosarcoma NOS1
Renal cell carcinoma2Neurilemmoma NOS1
Leiomyosarcoma NOS2Leiomyosarcoma NOS1
Dermatofibrosarcoma NOS2
Oxyphilic adenoma1
Rhabdomyosarcoma NOS1
ThyroidKaposi's sarcoma1
Papillary carcinoma NOS5Papillary carcinoma NOS1
Papillary carcinoma, follicular variant4Papillary carcinoma, follicular variant2
OtherSquamous cell carcinoma in situ NOS3Basal cell carcinoma NOS1
Squamous cell carcinoma NOS3Squamous cell carcinoma NOS1
Adenocarcinoma NOS3
Serous cystadenoma, borderline malignancy2
Mucinous adenocarcinoma2
Choriocarcinoma NOS2
Neoplasm, malignant1
Carcinoma in situ NOS1
Carcinoma NOS1
Transitional cell carcinoma in situ1
Transitional cell carcinoma NOS1
Papillary transitional cell carcinoma1
Adenocarcinoma in situ1
Bronchiolo-alveolar adenocarcinoma1
Endometrioid carcinoma1Endometrioid carcinoma1
Mucoepidermoid carcinoma1
Serous surface papillary carcinoma1
Infiltrating duct carcinoma1
Germinoma1
Teratoma, malignant NOS1
Malignant lymphoma NOS1
Leukemia NOS1
Total14736

Abbreviations: CCSS, Childhood Cancer Survivor Study; NOS, not otherwise specified; SN, subsequent neoplasm.

Footnotes

Supported by the National Cancer Institute grant No. U24-CA55727 (L.L.R.), by the Cancer Center Support (CORE) grant No. CA 21765 (to St Jude Children's Research Hospital), and by the American Lebanese-Syrian Associated Charities.

Presented in part at the 46th Annual Meeting of the American Society of Clinical Oncology, June 4-8, 2010, Chicago, IL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Gregory T. Armstrong, Wendy Leisenring, Sue Hammond, Smita Bhatia, Joseph P. Neglia, Marilyn Stovall, Deokumar Srivastava, Leslie L. Robison

Collection and assembly of data: Gregory T. Armstrong, Wei Liu, Wendy Leisenring, Sue Hammond, Smita Bhatia, Joseph P. Neglia, Marilyn Stovall, Deokumar Srivastava, Leslie L. Robison

Data analysis and interpretation: Gregory T. Armstrong, Wei Liu, Wendy Leisenring, Yutaka Yasui, Sue Hammond, Smita Bhatia, Joseph P. Neglia, Marilyn Stovall, Deokumar Srivastava, Leslie L. Robison

Manuscript writing: All authors

Final approval of manuscript: All authors

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