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SECTION I: SYMPOSIUM I: Papers Presented at the 2005 Meeting of the Musculoskeletal Tumor Society

Prognosis of Radiation-induced Bone Sarcoma is Similar to Primary Osteosarcoma

Shaheen, Mahmood*; Deheshi, Benjamin, M; Riad, Soha*; Werier, Joel; Holt, Ginger, E; Ferguson, Peter, C*; Wunder, Jay, S*

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Clinical Orthopaedics and Related Research: September 2006 - Volume 450 - Issue - p 76-81
doi: 10.1097/01.blo.0000229315.58878.c1


Radiation-induced sarcoma of bone (RISB) is a rare entity that has been associated with a poor prognosis.1,18,21 Accounting for less than 1% of all sarcomas, information in the literature pertaining to etiology, treatment, and outcome is limited. The following criteria have been suggested for diagnosis of RISB: (1) histologic features of the radiation-induced sarcoma different from the original lesion; (2) development of a sarcoma in the irradiated field; and (3) a sufficiently long latent period between radiation and sarcoma diagnosis.6 The latent period was previously considered to be a minimum of 5 years, but more recently it has been suggested development of a sarcoma with a unique histology as early as 3 years after radiation to that site is adequate for considering the tumor to be radiation- induced.2,4,6,18 The minimum dose of radiation considered necessary for development of RISB has not been established.1,4,18,21,31

RISBs vary in histology, latency, and response to treatment.1,18,21 Historically, secondary sarcomas of bone have been associated with a poor prognosis with disease-free survival as low as 15%.15-17,21,26,30 It has been suggested chemotherapy is not as effective in secondary sarcomas of the bone, compared with more conventional primary bone sarcomas.4,15,16,26,30 As a result, there are no standard treatment protocols for RISB, and chemotherapy regimens are frequently less intensive.4,15,16,21 Recent studies have shown an aggressive treatment approach with both intensive chemotherapy and surgery may lead to improved survival rates in secondary sarcomas.4,18,21,29,34 However, the literature on RISB is limited to small case series often combining radiation-induced bone and soft tissue sarcomas.1,2,4-8,15-18,20,21,25,26,28-31,33,34

We determined the disease-free and overall survival rates of patients treated for RISB. We also ascertained the recurrence and complication rates of limb salvage surgery and compared the functional outcome to a matched group of patients treated for primary osteosarcoma.


We searched the prospective databases at three musculoskeletal tumor specialty centers (Mount Sinai Hospital, Toronto, Canada; The Ottawa Hospital [General Campus], Ottawa, Canada; and Vanderbilt University Medical Centre, Nashville, TN) and identified 24 patients with RISB treated between 1989 and 2003. The clinical charts, database records and pathology reports were reviewed to identify gender, age at diagnosis of index tumor as well as its anatomic location, histology, and radiation dose. Information collected relating to the RISB included age at diagnosis and latency period between the two tumors, histology, surgical and adjuvant treatments, histologic response to chemo- therapy, local recurrence, disease-free and overall survival, and surgical complications. Patients with postirradiation soft tissue sarcomas were excluded from this study. Minimum followup was 24 months unless the patient died. Mean followup time was 48 months (range, 1-153 months).

There were eight male and 16 female patients with a mean age at diagnosis of the index tumors of 30 years (range, 1-76 years). Index tumors treated with radiation included Ewing sarcoma (n = 6), breast carcinoma (n = 3), lymphoma (n = 3), osteosarcoma (n = 2), uterine carcinoma (n = 2), and one case each of ovarian carcinoma, prostatic carcinoma, Wilms' tumor, fibrosarcoma of bone, soft tissue malignant fibrous histiocytoma (MFH), neuroblastoma, and two benign tumors (fibromatosis and giant cell tumor of bone). The mean radiation dose for the index tumors for 15 patients with available data was 50 Gy (range, 25-72 Gy). The mean latent period from irradiation to diagnosis of the secondary sarcoma of bone was 16 years (range, 3-48 years). The most common RISB was osteosarcoma, which occurred in 17 patients. All six patients who presented with lung metastases had osteosarcoma. The histology of the other RISB included MFH of bone (n = 4) and one case each of chondrosarcoma, fibrosarcoma, and leiomyosarcoma. All 24 RISB were high grade and extracompartmental.12 Tumor location included pelvis (n = 8), sacrum (n = 1), clavicle (n = 2), femur (n = 7), humerus (n = 4), and tibia (n = 2). Four of the six metastatic osteosarcomas were located in the pelvis.

Twenty patients had surgical resection including eight amputations and 12 limb salvage procedures. Fourteen of 20 surgically treated patients received neoadjuvant chemotherapy as part of a curative treatment approach. The chemotherapy protocols were varied and frequently shorter than initially planned. Of the 13 patients with available chemotherapy information, only five received traditional osteosarcoma protocols including adriamycin and cisplatin with or without methotrexate and ifosfamide. Surgery was not possible for four patients with pelvic RISB and these patients were treated palliatively. Three patients with pelvic sarcomas presented with unresectable tumors (n = 2) or refused radical pelvic surgery (n = 1) and were treated with palliative chemotherapy. One patient with pelvic RISB was medically unfit for surgery or chemotherapy. Four other patients with pelvic sarcomas had amputation (n = 1) or limb salvage surgery (n = 3).

Patients with RISB who had limb salvage surgery and no disease relapse underwent functional evaluation at a minimum 1 year postoperatively using three methods of assessment. The Toronto Extremity Salvage Score (TESS) is a patient-based measure of physical disability developed specifically for the extremity sarcoma population.11 The Musculoskeletal Tumor Society 1987 (MSTS-87) and 1993 (MSTS-93) rating systems are clinician-completed measures of impairment.13,14 Each potential RISB limb salvage patient was matched 1:2 by age, gender, tumor location, tumor size and postoperative complications to patients with high grade primary osteosarcoma similarly treated with neoadjuvant chemotherapy and limb salvage surgery with minimum 1 year followup.

Descriptive statistics were calculated using means, ranges and proportions as appropriate. Statistical comparisons were performed using a t-test for continuous variables and Fisher's exact test for categorical variables. Disease-free and overall survival with confidence intervals were calculated using the Kaplan- Meier method.19 Functional results were available for 10 patients with RISB who were treated with limb salvage surgery and these were compared to 20 matched patients treated at Mount Sinai Hospital, Toronto, Canada for high grade primary osteosarcoma.


The outcome for six patients with localized tumors who were treated with surgery alone was inferior. Of 10 patients with localized RISB at diagnosis who were treated with both surgery and chemotherapy, six remain alive with no evidence of disease, three were dead of disease, and one died of a third new and unrelated cancer at a mean followup of 70 months (range, 6-155 months) (Table 1). The estimated 5-year disease-free and overall survival rates for these 10 patients was 58% (95% confidence interval [CI] = 26-90) and 69% (95% CI = 39-99) respectively (Figs 1, 2). Only two of six patients treated with surgery alone remain alive with no detectable disease, three were dead of disease, and one died from the index breast cancer which recurred 49 years after the initial diagnosis. RISB that was metastatic at presentation had the worst prognosis. Despite aggressive treatment with both surgery and chemotherapy, three of four patients were dead of disease and only one remained alive with no detectable disease at 128 months.

Outcome for 24 Patients with RISB
Fig 1
Fig 1:
Kaplan-Meier survival curves are shown for metastasis- free survival of 10 patients without metastases at presentations treated with both chemotherapy and surgery. The estimated 5-year disease free survival was 58% (95% CI, 26-90).
Fig 2
Fig 2:
Kaplan-Meier survival curves are shown for overall survival of 10 patients without metastases at presentations treated with both chemotherapy and surgery. The estimated 5-year overall survival was 69% (95% CI, 39-99).

Completion of a full course of neoadjuvant chemo- therapy was associated with a higher (p = 0.09) percentage of tumor necrosis and improved (p = 0.09) survival. Of 14 patients with RISB treated with preoperative chemotherapy together with surgical resection, only seven received their entire planned course of treatment and their tumors exhibited a mean 77% histologic necrosis (range, 10-90%). Although two of these seven patients relapsed with metastases, six of seven are currently alive with no detectable disease or deceased from other causes. In comparison, the other seven patients who received an incomplete course of chemotherapy had a mean 40% tumor necrosis after preoperative treatment (range, 20-80%), and only two of seven are alive with no detectable disease.

Patients treated by limb salvage surgery had similar survival compared to those who underwent amputation but had more frequent complications. Six of 12 patients in the limb-salvage group and five of eight patients in the amputation group are alive with no detectable disease or died of unrelated cancers. Surgical resection margins were negative following six of 12 limb salvage procedures compared to six of eight amputations. There were two local recurrences, both in patients who had limb salvage surgery and both following positive margin resections. One patient who was not fit for preoperative chemotherapy developed a local relapse four months after anterior pelvic resection for a large leiomyosarcoma. The other local relapse occurred 6 months after resection of the clavicle for an MFH of bone in a patient who received an incomplete course of chemotherapy and had a poor histologic response. In the limb salvage group there were: two wound complications; an infected nonunion of a proximal tibia autograft reconstruction ultimately requiring amputation; a fractured intercalary allograft which required revision; and one case of pulmonary embolism. Patients treated by amputation had fewer complications: one postoperative hematoma after direct trauma to the operative site treated with incision and drainage; and one fatal pulmonary tumor embolism early postoperatively.

We observed no functional difference between the group with RISB and the group with conventional osteosarcoma. For patients with RISB, at a mean followup of 48 months, the mean TESS score was 76 out of 100 (range, 20-91), MSTS-87 was 24 of 35 (range, 5-33) and MSTS- 93 was 68 of 100 (range, 7-93) (Table 2).

Comparison of Functional Outcomes


The goal in treatment of primary or secondary sarcomas of bone is prolonged relapse-free survival with optimal function. Treatment of primary osteosarcoma or other spindle cell sarcomas of bone with chemotherapy and surgery is associated with 50-80% overall survival rates.3,32 Most reports indicate RISB are more aggressive and have a worse prognosis than primary osteosarcoma or other bone sarcomas.15-17,21,26,27,30,31 Consistent with these reports, our study found six of 24 patients with RISB had metastases at diagnosis, and 13 of 24 died from the disease. However, we also identified a subset of 10 patients with RISB who presented without metastases, were managed aggressively with both surgery and chemotherapy, and achieved survival rates similar to patients treated for localized primary osteosarcoma: seven of these 10 patients with RISB remain alive with no detectable disease or died of an unrelated cancer. Similar to primary osteosarcoma, metastatic disease at presentation had the worst prognosis in this study with only one of four long-term survivors. These results suggest early detection and aggressive treatment of patients with RISB can yield similar outcomes to patients with primary bone sarcomas.

We note several limitations to this study, including small sample size, retrospective analysis, and inclusion of patients from three different centers. Because RISB is rare,1,18,21 a prospective or controlled study is not feasible. This small study does not have adequate power to ascertain definitive effects of confounding variables (eg, treatment) on outcomes. Although combining patients from three institutions improved our sample size, it may have introduced additional variability as adjuvant therapy and surgery were individualized based on multidisciplinary evaluation at each center. Although retrospective, no patient in this study was lost to followup.

The wide spectrum of age at presentation in our series is consistent with other studies of secondary sarcomas.1,4,18,21 Age at diagnosis of the index tumor was variable, with the youngest patient presenting with neuroblastoma at 1 year and the oldest with prostatic carcinoma at 76 years. Similar to other reports,1,4,6-8,16,18,21 the mean latency period in our study was 16 years (range, 3-48 years). No association has been described between the site of initial radiation, radiation dose, latency period and secondary sarcoma risk.4,16,18

Postirradiation sarcomas are considered to be radiation resistant, so the focus of management has been on chemotherapy and surgery.4,18,21,34 Chemotherapy protocols for secondary sarcomas are not standardized and are often of shorter duration and use lower drug dosages than regimens for primary osteosarcoma due to advanced age, medical co-morbidities and previous chemotherapy treatment.4,22,32 Only five patients in this study received a complete course of standard osteosarcoma chemotherapy. However, seven of 14 patients treated with chemotherapy and surgery completed their entire proposed chemotherapy regimen and exhibited better histologic response and had better outcomes than seven other patients who had incomplete chemotherapy. These results suggest an aggressive approach to treatment of patients with RISB is important to achieve the best outcomes. However, even suboptimal chemotherapy may be better than none, as two of seven patients who received incomplete treatment and had a poor histologic response remain alive with no detectable disease at 52 and 65 months.

Wide resection of a secondary sarcoma in a previously irradiated field poses a number of challenges for the surgical oncologist, especially in axial locations. For example, pelvic tumors are frequently larger, present at a more advanced stage and are associated with a worse prognosis.4,18,21 Of eight patients with pelvic RISB, four had metastases at diagnosis, four were managed palliatively, and only one remains alive with no detectable disease at seven years after surgical resection of a localized chondrosarcoma. High dose radiation used to treat the index tumors is associated with increased fibrosis, edema, pain and poor functional outcomes.9,10,23 As a result, most RISB in the literature received amputations.18,21,30,34 Although our mean radiation dose was 50 Gy, half the patients received higher amounts to a maximum of 72 Gy. However, 12 of 20 patients who had surgery underwent limb salvage procedures. Positive margin resections were more common in RISB patients following both limb salvage (6/12) and amputation (2/8) than would be expected following treatment for primary bone sarcomas, and lead to local tumor relapse in 2 cases. Postoperative complications were more frequent following limb salvage surgery for RISB and led to one late amputation.

Functional outcome following limb salvage postirradiation would be expected to be inferior to primary osteosarcoma due to soft tissue fibrosis, edema and higher postoperative complications.18,21,30,34 Surprisingly, functional comparison of RISB patients in our study who underwent limb salvage was similar to a matched control group of patients treated for primary osteosarcoma based on three different outcome measures. This clearly relates to the selection bias inherent in identifying suitable candidates for limb sparing procedures. It is likely only patients with minimal soft tissue fibrosis and edema would have been offered limb salvage.

Development of postirradiation sarcoma is likely multifactorial including genetic predisposition, chemotherapy treatment, radiation dose and other factors not yet identified.1,4,7,16,18,24,34 In our study, 10/24 patients received chemotherapy in addition to radiation during treatment of their index tumors. Three patients likely had underlying genetic influences as well because they developed additional cancers outside of the radiation field. One of these patients had Li-Fraumeni syndrome, and another was treated for bilateral retinoblastoma as an infant. This latter patient received chemotherapy and radiation for Ewing sarcoma of the proximal tibia at age 25, and developed a radiation-induced osteosarcoma of the distal femur 7 years later treated with chemotherapy and limb salvage with an excellent functional result. She had multiple subsequent surgeries for locally recurrent melanoma in the calf and soft tissue leiomyosarcoma in the thigh and ultimately required amputation. This patient remains alive with no detectable disease 155 months after RISB treatment.

Many factors must be considered for treatment of patients with RISB. This study supports recent findings that following aggressive management with both surgery and chemotherapy survival may be similar to patients treated for primary bone sarcomas. Limb salvage is also possible for the majority of patients with RISB, and they can expect reasonable functional outcomes, though with higher risks. Patients require careful long-term follow-up and counseling after radiation therapy. New clinical and laboratory studies are necessary to identify risk factors for radiation- induced sarcomas and to allow for future prevention and early detection.


We would like to thank Anthony Griffin, Catherine McLaughlin, Dr. Martin Blackstein, Dr. Robert Bell (Toronto), Dr. Richard Wupperman, and Dr. Herbert Schwartz (Nashville) for their assistance in completion of this multi-institutional project.


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