The optimal treatment of osteosarcoma is comprised of multiagent. Outcome after Local Recurrence of Osteosarcoma

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1 1928 Outcome after Local Recurrence of Osteosarcoma The St. Jude Children s Research Hospital Experience ( ) Carlos Rodriguez-Galindo, M.D. 1,2 Nirali Shah, M.D. 1 M. Beth McCarville, M.D. 3 Catherine A. Billups, M.D. 4 Michael N. Neel, M.D. 5 Bhaskar N. Rao, M.D. 5 Najat C. Daw, M.D. 1,2 1 Department of Hematology-Oncology, St. Jude Children s Research Hospital, Memphis, Tennessee. 2 Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, Tennessee. 3 Department of Radiological Sciences, St. Jude Children s Research Hospital, Memphis, Tennessee. 4 Department of Biostatistics, St. Jude Children s Research Hospital, Memphis, Tennessee. 5 Department of Surgery, St. Jude Children s Research Hospital, Memphis, Tennessee. BACKGROUND. Despite improvements in therapy for osteosarcoma, approximately 4 10% of patients experience a local recurrence and have a poor prognosis. METHODS. The authors analyzed prognostic factors for survival in 26 patients with a local recurrence of osteosarcoma who were treated between 1970 and RESULTS. The initial surgical procedure was amputation in 20 patients (76.9%) and limb salvage in 6 patients (23.1%). The median time from the diagnosis of osteosarcoma to local recurrence was 1.2 years (range, 1.2 months 6.1 years). Eleven patients (42.3%) developed an isolated local recurrence and 15 patients (57.7%) developed local and distant recurrence. The 5-year estimate of postrecurrence survival (PRS) ( 1 standard error) for the 26 patients was 19.2% 7.7%. Recurrence 2 years from the time of diagnosis was found to predict a better outcome (5-year PRS of 50.0% 20.4%) compared with earlier recurrence (10.0% 5.5%) (P 0.037). Patients with negative margins after initial surgery were found to have improved survival (5-year PRS of 33.3% 13.6%) compared with patients with positive margins (7.1% 4.9%) (P 0.015). Patients who underwent complete surgical resection at the time of recurrence were found to have a better PRS (5-year PRS of 41.7% 14.2%) compared with patients who did not undergo surgery (0% 0%) (P 0.001). CONCLUSIONS. The prognosis for patients after local recurrence of osteosarcoma is poor. Complete surgical resection at the time of recurrence is essential for survival. Positive margins at the time of initial surgical resection and early recurrence appear to be poor prognostic factors. Cancer 2004;100: American Cancer Society. KEYWORDS: osteosarcoma, local recurrence, children, limb-sparing. Supported in part by Cancer Center Support (CORE) Grant P30 CA21765, by Grant CA23099 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities (ALSAC). Address for reprints: Carlos Rodriguez-Galindo, M.D., Department of Hematology-Oncology, St. Jude Children s Research Hospital, 332 N. Lauderdale, Memphis, TN ; Fax: (901) ; carlos.rodriguez-galindo@stjude.org Received October 1, 2003; revision received January 5, 2004; accepted February 18, The optimal treatment of osteosarcoma is comprised of multiagent chemotherapy and local control measures such as amputation or limb-sparing surgical procedures. Different combinations of platinum compounds, doxorubicin, and high-dose methotrexate (HD- MTX) have formed the basis of standard chemotherapy regimens that are reported to produce cures in approximately 50 75% of patients with nonmetastatic disease. 1 4 With the exception of the rare cases of osteosarcoma arising in axial locations, local control usually can be achieved by surgery. Improvements in diagnostic imaging, surgical techniques, biomedical engineering, supportive care, and rehabilitation have allowed for more accurate planning of resection and limb preservation. Currently, surgeons are able to perform limb-salvage surgery using custom-made endoprostheses, allografts, or composite reconstructions in 80 90% of the affected children. 4 6 Unlike certain other sarcomas, the ability to achieve surgical disease remission in patients with localized osteosarcoma is very important for cure 4,7 ; therefore, every effort must be made to achieve adequate margins at 2004 American Cancer Society DOI /cncr Published online 22 March 2004 in Wiley InterScience (

2 Local Recurrence of OS/Rodriguez-Galindo et al the time of the local control procedure. With the more routine use of limb-sparing surgeries, the risk of obtaining suboptimal margins and thus increasing the risk of local recurrence may increase. In the past, there has been significant controversy regarding the safety of limb salvage versus amputation. However, with modern multimodal therapies, the type of surgical procedure does not appear to impact survival; local recurrences are reported to develop in 4 10% of patients, and there appears to be no significant difference between ablative and limb-sparing procedures. 4,5,8,9 Most treatment failures in osteosarcoma patients who initially have nonmetastatic disease are systemic (usually pulmonary) and the natural history of this complication and others that are predictive of survival have been well defined in the literature. 5,10 14 However, to our knowledge, the impact of local recurrence on survival is less well understood. Some studies have suggested that the outcome for these patients is very poor, 8 10,15 17 but the literature to support this premise is limited. Therefore, we sought to identify prognostic indicators of survival in patients with locally recurring osteosarcoma through a review of our institutional experience over the past 30 years. MATERIALS AND METHODS Patients Between 1970 and 2000, 397 patients were treated for osteosarcoma at the St. Jude Children s Research Hospital. Using a computerized database, we retrospectively identified all patients with osteosarcoma who had experienced a local tumor recurrence. Patients who experienced disease progression before local control therapy could be performed were excluded. We reviewed the medical records of the 26 identified patients and the imaging findings at the time of recurrence. Statistical Methods Postrecurrence survival (PRS) was defined as the time interval from the date of initial local recurrence to the date of death from any cause. PRS was estimated using the method of Kaplan and Meier 18 ; standard errors were calculated according to the method of Peto et al. 19 Differences in PRS distributions were examined using the exact log-rank test. Variables considered included time from diagnosis to recurrence (at 1.2 years and at 2 years), disease stage at the time of diagnosis (localized or metastatic), initial chemotherapy, type of initial surgery, status of surgical margins at the time of the initial resection, type of recurrence, stage of disease at the time of recurrence, chemotherapy at the time of recurrence, radiation at the time of recurrence, and surgery at the time of recurrence. RESULTS Patient Characteristics Twenty-six patients (6.5% of all patients with osteosarcoma who were treated at St. Jude) with local recurrences were identified. The median age at the time of the diagnosis of osteosarcoma was 16.6 years (range, years). There were 16 males (61.5%) and 21 patients were white (80.8%). Five of the 26 patients had prior malignancies, which included bilateral retinoblastoma (n 2), malignant fibrous histiocytoma of soft tissue (n 1), Hodgkin disease (n 1), and embryonal rhabdomyosarcoma (n 1). In all five of these patients, osteosarcoma developed as a second malignancy in a previously irradiated field (the skull in three patients, the clavicle in one patient, and the iliac bone in one patient). Nineteen patients had localized disease at the time of diagnosis and 7 presented with metastatic disease. Six of the seven patients with metastatic disease had metastases to the lungs. The most common primary site was the femur (12 patients; 46.2%), followed by bones of the face and skull (7 patients; 26.9%), the humerus (4 patients; 15.4%), and the pelvic bones (3 patients; 11.5%). Frontline Treatment Chemotherapy and surgical management varied over the time period of the current study. No patient received radiation as part of the initial treatment of their osteosarcoma. All 26 patients underwent surgical procedures; 14 patients underwent surgery before chemotherapy and the remaining 12 patients underwent surgery after preoperative chemotherapy. Six patients underwent limb-salvage procedures. As a reference point, the local recurrence rate was 6% among the 100 patients with osteosarcoma who were treated with limb-salvage procedures during the same period. Resection margins at the time of initial surgery were positive in 14 patients (53.8%), including 1 of the 6 patients with a local recurrence after limb-salvage surgery. Positive margins by tumor site were the femur in 2 of 12 patients, the skull in 6 of 7 patients, the humerus in 4 of 4 patients, and the pelvis in 2 of 3 patients. None of the patients with positive margins received radiation therapy. The majority of patients (n 19) received chemotherapy. The regimens used are depicted in Table 1. Twelve patients were treated on institutional protocols as follows: OST-72 (n 2), OST-77 (n 1), OS-86 (n 2), and OS-91 (n 7). On the OST-72 and the OST-77 protocols, patients underwent amputation followed by adjuvant chemotherapy with cyclophosphamide, doxorubicin, and methotrex-

3 1930 CANCER May 1, 2004 / Volume 100 / Number 9 TABLE 1 Chemotherapy Regimens Used at the Time of Diagnosis of Osteosarcoma Protocol Preoperative Postoperative OST DOX/CYC, MTX OST DOX/CYC, MTX OS-86 2 IFO, MTX, DOX CDDP/DOX, IFO, MTX OS-91 2 IFO/CBP DOX, MTX, IFO/CBP T12 1 MTX, BCD, CDDP/DOX MTX, BCD, CDDP/DOX DOX: doxorubicin; CYC: cyclophosphamide; MTX: methotrexate; IFO: ifosfamide; CDDP: cisplatin; CBP: carboplatin; BCD: bleomycin, cyclophosphamide, and dactinomycin. ate, with an increased dose of methotrexate given in the OST-77 protocol. 20 Chemotherapy on the OS-86 protocol was comprised of cisplatin, doxorubicin, HD- MTX, and ifosfamide, and the chemotherapy on the OS-91 protocol included the same agents with the exception that carboplatin replaced cisplatin. 2 One patient was treated according to the Memorial Sloan Kettering Cancer Center T12 protocol 1 and two patients were treated with adjuvant chemotherapy comprised of cisplatin, doxorubicin, HDMTX, bleomycin, cyclophosphamide, and dactinomycin given after surgery. The four remaining patients were treated on nonprotocol treatments, with different combinations of vincristine, methotrexate, doxorubicin, and cisplatin. Histologic response to neoadjuvant chemotherapy was available in 11 of the 26 patients, 8 of whom (72.7%) had a poor response ( 90% tumor necrosis). Type and Timing of Tumor Recurrence The 26 patients developed local recurrences with or without distant recurrence after treatment for osteosarcoma. Eleven patients (42.3%) developed local recurrence only, 10 patients (38.5%) developed simultaneous local and distant recurrence, and 5 patients (19.2%) developed a local recurrence a median of 4 months (range, 2 26 months) after a distant recurrence. The lung was the most common site of distant recurrence (14 of 15 patients; 93.3%). The median time from the diagnosis of osteosarcoma to the time of the initial local recurrence was 1.2 years (range, 1.2 months 6.1 years). The median age at the time of disease recurrence was 17.8 years (range, years). Of the 15 patients who developed distant and local recurrence, 5 (33.3%) had lung metastases at the time of the initial diagnosis. Of the 11 patients who developed local recurrence only, 2 (18.2%) had lung metastases at the time of the initial diagnosis. Imaging Findings The imaging studies performed varied according to treatment era and the presence of endoprosthetic devices. The most prevalent methods of evaluating local recurrence were radiographic imaging (20 patients), magnetic resonance imaging (MRI) (9 patients), and computed tomography (CT) scans (8 patients). Tumor recurrence appeared as soft tissue calcifications on plain films in 7 of 20 patients (35%). These were described as chunky, dense, linear, and radiating, or a combination of these features. In the remaining 13 patients (65%), the tumor recurrence was not detected on plain radiography. In the 17 patients with either CT or MRI scans of the local recurrence site, 9 (52.9%) had evidence of soft tissue involvement only and 8 (47.1%) had evidence of both bone and soft tissue involvement, whereas no patient had evidence of isolated bone recurrence. Adenopathy was suspected by plain film in one patient who had calcifications resembling a lymph node, by CT in two patients, and by MRI in one patient. Treatment at the Time of Recurrence Treatment at the time of disease recurrence varied, and patients received different combinations of surgery, radiation, and chemotherapy. The majority of the patients (n 19) received chemotherapy (13 of these patients had previously received chemotherapy as part of their initial therapy) and 6 patients received radiation. Twelve patients (46.2%) underwent definitive surgery at the time of recurrence and resection margins were positive in 4 of these patients. Of the six patients who had undergone a limb-sparing surgery at the time of the initial treatment, three underwent amputation. Ten of the 14 remaining patients who did not undergo surgery for local control had concurrent distant metastases and the remaining 4 patients had skull primary tumors and were not candidates for surgery. Of the 14 patients with lung metastases at the time of recurrence, 11 underwent thoracotomies. Two patients did not receive any treatment at the time of disease recurrence. Survival after Recurrence At the time of last follow-up, only 3 of the 26 patients were still alive at 4.6 years, 19.5 years, and 21.1 years, respectively, after disease recurrence. All 3 survivors were contacted within the last 1.6 years. The majority of the deaths occurred within 1 year (14 of 23 patients; 60.9%) or within 2 years (21 of 23 patients; 91.3%) after disease recurrence. One patient died of disease 14.0 years after recurrence and another patient died from liver failure, free of disease, 21.5 years after recurrence. The 5-year estimate of PRS was 19.2% 7.7% (Fig. 1). For the 21 patients with primary osteosarcoma (after excluding those patients with radiation-induced disease), the 5-year estimate of PRS was 23.8% 9.3%.

4 Local Recurrence of OS/Rodriguez-Galindo et al found to have better survival compared with patients who did (P 0.004). FIGURE 1. Probability of survival after local recurrence of osteosarcoma in 26 patients. The estimated 5-year postrecurrence survival rate was 19.2% 7.7%. Factors Prognostic of Survival after Recurrence Factors related to initial presentation, initial treatment, clinical characteristics, and treatment at the time of disease recurrence were investigated as predictors of survival after recurrence (Table 2). Similar to findings observed in other malignancies, patients with longer times from diagnosis to disease recurrence had improved survival (Fig. 2). Recurrence 2 years from diagnosis was found to be predictive of a better outcome (5-year PRS of 50.0% 20.4%) compared with those with an earlier recurrence (10.0% 5.5%) (P 0.037). There was no evidence that the type of initial surgical procedure performed (surgical resection alone vs. limb-salvage surgery) influenced the PRS (P 0.92) but the status of resection margins was important; patients with negative margins after initial surgery were found to have an improved survival (5- year PRS of 33.3% 13.6%) compared with patients with positive margins (7.1% 4.9%) (P 0.015) (Fig. 3). Surgery at the time of disease recurrence was found to be an important predictor of survival. Patients who underwent surgery at the time of disease recurrence had a better PRS (5-year PRS of 41.7% 14.2%) compared with patients who did not undergo surgery (0% 0%) (P 0.001) (Fig. 4). The three patients who survived had undergone complete surgical resection; two of them also received chemotherapy. Although patients who had simultaneous local and distant recurrence appeared to fare worse (5-year PRS of 13.3% 8.8%) than patients who developed a local recurrence alone (27.3% 11.6%), the difference was not found to be statistically significant (P 0.29). Patients with localized disease at the time of diagnosis were found to have an improved PRS compared with patients with metastatic disease (5-year PRS estimates of 26.3% 10.1% vs. 0% 0%), but there was no evidence that these survival distributions differed significantly (P 0.44). Patients who did not receive chemotherapy as part of their initial treatment were DISCUSSION In the current study we reviewed the clinical characteristics of patients with a local recurrence of osteosarcoma and analyzed factors prognostic of survival. Although the outcome after local recurrence is dismal, patients developing late recurrences and patients in whom a surgical resection is possible may have a better outcome. Unfortunately, the patient population in the current series was small and very heterogeneous. In five patients, osteosarcoma had developed as a result of the radiation therapy given for a prior malignancy and in another four patients the osteosarcoma originated in the head and neck bones. It could be argued that those nine cases might not be entirely representative of the population being analyzed. However, studies have shown that with a multidisciplinary approach, the outcome of patients with radiation-induced osteosarcoma 21 or with osteosarcoma of the head and neck 7 is similar to patients with primary osteosarcoma. In addition, the heterogeneity in the medical and surgical treatment provided at the time of diagnosis and at the time of recurrence complicate the analysis even further. With improvements in diagnostic imaging and surgical techniques, the vast majority of patients with extremity osteosarcoma currently undergo limb-sparing procedures rather than ablative surgeries; nevertheless, local control rates continue to be very good. 4,5,8,9 As shown in the current series, local recurrences after treatment of osteosarcoma are rare (typically 10%). 4,8,9,15 17 However, given the retrospective nature of the current analysis, in which recurrences were clinically evident, it is possible that this figure is an underrepresentation of its true incidence in the study population. Several studies published to date have evaluated risk factors for local recurrence. Failure to achieve surgical remission is reported to be the most important risk factor in patients with nonmetastatic disease. 4,9,16 In the current series, 14 of the 26 patients had positive resection margins at the time of the initial surgery. In this regard, the specific soft tissue and bone margins that need to be secured during local control of osteosarcoma to our knowledge have not been defined. Furthermore, there is increasing evidence that histologic response to preoperative chemotherapy has a major impact on the development of local failures, regardless of the resection margins. 4,16 In the current series, 73% of the patients with local failure for whom information concerning histologic response was available had poor responses, and half

5 1932 CANCER May 1, 2004 / Volume 100 / Number 9 TABLE 2 Results of Univariate Analyses to Determine Factors Predictive of Postrecurrence Survival in 26 Patients with Local Recurrence of Osteosarcoma All patients (n 26) Patients with primary osteosarcoma (n 21) Factor No. 5-yr estimates ( 1 SE) P value No. 5-yr estimates ( 1 SE) P value Time from diagnosis to recurrence 1.2 yrs (5.2) (6.7) yrs (12.8) (14.5) Time from diagnosis to recurrence 2.0 yrs (5.5) (6.8) yrs (20.4) (21.9) Stage at diagnosis Localized (10.1) (12.2) 0.37 Metastatic 7 0 (0) 6 0 (0) Type of primary surgery Limb salvage (15.2) (15.2) 0.93 Surgical resection alone (8.0) (10.2) Resection margins at primary surgery Positive (4.9) (7.4) Negative (13.6) (13.6) Primary chemotherapy Yes (5.1) (6.4) No (16.7) (17.2) Stage at recurrence Localized (11.6) (16.2) 0.25 Metastatic (8.8) (9.4) Complete surgical resection Yes (14.2) (15.8) No 14 0 (0) 11 0 (0) Chemotherapy at recurrence Yes (9.4) (10.8) 0.73 No (9.4) (12.6) Radiation at recurrence Yes (10.8) (12.6) 0.84 No (8.9) (10.8) Primary site (1) a Extremity (10.3) (10.3) 0.78 Nonextremity (9.5) (15.7) Primary site (2) a Extremity (10.3) (10.3) 0.71 Skull (13.9) (20.4) SE: standard error. a Numeral indicates two different comparisons: extremity vs. nonextremity, or extremity vs. skull. of these patients had negative margins. In evaluating the experience at the Rizzoli Institute, Picci et al. 16 described the histologic differences between poor and good responders that could be correlated with the surgical approach. Tumors of patients with good histologic responses are reported to have a mature pseudocapsule that facilitates achieving surgical disease remission. Unlike good responders, patients with poor responses have a poorly formed, loosely arranged pseudocapsule formed by compressed normal tissues rather than mature collagen bundles, and which is easily penetrated by finger-like projections of viable tumor cells. In these cases, satellite tumor nodules responsible for local recurrences may develop. 16 Attempts to increase the proportion of patients with a good histologic response by means of preoperative intensification 1 or the intraarterial administration of cisplatin have not been reported to improve overall outcome. The combination of close margins and poor histologic response appears to be a strong predictor of local recurrence. Approximately one-third of the patients in the current study had metastatic disease at the time of the original diagnosis, and the prognosis for these patients

6 Local Recurrence of OS/Rodriguez-Galindo et al FIGURE 2. Probability of survival after local recurrence of osteosarcoma 2 years (n 6) or 2 years (n 20) after the primary diagnosis. The estimated 5-year postrecurrence survival rate was 50.0% 20.4% for patients whose tumors recurred 2 years after diagnosis and 10.0% 5.5% for patients whose tumors recurred 2 years after diagnosis (P 0.037). FIGURE 4. Probability of survival after local recurrence of osteosarcoma for patients who did (n 12) compared with patients who did not (n 14) undergo surgery at the time of local recurrence. The estimated 5-year postrecurrence survival rate was 41.7% 14.2% for patients who underwent surgery and 0% 0% for patients who did not undergo surgery (P 0.001). FIGURE 3. Probability of survival after local recurrence of osteosarcoma for patients who had positive (n 14) or negative (n 12) margins at the time of initial surgery. The estimated 5-year postrecurrence survival rate was 33.3% 13.6% for patients with negative margins and 7.1% 4.9% for patients with positive margins (P 0.015). was dismal. However, to our knowledge there are no data to suggest that patients with metastatic osteosarcoma have higher rates of local recurrence (a factor that would most likely dictate the type of local control procedure). However, as shown in the current series, metastatic disease is present at the time of local recurrence in the majority of the cases, suggesting that local recurrence may represent a manifestation of refractory disease. Therefore, an adverse biologic phenotype may be relevant in the development of a local failure. In fact, these patients appear to have a dismal outcome. As shown in the current series and other reports, survival after local recurrence is very rare, with reportedly 20% of patients being long-term survivors. 8 10,15 17 This is in contrast with the outcome of patients with metastatic failure, in whom survival rates in excess of 30% reportedly can be achieved with appropriate aggressive surgical management Despite the small number of patients in the current series and the poor outcome reported, we were able to identify some factors that may impact survival. As reported for patients with metastatic osteosarcoma and for patients with recurrence of other sarcomas, 25 the time to disease recurrence and the possibility of achieving a second surgical disease remission were found to be the most important prognostic indicators for patients with local failure. It is important to note that we also found that the status of the surgical margins at the time of the initial surgery had an impact on the outcome after local recurrence; patients with positive margins after the initial surgery was performed were less likely to survive after local failure. However, 12 of these 14 patients had tumors in the head and neck, humerus, or pelvic bones. It is probable that the margins obtained after the first surgery was performed were the best possible in those areas and it also is probable that the location limited further surgical resection at the time of the recurrence. Nevertheless, data from the current study underscore the need to achieve a complete surgical disease remission at the time of the first local control procedure. The biologic characteristics of the individual tumor ultimately may dictate the outcome, but given the dismal outcome for patients with local disease recurrence, every effort must be made to minimize the risk of failure. Good characterization of the extent of the tumor is crucial before local control is attempted. 4 Because the degree of histologic response to preoperative chemotherapy is a factor in determining the risk of local failure, noninvasive methods that monitor tumor response are important. Dynamic-enhanced MRI (DEMRI) can be used to evaluate changes of regional contrast access during chemotherapy, and these changes appear to correlate accurately with histologic response and outcome. 26 DEMRI potentially may be used for the early identification of patients at risk of recurrence, and the appropriate measures therefore can be under-

7 1934 CANCER May 1, 2004 / Volume 100 / Number 9 taken during the surgical procedure, such as more aggressive surgery. Although osteosarcoma patients treated with surgical resection are followed by plain film radiography, small soft tissue recurrences can be difficult to detect using this modality. Although the presence of bone involvement or soft tissue calcification can make local recurrences more evident on plain film, it occasionally can be challenging to distinguish malignant from normal reparative processes around a limb-sparing prosthesis or a bony allograft. Furthermore, patients who have undergone amputation and wear external prostheses may traumatize adjacent muscle, resulting in myositis ossificans. We found that soft tissue calcifications in patients with local disease recurrences were either chunky, dense, or linear and radiating in appearance. By contrast, early myositis ossificans generally appears as a hazy calcification within a soft tissue mass that matures to a lacy pattern, with the periphery becoming more densely ossified than the center. 27,28 Reparative bone, adjacent to a limb-sparing prosthesis or allograft, generally bridges the osteotomy site and is smooth and thick. 29 Awareness of these imaging features is helpful but nevertheless, it is not always possible to confidently identify a soft tissue recurrence by plain film radiography, especially if calcification or bone involvement is absent. When there is clinical suspicion of a local recurrence but a lack of convincing plain film evidence, further imaging is warranted. Patients who do not have internal metallic hardware are best evaluated by MRI because it provides excellent soft tissue definition. We have found that MRI, using the metal suppression technique described by Viano et al., also is useful in identifying soft tissue recurrences in patients with metallic hardware. 30 Alternatively, ultrasonography may identify a soft tissue mass when MRI is not feasible. Investigators at the Memorial Sloan-Kettering Cancer Center found that thallium bone scanning combined with three-phase technetium-labeled methyl-diphosphonate bone scanning was useful in detecting local recurrences of bone and soft tissue sarcomas. These investigators found that a higher ratio between tumor uptake and background activity on the thallium scan compared with that obtained during the blood pool phase of the corresponding technetium bone scan indicated a local recurrence, 31 and that thallium bone scanning alone was accurate in detecting local recurrences when the tumor-to-background ratio was ,32 Finally, although positron emission tomography scanning eventually may be proven to be of value in detecting recurrent osteosarcoma, to our knowledge its usefulness in this setting has not yet been validated. Local recurrence of osteosarcoma is rare and carries a very poor prognosis. Based on the findings of the current study, every effort should be made to perform a complete surgical resection after disease recurrence, whereas the role of adjuvant chemotherapy for patients with an isolated local recurrence is not clear. It is likely that the biologic phenotype is what ultimately dictates the outcome. 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