Nonmetastatic High-grade Osteosarcoma Research Articles

Does joint-sparing tumor resection jeopardize oncologic and functional outcomes in non-metastatic high-grade osteosarcoma around the knee?

BackgroundWe previously reported joint-sparing tumor resection for osteosarcoma with epiphyseal involvement in which transepiphyseal osteotomy went through the in situ ablated epiphysis. However, we do not know whether this is a safe approach when compared with joint-sacrificed tumor resection. Our objective was to compare oncologic and functional outcomes between patients who underwent joint preservation (JP) and joint replacement (JR) tumor resection. Furthermore, we identified the risk factors of local recurrence, metastasis and survival.MethodsEighty-nine patients with non-metastatic high-grade osteosarcoma around the knee were treated with limb-salvage surgery (JP in 47 and JR in 42). Age, gender, tumor location, pathologic fracture, plain radiographic pattern, limb diameter change, perivascular space alteration, surgical margin, local recurrence, metastasis, death, and the Musculoskeletal Tumor Society (MSTS)-93 scores were extracted from the records. Univariate analysis was performed to compare oncologic and functional outcomes. Binary logistic and cox regression models were used to identify predicted factors for local recurrence, metastasis, and survival.ResultsLocal recurrence, metastasis and overall survival were similar in the JP and JR group (p = 0.3; p = 0.211; p = 0.143). Major complications and limb survival were also similar in the JR and JP group (p = 0.14; p = 0.181). The MSTS score of 27.06 ± 1.77 in the JP group was higher than that of 25.88 ± 1.79 in the JR group (p = 0.005). The marginal margin of soft tissue compared with a wide margin was the only independent predictor of local recurrence (p = 0.006). Limb diameter increase and perivascular fat plane disappearance during neoadjuvant chemotherapy were independent predictors for metastasis (p = 0.002; p = 0.000) and worse survival (p = 0.000; p = 0.001).ConclusionsJoint-sparing tumor resection with the ablative bone margin offers advantage of native joint preservation with favorable functional outcomes while not jeopardizing oncologic outcomes compared with joint-sacrificed tumor resection. Surgeon should strive to obtain adequate soft tissue surgical margin decreasing risk of local recurrence. Novel drug regimens might be reasonable options for patients with obvious limb diameter increase and perivascular fat disappearance during chemotherapy.

ABCB1/P-glycoprotein (Pgp) expression as stratification factor for treatment of patients with non-metastaticextremity high-grade osteosarcoma: A merged analysis of an Italian (ISG) and a Spanish (GEIS) sarcoma groups' multicentric prospective trials.

11527 Background: Overexpression of ABCB1/P-glycoprotein (Pgp) predicts poor outcome in retrospective osteosarcoma series.Two prospective trials with Pgp expression and post-induction histologic response as stratification factors were activated in Italy (ISG/OS-2) and Spain (GEIS-33). Methods: Patients ≤ 40 years with extremity non-metastatic high-grade osteosarcoma were eligible. Analysisi of Pgp expression from diagnostic biopsy was centralized. Preoperatively, all patients received methotrexate, adriamycin, cisplatinum (MAP). Surgery was performed at week 8. All patients received a dose of adriamycin following surgery. In case of Pgp overexpression (Pgp+), mifamurtide (2 mg/m2 twice/week for 3 months then weekly for 6 months) was added after surgery, with 4 consecutive cycles of ifosfamide 3 gr/m2/day, day 1-5 (HDIFO) in case of poor histologic response (necrosis < 90%) to MAP. Patients without overexpression of Pgp (Pgp-) received MAP postoperatively, regardless the pathological response. From March 2013, an amendment increased high dose methotrexate cumulative dose from 60 g/m2 (5 cycles) to 120 mg/m2 (10 cycles). The post-amendment regimen was adopted in the observational prospective study by GEIS. Here we present the merged analysis of ISG/OS-2 patients treated post-amendment and GEIS-33. Results: From March 2013 to April 2018, 274 patients were included. Median age was 14 years (range 4-38), male/female: 163/111; 90 were Pgp-, 164 were Pgp+, 20 not evaluable. With a median follow-up of 48 months (1.3-78.5 months), the 3-year EFS and OS were 71.9% (95%CI 66-76.9) and 88% (95%CI: 83.2-91.5) respectively, with no inferior survival for Pgp positive patients and improved survival for good responders (Table). Conclusions: In this prospective uncontrolled study with a risk-adapted strategy for non-metastatic osteosarcoma, survival is superior to that of all ISG/GEIS previous series. The 3-year EFS of 71.9% compares favorably with other reports. Pgp+ patients performed well in this study, in which mifamurtide and HDIFO were added after a poor response to MAP. Clinical trial information: NCT01459484; NCT04383288. [Table: see text]

Effect of Cisplatin Arterial Infusion (CAI) on Primary Nonmetastatic Pelvic Osteosarcoma: A Preliminary Study.

PurposeThe critical role of arterial infusion chemotherapy in the multimodal treatment of extremity bone cancer has been investigated extensively, but few studies have focused on pelvic osteosarcoma. Therefore, we attempted to evaluate the clinical significance of arterial infusion chemotherapy in the treatment of pelvic osteosarcoma.Patients and MethodsWe combined a cisplatin arterial infusion regimen with multidrug systematic chemotherapy as a neoadjuvant protocol for the treatment of pelvic osteosarcoma. The course number and dosage of cisplatin arterial infusion were adjusted to achieve a maximal tumor response evaluated by contrast-enhanced MRI per RECIST 1.1. Good responders received the same systematic combination for postoperative chemotherapy, and poor responders received second-line therapy. Twelve patients with nonmetastatic high-grade pelvic osteosarcoma were included. Survival, chemotherapy response and adverse events data were analyzed.ResultsThe mean follow-up period was 56.1 months. Four patients died of refractory tumor progression, and 1 patient with local recurrence had no evidence of disease for 27 months after receiving secondary amputation and resection. Kaplan-Meier survival analysis demonstrated a 57.8% overall survival and 52.5% event-free survival rate at 5 years. Eight of 12 patients had a >90% tumor necrosis rate according to histopathologic examinations. The rates of local adverse events were lower than those reported for extremity osteosarcoma.ConclusionOur study initially indicated that the cisplatin arterial infusion regimen was a potential therapy with good tolerance in the treatment of pelvic osteosarcoma.

Preoperative surgical risk stratification in osteosarcoma based on the proximity to the major vessels.

The aim of this study was to determine the risk of local recurrence and survival in patients with osteosarcoma based on the proximity of the tumour to the major vessels. A total of 226 patients with high-grade non-metastatic osteosarcoma in the limbs were investigated. Median age at diagnosis was 15 years (4 to 67) with the ratio of male to female patients being 1.5:1. The most common site of the tumour was the femur (n = 103) followed by tibia (n = 66). The vascular proximity was categorized based on the preoperative MRI after neoadjuvant chemotherapy into four types: type 1 > 5 mm; type 2 ≤ 5 mm, > 0 mm; type 3 attached; type 4 surrounded. Limb salvage rate based on the proximity type was 92%, 88%, 51%, and 0% for types 1 to 4, respectively, and the overall survival at five years was 82%, 77%, 57%, and 67%, respectively (p < 0.001). Local recurrence rate in patients with limb-salvage surgery was 7%, 8%, and 22% for the types 1 to 3, respectively (p = 0.041), and local recurrence at the perivascular area was observed in 1% and 4% for type 2 and 3, respectively. The mean microscopic margin to the major vessels was 6.9 mm, 3.0 mm, and 1.4 mm for types 1 to 3, respectively. In type 3, local recurrence-free survival with limb salvage was significantly poorer compared with amputation (p = 0.025), while the latter offered no overall survival benefit. In this group of patients, factors such as good response to chemotherapy or limited vascular attachment to less than half circumference or longitudinal 10 mm reduced the risk of local recurrence. The proximity of osteosarcoma to major blood vessels is a poor prognostic factor for local control and survival. Amputation offers better local control for tumours attached to the blood vessels but does not improve survival. Limb salvage surgery offers similar local control if the tumour attachment to blood vessels is limited. Cite this article: Bone Joint J 2019;101-B:1024-1031.

CORR Insights®: Neoadjuvant Chemotherapy Followed by Delayed Surgery: Is it Necessary for All Patients With Nonmetastatic High-Grade Pelvic Osteosarcoma?

CORR Insights®: Neoadjuvant Chemotherapy Followed by Delayed Surgery: Is it Necessary for All Patients With Nonmetastatic High-Grade Pelvic Osteosarcoma?

Neoadjuvant Chemotherapy Followed by Delayed Surgery: Is it Necessary for All Patients With Nonmetastatic High-Grade Pelvic Osteosarcoma?

Neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy is the most-frequently employed strategy for patients with high-grade osteosarcoma. However, the contribution of neoadjuvant chemotherapy compared with postoperative adjuvant chemotherapy has not been tested rigorously in patients with nonmetastatic high-grade pelvic osteosarcoma. (1) Does neoadjuvant chemotherapy followed by delayed surgery offer a survival benefit to patients with nonmetastatic high-grade pelvic osteosarcoma compared with immediate surgery and adjuvant chemotherapy? (2) Is the timing of chemotherapy and surgery associated with a difference in the survivorship free from local recurrence and the risk of complications? (3) Is the threshold of 90% necrosis after neoadjuvant chemotherapy appropriate to distinguish responders from nonresponders in patients with pelvic osteosarcoma? Between 2000 and 2015, our center treated 112 patients with nonmetastatic high-grade primary pelvic osteosarcoma, of whom 93 underwent tumor resection with chemotherapy. Four patients (4%) were lost to followup before 24 months but were not known to have died; the remaining 89 patients were included in this retrospective study. Based on the timing of surgery and chemotherapy, patients were analyzed in two groups: (1) neoadjuvant chemotherapy followed by delayed surgery and adjuvant chemotherapy (n = 56; mean followup of 61 months, range 27-137 months), and (2) immediate surgery followed by adjuvant chemotherapy (n = 33; mean followup of 77 months, range 25-193 months). The total duration and intensity of chemotherapy was similar in both groups. During the period in question, we generally used neoadjuvant therapy followed by delayed surgery and adjuvant chemotherapy when patients received their biopsies in our center. We typically used immediate surgery with adjuvant chemotherapy when patients initially refused chemotherapy or when they had severe pain or poor walking function. Patients in the neoadjuvant chemotherapy group had a higher proportion of sacral infiltration; other factors such as sex, age and tumor size were well balanced between groups. We compared overall survival and local recurrence-free survival rates between the two groups. We completed univariate log-rank tests and multivariate Cox analyses in all patients to identify factors associated with survival and local recurrence using the Kaplan-Meier method. No survival benefit was found in the patients treated with neoadjuvant chemotherapy followed by delayed surgery compared with the group treated with immediate surgery and adjuvant chemotherapy. At 5 years, the overall survival (OS) was 42% (95% CI, 33-52) for all patients in this study, 43% (95% CI, 30-56) for the neoadjuvant group, and 40% (95% CI, 25-55) for the immediate surgery group; p = 0.709. With the numbers available, there was no difference in the likelihood of successful limb salvage (five of 56 patients [89%] in the neoadjuvant chemotherapy group versus three of 33 patients [91%] in the immediate surgery group; p = 0.557). The 5-year local recurrence-free survival was 67% (95% CI, 59-76) with no difference between the two groups (68%; 95% CI, 57-78% versus 67%; 95% CI, 52-81; p = 0.595). With the numbers available, there was no difference in survival between patients whose tumors demonstrated more than 90% necrosis; however, only four of 56 patients in the neoadjuvant chemotherapy group demonstrated 90% necrosis. We found no survival advantage with chemotherapy before surgery compared with immediate surgery in patients with nonmetastatic high-grade pelvic osteosarcoma. The decision on chemotherapy timing should be made for reasons other than survival. A prospective trial is needed to confirm this conclusion. Level III, therapeutic study.

Candidate germline polymorphisms of genes belonging to the pathways of four drugs used in osteosarcoma standard chemotherapy associated with risk, survival and toxicity in non-metastatic high-grade osteosarcoma

This study aimed to identify associations between germline polymorphisms and risk of high-grade osteosarcoma (HGOS) development, event-free survival (EFS) and toxicity in HGOS patients treated with neo-adjuvant chemotherapy and surgery.Germline polymorphisms of 31 genes known to be relevant for transport or metabolism of all four drugs used in HGOS chemotherapy (methotrexate, doxorubicin, cisplatin and ifosfamide) were genotyped in 196 patients with HGOS and in 470 healthy age and gender-matched controls. Of these 196 HGOS patients, a homogeneously treated group of 126 patients was considered for survival analyses (survival cohort). For 57 of these, treatment-related toxicity data were available (toxicity cohort).Eleven polymorphisms were associated with increased risk of developing HGOS (p < 0.05). The distribution of polymorphisms in patients was characterized by a higher Shannon entropy. In the survival cohort (n = 126, median follow-up = 126 months), genotypes of ABCC2_1249A/G, GGH_452T/C, TP53_IVS2+38G/C and CYP2B6*6 were associated with EFS (p < 0.05). In the toxicity cohort (n = 57), genotypes of ABCB1_1236T/C, ABCC2_1249A/G, ABCC2_3972A/G, ERCC1_8092T/G, XPD_23591A/G, XRCC3_18067T/C, MTHFR_1298A/C and GGH_16T/C were associated with elevated risk for toxicity development (p < 0.05).The results obtained in this retrospective study indicate that the aforementioned germline polymorphisms significantly impact on the risk of HGOS development, EFS and the occurrence of chemotherapy-related toxicity. These findings should be prospectively validated with the aim of optimizing and tailoring HGOS treatment in the near future.

Postrelapse Prognostic Factors in Nonmetastatic Osteosarcoma: A Single-institution Experience.

The purpose of this study was to analyze the prognostic factors that influence postrelapse survival (PRS) in children and adolescents with initial localized high-grade osteosarcoma. This is a retrospective evaluation of patients aged 21 years and below with nonmetastatic high-grade osteosarcoma treated at our institution from 1985 to 2011 who developed recurrent disease after achievement of an initial complete response (CR). PRS and postrelapse event-free survival (PREFS) analyses were performed using the Kaplan-Meier method and log-rank test. Multivariate Cox regression analysis was used to determine which variables were independently prognostic. Thirty-one patients were included. Median age at primary diagnosis was 13.7 years (range, 1.9 to 21.0 y). Median time to first relapse was 16 months (range, 3 to 36 mo). Fourteen patients achieved a second CR (CR2) after surgery±chemotherapy treatment. The 5-year PRS and PREFS were both 26% (95% confidence interval, 14%-49%), with a median follow-up of 99 months (range, 27 to 271 mo). Multivariate analysis showed that achievement of CR2 (P<0.001) and histologic response to first-line treatment (P=0.02) were significantly associated with PRS, whereas time to first relapse did not retain univariate significance. Achievement of CR2 and histologic response to preoperative first-line treatment are independent survival prognostic factors in osteosarcoma recurrence.

Prognostic effect of erroneous surgical procedures in patients with osteosarcoma: evaluation using propensity score matching.

Little is known concerning erroneous surgical procedures of malignant bone tumors, and the prognostic effect of erroneous surgical procedures in osteosarcoma has not been determined. We retrospectively reviewed 240 patients with initially non-metastatic high-grade osteosarcoma of the pelvis and extremities and, of these, identified twenty-six who had undergone previous less appropriate surgical procedures due to misdiagnosis followed by adequate treatment at our institution. We evaluated the clinicopathologic characteristics of these twenty-six patients compared with the remaining 214 patients treated with regular protocol. Subsequently, thirty-eight patients (nineteen in the matched case group and nineteen in the matched control group) were matched for multiple different variables using propensity score matching, and the oncologic results in terms of event-free survival and overall survival were analyzed. The patients undergoing erroneous surgical procedures were typically older, with small, non-osteoblastic-type tumors that were in an unusual location, showed an osteolytic pattern on radiographs, had a tendency toward marginal or intralesional excision with positive histologic margin, and had not been treated with neoadjuvant chemotherapy (all p < 0.05). After adjustment of confounding variables by propensity score matching, there was no significant difference between matched groups with regard to event-free survival (p = 0.46) and overall survival (p = 0.99). Distinct differences existed in the clinicopathologic characteristics of the patients who underwent erroneous surgical procedures due to misdiagnosis. We failed to detect a prognostic relevance of the presence of previous erroneous procedures followed by adequate treatment.

PCN26 Long-Term Fiscal Implications of Mepact in the Treatment of High-Grade Non-Metastatic Osteosarcoma: A Budget Impact Model and A Lifetime Tax Perspective

PCN26 Long-Term Fiscal Implications of Mepact in the Treatment of High-Grade Non-Metastatic Osteosarcoma: A Budget Impact Model and A Lifetime Tax Perspective

Clinical Observations of Caffeine-Potentiated Chemotherapy

Caffeine, which has a DNA-repair inhibiting effect, enhances the cytocidal effects of anticancer agents or radiation. We began clinical use of caffeine-potentiated chemotherapy for malignant bone and soft tissue tumors in 1989. Herein, we report clinical observations suggesting that caffeine-potentiated chemotherapy may produce improved outcomes compared with historical controls. For this chemotherapy, we utilized ifosfamide, or the combination of cisplatin and doxorubicin, combined with caffeine. In all variants of the caffeine-potentiated chemotherapy protocol, we administered a major tranquillizer to reduce possible caffeine-induced sleep disturbances. Also, to prevent severe adverse effects, we monitored serum levels of caffeine at 24, 48, and 72 hours after the start of continuous infusion at a dose of 1.5 g/m2/day. In patients with nonmetastatic high-grade osteosarcoma, the overall 5-year cumulative survival rate was 90% and the 5-year event-free survival rate was 75%. In high-grade soft tissue sarcoma patients with nonmetastatic lesions, the overall 5-year cumulative survival rate for patients with nonmetastatic sarcoma (stages II and III) was 80.7%. In cases that were radiologically evaluated as a complete response, intentional marginal excision was performed and the average functional evaluation of the patients was 91% of normal. Caffeine-potentiated chemotherapy was also used in patients with metastatic carcinoma and lymphoma. Caffeine-potentiated chemotherapy is a promising novel therapy not only for sarcomas, but also for carcinomas. Future studies require randomized, controlled trials.

Survival after recurrent osteosarcoma: Data from 3 European Osteosarcoma Intergroup (EOI) randomized controlled trials

BackgroundRecurrence after osteosarcoma usually leads to death; thus prognostic factors for survival are of great importance. MethodsBetween 1983 and 2002, the European Osteosarcoma Intergroup accrued 1067 patients to 3 randomized controlled trials of pre- and post-operative chemotherapy for patients with resectable non-metastatic high-grade osteosarcoma of the extremity. Control treatment in all trials was doxorubicin 75mg/m2 and cisplatin 100mg/m2. The comparators were additional high-dose methotrexate (BO02), T10-based multi-drug regimen (BO03) and G-CSF intensified-DC (BO06). Post-recurrence survival (PRS) was investigated on combined data with standard survival analysis methods. ResultsMedian recurrence-free survival was 31months; 8 recurrences were reported more than 5years after the diagnosis. In 564 patients with a recurrence (median 13months post-randomisation), there was no difference in post-relapse survival between treatment arms. Patients whose disease recurred within 2years after randomization had a worse prognosis than those recurring after 2years. Patients with good initial histological response to pre-operative chemotherapy had a better overall survival after recurrence than poor responders. Local relapse was more often reported after limb-saving procedures (2 versus 8%; amputation versus limb-saving), independent of the primary tumour site. Site of first recurrence (local 20%, lung 62%, “other” 19%) affected survival, as patients recurring with non-lung distant metastases only or any combination of local relapse, lung metastases and non-lung metastases (=group “other”) had significantly worse overall survival (local 39%, lung 19%, “other” 9% at 5years). ConclusionsThese data describing a large series of patients with recurrent extremity osteosarcoma confirm the relationship between early recurrence and poor survival. There was better PRS in patients after good histological response to pre-operative chemotherapy, or with local-only recurrence.

Non‐metastatic osteosarcoma of the extremities in children aged 5 years or younger

The occurrence of high-grade osteosarcoma is rare in children aged 5 years or younger and only limited series or case reports have been described. The records of patients aged 5 years or younger with non-metastatic high-grade osteosarcoma of the extremities treated with surgery and adjuvant or neo-adjuvant chemotherapy at Rizzoli Institute between 1972 and 1999 were retrospectively evaluated in relation to gender, primary tumor site, histological subtype, surgical treatment, chemotherapy-induced tumor necrosis, 5- and 10-year event-free survival (EFS), and rate of local recurrence. Data were compared to patients aged 6-40 years entered with the same diagnosis and over the same time interval. Data from 20 patients were collected. Comparing these data with those from 1,106 patients 6-40 years of age only two main differences resulted: the younger group showed a higher rate for fibroblastic subtype (P < 0.01) and for amputation surgery (P < 0.01). Among the two groups, no statistical difference was observed for the 5-year EFS (60% vs. 53.8%; P = 0.6) and 10-year EFS (60% vs. 52.1%; P = 0.5). The rate of local recurrence was 5.0% and 5.4%. These findings suggest that in non-metastatic osteosarcoma of the extremities outcome and clinical characteristics are similar among children 5 years of age or younger and older patients. However, in the younger group we have observed a significant higher rate of fibroblastic subtype as well as a significant higher rate of mutilating surgery. Pediatr Blood Cancer.

Molecular characterization of the response to chemotherapy in conventional osteosarcomas: Predictive value of HSD17B10 and IFITM2

The therapy regimen of high-grade osteosarcoma includes chemotherapy followed by surgical resection and postoperative chemotherapy. The degree of necrosis following definitive surgery remains the only reliable prognostic factor and is used to guide the choice of postoperative chemotherapy. The aim of this study was to find molecular markers able to classify patients with an osteosarcoma as good or poor responders to chemotherapy before beginning treatment. Gene expression screening of 20 nonmetastatic high-grade osteosarcoma patients was performed using cDNA microarray. Expression of selected relevant genes was validated using QRT-PCR. Immunohistochemistry on tissue microarrays sections of 73 biopsies was performed to investigate protein expression. Fluorescent in situ hybridization was performed for RPL8 gene. We have found that HSD17B10 gene expression was up-regulated in poor responders and that immunohistochemistry expression of HSD17B10 on biopsy before treatment was correlated to response to chemotherapy. Other results include correlation of IFITM2, IFITM3, and RPL8 gene expression to chemotherapy response. A statistical correlation was found between polysomy 8 or gain of RPL8 and good response to chemotherapy. These data suggest that HSD17B10, RPL8, IFITM2, and IFITM3 genes are involved in the response to the chemotherapy and that HSD17B10 may be a therapeutic target. RPL8 and IFITM2 may be useful in the assessment at diagnosis and for stratifying patients taking part in randomized trials.

Risk of local recurrence after deltoid‐sparing resection for osteosarcoma of the proximal humerus

The anatomy of the shoulder poses special challenges with regard to limb-sparing surgery. Resection of the deltoid muscle is considered by some surgeons to be necessary to achieve adequate margins for osteosarcoma of the proximal humerus. However, this can compromise the functional results after reconstruction of the shoulder. The goal of the current study was to determine whether deltoid-sparing resection can be safely performed for osteosarcoma of the proximal humerus. Between 1978 and 2005, 23 consecutive patients with high-grade nonmetastatic osteosarcoma of the proximal humerus underwent limb-sparing surgery with preservation of the deltoid muscle. All patients received neoadjuvant chemotherapy followed by surgery and postoperative chemotherapy. The mean follow-up was 90 months (range, 7 months-279 months). The overall survival at 5 years was 77%. At the time of last follow-up, 14 (61%) of 23 of patients were alive without evidence of disease. Three (13%) patients developed local recurrence. Two of these patients had poor responses to chemotherapy, with tumor necrosis of 50% and 70%. The third patient had a pathologic fracture of the humerus. Positive surgical margins were associated with local recurrence, and 2 of 4 patients with a positive surgical margin developed local recurrence (P = .01). Preservation of the deltoid muscle can be performed for carefully selected patients with osteosarcoma of the proximal humerus. Routine use of the procedure is not justified, because it may be associated with an elevated risk of recurrence. The risk of local recurrence appears to be related to positive surgical margins and possibly the percentage of tumor necrosis.

Long-term results of the Spanish Protocol SO-95 for the treatment of non-metastatic high-grade osteosarcoma of the extremities in children

The long-term results of the Spanish Study Protocol SEOP-SO-95 for treatment of localised osteosarcoma of the extremities in children were evaluated. One hundred consecutive patients under 18 years of age from 22 institutions were enrolled from January 1995 to December 2000. Immunohistochemical expression of p53, HER/erbB-2 and P-glycoprotein were retrospectively studied in 27 patients. Treatment consisted of: preoperative chemotherapy with doxorubicin, cisplatin, high-dose methotrexate with leucovorin rescue and ifosfamide for 14 weeks; surgery of primary tumour in week 16; postoperative chemotherapy with the above-mentioned drugs for 25 weeks. With a median follow-up of 124 months (range 84-158 months), 69 patients (69%) were continuously event-free survivors; the 10-year probability of event-free survival (EFS) was 62%. Conservative surgery was performed in 85% of patients. Twenty-six patients had local recurrence or distant relapse. The median time to recurrence/ relapse was 27 months (range 17-93 months). The local recurrence rate was 7% (7 of the 100 patients); 4 had wide surgical margins, 2 marginal and 1 intralesional. Four patients died as a result of chemotherapy-related toxicity and 1 developed a second neoplasia (acute myeloid leukaemia). p53 expression and HER2/erbB-2 expression showed no effect on survival or EFS. This therapeutic protocol achieved good oncologic and orthopaedic results. We observed a significant treatment-related toxicity.

A Bayesian nonparametric method for model evaluation: application to genetic studies

Statistical models applied to genetic studies commonly assume linear relationships (between disease and risk factors) and simple distributional forms (by relying on asymptotic methods) for inference. However, when the sample size is small, inference using traditional asymptotic models can be problematic. Moreover, the gene-disease relationship is not always linear. In this article, we present a new nonparametric Bayesian method for model assessment, and we demonstrate the advantages of this approach particularly when the sample size is small and/or the true model is non-linear. We evaluate our approach on simulated data and find that it performs substantially better than alternative models. We also apply our method to two real studies: diagnosis of conventional high-grade non-metastatic osteosarcoma, and survival in Burkitt's lymphoma.

Neoadjuvant Chemotherapy for Osteosarcoma of the Extremities in Preadolescent Patients

Medical records of 133 patients, 10 years old or younger with primary high-grade nonmetastatic osteosarcoma of the extremities treated at the Rizzoli Institute between 1983 and 1999 with neoadjuvant chemotherapy were reviewed and compared with those of 782 patients aged 11 to 40 years treated in the same period with the same chemotherapy protocols. In comparison to the older group, the younger group had more females, more patients with normal lactic dehydrogenase levels, and more non-limb-salvage procedures (amputation or rotationplasty). Five-year event-free and overall survivals were essentially the same in the two groups (63% and 71% vs. 60% and 70%) as were the patients rescued after relapse and presently event-free (18% vs. 20%). The authors conclude that there does not seem to be any indication to treat preadolescent primary high-grade nonmetastatic osteosarcoma patients by alternative and/or more aggressive therapies.

Survival after recurrent osteosarcoma: Data from three European Osteosarcoma Intergroup (EOI) randomized controlled

10505 Background: Between 1983 and 2002, the EOI accrued to three randomized controlled trials of pre- and postoperative chemotherapy for patients (pts) with resectable nonmetastatic high-grade osteosarcoma of the extremity: MRC-BO02, BO03 and BO06 (also known as EORTC-80831, 80861 and 80931) with n=179, 391 and 497 pts randomised, respectively. Control treatment in all trials was doxorubicin 75 mg/m2 + cisplatin 100 mg/m2 (DC). The comparators were additional high-dose methotrexate (BO02), T10-based multi- drug regimen (BO03) and G-CSF intensified-DC (BO06). No statistically significant differences between treatments were reported in the original trial reports. Methods: Survival after recurrence was investigated with standard survival analysis methods, including all 1,067 pts from the 3 trials. Results: Median recurrence-free survival was 31 months (m); only 4 recurrences were reported later than 5 years. In 564 pts with recurrence (median 13m post-randomisation), there was no difference in 5-year survival between first-line treatment arms (13–19%). Pts with good histologic response to preoperative chemotherapy had better overall survival after recurrence than poor responders (p=0.015). Pts whose disease recurred within 2 years after randomization had worse prognosis than those recurring after 2 years (14 vs 35% at 5 years; p<0.001). Local relapse was more often reported after limb saving procedures (5 vs 25%), independent of the primary tumor site. Site of first recurrence (in total: local 20%, lung 62%, other 18%) affected survival as pts recurring with metastases other than lung had significantly worse overall survival (local 27%, lung 18%, other 10% at 5 years, p=0.001). Conclusions: These data describe the largest series of pts with recurrent osteosarcoma. They confirm the relationship between early recurrence and poor survival. New findings include worse survival in pts with a recurrence after poor histologic response to preoperative chemotherapy. No significant financial relationships to disclose.

7518 POSTER The results of preoperative chemotherapy with or without radiotherapy in nonmetastatic high-grade osteosarcoma of the extremities

Background: Anemia is a common complication of chronic kidney disease (CKD). The approved dosing interval for currently available erythropoiesis-stimulating agents (ESAs) is 2 to 3 times weekly for epoetin alfa (EPO) and every 1 to 2 weeks for darbepoetin alfa (DARB). However, clinicians sometimes use less frequent dosing in the interest of convenience.Objectives: This study investigated patterns of actual ESA use (doses and dosing intervals) and hemoglo- bin (Hb) control in adult outpatients with CKD not requiring dialysis at the Cleveland Clinic Foundation anemia clinic. The distribution of and variability in Hb levels in these patients were also examined.Methods: The clinical charts and electronic records of adult outpatients with CKD who initiated ESA therapy before March 2005 were reviewed to identify the initial, dominant (used for the longest consecutive period), and final dosing intervals and mean weekly doses of EPO and DARB. Hb control was examined in terms of maximum deviations >12 g\dL and <11 g\dL, and the proportions of measurements outside these values.Results: The analysis included data from 111 outpatients (mean [SD] age, 65.9 [14.4] years; 53.2% male; 66.7% white, 29.7% black, 2.7% other, 0.9% unknown ethnicity). Twenty-one patients received EPO only, 74 received DARB only, and 16 switched ESAs. The mean duration of follow-up was 20.5 months. The most common initial dosing intervals were qwk for EPO (66.7%) and q2wk for DARB (90.5%). The dominant dosing intervals were q2wk in 61.9% of EPO patients and q3wk in 62.3% of DARB patients. However, 80.0% of those who received EPO q2wk and 63.2% of those who received DARB q3wk eventually returned to their initial dosing intervals. The largest proportions of Hb mea- surements <11 g\dL occurred at dominant dosing intervals of qwk for EPO and q2wk for DARB (both, 46.0%; 11 and 26 patients, respectively), whereas the largest proportions of measurements >12 g\dL occurred with EPO dosed at q2wk (44.0%; 5 patients) and DARB dosed at >q4wk (62.0%; 5 patients).Conclusions: The patterns of ESA usage in adult outpatients with CKD at this center indicated that clinicians extended dosing intervals beyond those in the approved prescribing information. However, variations in Hb concentrations occurred during maintenance therapy administered at extended dosing intervals, resulting in the resumption of shorter dosing intervals in the majority of patients.