The prognosis of osteosarcoma occurring as second malignancy of childhood cancers may be favorable: experience of two cancer centers in Japan
Tsukasa Yonemoto . Ako Hosono . Shintaro Iwata ·
Hiroto Kamoda . Yoko Hagiwara . Tomohiro Fujiwara .
Akira Kawai . Takeshi Ishii
Received: 23 May 2014/ Accepted: 25 June 2014 @ Japan Society of Clinical Oncology 2014
Abstract
Background Osteosarcoma as second malignancy of childhood cancers rarely occurs, and its clinical charac- teristics are unclear.
Methods Patients with osteosarcoma occurring as second malignancy of childhood cancers were retrospectively surveyed.
Results Of 323 patients with osteosarcoma registered in the database, 10 (3.1 %) had a past history of childhood cancers. The mean age at the onset of the first childhood cancer was 2.7 years, and the diagnosis of the first child- hood cancer was adrenocortical carcinoma, malignant ter- atoma, ovarian carcinoma, Ewing’s sarcoma, and rhabdomyosarcoma in 1 patient each, and retinoblastoma in 5 patients. Osteosarcoma as second malignancy occurred 14.6 years after the first childhood cancer on average. Seven patients were alive and 3 died. In 1 patient, the cause of death was related to a complication of treatment for the first childhood cancer. Except for this patient, 7 (77.8 %) of
T. Yonemoto ☒ . S. Iwata . H. Kamoda . Y. Hagiwara ·
T. Ishii
Division of Orthopaedic Surgery, Chiba Cancer Center, 666-2 Nitona-cho, Chuo-ku, Chiba 260-8717, Japan
e-mail: tyonemot@chiba-cc.jp
T. Yonemoto . S. Iwata . H. Kamoda . Y. Hagiwara . T. Ishii Chiba Pediatric Orthopaedic Group (CPOG), Chiba, Japan
A. Hosono
Division of Pediatrics, National Cancer Center Hospital,
5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
T. Fujiwara · A. Kawai
Division of Musculoskeletal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
9 patients survived with no disease (mean follow-up per- iod: 10.9 years).
Conclusions Attention should be paid to complications of treatment for the first childhood cancer in the treatment for osteosarcoma occurring as second malignancy. The prog- nosis of osteosarcoma as second malignancy of childhood cancers may be more favorable than that of conventional osteosarcoma.
Keywords Osteosarcoma . Second malignant neoplasm . Childhood cancer . Multiple primary cancers
Introduction
Rare occurrences of osteosarcoma as second malignancy of childhood cancers are known [1-3], but the incidence is very low. Genetic and environmental factors are considered as risk factors. Germ-line mutations of p53 and RB have been reported as genetic factors [4, 5], and radiotherapy and chemotherapy (bone marrow transplantation and alkylating agents) have been reported as environmental factors [6-10].
Retinoblastoma, malignant lymphoma, leukemia, mela- noma, neuroblastoma, rhabdomyosarcoma, Ewing’s sar- coma, malignant fibrous histiocytoma, Wilms’ tumor, and adrenocortical carcinoma have been reported as the path- ological diagnoses of first childhood cancers for osteosar- coma occurring as second malignancy [5, 11-19], but their clinical characteristics have not been clarified.
To clarify the clinical characteristics of osteosarcoma occurring as second malignancy of childhood cancers, we retrospectively surveyed patients treated at 2 cancer centers in Japan.
Patients and methods
Patients
From patients with osteosarcoma registered in the dat- abases of 2 cancer centers in Japan (Chiba Cancer Center and the National Cancer Center) after 1985, those who had a past medical history of childhood cancers were extracted.
Investigation items
The following items were retrospectively surveyed in these patients: the diagnosis, onset age, gender, and treatment (the presence or absence of chemotherapy, surgery, and radiotherapy) for first childhood cancers, the onset age and treatment (the presence or absence of chemotherapy, sur- gery, and radiotherapy) for osteosarcoma as second malignancy, interval from first childhood cancer to osteo- sarcoma as second malignancy, the anticancer drugs used to treat the first childhood cancer and osteosarcoma as second malignancy, the presence or absence of a third malignancy (onset age), and oncological outcomes.
Approval was obtained from the Institutional Review Boards of Chiba Cancer Center and National Cancer Center before the study.
Results
The clinical characteristics of the patients are shown in Table 1, and treatments are outlined in Table 2.
After 1985, a total of 323 patients with osteosarcoma were registered in the databases of the 2 cancer centers (163 patients in Chiba Cancer Center and 160 patients in National Cancer Center), and 10 patients of them had a past medical history of childhood cancers. There were 4 males and 6 females, and the age at onset of the first childhood cancers ranged from 0 to 10 years (mean 2.7 years). The diagnosis of the first childhood cancer was adrenocortical carcinoma, malignant teratoma, ovarian carcinoma, Ewing’s sarcoma, and rhabdomyo- sarcoma in 1 patient each, and retinoblastoma in 5 patients. Osteosarcoma as second malignancy occurred 5-34 years (mean 14.8 years) after the first childhood cancer occurrence. The age at onset of osteosarcoma as second malignancy was 8-34 years (mean 17.5 years). Osteosarcoma as second malignancy was pathologically low-grade in Case 1, and high-grade (conventional type) in the other cases. A third malignancy occurred in Case 1 (thyroid carcinoma 23 years). The oncological out- come was: no evidence of disease (NED) in 7 patients (mean follow-up period 10.9 years); died of other
| Case | Sex | First malignant neoplasm (FMN) | Interval from FMN to SMN (years) | Second malignant neoplasm (SMN) | Age at final follow-up (years) | Outcome | ||
|---|---|---|---|---|---|---|---|---|
| Age (years) | Diagnosis | Age (years) | Diagnosis | |||||
| 1 | F | 0 | Adrenocortical carcinoma | 11 | 11 | Osteosarcoma of right femur | 26 | NED |
| 2 | F | 2 | Malignant teratoma of sacrum | 12 | 14 | Osteosarcoma of left femur | 30 | NED |
| 3 | F | 8 | Ovarian cancer (yolk sac tumor) | 16 | 24 | Osteosarcoma of right ilium | 39 | NED |
| 4 | M | 10 | Ewing's sarcoma of left humerus | 5 | 15 | Osteosarcoma of right femur | 18 | DOO |
| 5 | F | 4 | Rhabdomyosarcoma of bladder | 16 | 20 | Osteosarcoma of left ilium | 36 | NED |
| 6 | M | 0 | Retinoblastoma of bilateral eyes | 34 | 34 | Osteosarcoma of left femur | 36 | DOD |
| 7 | M | 1 | Retinoblastoma of bilateral eyes | 24 | 25 | Osteosarcoma of right middle cranial fossa | 27 | DOD |
| 8 | F | 1 | Retinoblastoma of bilateral eyes | 7 | 8 | Osteosarcoma of left tibia | 17 | NED |
| 9 | M | 0 | Retinoblastoma of right eye | 13 | 13 | Osteosarcoma of right femur | 15 | NED |
| 10 | F | 1 | Retinoblastoma of bilateral eyes | 10 | 11 | Osteosarcoma of right tibia | 14 | NED |
M male, F female, NED no evidence of disease, DOO died of other disease, DOD died of disease
| Table 2 Treatment for FMN and SMN | Case | FMN | SMN | ||||
|---|---|---|---|---|---|---|---|
| Surgery | Chemotherapy | Radiation therapy | Surgery | Chemotherapy | Radiation therapy | ||
| 1 | (+) | (-) | (-) | (+) | (-) | (-) | |
| 2 | (+) | CPM, DXR, ACD, VCR, VLB | (-) | (+) | IFM, CPM, VP- 16 | (-) | |
| 3 | (+) | BML, ACD, VLB | (+) | (+) | MTX, CDDP, DXR, IFM | (-) | |
| FMN first malignant neoplasm, | 4 | (+) | VCR, DXR, CPM, ACD, VP-16, | (+)ª | (+) | VP-16, CPM, | (-) |
| SMN second malignant | CDDP, PBSCT (BUS, L-PAM, | IFM, CDDP, | |||||
| neoplasm, CPM | TESPA) | VDS, MTX | |||||
| cyclophosphamide, DXR doxorubicin, ACD | 5 | (-) | (+) (details unknown) | (+) | (+) | IFM, DXR | (-) |
| dactinomycin, VCR vincristine, | 6 | (+) | (-) | (+)ª | (+) | (-) | (-) |
| VLB vinblastine, BLM | 7 | (+) | (-) | (+) | (-) | MTX, CDDP, | (+) |
| bleomycin, VP-16 etoposide, | DXR | ||||||
| CDDP cisplatin, BUS busulfan, L-PAM melphalan, TESPA | 8 | (+) | VCR, THP, CPM, CDDP, VP-16 | (+)ª | (+) | MTX, CDDP, DXR, IFM | (-) |
| tespamin, IFM ifosphamide, MTX methotrexate, VDS | 9 | (+) | (-) | (+)ª | (+) | MTX, CDDP, DXR | (-) |
| vindesine, THP pirarubicin | 10 | (+) | VCR, VP-16, CBDCA | (+)ª | (+) | MTX, CDDP, | (-) |
| a Osteosarcoma occurred distant from radiation field | DXR |
disease (DOO) in 1 (follow-up period 3 years); and died of disease (DOD) in 2 (mean follow-up period 2 years).
Eight patients received radiotherapy for first childhood cancers, and osteosarcoma as second malignancy occurred at a site within and outside the irradiated region in 3 and 5 patients, respectively.
Death cases
In Case 4, pulmonary fibrosis was induced by irradiation of the whole lung for lung metastasis of the first childhood cancer, and the patient died of chronic respiratory failure. In Case 6, it was impossible to perform chemotherapy for osteosarcoma as second malignancy because irradiation for the first childhood cancer caused encephalopathy (marked mental retardation), and the patient died of lung metastasis of osteosarcoma as second malignancy. In Case 7, osteosarcoma as second malignancy could not be controlled in the local region, and the patient died of osteosarcoma as second malignancy.
Discussion
A large-scale survey has been reported by the Childhood Cancer Survivor Study, in which osteosarcoma as second malignancy occurred in 31 of 14,372 survivors from child- hood cancers [3]. In our study, 10 (3.1 %) of 323 patients with osteosarcoma registered in the databases had a past history of childhood cancers. The incidence of the patients with osteosarcoma occurring as second malignancy of
childhood cancers is expected to slowly rise with an increase in survivors from childhood cancers.
Genetic and environmental factors (radiotherapy and chemotherapy) have been reported as risk factors of oste- osarcoma occurring as second malignancy of childhood cancers 4-10]. The patients in our study also possessed these risk factors, but statistical analysis of risk factors could not be performed because the diagnosis of first childhood cancer varied, various treatments were per- formed, and the numbers of patients were limited.
A third malignancy (thyroid cancer) occurred in Case 1. A high risk of multiple primary cancers is predicted for patients with osteosarcoma as second malignancy of childhood cancers. Continuation of strict follow-up would be neces- sary. When the dose of doxorubicin exceeds the tolerable dose in the treatment for first childhood cancer, as noted in Cases 2 and 4, doxorubicin should be excluded from the treatment for osteosarcoma as second malignancy. In Case 4, the cause of death was a complication related to treatment for the first childhood cancer. In the treatment for osteosarcoma occurring as second malignancy, attention should be paid to complications of treatment for the first childhood cancer.
In Case 1, osteosarcoma occurring as second malig- nancy was pathologically low-grade and p53 germ-line mutation was present [20]. Radig et al. [21] also reported that low-grade osteosarcoma was noted in many patients with p53 germ-line mutation. In our study, except for 1 patient who died of a complication related to treatment for the first childhood cancer, 7 (77.8 %) of 9 patients survived with no disease (mean follow-up period 10.9 years). The
5-year survival rate in conventional osteosarcoma patients is reportedly 60-70 %. Smith et al. [22] reported it to be 68 %. Cho et al. [23] indicated that the 5- and 10-year survival rates in stage IIB osteosarcoma patients were 60.2 and 44.8 %, respectively. The prognosis of osteosarcoma occurring as second malignancy of childhood cancers may be more favorable than that of conventional osteosarcoma.
In conclusion, attention should be paid to complications of treatment for the first childhood cancers in the treatment for osteosarcoma occurring as second malignancy. The prognosis of osteosarcoma as second malignancy of childhood cancers may be more favorable than that of conventional osteosarcoma.
Acknowledgments This study was performed as the Higashinihon Orthopedic and Pediatric Sarcoma Group (HOPES) Study #006. The authors thank the members of the HOPES and the Chiba Pediatric Orthopaedic Group (CPOG) for their encouragement.
Conflict of interest The authors declare that they have no conflict of interest.
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