Opioid Use in Surgical Management in Musculoskeletal Oncology.

BACKGROUND: Opioid prescribing in the context of orthopaedic surgery has been recognized as having a critical role in the ongoing opioid epidemic. Given the negative consequences of chronic opioid use, great efforts have been made to reduce both preoperative and postoperative opioid prescribing and consumption in orthopaedic surgery. Musculoskeletal oncology patients represent a unique subset of patients, and there is a paucity of data evaluating perioperative opioid consumption and the risk for chronic use. The objective of the present study was to describe opioid consumption patterns and evaluate predictors of chronic opioid use in musculoskeletal oncology patients undergoing limb-salvage surgery and endoprosthetic reconstruction. METHODS: The present study was a secondary analysis of the recently completed PARITY (Prophylactic Antibiotic Regimens in Tumor Surgery) trial and included musculoskeletal oncology patients undergoing lower-extremity endoprosthetic reconstruction. The primary outcome was the incidence of opioid consumption over the study period. A multivariate binomial logistic regression model was created to explore predictors of chronic opioid consumption at 1 year postoperatively. RESULTS: Overall, 193 (33.6%) of 575 patients were consuming opioids preoperatively. Postoperatively, the number of patients consuming opioids was 82 (16.7%) of 492 at 3 months, 37 (8%) of 460 patients at 6 months, and 28 (6.6%) of 425 patients at 1 year. Of patients consuming opioids preoperatively, 12 (10.2%) of 118 had continued to consume opioids at 1 year postoperatively. The adjusted regression model found that only surgery for metastatic bone disease was predictive of chronic opioid use (odds ratio, 4.90; 95% confidence interval, 1.54 to 15.40; p = 0.007). Preoperative opioid consumption, older age, sex, longer surgical times, reoperation rates, and country of origin were not predictive of chronic use. CONCLUSIONS: Despite a high prevalence of preoperative opioid use, an invasive surgical procedure, and a high rate of reoperation, few patients had continued to consume opioids at 1 year postoperatively. The presence of metastases was associated with chronic opioid use. These results are a substantial departure from the existing orthopaedic literature evaluating other patient populations, and they suggest that specific prescribing guidelines are warranted for musculoskeletal oncology patients. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Pediatric and Adult Patients Have Similar Functional Improvement After Endoprosthetic Reconstruction of Lower-Extremity Tumors.

BACKGROUND: Although the treatment of lower-extremity bone tumors is similar between adult and pediatric patients, differences in outcomes are unknown. Outcomes for lower-extremity oncologic reconstruction have been challenging to study because of the low incidence and heterogeneity in disease and patient characteristics. The PARITY (Prophylactic Antibiotic Regimens in Tumor Surgery) trial is the largest prospective data set assembled to date for patients with lower-extremity bone tumors and presents an opportunity to investigate differences in outcomes between these groups. METHODS: Patient details were acquired from the prospectively collected PARITY trial database. The 1993 Musculoskeletal Tumor Society (MSTS-93) and Toronto Extremity Salvage Score (TESS) questionnaires were administered preoperatively and at 3, 6, and 12 months postoperatively. Continuous outcomes were compared between groups with use of the Student t test, and dichotomous outcomes were compared with use of the Pearson chi-square test. RESULTS: A total of 150 pediatric and 447 adult patients were included. Pediatric patients were more likely than adult patients to have a primary bone tumor (146 of 150 compared with 287 of 447, respectively; p < 0.001) and to have received adjuvant chemotherapy (140 of 149 compared with 195 of 441, respectively; p < 0.001). Reoperation rates were not significantly different between age groups (45 of 105 pediatric patients compared with 106 of 341 adult patients; p ≤ 0.13). Pediatric patients had higher mean MSTS-93 scores (64.7 compared with 53.8 among adult patients; p < 0.001) and TESS (73.4 compared with 60.4 among adult patients; p < 0.001) at baseline, which continued to 1 year postoperatively (mean MSTS-93 score, 82.0 compared with 76.8 among adult patients; p = 0.02; mean TESS, 87.7 compared with 78.6 among adult patients; p < 0.001). Despite the differences in outcomes between cohorts, pediatric and adult patients demonstrated similar improvement in MSTS-93 scores (mean difference, 17.4 and 20.0, respectively; p = 0.48) and TESS (mean difference, 14.1 and 14.7, respectively; p = 0.83) from baseline to 1 year postoperatively. CONCLUSIONS: Pediatric patients had significantly better functional outcomes than adult patients at nearly all of the included postoperative time points; however, pediatric and adult patients showed similar mean improvement in these outcomes at 1 year postoperatively. These findings may be utilized to help guide the postoperative expectations of patients undergoing oncologic reconstruction. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Survival and failure modes of the Compress® spindle and expandable distal femur endoprosthesis among pediatric patients: A multi-institutional study.

BACKGROUND: Expandable endoprostheses can be used to equalize limb length for pediatric patients requiring reconstruction following large bony oncologic resections. Outcomes of the Compress® Compliant Pre-Stress (CPS) spindle paired with an Orthopedic Salvage System expandable distal femur endoprosthesis have not been reported. METHODS: We conducted a multi-institutional retrospective study of pediatric patients with distal femoral bone sarcomas reconstructed with the above endoprostheses. Statistical analysis utilized Kaplan-Meier survival technique and competing risk analysis. RESULTS: Thirty-six patients were included from five institutions. Spindle survivorship was 86.3% (95% confidence interval [CI], 67.7-93.5) at 10 years. Two patients had a failure of osseointegration (5.7%), both within 12 months. Twenty-two (59%) patients had 70 lengthening procedures, with mean expansions of 3.2 cm (range: 1-9) over 3.4 surgeries. The expandable mechanism failed in eight patients with a cumulative incidence of 16.1% (95% CI, 5.6-31.5) at 5 years. Twenty-nine patients sustained International Society of Limb Salvage failures requiring 63 unplanned surgeries. Periprosthetic joint infection occurred in six patients (16.7%). Limb preservation rate was 91% at 10 years. CONCLUSIONS: There is a high rate of osseointegration of the Compress® spindle among pediatric patients when coupled with an expandable implant. However, there is a high rate of expansion mechanism failure and prosthetic joint infections requiring revision surgery. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Is the Addition of Anaerobic Coverage to Perioperative Antibiotic Prophylaxis During Soft Tissue Sarcoma Resection Associated With a Reduction in the Proportion of Wound Complications?

BACKGROUND: Wound complications are common after resection of soft tissue sarcomas, with published infection rates ranging from 10% to 35%. Multiple studies have reported on the atypical flora comprising these infections, which are often polymicrobial and contain anaerobic bacteria, and recent studies have noted the high prevalence of anaerobic bacterial infections after soft tissue sarcoma resection [ 26, 35 ]. Based on this, our institution changed clinical practice to include an antibiotic with anaerobic coverage in addition to the standard first-generation cephalosporin for prophylaxis during soft tissue sarcoma resections. The current study was undertaken to evaluate whether this change was associated with a change in major wound complications, and if the change should therefore be adopted for future patients. QUESTIONS/PURPOSES: (1) After controlling for potentially confounding variables, was the broadening of the prophylactic antibiotic spectrum to cover anaerobic bacteria associated with a lower odds of major wound complications after soft tissue sarcoma resection? (2) Was the broadening of the prophylactic antibiotic spectrum to cover anaerobic bacteria associated with a lower odds of surgical site infections with polymicrobial or anaerobic infections after soft tissue sarcoma resection? (3) What are the factors associated with major wound complications after soft tissue sarcoma resection? METHODS: We retrospectively identified 623 patients who underwent soft tissue sarcoma resection at a single center between January 2008 and January 2021 using procedural terminology codes. Of these, four (0.6%) pediatric patients were excluded, as were five (0.8%) patients with atypical lipomatous tumors and two (0.3%) patients with primary bone tumors; 5% (33 of 623) who were lost to follow-up, leaving 579 for final analysis. The prophylactic antibiotic regimen given at the resection and whether a wound complication occurred were recorded. Patients received the augmented regimen based on whether they underwent resection after the change in practice in July 2018. A total of 497 patients received a standard antibiotic regimen (usually a first-generation cephalosporin), and 82 patients received an augmented regimen with anaerobic coverage (most often metronidazole). Of the 579 patients, 53% (307) were male (53% [264 of 497] in the standard regimen and 52% [43 of 82] in the augmented regimen), and the mean age was 59 ± 17 years (59 ± 17 and 60 ±17 years in the standard and augmented groups, respectively). Wound complications were defined as any of the following within 120 days of the initial resection: formal wound debridement in the operating room, other interventions such as percutaneous drain placement, readmission for intravenous antibiotics, or deep wound packing for more than 120 days from the resection. Patients were considered to have a surgical site infection if positive cultures resulted from deep tissue cultures taken intraoperatively at the time of debridement. The proportion of patients with major wound complications was 26% (150 of 579); it was 27% (136 of 497) and 17% (14 of 82) in the standard and augmented antibiotic cohorts, respectively (p = 0.049). With the numbers we had, we could not document that the addition of antibiotics with anaerobic coverage was associated with lower odds of anaerobic (4% versus 6%; p = 0.51) or polymicrobial infections (9% versus 14%; p = 0.25). Patient, tumor, and treatment (surgical, radiotherapy, and chemotherapy) variables were collected to evaluate factors associated with overall infection and anaerobic or polymicrobial infection. Patient follow-up was 120 days to capture early wound complications. A multivariable analysis was performed for all variables found to be significant in the univariate analysis. A p value < 0.05 was used as the threshold for statistical significance for all analyses. No patients were found to have an adverse reaction to the augmented regimen, including allergic reactions or Clostridioides (formerly Clostridium) difficile infection. RESULTS: After controlling for other potentially confounding factors such as neoadjuvant radiation, tumor size and anatomic location, as well as patient BMI, anaerobic coverage was associated with smaller odds of wound complications (OR 0.36 [95% confidence interval (CI) 0.18 to 0.68]; p = 0.003). Other factors associated with major wound complications were preoperative radiation (versus no preoperative radiation) (OR 2.66 [95% CI 1.72 to 4.15]; p < 0.001), increasing tumor size (OR 1.04 [95% CI 1.00 to 1.07]; p = 0.03), patient BMI (OR 1.07 [95% CI 1.04 to 1.11]; p < 0.001), and tumor in the distal upper extremity (versus proximal upper extremity, pelvis/groin/hip, and lower extremity) (OR 0.18 [95% CI 0.04 to 0.62]; p = 0.01). CONCLUSION: The addition of anaerobic coverage to the standard prophylactic regimen during soft tissue sarcoma resection demonstrated an association with smaller odds of major wound complications and no documented adverse reactions. Treating physicians should consider these findings but note that they are preliminary, and that further work is needed to replicate them in a more controlled study design such as a prospective trial. LEVEL OF EVIDENCE: Level III, therapeutic study.

Compressive osseointegration for endoprosthetic reconstruction.

This review summarizes the biomechanical concepts, clinical outcomes and limitations of compressive osseointegration fixation for endoprosthetic reconstruction. Compressive osseointe - gration establishes stable fixation and integration through a novel mechanism; a Belleville washer system within the spindle applies 400-800 PSI force at the boneimplant interface. Compressive osseointegration can be used whenever standard endoprosthetic reconstruction is indicated. However, its mode of fixation allows for a shorter spindle that is less limited by the length of remaining cortical bone. Most often compressive osseointegration is used in the distal femur, proximal femur, proximal tibia, and humerus but these devices have been customized for use in less traditional locations. Aseptic mechanical failure occurs earlier than with standard endoprosthetic reconstruction, most often within the first two years. Compressive osseointegration has repeatedly been proven to be non-inferior to standard endoprosthetic reconstruction in terms of aseptic mechanical failure. No demographic, device specific, oncologic variables have been found to be associated with increased risk of aseptic mechanical failure. While multiple radiographic parameters are used to assess for aseptic mechanical failure, no suitable method of evaluation exists. The underlying pathology associated with aseptic mechanical failure demonstrates avascular bone necrosis. This is in comparison to the bone hypertrophy and ingrowth at the boneprosthetic interface that seals the endosteal canal, preventing aseptic loosening.

Radiographic parameter-driven decision tree reliably predicts aseptic mechanical failure of compressive osseointegration fixation.

Background and purpose - Compressive osseointegration fixation is an alternative to intramedullary fixation for endoprosthetic reconstruction. Mechanical failure of compressive osseointegration presents differently on radiographs than stemmed implants, therefore we aimed to develop a reliable radiographic method to determine stable integration.Patients and methods - 8 reviewers evaluated 11 radiographic parameters from 29 patients twice, 2 months apart. Interclass correlation coefficients (ICCs) were used to assess test-retest and inter-rater reliability. We constructed a fast and frugal decision tree using radiographic parameters with substantial test-retest agreement, and then tested using radiographs from a new cohort of 49 patients. The model's predictions were compared with clinical outcomes and a confusion matrix was generated.Results - 6 of 8 reviewers had non-significant intra-rater ICCs for ≥ one parameter; all inter-rater ICCs were highly reliable (p < 0.001). Change in length between the top of the spindle sleeve and bottom of the anchor plug (ICC 0.98), bone cortex hypertrophy (ICC 0.86), and bone pin hypertrophy (ICC 0.81) were used to create the decision tree. The sensitivity and specificity of the training cohort were 100% (95% CI 52-100) and 87% (CI 74-94) respectively. The decision tree demonstrated 100% (CI 40-100) sensitivity and 89% (CI 75-96) specificity with the test cohort.Interpretation - A stable spindle length and at least 3 cortices with bone hypertrophy at the implant interface predicts stable osseointegration; failure is predicted in the absence of bone hypertrophy at the implant interface if the pin sites show hypertrophy. Thus, our decision tree can guide clinicians as they follow patients with compressive osseo-integration implants.

Utility of the Current Procedural Terminology Codes for Prophylactic Stabilization for Defining Metastatic Femur Disease.

INTRODUCTION: Cohorts from the electronic health record are often defined by the Current Procedural Terminology (CPT) codes. The error prevalence of CPT codes for patients receiving surgical treatment of metastatic disease of the femur has not been investigated, and the predictive value of coding ontologies to identify patients with metastatic disease of the femur has not been adequately discussed. METHODS: All surgical cases at a single academic tertiary institution from 2010 through 2015 involving prophylactic stabilization of the femur or fixation of a pathologic fracture of the femur were identified using the CPT and International Classification of Disease (ICD) codes. A detailed chart review was conducted to determine the procedure performed as documented in the surgical note and the patient diagnosis as documented in the pathology report, surgical note, and/or office visit notes. RESULTS: We identified 7 CPT code errors of 171 prophylactic operations (4.1%) and one error of 71 pathologic fracture fixation s(1.4%). Of the 164 prophylactic operations that were coded correctly, 87 (53.0%) had metastatic disease. Of the 70 pathologic operations that were coded correctly, 41 (58%) had metastatic disease. DISCUSSION: The error prevalence was low in both prophylactic stabilization and pathologic fixation groups (4.1% and 1%, respectively). The structured data (CPT and ICD-9 codes) had a positive predictive value for patients having metastatic disease of 53% for patients in the prophylactic stabilization group and 58% for patients in the pathologic fixation group. The CPT codes and ICD codes assessed in this analysis do provide a useful tool for defining a population in which a moderate proportion of individuals have metastatic disease in the femur at an academic medical center. However, verification is necessary.

Oncology Patients Are High Cost Outliers in Total Joint Replacement Bundled Payment Systems.

BACKGROUND: In 2016, the Centers for Medicare and Medicaid Services began its first mandatory bundled payment program, the Comprehensive Care for Joint Replacement (CJR) model, which covers a 90-day episode of care. This study determined whether oncology patients enrolled in the CJR bundle incur higher hospital costs than patients with osteoarthritis (OA). METHODS: A retrospective review of all patients enrolled in the CJR bundled payments system from April 1, 2016 to June 31, 2018 at a single academic medical center was conducted. To determine whether tumor patients had higher total episode costs, this group was compared to patients diagnosed with OA using a 2-tailed t-test. To adjust for moderators of total hospital costs, we used generalized linear regression with a log-link, including multiple variables abstracted from chart review. RESULTS: Three hundred fourteen patients met inclusion criteria (12 primary or metastatic tumors, 302 OA). Fifty-eight percent of tumor patients were over the target price vs 16% of OA patients. The mean tumor patient had $40,862 for total internal hospital costs compared to $16,356 in the OA group (P < .001). Length of stay was greater in the tumor group (6.75 vs 2.0 days, P < .001). A greater percentage of tumor patients were discharged to a skilled nursing facility (67% vs 27%, P = .006) with significantly higher skilled nursing facility episode costs ($18,852 vs $7731, P = .04). With adjustment for fracture status, tumor patients were 5.36 times more likely to exceed the CJR target price than OA patients (risk ratio 5.36, confidence interval 3.44-8.35, P < .001) and 50 times more likely to be outliers over the regional threshold than OA patients (risk ratio 50.33, confidence interval 16.33-155.19, P < .001). CONCLUSION: Oncology patients enrolled in the CJR bundled payment model incur significantly higher costs and have higher cost variability than patients with OA. We recommend that oncology patients be excluded from the CJR bundle.

Epirubicin and Ifosfamide with Preoperative Radiation for High-Risk Soft Tissue Sarcomas.

BACKGROUND: The optimal treatment of high-risk soft tissue sarcomas (STS) of the extremities remains controversial. We report follow-up from a phase II study of dose-intense chemotherapy with preoperative hypofractionated radiation in this population supplemented with subsequent data from an extensive institutional experience using this regimen. METHODS: Patients with localized, intermediate- or high-grade STS of the extremity or body wall measuring > 5 cm were treated with epirubicin 30 mg/m2/day and ifosfamide 2.5 g/m2/day on days 1-4 every 21 days for 3 preoperative and 3 postoperative cycles. During cycle 2 of preoperative therapy, epirubicin was omitted, and a total of 28 Gy of radiation (8 fractions) was delivered. Twenty-five patients were treated on the phase II study (2002-2005). Fifty-one additional patients were identified from a retrospective chart review (2005-2014). RESULTS: The 5-year rates for overall survival, distant disease-free survival, and freedom from local regional failure were 70.4% (95% CI 59.2-83.7%), 55.9% (95% CI 44.5-70.2%), and 87.2% (95% CI 77.9-96.5%) respectively. Thirty-eight percent of tumors (29/76) demonstrated ≥ 90% pathologic response. Wound complications occurred in 32% (24/76) of patients. DISCUSSION: Treatment with preoperative radiation and pre- and post-operative epirubicin and ifosfamide was associated with favorable clinical outcomes. Survival and recurrence rates were comparable to those reported with other preoperative chemotherapy regimens in high-risk extremity sarcomas. Use of trimodality therapy should be considered for appropriate high-risk STS patients.

Preclinical testing of the glycogen synthase kinase-3ß inhibitor tideglusib for rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. RMS often arise from myogenic precursors and displays a poorly differentiated skeletal muscle phenotype most closely resembling regenerating muscle. GSK3ß is a ubiquitously expressed serine-threonine kinase capable of repressing the terminal myogenic differentiation program in cardiac and skeletal muscle. Recent unbiased chemical screening efforts have prioritized GSK3ß inhibitors as inducers of myodifferentiation in RMS, suggesting efficacy as single agents in suppressing growth and promoting self-renewal in zebrafish transgenic embryonal RMS (eRMS) models in vivo. In this study, we tested the irreversible GSK3ß-inhibitor, tideglusib for in vivo efficacy in patient-derived xenograft models of both alveolar rhabdomyosarcoma (aRMS) and eRMS. Tideglusib had effective on-target pharmacodynamic efficacy, but as a single agent had no effect on tumor progression or myodifferentiation. These results suggest that as monotherapy, GSK3ß inhibitors may not be a viable treatment for aRMS or eRMS.

Evaluation of Soft Tissue Sarcoma Response to Preoperative Chemoradiotherapy Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging.

This study aims to assess the utility of quantitative dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) parameters in comparison with imaging tumor size for early prediction and evaluation of soft tissue sarcoma response to preoperative chemoradiotherapy. In total, 20 patients with intermediate- to high-grade soft tissue sarcomas received either a phase I trial regimen of sorafenib + chemoradiotherapy (n = 8) or chemoradiotherapy only (n = 12), and underwent DCE-MRI at baseline, after 2 weeks of treatment with sorafenib or after the first chemotherapy cycle, and after therapy completion. MRI tumor size in the longest diameter (LD) was measured according to the RECIST (Response Evaluation Criteria In Solid Tumors) guidelines. Pharmacokinetic analyses of DCE-MRI data were performed using the Shutter-Speed model. After only 2 weeks of treatment with sorafenib or after 1 chemotherapy cycle, Ktrans (rate constant for plasma/interstitium contrast agent transfer) and its percent change were good early predictors of optimal versus suboptimal pathological response with univariate logistic regression C statistics values of 0.90 and 0.80, respectively, whereas RECIST LD percent change was only a fair predictor (C = 0.72). Post-therapy Ktrans, ve (extravascular and extracellular volume fraction), and kep (intravasation rate constant), not RECIST LD, were excellent (C > 0.90) markers of therapy response. Several DCE-MRI parameters before, during, and after therapy showed significant (P < .05) correlations with percent necrosis of resected tumor specimens. In conclusion, absolute values and percent changes of quantitative DCE-MRI parameters provide better early prediction and evaluation of the pathological response of soft tissue sarcoma to preoperative chemoradiotherapy than the conventional measurement of imaging tumor size change.

Phase I trial of preoperative chemoradiation plus sorafenib for high-risk extremity soft tissue sarcomas with dynamic contrast-enhanced MRI correlates.

PURPOSE: We conducted a phase I trial of the addition of sorafenib to a chemoradiotherapy regimen in patients with high-risk (intermediate/high grade, >5 cm) extremity soft tissue sarcoma undergoing limb salvage surgery. We conducted a correlative study of quantitative dynamic contrast-enhanced MRI (DCE-MRI) to assess response to treatment. EXPERIMENTAL DESIGN: Patients were treated at increasing dose levels of sorafenib (200 mg daily, 400 mg daily, 400 mg twice daily) initiated 14 days before three preoperative and three postoperative cycles of epirubicin/ifosfamide. Radiation (28 Gy) was administered during cycle 2 with epirubicin omitted. The primary objective was to determine the maximum tolerated dose (MTD) of sorafenib. DCE-MRI was conducted at baseline, after 2 weeks of sorafenib, and before surgery. The imaging data were subjected to quantitative pharmacokinetic analyses. RESULTS: Eighteen subjects were enrolled, of which 16 were evaluable. The MTD of sorafenib was 400 mg daily. Common grade 3-4 adverse events included neutropenia (94%), hypophosphatemia (75%), anemia (69%), thrombocytopenia (50%), and neutropenic fever/infection (50%). Of note, 38% developed wound complications requiring surgical intervention. The rate of ≥95% histopathologic tumor necrosis was 44%. Changes in DCE-MRI biomarker ΔK(trans) after 2 weeks of sorafenib correlated with histologic response (R(2) = 0.67, P = 0.012) at surgery. CONCLUSION: The addition of sorafenib to preoperative chemoradiotherapy is feasible and warrants further investigation in a larger trial. DCE-MRI detected changes in tumor perfusion after 2 weeks of sorafenib and may be a minimally invasive tool for rapid assessment of drug effect in soft tissue sarcoma.

Histologic response of dose-intense chemotherapy with preoperative hypofractionated radiotherapy for patients with high-risk soft tissue sarcomas.

BACKGROUND: The authors studied a dose-intense regimen of epirubicin and ifosfamide with hypofractionated preoperative radiotherapy for high-risk soft tissue sarcomas. The primary objective was estimation of the rate of >or=95% pathologic necrosis. METHODS: Twenty-five patients with intermediate-grade or high-grade, localized soft tissue sarcomas of the extremity or body wall measuring >5 cm were treated with epirubicin at a dose of 30 mg/m(2)/day on Days 1 to 4 and ifosfamide at a dose of 2.5 g/m(2)/day on Days 1 to 4 every 21 days for 3 preoperative and 3 postoperative cycles. A total of 28 grays of radiation was administered over 8 fractions during Cycle 2 of preoperative therapy (epirubicin was omitted). RESULTS: Sixteen patients (64%) completed all chemotherapy cycles and the average delivered dose intensity relative to intended therapy was 69%. Twenty-one patients (84%) experienced grade 4 toxicity (using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 2.0]), which was predominantly hematologic. Notable toxicities included neutropenic fever (40%), ifosfamide-induced encephalopathy (24%), and grade 3/4 anemia (64%). Postoperative wound complications requiring a surgical procedure occurred in 20% of patients. The rate of >or=95% pathologic necrosis was 40% (95% confidence interval [95% CI], 21-59%). Estimates of 2-year overall and disease-free survival were 84% (95% CI, 66-100%) and 62% (95% CI, 37-86%), respectively. CONCLUSIONS: A high rate of >or=95% pathologic necrosis was noted with this aggressive chemoradiotherapy regimen. The occurrence of significant acute toxicities limited the delivery of the intended dose intensity.

Osteosarcoma: basic science and clinical implications.

Current therapy for osteosarcoma successfully treats 60% to 70% of patients. Attempts to identify patients who will respond poorly to therapy has focused on the use of new biologic markers or microarray cluster analysis. New potential therapeutic targets, including growth factors, chemokines, transcription factors, and angiogenic factors, are being evaluated for their roles in osteosarcoma. These new targets may provide mechanisms to treat the patients who would respond poorly to standard therapy.