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Outcome of Radiation-Related Osteosarcoma After Treatment of Childhood and Adolescent Cancer: A Study of 23 Cases

From the French Society of Pediatric Oncology, Paris, France.

Address reprint requests to Chantal Kalifa, MD, Service d'Oncologie Pédiatrique, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France; email kalifa{at}igr.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: We analyzed the clinical features and outcome of patients with radiation-associated osteosarcoma treated during the era of contemporary chemotherapy.

PATIENTS AND METHODS: The characteristics and outcome of 23 patients (17 males and six females) treated during childhood or adolescence for a solid tumor who later developed osteosarcomas within the radiation field between 1981 and 1996 were reviewed.

RESULTS: The median dose of radiation delivered to the first cancer was 47 Gy. Nineteen patients also received chemotherapy. The median time between radiotherapy and the diagnosis of secondary osteosarcoma was 8 years. Histologic slide review showed conventional central osteosarcoma with various differentiation patterns in 21 cases, together with one case of high-grade surface osteosarcoma and one of periosteal osteosarcoma. The sites of involvement were the craniofacial bones in six cases, the first cervical vertebra in one, the girdle bones in seven, and the extremities of long bones in nine. Three patients had metastatic disease at the diagnosis of osteosarcoma. Palliative therapy was administered to seven patients. The aim of treatment was curative for 16 patients, two of whom underwent amputation without further therapy. Intensive chemotherapy regimens were administered to 14 patients before and/or after surgery. Fifteen patients achieved complete surgical remission. Twelve patients were alive and disease-free at a median follow-up duration of 7.5 years. Overall and event-free survivals at 8 years were 50% and 41%, respectively.

CONCLUSION: Patients with radiation-related osteosarcoma and resectable lesions can be cured with surgery and intensive preoperative and postoperative chemotherapy.

	INTRODUCTION

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MANY CHILDHOOD cancers have been treated successfully with regimens that include radiation therapy. The adverse effects of ionizing radiation on bone in children include bone necrosis, osteitis, pathologic fracture, and growth retardation, but the most serious is radiation-related sarcoma. Since the first report by Beck in 1922,¹ many studies have documented the association between administration of ionizing radiation and the subsequent development of sarcoma. However, most of these studies included a heterogeneous population of patients who were irradiated at different age groups and developed various histologic types of sarcoma.^2-6 In 1985, Huvos et al⁷ reported a study of postradiation osteogenic sarcoma developed in bones or soft tissues. Since the advent of intensive chemotherapy, the treatment of patients with radiation-associated osteosarcoma as second malignancy has scarcely been described, except in case reports,^8,9 small series,¹⁰ and a report that compared primary osteosarcoma of flat bones with secondary osteosarcoma of any site.¹¹ We analyzed the clinical characteristics and therapeutic modalities offered to 23 young patients and evaluated their outcome.

	PATIENTS AND METHODS

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Eligibility for this retrospective study was based on the criteria of Cahan et al¹² for postirradiation osteosarcoma, as modified by Arlen et al.¹³ All patients had a histologically proven primary malignant tumor devoid of osteoblastic activity; all received radiation therapy, and the second neoplasm developed in the radiation field after a latent period of some years.

We only included patients with postradiation bone osteosarcoma diagnosed between January 1981 and January 1996, representing the era of contemporary intensive chemotherapy. Data were collected through a questionnaire sent to physicians who worked in centers of the French Society of Pediatric Oncology.

Because the retinoblastoma gene abnormality is associated with an increased risk of osteosarcoma, even in nonirradiated areas, patients with primary retinoblastoma were excluded from the analysis^14-16; second malignancies in this population are the subject of a separate study by the French Society of Pediatric Oncology.

Central review of histologic slides was performed by one pathologist, who classified the findings according to the World Health Organization histologic typing of bone tumors. Patients with radiation-related bone tumors other than osteosarcoma, such as malignant fibrous histiocytoma, were excluded so that a homogeneous population could be analyzed.

Follow-up was calculated from the time of diagnosis of postradiation osteosarcoma to the last contact. Actuarial survival curves were plotted from the diagnosis of the radiation-related osteosarcoma using the Kaplan-Meier method.¹⁷ Statistical analysis was based on Fisher's exact test.

	RESULTS

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Patient Characteristics
Twenty-three patients (17 males and six females) initially treated in five pediatric oncology centers were included in the study. Five patients had a personal or family history of excessive occurrence of cancer, consistent with Li-Fraumeni cancer syndrome in two cases. Germline mutations of the p53 gene were investigated in one patient with a Li-Fraumeni family history and in one patient who developed three different neoplasms, but no molecular abnormalities were detected. One patient had neurofibromatosis. Another patient developed a radiation-associated osteosarcoma after treatment of Ewing's sarcoma on a previous fibro-osseous dysplasia.

Initial diagnoses and treatments are listed in Table 1. Median age at the time of the first cancer was 6.5 years (range, 1 to 20.5 years). Nine patients had Ewing's sarcoma. Radiation therapy was delivered to the site of the primary tumor in eight cases and to the site of recurrence in two. Four patients were irradiated at the site of a primary rhabdomyosarcoma, together with lymph node irradiation in one case. Three patients with medulloblastoma received radiation therapy at the site of the primary tumor and a lower dose to the neuraxis. Hodgkin's disease was the initial diagnosis in two patients. Malignant mesenchymoma, nephroblastoma, and optic glioma were initial diagnoses in one case each. One patient with neuroblastoma was irradiated on the primary tumor and bone metastases, and one patient with a malignant germ cell tumor received radiotherapy for lymph node involvement.

Data on the type of ionizing radiation were available for 19 patients, all of whom received megavoltage therapy (photons alone in 15, photons and electrons in two, and electrons alone in two). The median dose of radiation given to the 20 patients for whom this information was available was 47 Gy (range, 25 to 60 Gy) for the volume in which secondary osteosarcoma have developed. Nineteen patients received chemotherapy, which included a high-dose alkylating agent in 18. None underwent bone marrow transplantation.

Radiation-Related Osteosarcoma
All postradiation osteosarcoma developed within the radiation field. The median time between radiotherapy and the diagnosis of osteosarcoma was 8 years (range, 3.5 to 26 years). The median age at diagnosis was 17 years (range, 7 to 34 years). Histologic slide review showed high-grade surface osteosarcoma and periosteal osteosarcoma in one patient each. All other patients had a conventional central osteosarcoma, which was osteoblastic in 12 cases, chondroblastic in six, and fibrohistiocytic in three.

The sites of involvement (Table 1) were craniofacial bones in six cases, the first cervical vertebra in one, girdle bones in seven, and long bones of the limbs in nine. Twenty patients had localized lesions at diagnosis, and three had metastatic disease (lung and bone metastases in one patient, a bone lesion in one, and lymph node involvement in one).

Treatment
The treatment of patients with radiation-related osteosarcoma is listed in Table 1. Palliative treatment was given to seven patients who had either bone metastases at diagnosis or unresectable lesions that involved sites such as the orbit, malar bone, or first cervical vertebra. They received various chemotherapy regimens (including ifosfamide and cisplatin for two patients, high-dose methotrexate for three patients, and etoposide or cisplatin alone for one patient each), combined with incomplete surgical resection in one case.

Sixteen patients were treated with curative intent. One patient had macroscopically incomplete surgical resection, and 15 patients achieved complete resection. Among the patients who underwent complete resection, eight had extremity disease. Four underwent amputation (without further therapy in two cases), and four underwent conservative surgery. Intensive chemotherapy regimens were administrated to 14 patients, 11 of whom received chemotherapy before and after complete surgical resection. Eight patients received regimens based on high-dose methotrexate (HDMTX; 8 to 12 g/m²) according to the modified T10 protocol,¹⁸ with five to eight (median, seven) preoperative HDMTX courses. Three of these eight patients received preoperative ifosfamide instead of doxorubicin because of high cumulative doses for the primary cancer. One patient received ifosfamide (6 g/m²) and cisplatin (100 mg/m²) in three preoperative courses of each drug. Nine of the 11 patients were assessable for histologic response to preoperative chemotherapy. The postoperative results and details are listed in Table 2. Two other patients underwent early surgical treatment despite good clinical response after two courses of ifosfamide, or stable disease after three courses of HDMTX, respectively. Three patients only received chemotherapy postoperatively as adjuvant treatment. Two of these patients received regimens that included eight courses of HDMTX plus three courses of bleomycin/dactinomycin/cyclophosphamide and four courses of cisplatin, or two courses of ifosfamide and carboplatin. Nine courses of ifosfamide and cisplatin were administered to the patient whose surgical resection was macroscopically incomplete.

Follow-Up and Outcome
The outcome of all 23 patients with postradiation bone osteosarcoma is shown in Fig 1. Four of the 15 patients who achieved complete remission relapsed. At the time of this analysis, 12 patients were alive and disease-free, with a median follow-up duration of 7.5 years from the diagnosis of osteosarcoma (range, 2.5 to 12.5 years). Two of the 12 patients developed recurrent disease. The interval between the recurrence and this analysis was 3.5 years in one patient who underwent disarticulation for a local recurrence and 6 months in one patient with a pulmonary metastasis treated by surgical resection. None of the four patients treated with limb-conserving surgery developed a local recurrence, but one subsequently underwent amputation because of pressure ulcers and skin fistula.

View larger version (19K): [in this window] [in a new window]   Fig 1. General clinical course of patients with postradiation osteosarcoma. CR, complete remission; CR2, second complete remission; ANED, alive and no evidence of disease; DOD, dead of disease.

Ten patients died of disease progression a median of 1 year after the diagnosis of osteosarcoma. Two of these patients initially entered complete remission but then developed lung and/or bone metastases and were not amenable to second complete resection. The patients who never achieved complete remission survived for 4 months to 3 years. One patient died 7 years after the diagnosis of osteosarcoma from chondrosarcoma as a third neoplasm. Kaplan-Meier estimates of overall and event-free survival rates of the 23 patients were 50% (± 10%) and 41% (± 10%), respectively, at 8 years (Fig 2). Overall and event-free survival rates of the subgroup of 20 patients with nonmetastatic disease were 57% (± 12%) and 48% (± 12%), respectively, at 8 years.

View larger version (12K): [in this window] [in a new window]   Fig 2. Survival rates from the diagnosis of radiation-related osteosarcoma: (—), overall survival (n = 23); (– – –) event-free survival (n = 23).

Prognostic Indicators
None of the three patients with metastases at diagnosis survived, whereas 12 of the 20 patients with nonmetastatic disease are alive. However, the number of patients is small, and the difference in survival is not statistically significant (P = .09; Fisher's exact test). Complete surgical resection was an important prognostic factor: none of the eight patients treated with chemotherapy alone or chemotherapy and incomplete tumor resection survived, compared with 12 survivors of the 15 patients who underwent complete resection (P = .003). With regard to histologic subtype, all patients with surface osteosarcoma or fibrohistiocytic conventional central osteosarcoma remained alive and disease-free. Two of the six patients with chondroblastic osteosarcoma and five of the 12 patients with osteoblastic bone sarcoma survived. The number of patients in each histologic subtype is too small to allow statistical comparison.

The latency period between radiotherapy and the diagnosis of osteosarcoma did not affect outcome. Using the median as a cutoff, five of the 11 patients who developed osteosarcoma less than 8 years after their first cancer are alive and disease-free, compared with seven of the 12 who developed second cancer 8 years later (P = .42).

	DISCUSSION

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The reported cumulative incidence of second malignant neoplasms after childhood cancers vary from 3% at 20 years to 13% at 30 years.^15,19,20 The estimated 20-year cumulative risk of subsequent bone sarcoma was 2.8% in the study by Tucker et al.²¹ In a recent report, the overall cumulative incidence of osteosarcoma was 1% 20 years after the diagnosis of the first cancer.²² Postradiation osteosarcomas are rare, accounting for 3.1% to 5.5% of all cases of osteosarcoma.^4,6 However, they are one of the most frequent second malignancies in childhood cancer survivors.^23-25 In most studies, the risk of bone sarcoma is higher after megavoltage than after orthovoltage therapy.^5,22 In our series, at least 80% of the patients received megavoltage therapy.

Five of the 23 patients studied had a personal or family history of an excessive occurrence of cancer. The significant excess of second malignancies in families with Li-Fraumeni syndrome was established a long time ago.^26,27 Today, p53 mutations are identified in many, but not all cases of this syndrome.²⁸ The case-control study by Kony et al²⁹ provided a better understanding of the possible interplay between radiotherapy, the effect of unknown genetic factors suggested by the family history, and the onset of second malignancies. In our series, a relatively large proportion of patients initially was treated for Ewing's sarcoma, and patients with primary retinoblastoma were excluded from the study. This is consistent with reports of a higher risk of secondary bone sarcoma after therapy for Ewing's sarcoma.^21,30 The estimated 20-year cumulative incidence rate of secondary sarcoma was 6.5% in the study by Kuttesch et al³¹ and was radiation-dose dependent in survivors of Ewing's sarcoma.

In most series, the median latency period ranges from 10 to 14 years.^2,6,11,32 In our study, the median interval between initial treatment and diagnosis of the second malignancy was 8 years. This shorter period could be explained by the younger age of our patients; Huvos et al⁷ found a significantly shorter latency period in children and adolescents compared with that in adults. In addition, chemotherapy administered for the first cancer may accelerate the development of the second cancer.^23,33

Our study confirms that radiation-induced osteosarcoma often develops at sites different from those of de novo osteosarcoma with frequent involvement of flat bones, as reported by other investigators.^2,7,32 The number of patients with metastatic disease at diagnosis in our study (three of 23) was in the range of value for de novo osteosarcoma. In the study by Bechler et al,³³ the proportion of patients with metastases at diagnosis was six of nine children with osteosarcoma as second malignant tumor, whereas in the study by Wiklund et al,⁵ the proportion was none of 10 patients with radiation-induced osteosarcoma.

Histologic subtypes vary from one study to another, making it difficult to compare histologic distribution patterns observed in patients with secondary osteosarcoma. The dominant histologic subtype in our series, and in that of Weatherby et al,² was osteoblastic. However, in the study by Huvos et al,⁷ the most common postradiation osteosarcoma subtype was fibrohistiocytic.

Details of therapy are limited in most published studies. Treatment previously was based on surgery. In a report from the Mayo Clinic,² The majority of patients with postradiation osteosarcoma that involved the long bone of extremities, pelvis, or shoulder girdle were subjected to amputation. Various surgical resections were performed in patients with other sites of involvement, often combined with radiotherapy. The 5-year disease-free survival rate was 19%. Among the 23 patients with radiation-induced osteosarcoma studied by Smith,³² eight underwent surgical treatment alone, five received additional chemotherapy (no details), three underwent radiotherapy, and seven received palliative treatment. Only two patients were alive and disease-free at the time of publication. In 1985, Huvos et al⁷ described 39 patients with postradiation bone osteosarcoma treated before 1974. Amputation or disarticulation was the most frequent surgical strategy for patients with tumors of the extremities. Preoperative radiotherapy was administered in some circumstances, but in most cases the radiation was directed against incompletely resected tumors. Preoperative HDMTX followed by surgery and adjuvant chemotherapy was used to treat 14 patients. The cumulative 5-year survival rate remained poor (19%). The treatment of 17 patients after 1974 was not described in detail, but the survival rate was not significantly different. In 1992, Brady et al⁶ analyzed the impact of chemotherapy (usually doxorubicin in combination with other agents) on the survival of patients with radiation-associated sarcoma of bone. No statistically significant difference was found. However, the investigators emphasized that in the subgroup of five young patients with osteosarcoma who underwent resection and adjuvant chemotherapy, three remained alive and disease-free. The 5-year survival rate among patients with osteogenic sarcoma was 21%. More details on chemotherapy were given in a recent report by Pratt et al¹¹ of 18 secondary osteosarcomas. Fifteen patients received doxorubicin, 10 cisplatin, nine HDMTX, eight ifosfamide, and two cyclophosphamide. The response rate to initial chemotherapy was poor, and the 5-year survival rate was 24%, but half of the patients had unresectable lesions at diagnosis. In contrast, intensive chemotherapy had a major impact on the outcome of radiation-associated osteosarcoma in the small series reported by Cefalo et al.¹⁰ Five patients received intensive chemotherapy regimens that consisted of vincristine and HDMTX alternated with cisplatin and ifosfamide given for 12 months. Only one patient underwent surgery. All of the patients achieved complete clinical remission; four remained disease-free 1 to 12 years after diagnosis. One patient had a local recurrence, and a long-term second complete remission was achieved with the same regimen. Kellie et al⁸ reported a case of unresectable osteosarcoma with disease-free survival of at least 3 years after intensive chemotherapy alone. Nevertheless, it is difficult to recommend chemotherapy alone for radiation-related osteosarcoma amenable to resection.

In our series, patients treated curatively received ongoing protocols designed for de novo osteosarcoma, which include intensive chemotherapy. It is interesting that half of our patients with extremity lesions had limb-sparing treatment and no local recurrence. None of the patients received further radiotherapy. Despite a substantial number of unresectable tumors, the overall and event-free survival rates of 50% and 41%, respectively, are encouraging. In the subgroup of patients without metastases at diagnosis, the respective survival rates (57% and 48%) are slightly lower than those reported in series of patients with de novo osteosarcoma.³⁴

In our study, all the patients with metastases at presentation died. Unresectable lesion correlated with poor prognosis, consistent with the multivariate analysis performed by Brady et al,⁶ who identified three adverse prognostic factors: metastatic disease at diagnosis, incomplete or no operative resection, and tumor size of at least 5 cm.

Radiotherapy is now used more sparingly in most childhood cancer treatment programs. The advent of intensive chemotherapy and improvement of surgical techniques permit a larger number of young patients to be treated without radiotherapy. The dangers of ionizing radiation must be taken into account when treating children with cancer. Factors that carry an increased risk of second malignancies, such as p53 mutations, Li-Fraumeni syndrome, or an uncharacterized family history of cancer, and the cumulative adverse effects of alkylating agents also should be considered.^21,25,29,30 When radiation-related osteosarcoma occurs, our results show that patients with resectable lesions can be cured by means of surgery plus intensive preoperative and postoperative chemotherapy. The prognosis of patients not amenable to complete surgery or with metastatic lesions remains poor. Higher-dose chemotherapy regimens, such as high-dose thiotepa with stem-cell support, have given encouraging results in a phase II study in children with solid tumors, including osteosarcoma, and might be considered in this setting.³⁵

	ACKNOWLEDGMENTS

 
We thank the following pathologists for providing histopathologic material: C. Bailly, F. Dijoud, J. Floquet, P. Josset, L. Marcellin, L.M. Patricot, G. Saint-Pierre, P. Staub, P. Validire, and M. Lacroix-Ciaudo.

	NOTES

 
Presented in part at the Annual Meeting of the International Society of Pediatric Oncology, Vienna, Austria, October 1-5, 1996.

	REFERENCES

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Submitted October 20, 1998; accepted May 18, 1999.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tabone, M.-D. Articles by Kalifa, C. Search for Related Content PubMed PubMed Citation Articles by Tabone, M.-D. Articles by Kalifa, C.