Localized Osteosarcoma Research Articles

Prise en charge des ostéosarcomes en 2009

Curative treatment for high-grade osteosarcoma consists in surgery of the primary tumor and chemotherapy, in order to achieve a limb salvage surgery and increase the disease-free survival rate. Patients with suggestive diagnosis of osteosarcoma should be sent to a reference center before biopsy. Confirmation of diagnosis by a pathologist with particular expertise in bone tumors is recommended. Multimodal treatment is often given within the framework of prospective collaborative studies. Currently, doxorubicin, cisplatinum, high-dose methotrexate and ifosfamide are considered the most active agents against osteosarcoma. High-dose methotrexate with leucovorin rescue always takes part of first-line regimen in children and adolescents, alternative regimens are proposed for adults because of excessive toxicity despite appropriate management by skilled teams. Compared with surgery alone, multimodal treatment of localized high-grade osteosarcoma improves outcome for patients from 20% to more than 60% of them been alive 5-year after diagnosis.

Abstract A77: RNA helicase DDX3 – A novel therapeutic target in sarcoma

Abstract High grade sarcomas are among the most common solid tumors in childhood. Although intensive chemotherapy has dramatically improved the outcome of children with localized osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma, the prognosis for children with metastatic or recurrent disease remains dismal, with no substantial improvement since the introduction of multi-agent chemotherapy regimens 30 years ago. The identification of novel therapeutic targets, and the development of drugs to exploit these targets, is therefore an urgent need. RNA helicases are ubiquitous enzymes, aberrantly expressed in a variety of solid and hematologic malignancies, that are involved in all aspects of RNA metabolism, including transcription, translation, mRNA splicing, and regulation of other protein-RNA interactions. The RNA helicase DDX3 is essential for translation of key cell cycle regulatory mRNA transcripts including cyclin A, cyclin E1, TGFB1, STAT1 and others. Expression of DDX3 is dramatically upregulated in mammary epithelial cells exposed to BPDE, a toxin found in cigarette smoke, and overexpression of DDX3 in breast cancer cell lines correlates with invasiveness and aggressive activity. MCF10a mammary epithelial cells induced to overexpress DDX3 undergo epithelial-mesenchymal transition (EMT) with increased invasive behavior, motility, and colony-forming activity, consistent with neoplastic transformation. Novel DDX3 mutations have recently been identified in medulloblastoma. These data suggest DDX3 may play a key role in the development and progression of a wide variety of solid tumors. We therefore investigated DDX3 expression in sarcomas. We found that sarcomas, both cell lines and primary samples, commonly express high levels of DDX3. Knock down of DDX3 expression in cell lines impaired proliferation, clonogenic activity in soft agar, sphere formation when grown under nonadherent conditions, and tumorigenicity in immune deficient mice. We have developed a novel DDX3 inhibitor, known as RK-33, that binds to the ATP binding domain and impairs helicase activity in a DNA unwinding assay. We found that RK-33 is selectively cytotoxic to sarcoma cell lines, compared with normal mesenchymal cells, and that sensitivity correlates with DDX3 expression. Importantly, Ewing sarcoma cells with a stem-like phenotype, characterized by high expression of aldehyde dehydrogenase, are as sensitive to RK-33 as the bulk population, despite being resistant to standard cytotoxic agents. Finally, we found that RK-33 suppresses the growth of human sarcomas in a murine xenograft model, and that sensitivity correlates with DDX3 expression. Thus, we have evidence that the RNA helicase DDX3 is an important mediator of sarcoma proliferation and tumorigenesis, and that inhibition of DDX3 with the small molecule RK-33 is a novel way to target chemotherapy-resistant sarcomas. Citation Format: David M. Loeb, Breelyn A. Wilky, Catherine Kim, Elizabeth Montgomery, Venu Raman. RNA helicase DDX3 – A novel therapeutic target in sarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A77.

Characterization of Localized Osteosarcoma of the Extremity in Children, Adolescents, and Young Adults From a Single Institution in South Texas

Background:Osteosarcoma is the most common bone malignancy in children, adolescents, and young adults. Most study cohorts have 10% to 15% Hispanic patients that encompass many different Hispanic backgrounds. This study characterizes the effect of mainly Mexican American ethnicity on the outcome of children, adolescents, and young adults with osteosarcoma.Methods:A retrospective analysis of demographics, tumor characteristics, response to treatment, and survival outcome of all localized osteosarcoma of the extremity patients below 30 years of age was performed. A Kaplan-Meier estimates with log-rank tests and Cox proportional hazard regression models were used.Results:Fifty patients (median age, 15; range, 2 to 28 y) with localized high-grade osteosarcoma of the extremity were diagnosed between January 2000 and December 2010. The cohort was 70% Mexican Americans. With a median follow-up of 39 months (range, 5 to 142 mo), patients had a 5-year overall survival and event-free survival of 65% and 48%, respectively. We observed a significantly decreased 5-year event-free survival in patients diagnosed before age 12 relative to patients diagnosed between ages 12 and 29 (11% vs. 57%, P<0.001). We also found that tumor necrosis was not predictive of outcome in our patients.Conclusions:The preadolescent patients of predominately Mexican American ethnicity had an increased rate of relapse when compared with previous studies. Tumor necrosis is not directly predictive of outcome in this population.

Outcome and prognostic factors in localized osteosarcoma with uniform chemotherapy protocol: A single-center experience of 234 cases.

10540 Background: Data on outcome of localized Osteosarcoma (OS) treated with uniform protocol is limited from Asia. Methods: This is a single institutional review of patients treated between Jan 2...

Is it important to maintain high-dose intensity chemotherapy in the treatment of adults with osteosarcoma?

Neoadjuvant chemotherapy for osteosarcoma is the standard of care, but there is still confusion regarding the best chemotherapy regimen and the optimal intensity. This retrospective study intends to evaluate whether there is a clear correlation between the chemotherapy dose intensity (DI) and the percentage of tumor necrosis, the risk of tumor recurrence after surgery and patient survival. The medical records of all adult patients with localized osteosarcoma that received treatment between the years of 1998 and 2009 at the Tel Aviv Sourasky Medical Center were analyzed. We used multiple logistic/linear regression models to test the effect of the neoadjuvant chemotherapy relative DI (RDI) on histological response, recurrence and time to recurrence. A Cox regression analysis was conducted for the effects of neoadjuvant chemotherapy RDI, histological response, tumor location, gender and age on patient survival. Thirty medical records were analyzed. Survival, histological response, recurrence and time to recurrence were not affected by the chemotherapy RDI. The 5-year overall survival of the patient's population was found to be 63% with a median survival of 9.4 years. Patients with a good histological response had a longer survival than those with a bad response (mean survival times 11.0 vs. 6.6 years, log-rank test, P = 0.046). High DI is not a prognostic factor in osteosarcoma and maintaining it should not be a prime priority. Histological response is a prognostic but possibly not a reliable predictive factor, and further research is needed in order to find other reliable factors.

Osteosarcoma with Adenocarcinoma of Lung in Li-Fraumeni Syndrome: A Case Report

typically occurs in adolescents and young adults. Patients with localized osteosarcoma at presentation have a 60~80% rate of long-term survival. But carriers of a p53 germline mutation, Li-Fraumeni syndrome (LFS), have a life-time risk of 90% of developing a malignancy. LFS, which was first described in 1969 by Li and Fraumeni, is a cancer predisposition syndrome associated with sarcoma and wide spectrum of tumors. Here, we report a p53 germline mutation in a 17-year-old girl LFS patient with osteosarcoma in proximal tibia and adenocarcinoma of lung.

Analysis of Outcomes in Extraskeletal Osteosarcoma

Extraskeletal osteosarcoma is a rare soft-tissue sarcoma about which little is known. The objectives of this study were to describe the clinical features and natural history of extraskeletal osteosarcoma and to investigate factors affecting outcomes. A retrospective review of a prospectively maintained database of patients diagnosed with soft-tissue sarcoma was conducted. Patients with pathologically confirmed extraskeletal osteosarcoma from 1982 to 2012 were identified and were included in the analysis. Medical records were reviewed for clinical features, treatment, and outcomes. Fifty-three patients were identified from the database: forty-two presented with localized disease, two presented with metastatic disease, and nine presented with recurrent (local and/or distant) disease. The median patient age at diagnosis was sixty-four years, with a median follow-up time of thirty-four months (range, one to 290 months) for survivors. Of the fifty-three patients who were identified, forty-one had lesions in the extremities, fifty-one had high-grade lesions, forty had lesions >5 cm, and forty-two had deep lesions. For patients presenting with localized disease, the median survival was 45.8 months with a three-year cumulative incidence of death due to disease of 39%. All patients with localized disease were managed with surgical resection of the primary tumor: nineteen with surgery only, ten with adjuvant radiation, five with adjuvant chemotherapy, and eight with both radiation and chemotherapy. Eighteen patients relapsed: two patients had local recurrences, ten patients had distant metastases, and six patients had local recurrences and distant metastases. In log-rank analysis, patients with superficial tumors and negative margins at resection had a higher three-year event-free survival. No significant association of disease-specific or event-free survival was found with the addition of radiation, chemotherapy, or both to surgery. For patients presenting with localized extraskeletal osteosarcoma, three-year event-free survival was higher for patients with superficial tumors and negative margins at resection. Radiation and chemotherapeutic treatment were not associated with a lower incidence of death due to disease or a longer event-free survival.

Muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) in the treatment of osteosarcoma.

Bacille Calmette-Guerin (BCG) has been used for decades as an immune stimulant to treat cancer. Early work by Fidler and Kleinerman identified muramyl dipeptide (MDP) as a critical component of the BCG cell wall which retained most of the immunostimulatory properties of the native BCG. Addition of a peptide to MDP resulted in muramyl tripeptide (MTP) which allowed incorporation into liposomal membranes. The resulting pharmaceutical, liposomal muramyl tripeptide phosphatidyl ethanolamine (L-MTP-PE or mifamurtide) showed activity in preclinical models of human cancers. Phase I studies documented the safety of the compound for human administration. These trials did not reach a maximally tolerated dose (MTD), and the dose chosen for phase II trials was a biologically optimized dose, not an MTD. Phase II studies showed decreased risk of further recurrence in patients who received mifamurtide after surgical ablation of metastatic osteosarcoma. A phase III prospective randomized trial demonstrated a statistically significant reduction in the risk of death from osteosarcoma when MTP was added to systemic chemotherapy for the treatment of localized osteosarcoma. The same trial allowed treatment of patients who presented with initially metastatic disease. While the overall and event-free survival was improved in patients with metastatic osteosarcoma who received L-MTP-PE, the sample size was small and the improvement did not achieve conventional statistical significance. From 2008 to 2012, patients with metastatic and recurrent osteosarcoma were given L-MTP-PE in an expanded access trial, and the results suggest a decreased risk of subsequent recurrence and death with the inclusion of L-MTP-PE in the treatment strategy for these high-risk patients.

Analysis of serum insulin growth factor‐1 concentrations in localized osteosarcoma: A children's oncology group study

To investigate the role of insulin-like growth factor-1 (IGF-1), in localized osteosarcoma, serum levels of IGF-1, IGFBP-2, and IGFBP-3 were measured in 224 similarly treated, newly diagnosed patients. We demonstrated that younger patients had lower concentrations of IGF-1 and IGFBP-3 compared to older (P < 0.001) along with lower IGFBP-3:IGF-1 and IGFBP-2:IGF-1 ratios (P < 0.001). IGFBP-2 did not correlate with age (P = 0.16), yet IGFBP-2:IGF-1 ratios were higher in the younger population (P < 0.001). These findings show that older patients have higher concentrations of free IGF-1. None of IGF-1, IGFBP-2, nor IGFBP-3 concentrations were associated with event-free nor overall survival.

Conditional Survival Is Greater Than Overall Survival at Diagnosis in Patients With Osteosarcoma and Ewing’s Sarcoma

Conditional survival is a measure of the risk of mortality given that a patient has survived a defined period of time. These estimates are clinically helpful, but have not been reported previously for osteosarcoma or Ewing's sarcoma. We determined the conditional survival of patients with osteosarcoma and Ewing's sarcoma given survival of 1 or more years. We used the Surveillance, Epidemiology, and End Results (SEER) Program database to investigate cases of osteosarcoma and Ewing's sarcoma in patients younger than 40 years from 1973 to 2009. The SEER Program is managed by the National Cancer Institute and provides survival data gathered from population-based cancer registries. We used an actuarial life table analysis to determine any cancer cause-specific 5-year survival estimates conditional on 1 to 5 years of survival after diagnosis. We performed a similar analysis to determine 20-year survival from the time of diagnosis. The estimated 5-year survival improved each year after diagnosis. For local/regional osteosarcoma, the 5-year survival improved from 74.8% at baseline to 91.4% at 5 years-meaning that if a patient with localized osteosarcoma lives for 5 years, the chance of living for another 5 years is 91.4%. Similarly, the 5-year survivals for local/regional Ewing's sarcoma improved from 72.9% at baseline to 92.5% at 5 years, for metastatic osteosarcoma 35.5% at baseline to 85.4% at 5 years, and for metastatic Ewing's sarcoma 31.7% at baseline to 83.6% at 5 years. The likelihood of 20-year cause-specific survival from the time of diagnosis in osteosarcoma and Ewing's sarcoma was almost 90% or greater after 10 years of survival, suggesting that while most patients will remain disease-free indefinitely, some experience cancer-related complications years after presumed eradication. The 5-year survival estimates of osteosarcoma and Ewing's sarcoma improve with each additional year of patient survival. Knowledge of a changing risk profile is useful in counseling patients with time. The presence of cause-specific mortality decades after treatment supports lifelong monitoring in this population. Level II, prognostic study. See the Instructions for Authors for a complete description of levels of evidence.

MAP plus maintenance pegylated interferon α-2b (MAPIfn) versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: First results of the EURAMOS-1 “good response” randomization.

LBA10504 Background: EURAMOS-1 (NCT00134030) is an international randomized controlled trial investigating treatment optimization in osteosarcoma on the basis of histologic response to preoperative chemotherapy (CT). In patients (pts) with “good response” (GR; &lt;10% viable tumor at surgery) to induction CT, efficacy of maintenance therapy with pegylated interferon α-2b (Ifn) was investigated. Methods: Pts ≤40yrs with resectable localized or primary metastatic high-grade extremity or axial osteosarcoma were eligible for registration at diagnosis. Eligibility for randomization included: [a] receipt of two cycles pre-op methotrexate, doxorubicin, cisplatin (MAP); [b] complete macroscopic resection of primary tumor; and [c] no disease progression. GR pts were randomized (1:1) after surgery to four cycles MAP +/-Ifn. Ifn (0.5-1.0 μg/kg/wk) was given after CT until 2yr post registration. Primary endpoint: event free survival (EFS); secondary: overall survival, toxicity. The trial design sought improved 3yr EFS from 70% to 80% (80% power, 2-sided alpha 5%). The final analysis was planned after 147 EFS events. Results: 2,260 pts were registered (Apr 05 to Jun 11) from 17 countries (326 sites) making it the largest trial in this rare cancer. GR was reported in 1,034 pts and 715 consented to randomization (358 MAP, 357 MAPIfn) with baseline characteristics balanced by arm: median age 14yr, 59% male, 79% localized disease. 271/357 (76%) pts started Ifn; main reason for not starting was treatment refusal, 66/86. By Feb 13 234/271 had stopped Ifn. Median duration of Ifn if started was 455 days; grade 3+ toxicity during Ifn reported by 81pts (30%). Median follow-up is 3.1yr with 174 EFS events reported: 93 MAP, 81 MAPIfn. Hazard ratio for EFS from adjusted Cox model was 0.82 (95% CI 0.61-1.11; p=0.201) in favor of MAPIfn. Conclusions: With current follow-up, EFS for MAPIfn is not statistically superior to MAP alone in pts with high-grade osteosarcoma and good response to pre-op MAP. One-quarter of pts did not start Ifn, which may have influenced this finding. Further follow-up for events and survival continues. Clinical trial information: NCT00134030.

Febrile Response Following Megaprosthesis Replacement for Primary Bone Sarcoma

The presence of early postoperative fever after megaprosthesis replacement surgery is a concern for orthopedic oncologists due to the possibility of infection. The aims of the current study were to determine the incidences and patterns of fever and factors associated with its development and to determine the clinical significance of fever after megaprosthesis replacement surgery. Seventy-one patients who had undergone megaprosthesis reconstruction for previously unoperated localized lower-extremity osteosarcoma were reviewed. No patient had evidence of infection preoperatively. Mean patient age was 23.72±16.84 years (range, 6.7-74 years), and average follow-up was 59.5 months (range, 4-240 months). Five postoperative surgical wound infections (4 deep, 1 superficial) occurred on postoperative days 5, 13, 14, 20, and 21. Fevers (body temperature of 38 °C or higher) were present in 62 patients (87.3%) at some point during the first 2 postoperative weeks. Peak body temperature was observed on postoperative day 1 in 62% of the febrile patients. Of the 62 febrile patients, 94% were relieved of fever by postoperative day 5. No significant association was observed between the presence of fever and surgical wound infection. Body temperature curves in patients with infection showed that several atypical patterns, such as multiple fever peaks and persistent fever, were accompanied by physical findings within the normalization period. Fever during the first 5 postoperative days is common after megaprosthesis replacement for bone sarcomas and seems to be a normal physiologic response to surgery. However, atypical fever patterns or additional physical findings require investigation.

Current Therapeutic Strategies and Novel Approaches in Osteosarcoma

Osteosarcoma is the most frequent malignant primary bone tumor and a main cause of cancer-related death in children and adolescents. Although long-term survival in localized osteosarcoma has improved to about 60% during the 1960s and 1970s, long-term survival in both localized and metastatic osteosarcoma has stagnated in the past several decades. Thus, current conventional therapy consists of multi-agent chemotherapy, surgery and radiation, which is not fully adequate for osteosarcoma treatment. Innovative drugs and approaches are needed to further improve outcome in osteosarcoma patients. This review describes the current management of osteosarcoma as well as potential new therapies.

Abstract 5034: Quantification of required surgical margins in a xenograft osteosarcoma model with and without single-agent chemotherapy.

Abstract In addition to systemic therapy, complete surgical excision is essential for successful treatment of osteosarcoma. Currently, the gold standard is to perform a "wide excision," however the definition of a wide excision is descriptive only. There is no current clear consensus on what constitutes an adequate "wide excision." The purpose of this project is to quantify an adequate "wide excision," defined by lack of local and/or distant recurrence using a xenograft murine model both with and without single agent chemotherapy. Patient-derived osteosarcoma tumor cells (OS17 and 187) were cultured and surgically implanted into the proximal metaphyseal tibia of female SCID mice. Once tumors were papable, amputations were performed under general anesthesia in either an intralesional, marginal, or wide manner. Histological sectioning was conducted in a standardized fashion to obtain measurements of bone and soft tissue margins. Mice were followed for six weeks, after which amputation stumps were evaluated for local recurrence while both the lungs and livers were assessed for metastatic dissemination. Thereafter, a second group of mice underwent implantation and amputation as previously described. They were thereafter treated with either cisplatin or doxorubicin over a course 4 weeks and followed for an additional 6 weeks to identify local and distant recurrence. In mice implanted with either OS17 or 187 and treated without chemotherapy, surgical bone margins lower than 100μm reliably resulted in local recurrence while margins greater than 700μm showed no recurrence. A variable recurrence rate was found between margins of 100μm and 700 μm. Similarly, soft-tissue margins below 50μm reliably resulted in local recurrence while margins greater then 600μm showed no recurrence. In mice implanted with OS17 and thereafter treated with chemotherapy, no recurrence was seen above bone or soft-tissue margins of 14μm while mice implanted with 187 showed no recurrence above bone margins of 25μm or soft tissue margins above 10μm. Metastatic disease did not overtly develop and may require a longer period of observation. In conclusion, single agent chemotherapy appears to reliably decrease the surgical margin required to obtain adequate local control in this xenograft model. Combination chemotherapy may prove to further decrease necessary margins, which ultimately may have ramifications on surgical morbidity and long-term reconstructive and functional outcome for patients with localized high-grade osteosarcoma. Citation Format: David S. Geller, Michael Singh, Wendong Zhang, Esperanza Vilanueva-Siles, Amy Park, Sajida Piperdi, Richard Gorlick. Quantification of required surgical margins in a xenograft osteosarcoma model with and without single-agent chemotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5034. doi:10.1158/1538-7445.AM2013-5034

Role of vascular endothelial growth factor as a tumour marker in osteosarcoma: a prospective study

A prospective study was undertaken to evaluate the diagnostic and prognostic significance of serum levels of vascular endothelial growth factor (VEGF) in patients with primary localised osteosarcoma. Serum VEGF levels were measured by an enzyme-linked immunosorbent assay (ELISA) in blood samples collected prechemotherapy, postchemotherapy, and postsurgery in 40 patients with histologically proven primary osteosarcoma. Comparison was made between serum VEGF level of healthy controls (n = 10) and prechemotherapy patient sera to evaluate its diagnostic potential. Serum VEGF levels of patients with and without metastasis were compared. Immunohistochemical staining was done to establish the correlation between serum and tissue VEGF expression. The Kaplan-Meier curve was used for survival analysis No significant relationship was observed between serum VEGF levels and age, gender, tumour size, local recurrence or histopathological subtypes of osteosarcoma. We observed significantly raised mean serum VEGF in patient sera compared with healthy controls (p = 0.001). Significant fall in mean serum VEGF level was observed following chemotherapy (p = 0.001). Patients who developed metastases had significantly higher serum VEGF levels compared with the nonmetastatic group (P = 0.001). Serum VEGF levels correlated well with VEGF expression in tissues. Serum VEGF levels might prove to be of diagnostic, predictive and prognostic value in patients with primary osteosarcoma, although further studies with larger sample size and longer follow-up is needed to support the hypothesis.

Targeting hedgehog‐GLI‐2 pathway in osteosarcoma

Osteosarcoma is the most common primary malignant tumor of bone. Patients with localized osteosarcoma are routinely treated with chemotherapy and surgery. However, many of these patients eventually relapse after these treatments. In such cases, there are limited treatment options for these patients and most will eventually die with metastatic disease. Therefore, it is imperative to identify better therapeutic strategies. Hedgehog-GLI is responsible for the development of vertebrate embryonic and tumorigenesis. Specifically, the transcription factor, GLI-2, plays a key role in development of normal prostate. Aberrant activation of GLI-2 is correlated with various malignancies. We observe that GLI-2 is highly expressed in osteosarcoma cell lines, and this correlates with poor clinical outcomes in patients. Knockdown of GLI-2 by siRNA decreases osteosarcoma cell proliferation and viability, which eventually induces cell death as revealed in both in 2D and 3D cultures. In addition, we notice that administration of GLI-2 siRNA can increase the sensitivity of osteosarcoma cells to chemotherapeutic drugs. These findings suggest GLI-2 is required for osteosarcoma cell proliferation and survival. GLI-2 may be exploited as a therapeutic target for the treatment of osteosarcoma patients.

Meta-analysis of limb salvage versus amputation for treating high-grade and localized osteosarcoma in patients with pathological fracture

The goal of this study was to determine outcomes related to limb salvage vs. amputation for treating high-grade and localized osteosarcoma in patients with pathological fractures. Literature search was conducted using Medline, Embase and the Cochrane Database. Two reviewers independently assessed all eligible publications. The primary outcome measurement was pooled odds ratio (OR) and 95% confidence interval (CI) for the risk of local recurrence, 5-year overall survival rate and metastatic occurrence calculated through the fixed-effects method. Seven eligible studies were identified, which included a total of 284 patients. The risk for local recurrence and 5-year overall survival rate did not differ significantly (P>0.05) between the limb salvage group and amputation group, with an OR of 1.48 (95% CI, 0.67–3.30) and 1.85 (95% CI, 0.86–3.98), respectively. The risk for metastatic occurrence differed significantly (P<0.05), with an OR of 0.30 (95% CI, 0.10–0.91). The occurrence of a pathological fracture is not regarded as an absolute contraindication to limb salvage in patients with high-grade and localized osteosarcoma. Limb salvage as an alternative for treating high-grade and localized osteosarcoma in patients with pathological fracture does not greatly increase the risk for local recurrence or 5-year overall survival rate compared to amputation and has a lower risk for metastatic occurrence.

Effects of Neoadjuvant Chemotherapy on Image-Directed Planning of Surgical Resection for Distal Femoral Osteosarcoma

Standard therapy for localized osteosarcoma includes neoadjuvant chemotherapy preceding local control surgery, followed by adjuvant chemotherapy. When limb-salvage procedures were being developed, preoperative chemotherapy allowed a delay in definitive surgery to permit fabrication of custom endoprosthetic reconstruction implants. One rationale for its continuation as the care standard has been the perception that it renders surgery easier and safer. Our objective was to compare surgical procedures planned on the basis of magnetic resonance images (MRIs) of distal femoral osteosarcomas acquired before neoadjuvant chemotherapy with surgical procedures planned on the basis of MRIs acquired after neoadjuvant chemotherapy as a measure of the surgically critical anatomic effects of the chemotherapy. Twenty-four consecutive patients with distal femoral osteosarcoma had available digital MRIs preceding and following neoadjuvant chemotherapy. Thorough questionnaires were used to catalogue surgically critical anatomic details of MRI-directed surgical planning. Four faculty musculoskeletal oncologic surgeons and two musculoskeletal radiologists evaluated the blinded and randomly ordered MRIs. Interrater and intrarater reliabilities were calculated with intraclass correlation coefficients. The Student t test and chi-square test were used to compare pre-chemotherapy and post-chemotherapy continuous and categorical variables on the questionnaire. Mixed-effect regression models were employed to compare surgical procedures planned on the basis of pre-chemotherapy MRIs and with those planned on the basis of post-chemotherapy MRIs. The blinded reviews generated strong intraclass correlation coefficients for both interrater (0.772) and mean intrarater (0.778) reliability. The MRI-planned resections for the majority of tumors changed meaningfully after chemotherapy, but in inconsistent directions. On the basis of mixed-effect regression modeling, it appeared that more amputations were planned on the basis of post-chemotherapy MRIs. No other parameters differed in a significant and clinically meaningful fashion. Surgeons demonstrated their expectation that neoadjuvant chemotherapy would improve resectability by planning more radical surgical procedures on the basis of scans that they predicted had been obtained pre-chemotherapy. Surgeons can reliably record the anatomic details of a planned resection of an osteosarcoma. Such methods may be useful in future multi-institutional clinical trials or registries. The common belief that neoadjuvant chemotherapy increases the resectability of extremity osteosarcomas remains anecdotally based. Rigorous assessment of this phenomenon in larger cohorts and at other anatomic sites as well as re-evaluation of other arguments for neoadjuvant chemotherapy should be considered.

Pathologic fracture does not influence local recurrence and survival in high‐grade extremity osteosarcoma with adequate surgical margins

The purpose of this study was to estimate the risk factors having relationships with pathologic fracture of osteosarcoma of extremities and to evaluate the role of limb salvage surgery in this group of patients. We retrospectively analyzed 28 consecutive cases of pathologic fracture of primary high-grade localized osteosarcoma of extremities between June 1, 2001 and June 30, 2009. All patients underwent limb salvage surgery and neo-adjuvant chemotherapy. They had a median age of 14 years (range, 6-30 years). The average follow-up time was 40.7 months (range, 9-108 months). Clinicopathological factors were analyzed in relation to pathologic fracture. Their recurrence and survival rates were compared to those in cohort of 171 osteosarcoma patients without pathologic fracture who underwent limb salvage surgery during the same period at the same institution. Less than 15 years, telangiectatic histological subtype, tumor located at the proximal humerus, and radiographical manifested as osteolytic features were risk factors in relation to pathologic fracture. The overall 3- and 5-year survival rates were 50.5% and 45.4%, respectively, in the fracture group, and were not significantly different from those in the control group (71.0% and 61.9%, respectively). Of all 28 fracture patients, 4 experienced local recurrences (14.2%) and 14 developed distant metastasis (50%), which were not significantly different from the rates in the control group (8.8% and 37.4%, respectively). Limb salvage surgery with adequate margins combined with neo-adjuvant chemotherapy for pathologic fracture of osteosarcoma did not seem to significantly increase the risk of local recurrence or distal metastasis.

Survival from high-grade localised extremity osteosarcoma: combined results and prognostic factors from three European Osteosarcoma Intergroup randomised controlled trials

Neoadjuvant chemotherapy improves outcome in osteosarcoma. Determination of optimum regimens for survival, toxicity and prognostic factors requires randomised controlled trials to be conducted. Between 1983 and 2002, the European Osteosarcoma Intergroup recruited 1067 patients with localised extremity osteosarcoma to three randomised controlled trials. Standard treatment in each was doxorubicin 75 mg/m(2) and cisplatin 100 mg/m(2). Comparators were addition of methotrexate (BO02/80831), a multidrug regimen (BO03/80861) and a dose-intense schedule (BO06/80931). Standard survival analysis methods were used to identify prognostic factors, temporal and other influences on outcome. Five- and 10-year survival were 56% (95% confidence interval 53% to 59%) and 52%, respectively (49% to 55%), with no difference between trials or treatment arms. Median follow-up was 9.4 years. Age range was 3-40 years (median 15). Limb salvage was achieved in 69%. Five hundred and thirty-three patients received the standard arm, 79% completing treatment. Good histological response to preoperative chemotherapy, distal tumour location (all sites other than proximal humerus/femur) and female gender were associated with improved survival. Localised osteosarcoma will be cured in 50% of patients with cisplatin and doxorubicin. Large randomised trials can be conducted in this rare cancer. Failure to improve survival over 20 years argues for concerted collaborative international efforts to identify and rapidly test new treatments.