To determine whether the administration of histology-tailored neoadjuvant chemotherapy (HT) was superior to the administration of standard anthracycline plus ifosfamide neoadjuvant chemotherapy (A+I) ...in high-risk soft tissue sarcoma (STS) of an extremity or the trunk wall.
This was a randomized, open-label, phase III trial. Patients had localized high-risk STS (grade 3; size, ≥ 5 cm) of an extremity or trunk wall, belonging to one of the following five histologic subtypes: high-grade myxoid liposarcoma (HG-MLPS); leiomyosarcoma (LMS), synovial sarcoma (SS), malignant peripheral nerve sheath tumor (MPNST), and undifferentiated pleomorphic sarcoma (UPS). Patients were randomly assigned in a 1:1 ratio to receive three cycles of A+I or HT. The HT regimens were as follows: trabectedin in HG-MLPS; gemcitabine plus dacarbazine in LMS; high-dose prolonged-infusion ifosfamide in SS; etoposide plus ifosfamide in MPNST; and gemcitabine plus docetaxel in UPS. Primary and secondary end points were disease-free survival (DFS) and overall survival (OS), estimated using the Kaplan-Meier method and compared using Cox models adjusted for treatment and stratification factors. The study is registered at ClinicalTrials.gov (identifier NCT01710176).
Between May 2011 and May 2016, 287 patients (UPS: n = 97 33.8%; HG-MLPS: n = 65 22.6%; SS: n = 70 24.4%; MPNST: n = 27 9.4%; and LMS: n = 28 9.8%) were randomly assigned to either A+I or HT. At the final analysis, with a median follow-up of 52 months, the projected DFS and OS probabilities were 0.55 and 0.47 (log-rank
= .323) and 0.76 and 0.66 (log-rank
= .018) at 60 months in the A+I arm and HT arm, respectively. No treatment-related deaths were observed.
In a population of patients with localized high-risk STS, HT was not associated with a better DFS or OS, suggesting that A+I should remain the regimen to choose whenever neoadjuvant chemotherapy is used in patients with high-risk STS.
Background
Reference centers (RCs) are a key point for improving the survival of patients with soft‐tissue sarcomas (STS). The aim of this study was to evaluate selected items in the management of ...patients with STS, comparing results between RC and local hospitals (LHs).
Materials and Methods
Diagnostic and therapeutic data from patients diagnosed between January 2004 and December 2011 were collected. Correlation with outcome was performed.
Results
A total of 622 sarcomas were analyzed, with a median follow‐up of 40 months. Imaging of primary tumor preoperatively (yes vs. no) correlated with a higher probability of free surgical margins (77.4% versus 53.7%; p = .006). The provenance of the biopsy (RC vs. LH) significantly affected relapse‐free survival (RFS; 3‐year RFS 66% vs. 46%, respectively; p = .019). Likewise, 3‐year RFS was significantly worse in cases with infiltrated (55.6%) or unknown (43.4%) microscopic surgical margins compared with free margins (63.6%; p < .001). Patients managed by RCs had a better 3‐year overall survival compared with those managed by LHs (82% vs. 70.4%, respectively; p = .003). Perioperative chemotherapy in high‐risk STS, more frequently administered in RCs than in LHs, resulted in significantly better 3‐year RFS (66% vs. 44%; p = .011). In addition, patients with stage IV disease treated in RCs survived significantly longer compared with those in LHs (30.4 months vs. 18.5 months; p = .036).
Conclusion
Our series indicate that selected quality‐of‐care items were accomplished better by RCs over LHs, all with significant prognostic value in patients with STS. Early referral to an RC should be mandatory if the aim is to improve the survival of patients with STS.
Implications for Practice
This prospective study in patients diagnosed with soft‐tissue sarcoma shows the prognostic impact of reference centers in the management of these patients. The magnitude of this impact encompasses all steps of the process, from the initial management (performing diagnostic biopsy) to the advanced disease setting. This is the first prospective evidence showing improvement in outcomes of patients with metastatic disease when they are managed in centers with expertise. This study provides extra data supporting referral of patients with sarcoma to reference centers.
Management of soft‐tissue sarcoma is challenging. This article reports on sarcoma clinical management in cancer centers in Spain, based on information from a prospective registry launched by the Spanish Group for Research in Sarcoma.
Background
The value of neoadjuvant chemotherapy in soft tissue sarcoma (STS) is not completely understood. This study investigated the benefit of neoadjuvant chemotherapy according to prognostic ...stratification based on the Sarculator nomogram for STS.
Methods
This study analyzed data from ISG‐STS 1001, a randomized study that tested 3 cycles of neoadjuvant anthracycline plus ifosfamide (AI) or histology‐tailored (HT) chemotherapy in adult patients with STS. The 10‐year predicted overall survival (pr‐OS) was estimated with the Sarculator and was stratified into higher (10‐year pr‐OS < 60%) and lower risk subgroups (10‐year pr‐OS ≥ 60%).
Results
The median pr‐OS was 0.63 (interquartile range IQR, 0.51‐0.72) for the entire study population, 0.62 (IQR, 0.51‐0.70) for the AI arm, and 0.64 (IQR, 0.51‐0.73) for the HT arm. Three‐ and 5‐year overall survival (OS) were 0.86 (95% confidence interval CI, 0.82‐0.93) and 0.81 (95% CI, 0.71‐0.86) in lower risk patients and 0.69 (95% CI, 0.70‐0.85) and 0.59 (95% CI, 0.51‐0.72) in the higher risk patients (log‐rank test, P = .004). In higher risk patients, the 3‐ and 5‐year Sarculator‐predicted and study‐observed OS rates were 0.68 and 0.58, respectively, and 0.85 and 0.66, respectively, in the AI arm (P = .04); the corresponding figures in the HT arm were 0.69 and 0.60, respectively, and 0.69 and 0.55, respectively (P > .99). In lower risk patients, the 3‐ and 5‐year Sarculator‐predicted and study‐observed OS rates were 0.85 and 0.80, respectively, and 0.89 and 0.82, respectively, in the AI arm (P = .507); the corresponding figures in the HT arm were 0.87 and 0.81, respectively, and 0.86 and 0.74, respectively (P = .105).
Conclusions
High‐risk patients treated with AI performed better than predicted, and this adds to the evidence for the efficacy of neoadjuvant AI in STS.
Lay Summary
People affected by soft tissue sarcomas of the extremities and trunk wall are at some risk of developing metastasis after surgery.
Preoperative or postoperative chemotherapy has been tested in clinical trials to reduce the chances of distant metastasis. However, study findings have not been conclusive.
This study stratified the risk of metastasis for people affected by sarcomas who were included in a clinical trial testing neoadjuvant chemotherapy. Exploiting the prognostic nomogram Sarculator, it found a benefit for chemotherapy when the predicted risk, based on patient and tumor characteristics, was high.
This analysis of the ISG‐STS 1001 trial, which compares anthracycline plus ifosfamide and histology‐tailored chemotherapy in 5 high‐risk soft tissue sarcomas of the extremities and trunk wall, supports the Sarculator nomogram for stratifying patient risk in clinical practice and in clinical trials that will investigate perioperative therapies for soft tissue sarcomas.
A randomized trial was conducted to compare neoadjuvant standard (S) anthracycline + ifosfamide (AI) regimen with histology-tailored (HT) regimen in selected localized high-risk soft tissue sarcoma ...(STS). The results of the trial demonstrated the superiority of S in all STS histologies except for high-grade myxoid liposarcoma (HG-MLPS) where S and HT appeared to be equivalent. To further evaluate the noninferiority of HT compared with S, the HG-MLPS cohort was expanded.
Patients had localized high-grade (cellular component >5%; size ≥5 cm; deeply seated) MLPS of extremities or trunk wall. The primary end point was disease-free survival (DFS). The secondary end point was overall survival (OS). The trial used a noninferiority Bayesian design, wherein HT would be considered not inferior to S if the posterior probability of the true hazard ratio (HR) being >1.25 was <5%.
From May 2011 to June 2020, 101 patients with HG-MLPS were randomly assigned, 45 to the HT arm and 56 to the S arm. The median follow-up was 66 months (IQR, 37-89). Median size was 107 mm (IQR, 84-143), 106 mm (IQR, 75-135) in the HT arm and 108 mm (IQR, 86-150) in the S arm. At 60 months, the DFS and OS probabilities were 0.86 and 0.73 (HR, 0.60 95% CI, 0.24 to 1.46; log-rank
= .26 for DFS) and 0.88 and 0.90 (HR, 1.20 95% CI, 0.37 to 3.93; log-rank
= .77 for OS) in the HT and S arms, respectively. The posterior probability of HR being >1.25 for DFS met the Bayesian monitoring cutoff of <5% (4.93%). This result confirmed the noninferiority of trabectedin to AI suggested in the original study cohort.
Trabectedin may be an alternative to standard AI in HG-MLPS of the extremities or trunk when neoadjuvant treatment is a consideration.
11506
Background: The ISG-STS 1001 was an international, randomized, phase III, clinical trial for localized, high-risk, soft tissue sarcoma comparing neoadjuvant chemotherapy (ChT) with a standard ...regimen of epirubicin plus ifosfamide (EI) versus an histology-tailored regimen (HT) in five histologic types, within the context of an integrated multimodality strategy. In addition, in this study, a parallel group of patients (pts) was not randomized but just registered and treated with EI. Radiation-therapy (RT) could be delivered either pre-operatively (concurrent to ChT) or post-operatively, according to clinical judgement. Final results of ISG-STS 1001, published in 2020, showed a benefit in favor of EI, in terms of overall survival, in comparison to HT. Herein, we analyzed tolerability and activity of ChT with EI either in the standard arm of the trial or in the parallel group, whether alone and concurrent to RT. Methods: The EI regimen was made up of epirubicin 120 mg/m² plus ifosfamide 9 g/m². RT was delivered at a dose of 44-50 Gy pre-operatively or 60-66 Gy post-operatively. In the current analysis, toxicities related to EI were analyzed separately in the group receiving concurrent pre-operative ChT and RT and in the group treated with pre-operative ChT alone and receiving RT post-operatively. Surgical complications and radiological response according to RECIST were analyzed in the above mentioned two groups. Data on ChT dose-intensity will be provided. Results: Among the 548 pts (287 randomized and 261 registered) included in the ISG-STS 1001, 289 pts were considered for the current analyses (111 pts randomized in the EI arm and 178 pts just registered). 146 pts were treated with pre-operative RT and 143 with post-operative RT. In regard to toxicities, no statistically significant differences were found between pts treated with pre-operative concurrent ChT and RT and pts treated with pre-operative ChT alone. When surgical post-operative complications were considered, a higher number of wound dehiscence (9% vs 3.5%, respectively, p = 0.053) and seroma (10.5% vs 3%, respectively, p = 0.009) were observed in pts treated with pre-operative concurrent ChT and RT compared to pts treated with pre-operative ChT alone. Finally, a statistically significant association between RECIST response and pre-operative RT was found (p = 0.041), RECIST partial responses (PR) being 19% and 10% in pts receiving concurrent pre-operative ChT plus RT and in pts treated with pre-operative ChT alone, respectively. Conclusions: The concurrent administration of EI and RT was confirmed to be feasible and safe, resulting in an increased number of PR. Also given the final results of this randomized trial, favoring the EI arm, this combination may help when tumors are of borderline resectability or function preservation is a goal.
Abstract only
11558
Background: We investigated the prognostic relevance of % change in LTD in patients (pts) with localized high-risk STS treated with neoadjuvant chemotherapy in a phase 3 ...randomized trial (NCT01710176), aimed at comparing 3 cycles of a neoadjuvant histology-tailored (HT) over 3 cycles of standard anthracycline + ifosfamide chemotherapy (S). Methods: Pts with localized high-risk STS of extremities or trunk wall, and a diagnosis of myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumors, undifferentiated pleomorphic sarcoma were randomly assigned to receive 3 cycles of S or HT. Pts affected by myxofibrosarcoma, pleomorphic liposarcoma, pleomorphic rhabomyosarcoma unclassified spindle cell sarcoma were prospectively registered and treated by S. Change of LTD was assessed comparing baseline dimension with that measured after 3 cycles of S or HT, before surgery. Only pts treated with neodjuvant chemotherapy alone were selected for the analysis. We first investigated Overall Survival (OS) from surgery of the groups identified by “any % reduction”, “no-change” or “increase” in LTD by Kaplan-Meier estimates and log-rank tests. Then we searched for cutoffs able to separate prognosis among pts with a LTD reduction applying the change-point method proposed by Contal - O’Quigley. Results: Of 325 pts who entered the study and evaluable for response, 181 received neoadjuvant chemotherapy alone (92 S and 89 HT group respectively) and were analyzed, while 144 received concurrent chemo-radiotherapy and were excluded. In the whole population, % changes in LTD were significantly associated (log rank p = 0.032) to OS. “Any % reduction in LTD (101/181pts) displayed a better prognosis compared to “no-change” (28/181 pts) or “any % increase” (52/181). The change-point analysis was applied to all, S and HT groups separately; a cutoff of = / > 18.75% decrease in LTD was the optimal predictor of outcome for the S group (p = 0.031), while no size cut-off could be identified for the HT group. Conclusions: In our study, % change in LTD of pts treated with neoadjuvant chemotherapy for localized high-risk STS correlated with OS. However, a % decrease in LTD cut-off able to predict the best outcome could be identified only for pts treated in the S group, while no differences in outcome were found by any % LTD change in the HT group. Interestingly, the LTD cut-off identified in the S group was lower than the one selected to define a response by RECIST ( = / > 18.75% decrease in LTD vs = / > 30%). Clinical trial information: NCT01710176 .
Summary
We have characterised 997 hip fracture patients from a representative 45 Spanish hospitals, and followed them up prospectively for up to 4 months. Despite suboptimal surgical delays (average ...59.1 hours), in-hospital mortality was lower than in Northern European cohorts. The secondary fracture prevention gap is unacceptably high at 85%.
Purpose
To characterise inpatient care, complications, and 4-month mortality following a hip or proximal femur fracture in Spain.
Methods
Design: prospective cohort study. Consecutive sample of patients ≥ 50 years old admitted in a representative 45 hospitals for a hip or proximal femur fragility fracture, from June 2014 to June 2016 and followed up for 4 months post-fracture. Patient characteristics, site of fracture, in-patient care (including secondary fracture prevention) and complications, and 4-month mortality are described.
Results
A total of 997 subjects (765 women) of mean (standard deviation) age 83.6 (8.4) years were included. Previous history of fracture/s (36.9%) and falls (43%) were common, and 10-year FRAX-estimated major and hip fracture risks were 15.2% (9.0%) and 8.5% (7.6%) respectively. Inter-trochanteric (44.6%) and displaced intra-capsular (28.0%) were the most common fracture sites, and fixation with short intramedullary nail (38.6%) with spinal anaesthesia (75.5%) the most common procedures. Surgery and rehabilitation were initiated within a mean 59.1 (56.7) and 61.9 (55.1) hours respectively, and average length of stay was 11.5 (9.3) days. Antithrombotic and antibiotic prophylaxis were given to 99.8% and 98.2% respectively, whilst only 12.4% received secondary fracture prevention at discharge. Common complications included delirium (36.1 %) and kidney failure (14.1%), with in-hospital and 4-month mortality of 2.1% and 11% respectively.
Conclusions
Despite suboptimal surgical delay, post-hip fracture mortality is low in Spanish hospitals. The secondary fracture prevention gap is unacceptably high at > 85%, in spite of virtually universal anti-thrombotic and antibiotic prophylaxis.
Soft tissue sarcomas (STS) constitute a rare heterogeneous group of tumours that include a wide variety of histological subtypes, which require a multidisciplinary and, frequently specialized and ...complex management. Despite advances in our understanding of the pathophysiology of the disease, there are no consensus multidisciplinary recommendations about its diagnosis and treatment in our country. The objective of these guidelines is to provide practical therapeutic recommendations that may contribute to improve the therapeutic results of this disease in our environment. With this purpose, the Spanish Group for Research in Sarcomas (GEIS) held a meeting with a multidisciplinary group of experts for the study and management of sarcomas. The results of this meeting are compiled in this document, in which recommendations on diagnosis, treatment and monitoring of soft tissue sarcomas are included. In summary, these guidelines aim to facilitate the identification and management of STS for clinical practice in Spain.
This study analyzed the impact of a categorized approach, based on patients' prognosis, on major outcomes and explanators in patients hospitalized for COVID-19 pneumonia in an academic center in ...Spain.
Retrospective cohort study (March 3 to May 2, 2020). Patients were categorized according to the followed clinical management, as maximum care or limited therapeutic effort (LTE). Main outcomes were all-cause mortality and need for invasive mechanical ventilation (IMV). Baseline factors associated with outcomes were analyzed by multiple logistic regression, estimating odds ratios (OR; 95%CI).
Thirty-hundred and six patients were hospitalized, median age 65.0 years, 57.8% males, 53.3% Charlson index ≥3. The overall all-cause fatality rate was 15.0% (n = 46). Maximum care was provided in 238 (77.8%), IMV was used in 38 patients (16.0%), and 5.5% died. LTE was decided in 68 patients (22.2%), none received IMV and fatality was 48.5%. Independent risk factors of mortality under maximum care were lymphocytes <790/mm3, troponin T >15ng/L and hypotension. Advanced age, lymphocytes <790/mm3 and BNP >240pg/mL independently associated with IMV requirement.
Overall fatality in the cohort was 15% but markedly varied regarding the decided approach (maximum care versus LTE), translating into nine-fold higher mortality and different risk factors.
Experimental studies on isolated cardiomyocytes from different animal species and human hearts have demonstrated that there are regional differences in the Ca2+ release, Ca2+ decay and sarcomere ...deformation. Local deformation heterogeneities can occur due to a combination of factors: regional/local differences in Ca2+ release and/or re-uptake, intra-cellular material properties, sarcomere proteins and distribution of the intracellular organelles. To investigate the possible causes of these heterogeneities, we developed a two-dimensional finite-element electromechanical model of a cardiomyocyte that takes into account the experimentally measured local deformation and cytosolic Ca2+ to locally define the different variables of the constitutive equations describing the electro/mechanical behaviour of the cell. Then, the model was individualised to three different rat cardiac cells. The local Ca2+ transients were used to define the Ca2+-dependent activation functions. The cell-specific local Young's moduli were estimated by solving an inverse problem, minimizing the error between the measured and simulated local deformations along the longitudinal axis of the cell. We found that heterogeneities in the deformation during contraction were determined mainly by the local elasticity rather than the local amount of Ca2+, while in the relaxation phase deformation was mainly influenced by Ca2+ re-uptake. Our electromechanical model was able to successfully estimate the local elasticity along the longitudinal direction in three different cells. In conclusion, our proposed model seems to be a good approximation to assess the heterogeneous intracellular mechanical properties to help in the understanding of the underlying mechanisms of cardiomyocyte dysfunction.
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