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Journal of Clinical Oncology, Vol 25, No 19 (July 1), 2007: pp. 2833-2839 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.6719 Treatment-Adjusted Predisposition to Second Malignant Neoplasms After a Solid Cancer in Childhood: A Case-Control Study
From L'Institut National de la Santé et de la Recherche Médicale; Gustave-Roussy Institute, Departments of Medical Physics and Radiotherapy and Pediatric Oncology, Villejuif, France; and the Centre for Childhood Cancer Survivor Studies, University of Birmingham, Birmingham, United Kingdom Address reprint requests to Florent de Vathaire, PhD, INSERM U605, Espace Maurice Tubiana, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France, e-mail: fdv{at}igr.fr
Purpose Previous therapy, genetic susceptibility, and the type of first malignant neoplasm (FMN) are known to be associated with the risk of second malignant neoplasm (SMN) among patients treated for a childhood cancer. The aim of this study was to investigate the independent role of the FMN in the onset of any SMN. Patients and Methods A case-control study nested in a European cohort of 4,581 patients treated for a solid cancer during childhood was conducted. One hundred forty-six patients with an SMN and 417 controls were matched for sex, age at FMN, chemotherapy, radiotherapy, the local radiation dose received at the site of SMN for patient cases and at the same site for the matched controls, and follow-up. Results A significantly increased risk of developing any SMN was observed after Hodgkin's lymphoma, retinoblastoma, malignant bone tumor, soft tissue sarcoma (STS), and germ cell tumor as FMN, after adjustment for chemotherapy and family cancer syndrome. No significant risk of developing a carcinoma was observed among patients who had developed Hodgkin's lymphoma as FMN. A significantly increased risk of developing a sarcoma was observed among patients who had developed a retinoblastoma (adjusted odds ratio [ORa] = 7.5; 95% CI, 1.2 to 46), a malignant bone tumor (ORa = 13.3; 95% CI, 1.5 to 117), an STS (ORa = 4.8; 95% CI, 1.3 to 18), or a carcinoma (ORa = 9.4; 95% CI, 1.1 to 82) as FMN. Conclusion Survivors of Hodgkin's lymphoma, retinoblastoma, malignant bone tumor, STS, and germ cell tumor should receive close surveillance because they are at increased risk of developing any SMN.
Long-term survivors of childhood and adolescent cancers continue to succumb to significant excess mortality, and recurrences of the primary disease and second malignant neoplasms (SMNs) are found to be the most common causes of death.1,2 Factors known to contribute to the risk of any SMN include previous therapy received,3,4 the time since the initial diagnosis, age at diagnosis,5,6 genetic susceptibility,7,8 and the type of first malignant neoplasm (FMN).9 Patients with a genetic predisposition, such as hereditary retinoblastoma,10-13 neurofibromatosis type 1 (NF1),14-16 or Li-Fraumeni syndrome (LFS),17,18 have been shown to have an increased risk of developing any SMN. Independently of genetic factors, associations between a specific type of FMN and a specific SMN have been evidenced, such as breast cancer,5,19-26 thyroid cancer,22,23 and leukemia after Hodgkin's lymphoma22,27 and malignant bone tumor after malignant bone tumor11,28,29 or STS.18,28 However, none of these studies was able to evidence a real association between the type of FMN and the type of SMN because, most often, the type of treatment (chemotherapy and/or radiotherapy) and the local radiation dose received at the site of SMN were not taken into account. We report the results of a case-control study nested in a cohort of 4,581 survivors of a childhood cancer. The aim of this study was to investigate the exact role of the type of FMN on the onset of any SMN, taking into account the type of treatment and the radiation dose received as treatment of FMN.
Patients A retrospective cohort of 4,581 patients, who were at least 2-year survivors of a solid cancer or a lymphoma that occurred between 0 and 16 years of age and who were treated between 1942 and 1986 in eight French and United Kingdom centers, was constituted.30 The cutoff date was January 1, 1993 for patients treated in French centers and January 1, 1991 for patients treated in United Kingdom centers. The median follow-up time of the whole cohort was 15.4 years (range, 2 to 49 years).
Patient cases were defined as patients who developed an SMN, excluding nonmelanoma skin cancer, at least 2 years after the diagnosis of the FMN. FMNs were grouped together according to the International Classification of Childhood Cancer,31 whereas SMNs were classified according to the International Classification of Disease for Oncology.32 Three controls for each patient case were matched for sex, age at FMN (± 1 year up to 4 years and ± 50% after 4 years), chemotherapy (yes or no), radiotherapy (yes or no), the local radiation dose received at the site of SMN for the patient case and at the same site for the matched controls (± 1 Gy for local doses < 2 Gy and ± 50% for local doses
Data Collected and Medical Records
Chemotherapy
Radiotherapy
Statistical Analysis
Of the 162 patient cases initially identified, eight patient cases were excluded from the matching procedure; the site of SMN was not definable for four of the patients, whereas dosimetric reconstruction was not possible for the other four patients. Among the remaining 154 patient cases, eight could not be matched with any controls; four patient cases developed an SMN more than 28 years after the diagnosis of their FMN, and four patient cases received a local radiation dose exceeding 32 Gy. All eight patient cases were excluded from the analysis. Thus, 563 patients were included in the final analysis (146 patient cases and 417 controls). Three controls were available for 131 patient cases, two controls were available for nine patient cases, and one control was available for six patient cases. As shown in Table 1, the quality of matching was quite good; 93% of controls had no more than a 2-year difference with the matched patient case for the age at diagnosis, and 89% of controls had a local radiation dose that did not exceed a 5-Gy difference with the matched patient case. The distributions of first and second cancers are listed in Table 2.
The characteristics of patient cases and controls are listed in Table 3. Fifty-six percent were male, the median age at diagnosis of FMN was 5.5 years (range, 0 to 15 years), 71% of the patients had received chemotherapy, 79% of the patients had received radiotherapy, and the median local radiation dose was 4.9 Gy (range, 0 to 98 Gy) for both patient cases and controls. The median interval between the diagnosis of FMN and the occurrence of SMN was 11.9 years (range, 2 to 40 years) among the 146 patient cases. Among the 563 patients, family cancer syndromes were known for 404 patients (72%); 309 (74%) were known among controls and 95 (65%) were known among patient cases. Thirteen of the 404 patients had NF1, and six had LFS (Table 3).
Regarding the number of patients exposed to each drug category, no significant difference was observed between patient cases and controls for eight of the nine drug categories. A significant difference between patient cases and controls was found within the dactinomycin category; 38% of patient cases had received dactinomycin, whereas 31% of controls had received dactinomycin (  2 = 4.4, P = .04), and mean dose was significantly higher among patient cases than among controls (3.3 v 2.2 mg/m2, respectively; P = .02; Table 3).
Role of the Type of FMN in the Risk of Any SMN
The new generated sample of patient cases and controls included 147 patient cases and 425 controls; 143 patient cases (98%) and 139 controls (33%) were also included in the first sample. Results from this new sample were similar to those of the main sample. Compared with patients who developed a Wilms’ tumor as FMN and after adjustment for all drug categories and family cancer syndromes, the risk of any SMN was multiplied by 3.3 (95% CI, 1.2 to 8.9), 5.6 (95% CI, 1.5 to 21), 4.3 (95% CI, 1.4 to 14), and 4.2 (95% CI, 1.8 to 10) for patients who had developed Hodgkin's lymphoma, retinoblastoma, malignant bone tumor, or STS, respectively (data not shown).
Role of the Type of FMN in the Risk of Carcinoma, Sarcoma, or Hematologic Cancer As shown in Figure 2, the risk of developing a carcinoma, sarcoma, or hematologic malignancy as SMN varied considerably according to the type of FMN. Patients who had a Wilms’ tumor during childhood were considered the reference group. After adjustment for all drug categories and family cancer syndromes, a strong but not significant correlation was observed between Hodgkin's lymphoma as FMN and carcinoma (ORa = 5.6; 95% CI, 0.7 to 42). A significant increased risk of developing any sarcoma was observed among patients who had retinoblastoma (ORa = 7.5; 95% CI, 1.2 to 46), malignant bone tumor (ORa = 13.3; 95% CI, 1.5 to 117), STS (ORa = 4.8; 95% CI, 1.3 to 18), or carcinoma (ORa = 9.4; 95% CI, 1.1 to 82) as FMN. No correlation was found between any type of FMN and hematologic malignancy.
This case-control study including 146 patient cases and 417 controls demonstrated a significant increased risk of developing any SMN after Hodgkin's lymphoma, retinoblastoma, STS, malignant bone tumor, or germ cell neoplasm independently of the type and cumulative dose of treatment and the family cancer syndrome. A significant increased risk of developing any sarcoma was observed among patients who had developed a retinoblastoma, malignant bone tumor, STS, or carcinoma as FMN. This study had some limitations including the exclusion of 16 unmatched patient cases, the high percentage of missing values for family cancer syndrome, and the limited number of patient cases and controls when investigating the role of FMN by type of SMN. The exclusion of the 16 patient cases should not bias our results because the distribution of sex, age at diagnosis, type of FMN, radiotherapy, and chemotherapy did not differ significantly between the 16 excluded patient cases and patient cases included in our study. The high proportion of missing values in the family cancer syndromes (28%) should not alter the quality of our results because a small proportion of cancer includes a genetic component. The power associated with each type of SMN study was 70%, 78%, and 37% when studying carcinoma, sarcoma, and hematologic malignancy as SMN, respectively, with the current sample size. The main interest of this study is the originality of its design (ie, a case-control study matched for sex, age at FMN, and type and dose of treatment). The stability of our results when comparing patient cases to a new control group strengthens the validity of our study. Our results are consistent with the literature. The risk of any SMN was found to increase among children with Hodgkin's lymphoma,5,21-23,26,27 with a standardized incidence ratio (SIR) ranging from 7.722 to 18.527 and a cumulative percentage of patients developing any SMN ranging from 6.9% to 10.6% at 20 years after the diagnosis and from 18% to 26.3% at 30 years after the diagnosis. The risk of any SMN was found to increase among children with a retinoblastoma, with the risk among patients with hereditary retinoblastoma (SIR = 19) exceeding the risk among patients with nonhereditary retinoblastoma (SIR = 1.2).10,12,40,41 The cumulative incidence of developing a new cancer at 50 years after the diagnosis of a retinoblastoma was 36% for patients with a hereditary syndrome and 5.7% for patients with no hereditary predisposition. STS as FMN was also found to significantly increase the risk of any SMN,5,18,30,41,42 with an SIR ranging from 2.8 to 13 and a cumulative incidence of an SMN at 20 years after the diagnosis ranging from 1.6% to 4.0%. Genetic syndromes, including NF1 and LFS, played a prominent role in the development of an SMN after therapy for a primary STS, particularly rhabdomyosarcoma.18,42 The risk of any SMN after treatment for a malignant bone tumor was found to increase but to a lower extent than after Hodgkin's lymphoma, STS, or retinoblastoma as FMN.5,30,41,43 None of these SIRs and cumulative incidence rates took into account the type and cumulative dose received of the treatment of the FMN. Only one study has investigated the joint effect of the type of FMN and treatment modalities on the risk of any SMN. The latter was found to be significantly associated with Hodgkin's lymphoma (P < .001) and STS (P = .01) as FMN, independently of therapeutic radiation exposure, sex, age at FMN, and type and dose of chemotherapy.5 Other studies evidenced the role of treatment on the risk of any SMN in a subgroup of patients treated for a specific type of FMN. Radiation was shown to increase the cumulative probability of developing any SMN among 963 patients with hereditary retinoblastoma as FMN (38.2% at 50 years after the diagnosis of retinoblastoma among irradiated patients v 21% among nonirradiated patients).12 Compared with surgery alone, initial therapy with radiation and chemotherapeutic agents was associated with a significantly higher risk of an SMN among 1,499 patients with an STS as FMN (SIR = 1.4 v 15.2, respectively). Among 1,770 patients with rhabdomyosarcoma as FMN, 10-year cumulative incidence estimates of an SMN were highest for patients who received both radiotherapy and an alkylating agent (2% ± 0.7%) compared with patients who received radiotherapy without any alkylating agent (1.4% ± 1.4%) or patients who received an alkylating agent without radiotherapy (0.8% ± 0.8%).42 Regarding the role of the type of FMN in the onset of a carcinoma, sarcoma, or hematologic malignancy, our results showed a strong and significant association between retinoblastoma, malignant bone tumors, STS, or carcinoma as FMN and sarcoma as SMN, independently of the type of treatment received for FMN and family cancer syndromes. Similar associations have been reported in the literature, but none of them were adjusted for treatment. A large excess risk of developing sarcoma was evidenced among hereditary retinoblastoma patients resulting from a strong radiation dose response among this subgroup of patients.12 Bone cancer as SMN was found to be significantly associated with bone tumor as FMN compared with leukemia (relative risk = 10.9; 95% CI, 2.2 to 55), independently of therapeutic radiation exposure, sex, age at FMN, and type and dose of chemotherapy.5 Among 1,499 patients treated for a childhood STS, the highest SIR was observed among patients who developed a bone cancer and a connective tissue tumor as SMN (SIR = 45.6; 95% CI, 17 to 99). This risk was increased 1.5-fold for patients treated with radiation.18 In the study by Neglia et al,5 bone cancer as SMN was found to be significantly associated with STS as FMN compared with leukemia (relative risk = 13.2; 95% CI, 3.2 to 55), independently of therapeutic radiation exposure, sex, age at FMN, and type and dose of chemotherapy. In our study, the well-known association between Hodgkin's lymphoma as FMN and carcinoma and, more specifically, breast cancer as SMN became nonsignificant after adjustment for all drug categories and family cancer syndromes (ORa = 5.6; 95% CI, 0.7 to 42). To our knowledge, this article is the first to investigate the actual role of FMN in the onset of any SMN, independently of the major known risk factors, namely previous therapy and genetic susceptibility. Patients and health care providers need to be aware of childhood cancer survivors who run the highest risk of developing an SMN so that surveillance is directed at potential primary and secondary prevention. The patients include those with retinoblastoma, Hodgkin's lymphoma, STS, or a malignant bone tumor as FMN. Further investigations are warranted to confirm these results.
The authors indicated no potential conflicts of interest.
Conception and design: Sylvie Guérin, Florent de Vathaire Financial support: Florent de Vathaire Administrative support: Sylvie Guérin Provision of study materials or patients: Mike Hawkins, Florent de Vathaire Collection and assembly of data: Sylvie Guérin, Mike Hawkins, Akhtar Shamsaldin, Ibrahima Diallo, Odile Oberlin, Florent de Vathaire Data analysis and interpretation: Sylvie Guérin Manuscript writing: Sylvie Guérin Final approval of manuscript: Sylvie Guérin, Mike Hawkins, Akhtar Shamsaldin, Catherine Guibout, Ibrahima Diallo, Odile Oberlin, Laurence Brugières, Florent de Vathaire
We thank Lorna Saint Ange for editing.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 Gy), and follow-up. The follow-up period of each control had to be at least as long as the study period of the matched patient case, which was defined as the time between the diagnosis of FMN and the onset of SMN. The study period for each control was restricted to the study period of the matched patient case. 
