Localized High-grade Osteosarcoma Research Articles

Long term survival in adult osteosarcoma patients treated with a two-drug regimen: Final results of the OSAD93 phase II study of the FSG-GETO

RationaleWe report a phase II trial (OSAD93) testing CDDP with ifosfamide (IFO), without doxorubicin in neoadjuvant phase, in adult osteosarcoma with a 25 years follow-up. Patients and methodsThis is a multicentric phase II study of neoadjuvant chemotherapy with IFO and CDDP in localized high-grade osteosarcoma of patients. Patients received 4 pre-operative courses of IFO 9 g/m2 and CDDP 100 mg/m2 on day 4 (SHOC regimen), followed by local treatment. Doxorubicin was added post-operatively (HOCA regimen) in patients with > 10 % residual tumor cells. A Good Histological Response (GHR), ie ≤ 10 % residual tumor cells in > 30 % of patients, was the primary objective. Disease-free survival (DFS), overall survival (OS) and toxicity were secondary objectives. ResultsFrom Jan 1994 to Jun 1998, 60 patients were included. Median age was 27 (range: 16–63). Primary tumor sites were limbs (76 %), trunk, head or neck (24 %). After neoadjuvant SHOC, grade 3–4 and febrile neutropenia, thrombopenia, and re-hospitalization occurred in 58 %, 17 %, 17 % and 22 % of SHOC courses and in 76 %, 28 %, 47 %, 47 % of HOCA courses, respectively. GHR was obtained in 16/60 (27.5 %) patients. With a median follow-up of 322 months, the DFS and OS were 51.8 % and 64.4 % at 5 years. At 10 years, DFS and OS were 49.9 % and 64.4 %. At 25 years, DFS and OS were 47.8 % and 55.9 %. No long-term cardiac toxicity was observed. Three patients developed a second malignancy (one fatal) after 300 months. ConclusionThough the primary endpoint of OSAD93 was not met, this pre-operative doxorubicin-free regimen led to excellent long-term survival with limited toxicity in localized osteosarcoma.

Prolonged 14-day continuous infusion of high-dose ifosfamide (14IFO) for relapsed/refractory high-grade osteosarcoma (R/R HOS): A retrospective multicenter cohort study.

11534 Background: The prognosis of patients (pts) with relapsed/refractory (R/R) High-Grade Osteosarcoma (HOS) remains dismal without an agreement on systemic therapy. The use of 14IFO with an external pump in outpatient setting (1g/sqm/day x 14 days every 21) in R/R HOS pts is limited. This is the first retrospective cohort study focused on 14IFO activity and toxicity in this setting (NCT04651569). Methods: Five Centers of the Italian Association of Pediatric Onco-Hematology and Italian Sarcoma Group participated to the study. Primary aim is to investigate 14IFO activity in pts with R/R HOS younger than 40 years. Secondary aim is to evaluate toxicity, according to CTCAE v.5, and clinical benefit. Progression Free Survival (PFS) and Overall Survival (OS) analysis are performed using the Kaplan Meier method with 95% confidence interval (CI). Results: Between 2012 and 2021, 26 R/R HOS pts were treated with 14IFO (median follow-up: 17,5 months, range: 4,6 – 83 months). Median age is 19 years at the beginning of 14IFO; eleven pts (42%) are ≤ 18 years. Three pts (12%) have a localized HOS, twelve pts (46%) have pulmonary disease only and eleven pts (42%) have a pluri-metastatic HOS. Eleven pts (42%) have a relapsed HOS with a median disease-free interval (DFI) of 13 months before 14IFO, the remaining (58%) have a refractory disease to two or more treatments. Overall, thirteen pts (50%) receive 14IFO as second line therapy and fifteen pts (57%) are pre-treated with Ifosfamide in first line. Disease Control Rate is 57,5% (5 Partial Response + 10 Stable Disease). Seven pts (27%) receive a local treatment after 14IFO (5 surgery, 1 Radiotherapy (Rt), 1 Carbon Ion Rt). The median PFS is 4,1 months (95% CI 2.13, 7.37). 6-month and 1-year PFS are 38% (95% CI 24-63) and 8% (95% CI 2-29), respectively. The median OS is 13.7 months (95% CI 10.6 – 23.7). 1-year and 2-year OS are 51% (95% CI 35-75) and 22% (95% CI 9.5-49), respectively. Relapsed pts have both longer median PFS and OS compared to pts with a refractory disease [PFS: 7.33 months vs 2.13 months (p = 0.02); OS: 19.4 months vs 10.7 months (p = 0.1)]. Sixteen pts (61%) receive at least 4 cycles and an amount of 101 cycles are evaluated for toxicity. Grade 4 hematological toxicity is reported in 15 cycles (14,8%) as follows: i) white-blood cell decrease in 6 cycles (6%); ii) neutropenia in 7 cycles (7%); iii) thrombocytopenia in 2 cycles (2%). One patient has one episode of febrile neutropenia. No grade 3-4 non hematological toxicities are reported. Conclusions: This trial shows a non inferiority activity of 14IFO compared to other treatments in this setting, despite the small number of pts. Therefore, 14IFO should be considered as a treatment option in R/R HOS, especially for its well tolerated toxicity profile and the home-administration that improve patient’s quality of life and it could significantly reduce cancer care cost. Clinical trial information: NCT04651569 .

First-in-Maintenance Therapy for Localized High-Grade Osteosarcoma: An Open-Label Phase I/II Trial of the Anti-PD-L1 Antibody ZKAB001.

We investigated the safety and preliminary efficacy of anti-PD-L1 antibody (ZKAB001) as maintenance therapy for localized patients with high-grade osteosarcoma to reduce the risk of recurrence and metastasis. This open-label Phase I/II study was divided into dose-escalation Phase I and expansion Phase II. Phase I used a 3+3 design with ZKAB001 at three escalating doses ranging: 5, 10, 15 mg/kg every 2 weeks in 9 patients with localized high-grade osteosarcoma and Phase II tested 10 mg/kg in 12 patients for up to 24 cycles. Primary endpoints were safety and tolerability assessed using CTCAE4.0.3. Between October 2018 and 2019, 21 eligible patients were enrolled and accepted ZKAB001 treatment: 9 in the dose-escalation phase, and 12 in expansion phase. Six patients with disease progression withdrew from this study and follow-up is ongoing. The MTD was not defined in Phase I. All doses had a manageable safety profile. The recommended dose in Phase II was set at 10 mg/kg. Most frequent immune-related adverse events were thyroiditis (76.2%) and dermatitis (42.9%). Only 1 (4.8%) of 21 patients had a Grade 3 skin rash. The median 3-year event-free survival (EFS) and overall survival (OS) were not established; however, 24-month EFS was 71.4% (95% confidence interval, 47.2-86.0) and 2-year OS was 100%. Preliminary efficacy data showed EFS benefits in patients with PD-L1 positive or an MSI-H sub-population. Switching to maintenance using ZKAB001 showed an acceptable safety profile and provided preliminary evidence of clinical activity in localized patients with osteosarcoma.

The prognostic significance of lymphovascular tumor invasion in localized high-grade osteosarcoma: Outcomes of a single institution over ten years.

e22013 Background: Lymphovascular tumor invasion (LVI) has shown evidence of an association with worse survival in high-grade osteosarcoma. The purpose of this investigation was to prognosticate LVI as a predictor of survival in these patients. Methods: This study was a retrospective review of high-grade, localized osteosarcoma patients diagnosed over a consecutive ten-year period. Cox proportional hazards regression was used to assess the prognostic significance of LVI on overall survival (OS). Results: A total of 42 cases met inclusion criteria with a median follow-up of 64 months (range, 6-158 months). LVI was present in 21.4% (n = 9) cases. The five and ten-year probabilities of OS in LVI (+) were 40% and 20%, respectively, compared to LVI (-) with five and ten-year estimates of 93% and 81%, respectively (p < 0.001). After controlling for confounding variables, advanced age at diagnosis (HR, 1.134; 95% CI, 1-1.2; p = 0.01) and LVI (HR, 21.768; 95% CI, 3-135; p = 0.001) were found to be significantly negative predictors of OS. Using a competing risk analysis and Gray's test of equality, LVI (+) and LVI (-) were not statistically different with respect to cumulative incidence of recurrence (p = 0.8118), though were highly significant for cumulative incidence of mortality over time (p = 0.0029). Conclusions: The presence of LVI in the setting of high-grade, localized osteosarcoma is associated with greater rates of mortality and tumor recurrence and portends a dismal prognosis.

Clinical significance of indeterminate pulmonary nodules on the survival of 364 patients with nonmetastatic, high‐grade, localized osteosarcoma: A 12‐year retrospective cohort study

We investigated the clinical significance of indeterminate pulmonary nodules (IPNs) in patients diagnosed with nonmetastatic, high-grade localized osteosarcoma. We retrospectively analyzed the clinical data of 364 patients with nonmetastatic, high-grade localized osteosarcoma. Based on pulmonary computed tomography findings at presentation, the patients were categorized into the no-nodules and the IPNs group and were further categorized into subgroups based on age (<18and ≥18 years). We performed an intergroup comparison of event-free survival (EFS) and overall survival (OS). At presentation, 276 (75.8%) patients showed no nodules, and 88 (24.2%) patients showed IPNs. The EFS and OS were similar between adults with IPNs (n = 54 [30.5%]) and without nodules (n = 123 [69.5%]) (p = .200 and p = .609, respectively). No significant intergroup difference in OS was observed in pediatric patients (p = .093). However, pediatric patients with IPNs (n = 34 [18.2%]) had poorer EFS than those without nodules (n = 153 [81.8%]) (p = .016). Multivariate analyses confirmed that IPNs were independently associated with poorer EFS in pediatric patients (hazard ratio 1.788, 95% confidence interval 1.092-2.926, p = .021). This study showed that IPNs at presentation did not affect the survival of adults with nonmetastatic, high-grade localized osteosarcoma but were associated with poorer EFS in pediatric patients.

Impact of chemotherapy-induced necrosis on event-free and overall survival after preoperative MAP chemotherapy in patients with primary high-grade localized osteosarcoma.

To assess the correlation between the histological response to preoperative chemotherapy and event-free survival (EFS) or overall survival (OS) in patients with high-grade localized osteosarcoma. Out of 625 patients aged ≤ 40 years treated for primary high-grade osteosarcoma between 1997 and 2016, 232 patients without clinically detectable metastases at the time of diagnosis and treated with preoperative high-dose methotrexate, adriamycin and cisplatin (MAP) chemotherapy and surgery were included. Associations of chemotherapy-induced necrosis in the resected specimen and EFS or OS were assessed using Cox model and the Pearson's correlation coefficients (r). Time-dependent receiver operating characteristic analysis was applied to determine the optimal cut-off value of chemotherapy-induced necrosis for EFS and OS. OS was 74% (95% confidence interval (CI) 67 to 79) at five years. Median chemotherapy-induced necrosis was 85% (interquartile range (IQR) 50% to 97%). In multivariate Cox model, chemotherapy-induced necrosis was significantly associated with EFS and OS (hazard ratio (HR) = 0.99 (95% CI 0.98 to 0.99); p < 0.001 and HR = 0.98 (95% CI 0.97 to 0.99); p < 0.001, respectively). Positive correlation was observed between chemotherapy-induced necrosis and five-year EFS and five-year OS (r = 0.91; p < 0.001, and r = 0.85; p < 0.001, respectively). The optimal cut-off value of chemotherapy-induced necrosis for five-year EFS and five-year OS was 85% and 72%, respectively. Chemotherapy-induced necrosis in the resected specimen showed positive correlation with EFS and OS in patients with high-grade localized osteosarcoma after MAP chemotherapy. In our analysis, optimal cut-off values of MAP chemotherapy-induced necrosis in EFS and OS were lower than the commonly used 90%, suggesting the need for re-evaluation of the optimal cut-off value through larger, international collaborative research. Cite this article: Bone Joint J 2020;102-B(6):795-803.

Whole‐body magnetic resonance imaging as surveillance for subsequent malignancies in preadolescent, adolescent, and young adult survivors of germline retinoblastoma: An update

Germline retinoblastoma (Rb) survivors are at lifelong risk for developing subsequent malignancies (SMNs). Optimal surveillance modalities are needed to detect SMN at an early stage in this high-risk cohort. We investigated the use of rapid whole-body magnetic resonance imaging (WB-MRI) as a noninvasive screening modality in this cohort. WB-MRI was performed in asymptomatic preadolescent, adolescent, or young adult survivors of germline Rb from February 1, 2008 to December 31, 2018 at a tertiary cancer center. We calculated sensitivity and specificity of WB-MRI and rate of false-positive findings requiring additional evaluation. Overall, 110 WB-MRI were performed in 47 germline Rb survivors (51% female; median age at initial WB-MRI: 15.5years [range 8-25.3]). Patients received 1-10 annual WB-MRI examinations (median: two). Thirteen patients had an abnormal WB-MRI; three findings were deemed to be likely benign and were not evaluated further. Ten patients required dedicated imaging and three required biopsy; two patients were diagnosed with localized high-grade osteosarcoma, while the other eight had benign findings. One patient was diagnosed with secondary osteosarcoma 3months after normal WB-MRI. In total, there were 96 true negatives, 11 false positives, two true positives, and one false negative. The sensitivity of WB-MRI in this cohort was 66.7% (95% confidence interval [CI], 14.2-96.0) and the specificity was 89.7% (95% CI, 83.6-93.7). Based on our 10-year experience, surveillance WB-MRI appears to have limited utility as a surveillance modality for SMN in germline Rb survivors. Alternate screening modalities should be investigated.

Is Microscopic Vascular Invasion in Tumor Specimens Associated with Worse Prognosis in Patients with High-grade Localized Osteosarcoma?

Other than metastases at diagnosis and histological response to preoperative chemotherapy, there are few reliable predictors of survival in patients with osteosarcoma. Microscopic vascular invasion (MVI) has been identified in the resection specimens of patients with osteosarcoma. However, it is unknown whether the MVI in resected specimens is associated with worse overall survival and higher cumulative incidence of local recurrence or metastasis in a large cohort of patients younger than 40 years with high-grade localized osteosarcoma. (1) Is MVI associated with worse overall survival and higher cumulative incidence of events (local recurrence or metastasis) in patients younger than 40 years with high-grade localized osteosarcoma? (2) What clinical characteristics are associated with MVI in patients with high-grade localized osteosarcoma? A total of 625 patients younger than 40 years with primary high-grade osteosarcoma between 1997 and 2016 were identified in our oncology database. We included patients younger than 40 years with primary high-grade osteosarcoma who underwent definitive surgery and preoperative and postoperative chemotherapy. The minimum follow-up period was 2 years after treatment. Patients with the following were excluded: metastasis at initial presentation (21%, n = 133), progression with preoperative chemotherapy precluding definitive surgery (6%, n = 38), surgery at another unit (2%, n = 13), lost to follow-up before 2 years but not known to have died (3%, n = 18), and death related to complications of preoperative chemotherapy (1%, n = 4). A retrospective pathologic and record review was conducted in the remaining 419 patients. The median follow-up period was 5 years (interquartile range [IQR] 3 to 9 years). The overall survival of the entire group (n = 419) was 67% [95% CI 63 to 72] at 5 years. Of the 419 patients, 10% (41) had MVI in their resection specimens. The Kaplan-Meier method was used to estimate overall survival. The cumulative incidence of events captured the first event of either metastasis or local recurrence. This analysis was completed with a competing risk framework: deaths without evidence of local recurrence or metastasis were regarded as a competing event. Clinical and histological variables (sex, age, tumor site, tumor largest dimension, surgical margin, chemotherapy-induced necrosis, type of surgery, histologic type of tumor, type of chemotherapy regimen, pathologic fracture, and MVI) were evaluated using the log-rank test or Gray test in the univariate analyses and Cox proportional hazard model or Fine and Gray model in the multivariate analyses. After adjusting for other factors, multivariate analyses showed that the presence of MVI in resection specimens was associated with worse overall survival and higher cumulative incidence of event (hazard ratio 1.88 [95% CI 1.22 to 2.89]; p = 0.004 and HR 2.33 [95% CI 1.56 to 3.49]; p < 0.001, respectively). A subgroup analysis demonstrated that the relationship between MVI and survival applied only to patients with a poor response to chemotherapy (less than 90% necrosis; overall survival at 5 years, MVI [+] = 24% [95% CI 11 to 39] versus MVI [-] = 60% [95% CI 52 to 66]; p < 0.001 and cumulative incidence of events at 5 years, MVI [+] = 86% [95% CI 68 to 94] versus MVI [-] = 54% [95% CI 46 to 61]; p < 0.001). The MVI (+) group had a higher proportion of patients with a poor response to chemotherapy (85% [35 of 41] versus 53% [201 of 378]; p < 0.001), involved margins (15% [6 of 41] versus 5% [18 of 378]; p = 0.021), and limb-ablative surgery (37% [15 of 41] versus 21% [79 of 378]; p = 0.022) than the MVI (-) group did. MVI is associated with lower overall survival and higher cumulative incidence of local recurrence or metastasis, especially in patients with a poor histologic response to preoperative chemotherapy. Future studies in patients treated for osteosarcoma should consider this observation when planning new trials. Level III, therapeutic study.

Limb salvage for treating pathological fracture at diagnosis in children and adolescents with localized high grade osteosarcoma

Limb salvage for treating pathological fracture at diagnosis in children and adolescents with localized high grade osteosarcoma

P16 expression as a prognostic and predictive marker in high-grade localized osteosarcoma of the extremities: an analysis of 357 cases

The potential prognostic and predictive value of p16 in high-grade localized osteosarcoma of the extremities has been recently investigated in small series of cases, and the results from different studies were somewhat controversial. A retrospective immunohistochemical analysis of p16 expression was performed in a series of 357 patients, included in different neoadjuvant chemotherapy protocols from 1986 to 2010, to explore its potential prognostic and predictive value. Immunohistochemistry was performed with a commercially available p16 monoclonal mouse antibody. Follow-up data were available in all cases with a median of 120 months. Positivity for p16 was detected in 70.6% (252/357) of cases. The p16 expression did not differ by age, sex, tumor site, histologic subtype, tumor volume, surgical margin, serum alkaline phosphatase levels, and lactate dehydrogenase levels. In the different chemotherapy protocols included, the incidence of p16 expression was similar. The absence of p16 expression was significantly associated with an adverse disease-free survival (P=.04) and overall survival (P=.05) when compared with the presence of p16 expression. At the multivariate Cox regression analysis, p16 expression lost its prognostic significance. Multivariate logistic regression analysis showed that as p16 expression was the only statistically significant parameter to predict the pathological response to neoadjuvant chemotherapy treatment with an odds ratio of 3.025 (P<.001) for "good" chemotherapy response. Our data indicate that the negative expression of p16 is associated with a reduced rate of good response to primary chemotherapy and to a worse probability of survival, although it was not confirmed as an independent prognostic biomarker after multivariate analysis.

Limb salvage for treating pathological fracture at diagnosis in children and adolescents with localized high grade osteosarcoma

Limb salvage for treating pathological fracture at diagnosis in children and adolescents with localized high grade osteosarcoma

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.

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.

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

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.

Influence of methotrexate dose intensity on outcome of patients with high grade osteogenic osteosarcoma: Analysis of the literature

BACKGROUND The authors surveyed the published clinical trial literature on the subject of localized high grade osteosarcoma in order to develop new hypotheses dealing with drug-dose combinations in the treatment of this disease. METHODS A computerized literature search was conducted to identify all available published reports of the clinical trials using high dose methotrexate (MTX) in multidrug protocols treating osteosarcoma. Thirty studies, including discussion of high dose MTX (> 7.5 g/m2 per course) and precise quantification of 5-year disease free survival (DFS), fulfilled the inclusion criteria of this dose-intensity analysis. The total number of patients treated in eligible studies was 1909. Correlation among the planned total doses, the dose intensities of the drugs, and the 5-year DFS were tested by regression analysis. RESULTS No correlation of any other drug dose or dose intensity with DFS appeared as important as the MTX finding. In multivariate analysis, the dose intensity of MTX was found to be the one most correlated with DFS. This correlation appeared to hold for adjuvant and neoadjuvant trials. CONCLUSIONS The dose intensity of MTX seems to be a major factor in predicting the outcome of patients with localized high grade osteosarcoma. Cancer 1996;78:2127-35.

Influence of methotrexate dose intensity on outcome of patients with high grade osteogenic osteosarcoma: Analysis of the literature

The authors surveyed the published clinical trial literature on the subject of localized high grade osteosarcoma in order to develop new hypotheses dealing with drug-dose combinations in the treatment of this disease. A computerized literature search was conducted to identify all available published reports of the clinical trials using high dose methotrexate (MTX) in multidrug protocols treating osteosarcoma. Thirty studies, including discussion of high dose MTX (> 7.5 g/m2 per course) and precise quantification of 5-year disease free survival (DFS), fulfilled the inclusion criteria of this dose-intensity analysis. The total number of patients treated in eligible studies was 1909. Correlation among the planned total doses, the dose intensities of the drugs, and the 5-year DFS were tested by regression analysis. No correlation of any other drug dose or dose intensity with DFS appeared as important as the MTX finding. In multivariate analysis, the dose intensity of MTX was found to be the one most correlated with DFS. This correlation appeared to hold for adjuvant and neoadjuvant trials. The dose intensity of MTX seems to be a major factor in predicting the outcome of patients with localized high grade osteosarcoma.