High-risk Soft Tissue Sarcoma Research Articles

Perioperative treatment of soft-tissue sarcoma

SummaryThe standard treatment of high-risk localized extremity and trunk soft-tissue sarcoma is wide local excision and radiation therapy, which can be delivered pre- or postoperatively. Improved care for sarcoma patients at expert centres with multidisciplinary tumour boards, specialized pathologists, surgeons, radio-oncologists, and medical oncologists, according to national or international guidelines, has improved outcomes. Yet, a substantial number of patients will experience disease recurrence with metastatic spread and ultimately die from their disease. In many solid tumours neo/adjuvant chemotherapy has become an accepted standard treatment, whereas in soft-tissue sarcoma discussions on the use of cytotoxic therapy in localized and resectable disease are ongoing. Some centres demonstrated the feasibility and now treat with concomitant neoadjuvant chemoradiotherapy as standard. Others argue that treatments should be given in the order of the accompanying evidence (surgery → radiotherapy → chemotherapy), which does not take biology of the disease into account and probably attempts to simplify complex decision making processes. It is important to enhance our ability to identify patients at highest risk of recurrence, and to generate data and develop tools to predict which patients will benefit from neo/adjuvant systemic therapy most.

A moderate thermal dose is sufficient for effective free and TSL based thermochemotherapy.

Hyperthermia, i.e. heating the tumor to a temperature of 40-43°C is considered by many a valuable treatment to sensitize tumor cells to radiotherapy and chemotherapy. In recent randomized trials the great potential of adding hyperthermia to chemotherapy was demonstrated for treatment of high risk soft tissue sarcoma: +11.4% 5yrs. overall survival (OS) and for ovarian cancer with peritoneal involvement nearly +12months OS gain. As a result interest in combining chemotherapy with hyperthermia, i.e. thermochemotherapy, is growing. Extensive biological research has revealed that hyperthermia causes multiple effects, from direct cell kill to improved oxygenation, whereby each effect has a specific temperature range. Thermal sensitization of the tumor cell for chemotherapy occurs for many drugs at temperatures ranging from 40 to 42°C with little additional increase of sensitization at higher temperatures. Increasing perfusion/oxygenation and increased extravasation are two other important hyperthermia induced mechanisms. The combination of free drug and hyperthermia has not been found to increase tumor drug concentration. Hence, enhanced effectiveness of free drug will depend on the thermal sensitization of the tumor cells for the applied drug. In contrast to free drugs, experimental animal studies combining hyperthermia and thermo-sensitive liposomal (TSL) drugs delivery have demonstrated to result in a substantial increase of the drug concentration in the tumor. For TSL based chemotherapy, hyperthermia is critical to both increase perfusion and extravasation as well as to trigger TSL drug release, whereby the temperature controlled induction of a local high drug concentration in a highly permeable vessel is driving the enhanced drug uptake in the tumor. Increased drug concentrations up to 26 times have been reported in rodents. Good control of the tissue temperature is required to keep temperatures below 43°C to prevent vascular stasis. Further, careful timing of the drug application relative to the start of heating is required to benefit optimal from the combined treatment. From the available experimental data it follows that irrespective whether chemotherapy is applied as free drug or using a thermal sensitive liposomal carrier, the optimal thermal dose for thermochemotherapy should be 40-42°C for 30-60min, i.e. equivalent to a CEM43 of 1-15min. Timing is critical: most free drug should be applied simultaneous with heating, whereas TSL drugs should be applied 20-30min after the start of hyperthermia.

Chemotherapy for Soft Tissue Sarcoma: Development of New Standard Treatments and Clinical Trials in Japan

Abstract Recently, pembrolizumab has been approved for microsatellite instability-high cancers, and genome profiling panel has also been approved for advanced refractory cancers including soft tissue sarcomas (STS) in Japan. However, efficacy and cost-benefit balance of these new strategies for STS should be confirmed by the future clinical trials. For localized STS, efficacy of perioperative chemotherapy has remained controversial. Meta-analysis of randomized controlled trials (RCT) comparing chemotherapy with surgery showed significant survival benefit of the chemotherapy for localized STS. Subsequently, recent RCT have compared chemotherapy regimens with each other especially in neoadjuvant setting, not with surgery. The Italian Sarcoma Group study ISG-STS1001 demonstrated significantly better survival by neoadjuvant epirubicin plus ifosfamide than histology-tailored regimens for high-risk STS. The 10-year follow-up of our trial, JCOG0304, also showed good stable results of neoadjuvant chemotherapy using adriamycin and ifosfamide (AI) for high-risk STS. These observations suggest that neoadjuvant AI could be recommended for localized high-risk STS. Besides high efficacy of AI, significant toxicities of the regimen should also be noted. We are now conducting a randomized phase II/III study, JCOG1306, to confirm the non-inferiority of neoadjuvant gemcitabine plus docetaxel (GD) to AI for high-risk STS. For advanced STS, adriamycin-based chemotherapy remains standard first-line treatment since phase III study of olaratumab resulted in negative. On the other hand, the standard second-line regimen for advanced STS has not been established yet. There are several options including GD, pazopanib, trabectedin and eribulin, however, no evidence has been shown which regimen is the best as second-line therapy. To establish the standard therapy of second-line treatment for advanced STS, we are currently conducting randomized phase II study comparing pazopanib, trabectedin and eribulin.

Radiation and Chemotherapy Improve Survival in Patients with High-Risk Soft Tissue Sarcomas of the Extremities: An Updated Analysis of the Surveillance, Epidemiology, and End Results (SEER) Database

The primary treatment modality for non-metastatic soft tissue sarcomas (STS) of the extremity is surgical resection. This can be accomplished with amputation, or limb sparing surgery (LSS) when feasible. Radiation therapy improved survival in patients with tumors that were high grade or undifferentiated and >5cm (high risk) in a prior SEER analysis. The role of chemotherapy remains controversial in STS. The SEER 18 registries database was queried to identify patients age 18 and older with pathologically confirmed STS of the extremity diagnosed in 2004 or later that underwent surgical resection. Patients with Kaposi’s sarcoma were excluded as well as those with metastatic disease, <3 months of follow up and if the type of surgery was not specified. The primary endpoint of this study was overall survival, which was determined using the Kaplan and Meier method. Survival curves were subsequently compared using log rank analysis. A total of 8,584 patients were identified that met inclusion criteria, Females comprised 3,862 patients and males 4,722 patients. The average age at diagnosis was 57 (range 18-98). Grade III or undifferentiated tumors were present in 3,860 patients while 4,915 patients had tumors >5cm. The 5 year OS for patients who underwent amputation was 53.4% compared to 77.0% with LSS, corresponding to a HR of 0.40 (p<0.001). Median OS was 68 months with amputation and not reached at 10 years with LSS. Of the 8,122 patients who underwent LSS, 4,369 patients were known to have received radiation therapy and 1,135 were known to have been treated with chemotherapy. Neither radiation therapy nor chemotherapy improved survival in the entire cohort of patients undergoing LSS. In a subset of 2,331 patients with high risk tumors, radiation improved 5 year OS from 51.1% to 59.6% while median OS improved from 71 to 97 months, corresponding to a HR of 0.78 (p=0.002). In the same subset of patients treated with radiation, 689 (37.2%) had neoadjuvant radiation with or without postoperative radiation (PORT) and 1,161 (62.8%) had PORT alone. 5 year OS was 58.5% with PORT and 61.5% with neoadjuvant radiation while median OS was 89 and 97 months respectively, corresponding to a HR of 0.97 (p=.671). For the 720 patients with high risk tumors who were known to have received chemotherapy, the 5 year OS and median OS were 61.7% and 117 months respectively versus 58.5% and 83 months respectively for patients not known to receive chemotherapy, corresponding to a HR of 0.83 (p=0.025). The findings of this analysis support continued use of LSS in surgically eligible patients with STS of the extremity. While neither radiation therapy nor chemotherapy improved survival in all comers treated with LSS, the subset of patients with high risk tumors (high grade/ undifferentiated and >5cm) showed a significant survival benefit from both modalities in addition to surgery. The timing of radiation therapy, neoadjuvant versus PORT did not impact survival in this subset of patients.

Assessing the Role of Neoadjuvant Chemotherapy in Primary High-Risk Truncal/Extremity Soft Tissue Sarcomas: An Analysis of the Multi-institutional U.S. Sarcoma Collaborative.

The role of neoadjuvant chemotherapy (NCT) for high-risk soft tissue sarcoma (STS) is questioned. This study aimed to define which patients may experience a survival advantage with NCT. All the patients from the U.S. Sarcoma Collaborative database (2000-2016) who underwent curative-intent resection of high-grade, primary truncal/extremity STS size 5cm or larger were included in this study. The primary end points were recurrence-free survival (RFS) and overall survival (OS). Of the 4153 patients, 770 were included in the study. The median tumor size was 10cm, and 669 of the patients (87%) had extremity tumors. The most common histology was undifferentiated pleomorphic sarcoma (UPS), found in 42% of the patients. Of the 770 patients, 216 (28%) received NCT. The patients who received NCT had deeper, larger tumors (p < 0.001). Of the patients with tumors 5cm or larger and 8cm or larger, NCT was not associated with improved RFS or OS. However for the patients with tumors 10cm or larger, NCT was associated with improved 5-year RFS (51% vs 40%; p = 0.053) and 5-year OS (58% vs 47%; p = 0.043). By location, the patients with extremity tumors 10cm or larger but not truncal tumors had improved 5-yearr RFS (54% vs 42%; p = 0.042) and 5-year OS (61% vs 47%; p = 0.015) with NCT. According to histology, no subtype had improved RFS or OS with NCT, although the patients with UPS had a trend toward improved 5-year RFS (56% vs 42%; p = 0.092) and 5-year OS (66% vs 52%; p = 0.103) with NCT. For the patients with high-grade STS, NCT was associated with improved RFS and OS when tumors were 10cm or larger and located in the extremity. However, no histiotype-specific advantage was identified. Future studies assessing the efficacy of NCT may consider focusing on these patients, with added focus on histology-specific strategies.

Neoadjuvant Pazopanib Treatment in High-Risk Soft Tissue Sarcoma: A Quantitative Dynamic 18F-FDG PET/CT Study of the German Interdisciplinary Sarcoma Group.

The outcome of high-risk soft tissue sarcoma (STS) is poor with radical surgery being the only potentially curative modality. Pazopanib is a multikinase inhibitor approved for the treatment of metastatic STS. Herein, in terms of the German Interdisciplinary Sarcoma Group (GISG-04/NOPASS) trial, we evaluate the potential role of kinetic analysis of fludeoxyglucose F-18 (18F-FDG) data derived from the application of dynamic positron emission tomography/computed tomography (PET/CT) in response assessment to pazopanib of STS patients scheduled for surgical resection. Sixteen STS patients treated with pazopanib as neoadjuvant therapy before surgery were enrolled in the analysis. All patients underwent dynamic PET/CT prior to and after pazopanib treatment. Data analysis consisted of visual (qualitative) analysis of the PET/CT scans, semi-quantitative evaluation based on standardized uptake value (SUV) calculations, and quantitative analysis of the dynamic 18F-FDG PET data, based on two-tissue compartment modeling. Resection specimens were histopathologically assessed and the percentage of regression grade was recorded in 14/16 patients. Time to tumor relapse/progression was also calculated. In the follow-up, 12/16 patients (75%) were alive without relapse, while four patients (25%) relapsed, among them one patient died. Median histopathological regression was 20% (mean 26%, range 5–70%). The studied population was dichotomized using a histopathological regression grade of 20% as cut-off. Based on this threshold, 10/14 patients (71%) showed partial remission (PR), while stable disease (SD) was seen in the rest 4 evaluable patients (29%). Semi-quantitative evaluation showed no statistically significant change in the widely used PET parameters, SUVaverage and SUVmax. On the other hand, 18F-FDG kinetic analysis revealed a significant decrease in the perfusion-related parameter K1, which reflects the carrier-mediated transport of 18F-FDG from plasma to tumor. This decrease can be considered as a marker in response to pazopanib in STS and could be due to the anti-angiogenic effect of the therapeutic agent.

Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: Final results of a randomized clinical trial from the Italian Sarcoma Group, the Spanish Sarcoma Group (GEIS), the French Sarcoma Group (FSG), and the Polish Sarcoma Group (PSG).

11000 Background: A ISG randomized trial on 5 cycles of adjuvant epirubicin+ifosfamide (EI) versus no chemotherapy suggested an OS benefit in localized high-risk STS (JCO 2001;19:1238). A subsequent trial showed no difference between 3 vs 5 cycles of the same neoadjuvant regimen (JCO 2012;30:850). The aim of this trial was to compare 3 cycles of EI versus a histology-tailored (HT) neoadjuvant regimen in selected localized high-risk STS. Methods: This is a multicenter European randomized trial comparing EI versus a HT regimen: gemcitabine+docetaxel in undifferentiated pleomorphic sarcoma (UPS); trabectedin in high-grade myxoid liposarcoma; high-dose prolonged-infusion ifosfamide in synovial sarcoma (SS); etoposide+ifosfamide in malignant peripheral nerve sheath tumors (MPNST); gemcitabine+dacarbazine in leiomyosarcoma (LMS). Patients had localized high-risk (grade = 3; size ≥5 cm) STS of extremities or trunk wall. Primary end-point was Disease Free Survival (DFS). The final analysis was planned after the observation of 130 events. This allows an 80% power to detect a significant difference at the 5% 2-sided level, if the true HR is 0.6 in favor of EI, as shown by the interim analysis (Lancet Oncol 2017;18:812-822). Results: From May 2011 to May 2016, 287 patients were randomized (97 = UPS; 65 = myxoid liposarcoma; 70 = SS; 27 = MPNST; 28 = LMS). The median follow-up was 51.75 months for the alive patients (IQ 28.03) The DFS and OS probability at 60 months were 0.48 and 0.55 (HR:1.232; 95%CI: 0.875-1.733; log rank p=0.323) and 0.66 and 0.76 (HR:1.766; 95%CI:1.101-2.831; log rank p=0.018), in the HT and EI arm, respectively. Conclusions: The final analysis shows a non-statistically significant DFS difference in favor of EI over HT chemotherapy with a larger and statistically significant OS difference. The outcome of patients on EI overlapped previous ISG trials. EI should remain the regimen of choice when neoadjuvant chemotherapy is used in high-risk localized STS. However this trial cannot be used as a formal proof of efficacy of (neo)adjuvant chemotherapy per se. EUDRACT 2010 – 023484 – 17. Funding source: Eurosarc FP7 278472. Clinical trial information: NCT01710176.

Does the addition of chemotherapy to neoadjuvant radiotherapy impact survival in high-risk extremity and trunk soft tissue sarcoma?

11054 Background: Large, high-grade extremity/trunk (ET) non-rhabdomyosarcoma soft-tissue sarcoma (STS) is at high risk for distant recurrence and death. The integration of chemotherapy (C) to standard of care neoadjuvant radiotherapy (RT) remains controversial, even for these patients. This study examines the impact of adding C to neoadjuvant RT on overall survival (OS) in high risk ET-STS. Methods: The National Cancer Data Base (NCDB) was queried for patients ≥18 years with high risk (≥5 cm + high grade) non-rhabdomyosarcoma ET-STS (WHO histology) who received neoadjuvant RT and limb sparing surgery from 2006-2014. Patients were next stratified based upon receipt of C (RT and CRT cohorts). Overall survival (OS) for RT vs CRT cohorts was analyzed using the Kaplan-Meier (KM) method, log-rank test, and Cox proportional hazards models. Propensity score-matched analysis (PSM) was employed to account for potential treatment selection bias between cohorts. Results: A total of 848 (71.1%) and 344 (28.9%) patients received RT and CRT, respectively. Patient cohorts were well-balanced except for the CRT cohort having higher rates of treatment in the West (22.1% vs 10.6%) &amp; Midwest (28.3% vs 22.7%), Charlson-Deyo [CD] score 0 vs ≥1 (85.5% vs 79.4%), younger age (≤50) (45.9% vs 21.7%), synovial sarcoma histology (18.9% vs 3.2%), earlier year of diagnosis (2006-2010) (39.5% vs 32.3%), and positive lymphovascular invasion (2.0 vs 1.51%), (p &lt; 0.05 each). The KM 5-year OS was significantly higher in the CRT vs RT cohort: 69.2% vs 58.1% on univariate (p &lt; 0.0001) and multivariate analysis (Hazard Ratio [HR]: 0.66; 95% Confidence Interval [CI]: 0.52-0.85; p = 0.001) even after adjusting for age, race, income, CD score, histology, tumor size, tumor grade, and primary site (lower extremity; upper extremity; trunk). PSM identified evenly matched cohorts of 300 patients each with respect to age, income, CD score, histology, grade, tumor size, and primary site. The addition of neoadjuvant C remained prognostic for OS on PSM (HR: 0.74 [0.56-0.99], p = 0.042). Conclusions: The addition of C to neoadjuvant RT was associated with improved OS in patients with high risk non-rhabdomyosarcoma ET-STS in the NCDB. These hypothesis generating results support prospective evaluation.

Benefit of intensified perioperative chemotherapy within high-risk CINSARC patients with resectable soft tissue sarcomas (CIRSARC).

TPS11078 Background: We have recently identified a gene expression signature so called “CINSARC” which is related with chromosomal instability and highly predictive of metastasis-free and overall survival in soft-tissue sarcoma (STS) patients. The prognostic relevance of this signature has been validated recently in an independent set of sarcomas from the Cancer Genome Atlas (TCGA) consortium. Despite optimal locoregional treatment, patients with high-risk CINSARC have a very poor outcome.However, the main issues with peri-operative chemotherapy in STS patients are the identification of patients who are more likely to benefit from this approach and the characterization of the best chemotherapy regimen. Indeed, in all clinical trials investigating peri-operative chemotherapy in STS, patients were included on the basis of classical histological criteria (grade, tumor size, deep location). The CINSARC is more discriminant than grade to evaluate the prognosis of STS patients (35% of grade 3 are low-risk CINSARC and 40% of grade are high-risk CINSARC). We hypothesize than: (1) 6 cycles of anthracyclines-ifosfamide is associated with improved outcome in comparison to 3 cycles of chemotherapy (ISG-STS 10-01) in patients with high-risk CINSARC STS; (2) Chemotherapy-free strategy is not associated with detrimental outcome in low-risk CINSARC STS. Methods: This is a multicenter phase III trial (sponsor: Institut Bergonié) which aims to evaluate the efficacy (intent-to-treat analysis) of 6 cycles of neoadjuvant doxorubicin + ifosfamide based chemotherapy+ surgery +/-radiotherapy (Arm B) in comparison with 3 cycles of neoadjuvant doxorubicin + ifosfamide based chemotherapy + surgery +/- radiotherapy (Arm A) in terms of 3-year progression-free survival (PFS) in high-risk CINSARC patients with resectable STS. Patients with low-risk CINSARC signature will be treated at investigator discretion. 334 patients will have to be recruited over 36 months in 10 centers of the French Sarcoma Group. This is the first study assessing the impact of peri-operative chemotherapy in STS based on a prognostic molecular signature. The study is open for accrual at time of submission. Clinical trial information: NCT03805022.

(Neo)adjuvant chemotherapy and interdigitated split-course hyperfractionated radiation in high risk soft tissue sarcoma \u2013 Results from a large single-institution series

A single-institution series using a (neo)adjuvant chemotherapy and interdigitated hyperfractionated split-course radiation therapy (CRT) treatment protocol for soft tissue sarcoma was reviewed. Our specific aims were to study recurrence rates and long-term toxicity. Between 1998 and 2016, 89 patients with non-metastatic soft tissue sarcoma were treated with surgery combined with six courses of doxorubicin and ifosfamide and hyperfractionated radiation therapy (42–60 Gy/1.5 Gy twice daily). Patients were considered being at high risk if tumour malignancy grade was high and the tumour fulfilled at least two of the following criteria: size >8 cm, presence of necrosis or vascular invasion. The mean age of the patients was 50.7 years. With a median follow-up of 5.4 years for survivors, the local control rate was 81.4%. Six (7%) patients progressed during neoadjuvant CRT. Seven (8%) patients discontinued the treatment due to toxicity. Eighty-six patients were operated and three (3%) of these developed a long-term complication. The estimated metastasis-free survival was 47.6% and overall survival 53.0% at five years. The limb-salvage rate was 93%. The limb-salvage rate, local control and complication rates were good in these patients with high risk soft tissue sarcoma. Metastases-free survival and overall survival rates were less satisfactory, reflecting the aggressive nature of these tumours.

Multimodale Therapien bei Sarkomen: Standards und Neues in der medikamentösen und radioonkologischen Behandlung

Patients with localized high-risk soft tissue sarcoma are at high risk for both local recurrence and distant metastases despite optimal surgical treatment. Importance of preoperative or postoperative chemotherapy and hyperthermia. Evaluation and overview of published study results. Preoperative or postoperative radiotherapy is considered as standard for patients with localized high-risk soft tissue sarcoma. The results of two randomized studies on neoadjuvant chemotherapy showed asurvival benefit. As both studies did not have acontrol arm without chemotherapy but in one case the superiority of anthracycline/ifosfamide-based chemotherapy in combination with hyperthermia over chemotherapy alone and in the other case the superiority of anthracycline/ifosfamide-based chemotherapy over histology-specific chemotherapy were shown, the formal proof of the superiority of this treatment is still missing. Stratifying the patients treated in the so far largest randomized adjuvant chemotherapy trial according to current risk criteria ( http://www.sarculator.com ) revealed asignificant survival benefit for patients at high risk of recurrence. For high-risk soft tissue sarcomas, multimodal treatment strategies involving perioperative chemotherapy, radiotherapy and, if possible, hyperthermia should be considered in addition to tumor resection. Preoperative chemotherapy should be given preference over postoperative chemotherapy based on available data.

ASO Author Reflections: Preoperative Pazopanib for High-Risk Soft Tissue Sarcoma: Better Patient Selection is Needed.

ASO Author Reflections: Preoperative Pazopanib for High-Risk Soft Tissue Sarcoma: Better Patient Selection is Needed.

One shot NEPA plus dexamethasone to prevent multiple-day chemotherapy in sarcoma patients

PurposeChemotherapy-induced nausea and vomiting (CINV) is one of the most feared and disturbing adverse events of cancer treatment associated with decreased adherence to effective chemotherapy regimens. For high-risk soft tissue sarcoma patients, receiving multiple-day chemotherapy (MD-CT), antiemetic guidelines recommend a combination of an NK1 receptor antagonist (NK1-RA), a 5-HT3 receptor antagonist (5HT3-RA), and dexamethasone on each day of the antineoplastic treatment. NEPA is the first oral fixed-dose combination of a highly selective NK1-RA, netupitant, and second-generation 5HT3-RA, palonosetron. So far, no data has been published in literature about the efficacy of a single dose of NEPA in MD-CT.MethodsWe performed a prospective, non-comparative study to assess the efficacy of one shot of NEPA plus dexamethasone in sarcoma patients receiving MD-CT. The primary efficacy endpoint was a complete response (CR: no emesis, no rescue medication) during the overall phase (0–120 h) in cycle 1. The main secondary endpoints were CR during the overall phase of cycles 2 and 3.ResultsThe primary endpoint was reached in 88.9% of patients. Cycles 2 and 3 overall CR rates were 88.9% and 82.4%, respectively. The antiemetic regimen was well tolerated.ConclusionsThis pilot study showed the benefit of one shot of NEPA to prevent CINV in sarcoma patients receiving MD-chemotherapy.

Investigating a chimeric anti-mouse PDGFRα antibody as a radiosensitizer in primary mouse sarcomas.

BackgroundOlaratumab (LY3012207/IMC-3G3/Lartruvo™) is a fully human monoclonal antibody specific for platelet-derived growth factor receptor alpha (PDGFRα). Phase Ib/II trial results of olaratumab plus doxorubicin in adult patients with advanced soft tissue sarcoma (STS) supported accelerated FDA approval of this regimen. Radiation therapy (RT) is frequently used for high-risk localized STS. However, olaratumab has not been tested with concurrent RT. Here, we evaluate the chimeric anti-mouse PDGFRα antibody 1E10Fc as a radiosensitizer in a primary mouse model of STS.MethodsPrimary STS were initiated in mice. When tumors reached 70 mm3, mice were allocated into treatment groups: 1) isotype, 2) 1E10Fc, 3) isotype + RT, 4) 1E10Fc + RT. 1E10Fc or isotype was given biweekly. RT (25 Gy delivered in 5 daily 5 Gy fractions) was initiated on Day 0 with first drug treatment. Tumors were measured 3× per week. Upon reaching 900 mm3, tumors and lungs were harvested. A two-way ANOVA was performed to compare tumor growth delay. Primary tumors were stained for CD31 and PDGFRα and lungs were assessed for micrometastases. A Chi-square test was performed to compare the development of micrometastases in the lungs after treatment with 1E10Fc or isotype.FindingsRT significantly delayed time to tumor quintupling compared to no RT (p < 0·0001) [two-way ANOVA], but no difference in tumor growth was seen between mice receiving isotype or 1E10Fc treatment regardless of concurrent RT. Lower microvessel density was observed in the 1E10Fc + RT group. Fewer mice treated with 1E10Fc had micrometastases, but this difference was not statistically significant (p < 0·09).Interpretation1E10Fc did not act as a radiosensitizer in this primary STS model.FundingThis study was funded by a research agreement from Eli Lilly and Company.

The impact of chemotherapy on survival of patients with extremity and trunk wall soft tissue sarcoma: revisiting the results of the EORTC-STBSG 62931 randomised trial

BackgroundThis study was aimed at determining whether patients with high-risk soft tissue sarcoma (STS), as identified using the nomogram Sarculator, benefitted from adjuvant chemotherapy in the EORTC-STBSG 62931 randomised controlled trial (RCT), which failed to detect an impact for adjuvant doxorubicin plus ifosfamide (Adj) over observation (Obs). MethodsPatients with extremity and trunk wall STS in the EORTC-STBSG 62931 RCT were analysed (N = 290/351). Ten-year predicted probability of overall survival (pr-OS) was calculated using the prognostic nomogram Sarculator. Patients were grouped into three categories of predicted pr-OS: high (pr-OS>66%), intermediate (51<pr-OS≤66) and low (pr-OS≤51%). OS and disease-free survival (DFS) were calculated. ResultsNomogram pr-OS was dispersed (median 72%, interquartile range 57–83%) and had prognostic value for OS and DFS (log-rank test: P < 0.001). One hundred seventy, 68 and 52 patients had high (58.6%, 90 Obs/80 Adj), intermediate (23.5%, 34 Obs/34 Adj) and low pr-OS (17.9%, 24 Obs/28 Adj), respectively. Adjuvant chemotherapy halved the risk of recurrence (hazard ratio [HR] = 0.46, 95% confidence interval [CI] 0.24–0.89) and death (HR = 0.46, 95% CI 0.23–0.94) in the low pr-OS category, while no effect was detected in intermediate and high pr-OS categories. To strengthen these findings, study participants with pr-OS<60% were combined (N = 80, 27.6%, 39 Obs/41 Adj), and a significant DFS (HR = 0.49, 95% CI 0.28–0.85) and OS (HR = 0.50, 95% CI 0.30–0.90) benefit was detected. ConclusionPatients of the EORTC-STBSG 62931 RCT with extremity and trunk wall STS and a low predicted pr-OS (high-risk patients) had better outcomes when treated with adjuvant chemotherapy. This may help reconcile the disparate results of clinical studies on adjuvant/neoadjuvant chemotherapy in STS.

Regional deep hyperthermia: quantitative evaluation of predicted and direct measured temperature distributions in patients with high-risk extremity soft-tissue sarcoma

Background: Temperature distributions resulting from hyperthermia treatment of patients with high-risk soft-tissue sarcoma (STS) were quantitatively evaluated and globally compared with thermal simulations performed by a treatment planning system. The aim was to test whether the treatment planning system was able to predict correct temperature distributions.Methods: Five patients underwent computed tomography (CT) fluoroscopy-guided placement of tumor catheters used for the interstitial temperature measurements. For the simulations, five 3 D patient models were reconstructed by segmenting the patient CT datasets into different tissues. The measured and simulated data were evaluated by calculating the temperature change (), T90, T50, T20, Tmean, Tmin and Tmax, as well as the 90th percentile thermal dose (CEM43T90). In order to measure the agreement between both methods quantitatively, the Bland–Altman analysis was applied.Results: The absolute difference between measured and simulated temperatures were found to be 2°, 6°, 1°, 4°, 5° and 4 °C on average for Tmin, Tmax, T90, T50, T20 and Tmean, respectively. Furthermore, the thermal simulations exhibited relatively higher thermal dose compared to those that were measured. Finally, the results of the Bland–Altman analysis showed that the mean difference between both methods was above 2 °C which is considered to be clinically unacceptable.Conclusion: Given the current practical limitations on resolution of calculation grid, tissue properties, and perfusion information, the software SigmaHyperPlan™ is incapable to produce thermal simulations with sufficient correlation to typically heterogeneous tissue temperatures to be useful for clinical treatment planning.

Relevance of Reference Centers in Sarcoma Care and Quality Item Evaluation: Results from the Prospective Registry of the Spanish Group for Research in Sarcoma (GEIS).

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). Diagnostic and therapeutic data from patients diagnosed between January 2004 and December 2011 were collected. Correlation with outcome was performed. 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). 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. 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.

ASO Author Reflections: Chemoradiation for High-Risk Soft Tissue Sarcomas.

ASO Author Reflections: Chemoradiation for High-Risk Soft Tissue Sarcomas.

Preoperative radiotherapy of soft-tissue sarcomas: surgical and radiologic parameters associated with local control and survival

BackgroundPreoperative radiotherapy is often used to facilitate excision of soft-tissue sarcomas. We aimed define factors that affect local tumour control and patient survival.MethodsA single institution registry study of 89 patients with non-metastatic soft-tissue sarcomas having preoperative radiotherapy between 1994 and 2014. Radiologic (presence of peritumoural oedema and volume change following radiotherapy) and histopathologic (tumour volume, grade and surgical margin) parameters were recorded. Outcomes were the events of local recurrence, amputation, metastasis and death.ResultsLocal recurrence rate was low (12%) and marginal excision gave equal local control to wide excision. Pelvic localization was associated with a higher risk for amputation. The absence of peritumoural oedema on MRI defined a subgroup of tumours with more favourable oncologic outcome. Reduction of tumour volume following radiotherapy was also associated with better patient survival. Both these radiologic parameters were associated with lower tumour grade. Tumour necrosis was not significant for patient survival. The local complication rate, mainly wound healing problems and infection, was high (40%), but did not lead to any amputation.ConclusionPreoperative radiotherapy of high-risk soft-tissue sarcomas allows for good local control rate at the expense of local wound complications, which are however manageable. Marginal excision is sufficient for local control. Absence of peritumoural oedema on MRI, as well as tumour size reduction following radiotherapy are associated to superior patient survival and can be used ass early prognostic factors.

1624P - Pathological grade of tumorregression after neoadjuvant chemotherapy with doxorubicin/ifosfamid and regional hyperthermia correlates with survival outcomes in patients with high-risk soft tissue sarcoma

1624P - Pathological grade of tumorregression after neoadjuvant chemotherapy with doxorubicin/ifosfamid and regional hyperthermia correlates with survival outcomes in patients with high-risk soft tissue sarcoma