E-TRAB was a non-interventional, prospective trial investigating the feasibility and predictive value of geriatric assessments (GA) in older STS patients treated with trabectedin as first-line therapy. Primary endpoints were overall survival (OS), quality of life and individual clinical benefit assessed by the patient-reported outcome measures QLQ-C30 and PRO-CTCAE. Further, several GA tools were applied and correlated with clinical outcomes and treatment-related toxicities. The final analyses included 69 patients from 12 German-speaking sites. The median age of patients was 78 years (range: 55 to 88). Baseline data on PROs and GA identified a diverse population of older patients with respect to their global health status, although a large proportion of them suffered from limitations, required geriatric help and had a high risk of morbidity. The Cancer and Age Research Group (CARG) score classified 38%, 29% and 23% of the patients with low, intermediate and high risks for therapy-related side effects, respectively. Median OS was 11.2 months [95%CI: 5.6; 19.4]. The study confirmed that trabectedin as first-line treatment in older patients with STS has an acceptable and manageable safety profile. Potential prognostic factors for clinical outcome and therapy-related toxicity were identified among the GA tools. Long Timed Up and Go (TUG) showed a significant correlation to OS and early death, whereas a high CARG score (>9) was associated with an increase in unplanned hospitalizations and the incidence of toxicities grade ≥ 3.

Myxofibrosarcoma (MFS) is a rare subtype of sarcoma, whose genetic basis is poorly understood. We analyzed 69 MFS cases using whole‐genome (WGS), whole‐exome (WES) and/or targeted‐sequencing (TS). Newly sequenced genomic data were combined with additional deposited 116 MFS samples. WGS identified a high number of structural variations (SVs) per tumor most frequently affecting the TP53 and RB1 loci, 40% of tumors showed a BRCAness‐associated mutation signature, and evidence of chromothripsis was found in all cases. Most frequently mutated/copy number altered genes affected known disease drivers such as TP53 (56.2%), CDKN2A/B (29.7%), RB1 (27.0%), ATRX (19.5%) and HDLBP (18.9%). Several previously unappreciated genetic aberrations including MUC17 , FLG and ZNF780A were identified in more than 20% of patients. Longitudinal analysis of paired diagnosis and relapse time points revealed a 1.2‐fold mutation number increase accompanied with substantial changes in clonal composition over time. Our study highlights the genetic complexity underlying sarcomagenesis of MFS.

Objective: The EPAZ study (NCT01861951) showed recently that pazopanib was non-inferior to doxorubicin in patients >60 years treated in first line for advanced soft tissue sarcoma . The current post-hoc analysis aimed to assess the prognostic impact of frailty. Methods: Geriatric assessments were evaluated at baseline. Age >75 years, liposarcoma, ECOG = 2, G8 <14, instrumental activities of daily living (IADL) >1 and Charlson Comor-bidity Index >2 were tested for their impact on progression-free survival (PFS), overall sur-vival (OS), CTCAE grade 3/4 adverse events (AEs) or serious AEs (SAEs), using univariate and multivariate analysis models. Results: univariate analysis showed an increased risk of grade 3/4 AEs and SAEs for ECOG = 2, G8 score <14 or IADL >1, independent of treatment. The multivariate analysis exhibited for pazopanib a significantly reduced risk for grade 3/4 AEs (HR 0.53; p = 0.033), and in patients with G8 <14 an increased risk for SAEs (HR 2.67; p = 0.011). In the multivariate analysis, G8 <14 was a negative prognostic factor for PFS (HR 1.82; p = 0.009) and IADL >1 for OS (HR 2.02; p = 0.007). ECOG = 2 was the strongest negative predictor for PFS (HR 4.39; p = 0.001) and OS (HR 3.74; p = 0.004). Neither age nor Charl-son Comorbidity Index showed any impact on PFS, OS, incidence of grade 3/4 AEs or SAEs. Conclusions: This post hoc analysis demonstrated that age is not a denominator for outcome or toxicity in elderly patients with soft tissue sarcoma . Instead, geriatric and functional assess-ments should be used to counsel patients and tailor therapy to individual needs. Moreover, pazopanib has a reduced risk for grade 3/4 AEs compared to doxorubicin.(c) 2022 Elsevier Ltd. All rights reserved.

OBJECTIVE:We investigated the health-related quality of life (HRQoL) of patients with gastrointestinal stromal tumours (GIST).METHODS:In the multicentre PROSa study, the HRQoL of adult GIST patients was assessed between 2017 and 2019 using the European Organisation for Research and Treatment of Cancer HRQoL questionnaire (EORTC QLQ-C30). We performed group comparisons and multivariate linear regressions.RESULTS:Among 130 patients from 13 centres, the mean global HRQoL was 63.3 out of 100 points. Higher sores indicate better HRQoL. The highest restrictions were in emotional, social, role functioning, insomnia, fatigue, and pain. In multivariate linear regression, we found no significant differences between patients receiving tyrosine kinase inhibitor (TKI) treatment and those without TKI treatment as well as between patients treated with curative or with palliative intent. Patients who received multiple lines of TKI treatment had the most restrictions, notably in physical (unstandardized regression coefficient [B] = -15.7), role (B = -25.7), social (B = -18.4), and cognitive functioning (B = -19.7); fatigue (B = 15.93); general health (B = -14.23); and EORTC-sum score (B = -13.82) compared to all other patients.CONCLUSION:The highest HRQoL restrictions were in GIST patients receiving multiple lines of TKI therapy. Underlying causes need further investigation.

Die guten funktionellen Ergebnisse der Tumorendoprothetik des Kniegelenks in Kombination mit modernen onkochirurgischen Konzepten haben in der Vergangenheit zu einer Abnahme der primären Amputationshäufigkeit bei Patienten mit malignen Tumoren der kniegelenknahen Region geführt. Der Extremitätenerhalt durch die Tumorendoprothetik resultiert in einem hohen Maß an Lebensqualität für die betroffenen Patienten. Ziel der Arbeit war die Aufarbeitung von Komplikationen, die insgesamt durch die Komplexität der Eingriffe sowie die Größe der notwendigen endoprothetischen Rekonstruktionen und neo-/adjuvanten Therapien häufiger sind als in der Primärendoprothetik bei Arthrose oder nach Trauma. Mögliche intra- und postoperative Komplikationen werden dargestellt und realisierbare Therapieoptionen aufgezeigt. Als intraoperative Komplikationen sind die fehlerhafte Ausrichtung des Implantats in Länge, Achse und Rotation, ungeplante Weichteildefekte, Probleme bei der Implantatverankerung bzw. intraoperative Frakturen, Gefäß- und Nervenverletzungen sowie Läsionen des Streckapparats zu nennen. Zu den relevanten postoperativen Komplikationen gehören das Lokalrezidiv, die periprothetische Infektion, periprothetische Frakturen, thrombembolische Ereignisse und das mechanische Implantatversagen (Lockerung bzw. Versagen des Kopplungsmechanismus). In Abhängigkeit von den lokalen anatomischen Verhältnissen und dem systemischen onkologischen Zustand des Patienten können diese Komplikationen zu großen Herausforderungen im Management werden. Durch die Kenntnis der potenziellen Probleme lassen sie sich aber vermeiden. Dazu ist eine profunde onkochirurgische und revisionsendoprothetische Erfahrung erforderlich.

Doxorubicin represents the standard first-line treatment for metastatic soft-tissue sarcoma. We assessed the efficacy and safety of trofosfamide in elderly patients. In this controlled phase II trial, we randomly (1:2) assigned 120 previously untreated patients with soft-tissue sarcoma, older than 60 years, with an Eastern Cooperative Oncology Group score of 0e2, to receive either doxorubicin for 6 cycles (arm A) or oral trofosfamide (arm B). The primary end-point was a 6-month progression-free rate (PFR) in the experimental arm (clinical trial information: NCT00204568). Between August 2004 and October 2012, forty and 80 patients were randomly assigned to arm A and arm B, respectively, in 16 centres. The median age was 70 years (range, 60-89). The primary study end-point (6-month PFR) was exceeded, with 27.6% in arm B (95% confidence interval [CI], 18.0-39.1) and 35.9% in arm A: (95% CI, 21.2-52.8). Survival data in terms of progression-free survival were 4.3 months (95% CI, 2.2 e6.3) and 2.8 months (95% CI, 1.7-3.6) and in terms of overall survival were 9.8 months (95% CI, 6.7-11.6) and 12.3 months (95% CI, 9.6-16.2), respectively. The number of serious adverse event (SAE) was 59% in arm A and 30.3% in arm B (p = 0.005). Trofosfamide caused more often dyspnoea and low-grade fatigue, whereas with doxorubicin, more often leukocytopenia, neutropenia and mucositis were seen. Discontinuation rates for reasons other than disease progression were 15.4% (arm A) vs. 7.9% (arm B). In an elderly population of patients, oral trofosfamide achieved the estimated primary end-point 6-month PFR and was associated with a favourable toxicity profile compared with doxorubicin. (C) 2019 Elsevier Ltd. All rights reserved.

Desmoid-type fibromatoses (or desmoid tumors) are entities of intermediate biological potential and are locally invasive. Radical surgery, as state of the art therapy, is frequently limited by incomplete resections. Hormone modifying therapies are promising but further research is required. Poly Adenosine Diphosphate Ribose Polymerase-1 (PARP-1), a DNA repairing enzyme, might be a pathogenetic factor and could become a potential target for therapy as shown by the successful treatment of selected carcinomas and sarcomas by PARP-inhibition. In this study, we investigated the expression of estrogen receptors (ER) α (1) and β (2), progesterone receptor (PR), androgen receptor (AR), as well as PARP-1 via immunohistochemistry and quantitative RT-PCR in 69 tissue samples of desmoid tumors. Immunohistochemistry was quantified using the Immunoreactivity Score (IRS). Overall expression patterns were correlated with clinical-pathologic parameters to determine their value as a prognostic factor. Among the investigated hormone receptors only ERβ showed partial cytoplasmic reactivity. PARP-1 revealed variable nuclear positivity with IRS ranging from 0 to 6. Univariate survival analysis showed that higher expression of estrogen receptor 1 was associated with shorter disease-free survival (p = 0.005). Uni- (p = 0.03) and multivariate (p = 0.003) analyses of mRNA data revealed that higher PARP-1 expression correlated with earlier recurrence. According to this study PARP-1 expression is associated with poorer prognosis, that is faster recurrence, highlighting the possibility of PARP-1-targeting agents as a therapeutic option. Hormone receptors were of minor prognostic relevance in this study.

PURPOSE Doxorubicin is a standard of care in patients with advanced, inoperable soft tissue sarcoma (STS). We tested whether pazopanib has efficacy comparable to that of doxorubicin in elderly patients with STS and offers superior tolerability for hematologic toxicity. PATIENTS AND METHODS Patients age 60 years or older without previous systemic treatment for progressive advanced or metastatic STS who had Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function were included. Treatment consisted of pazopanib 800 mg once per day or doxorubicin 75 mg/m2 once every 3 weeks (≤ 6 cycles) after being randomly assigned in a 2:1 ratio. Noninferiority was assumed for progression-free survival (PFS), if the upper limit of the 95% CI for the hazard ratio (HR) was less than 1.8. Neutropenia and febrile neutropenia were key secondary end points. The European Organisation for Research and Treatment of Cancer (30-item) Quality of Life Questionnaire and geriatric assessment were used to measure patient-reported outcomes. Cox regression analysis and Kaplan-Meier curves were used for analysis. RESULTS Pazopanib and doxorubicin were given to 81 and 39 patients, respectively. The median age was 71 years (range, 60-88 years). PFS was noninferior (HR, 1.00; 95% CI, 0.65 to 1.53) and the incidence of grade 4 neutropenia and febrile neutropenia favored pazopanib. Objective response rates for pazopanib and doxorubicin were 12.3% and 15.4%, respectively. Overall survival did not differ significantly between arms (HR, 1.08; 95% CI, 0.68 to 1.72; P = .735). Geriatric assessment revealed 2 or more comorbidities in 15.8% of the patients and impairment of activities of daily living in 28.3% of patients. CONCLUSION Pazopanib was noninferior to doxorubicin, rendering pazopanib a putative therapeutic option in the first-line treatment of STS in patients age 60 years or older. The distinct adverse event profile may be used to counsel patients and tailor therapy to individual needs.

ImportancePazopanib and gemcitabine have shown good tolerability, albeit modest single-agent activity in pretreated soft tissue sarcoma. A combined regimen to improve outcomes is required.ObjectiveTo determine the efficacy of gemcitabine and pazopanib compared with pazopanib alone.Design, Setting, and ParticipantsThis multicenter, randomized phase 2 clinical trial was conducted in Germany from September 2011 to July 2014 and included patients with an Eastern Cooperative Oncology Group performance status score of 0 to 2, adequate organ function, measurable lesion, and progression after at least 1 prior treatment with anthracyclines and/or ifosfamide. Data analysis was performed during 2019 and 2020.InterventionsPatients were randomized to pazopanib with gemcitabine (A) or without gemcitabine (B).Main Outcomes and MeasuresThe primary end point was progression-free survival rate (PFSR) at 12 weeks; secondary end points included toxicity, quality of life, overall survival, and response rates.ResultsA total of 90 patients were randomized, and 86 eligible patients (43 women [50%]) were evaluable, with a median age of 57 (range, 22-84) years and Eastern Cooperative Oncology Group performance status score of 0/1 in 77 participants (90%). The predominant histological subtypes were leiomyosarcoma (22 [26%]) and liposarcoma (16 [19%]). After a median follow-up of 12.4 (range, 1-48) months, the primary end point was met, with a PFSR at 12 weeks of 74% (A) vs 47% (B) (hazard ratio [HR], 1.60; 90% CI, 1.15-2.23; P = .01). In the combination arm, PFSR was significantly longer, with a median of 5.6 vs 2.0 months (HR, 0.58; 95% CI, 0.36-0.92; P = .02) compared with single-agent pazopanib, whereas overall survival was similar, with 13.1 vs 11.2 months (HR, 0.98; 95% CI, 0.60-1.58; P = .83). The objective response rate was overall low, with 11% (A) vs 5% (B) (P = .10). The toxicity of the combination of pazopanib and gemcitabine was increased, but it was manageable and mainly hematological.Conclusions and RelevanceThis phase 2 randomized clinical trial of patients with soft tissue sarcoma found that the addition of gemcitabine to pazopanib was tolerable, and PFSR at 12 weeks was significantly higher compared with pazopanib alone. These results suggest clinical activity of the combination, but they should be confirmed in a phase 3 trial in a more homogeneous population (eg, leiomyosarcoma).Trial RegistrationGerman Clinical Trials Identifier: DRKS00003139.

Objectives The choice of drug treatment in advanced soft tissue sarcoma (STS) continues to be a challenge regarding efficacy, quality of life (QoL) and toxicity. Unlike other cancer types, where integrating patient-reported outcomes (PRO) has proven to be beneficial for QoL, there is no such evidence in patients with STS as of now. The YonLife trial aimed to explore the effect of a tailored multistep intervention on QoL, symptoms and survival in patients with advanced STS undergoing treatment with trabectedin as well as identifying predictors of QoL. Design YonLife is a cluster-randomised, open-label, proof-of-concept study. The intervention incorporates electronic PRO assessment, a case vignette and expert-consented treatment recommendations. Participants Six hospitals were randomised to the control arm (CA) or interventional arm (IA). Seventy-nine patients were included of whom 40 were analysed as per-protocol analysis set. Primary and secondary outcome measures The primary end point was the change of Functional Assessment for Cancer Therapy (FACT-G) total score after 9 weeks. Secondary outcomes included QoL (FACT-G subscales), anorexia and cachexia (Functional Assessment of Anorexia/Cachexia Therapy (FAACT)), symptoms (MD Anderson Symptom Inventory (MDASI)), anxiety and depression (HADS), pain intensity and interference (Brief Pain Inventory (BPI)) and survival assessment. Results After 9 weeks of treatment, QoL declined less in the IA (ΔFACT-G total score: −2.4, 95% CI: −9.2 to 4.5) as compared with CA (ΔFACT-G total score: −3.9; 95% CI:−11.3 to 3.5; p = 0.765). In almost all FACT-G subscales, average declines were lower in IA, but without reaching statistical significance. Smaller adverse trends between arms were observed for MDASI, FAACT, HADS and BPI scales. These trends failed to reach statistical significance. Overall mean survival was longer in IA (648 days) than in CA (389 days, p = 0.110). QoL was predicted by symptom severity, symptom interference, depression and anxiety. Conclusion Our data suggest a potentially favourable effect of an electronic patient-reported outcomes based intervention on QoL that needs to be reappraised in confirmatory studies. Trial registration number ClinicalTrials.gov Identifier ( NCT02204111 ).

Background There is a need for novel therapies in metastatic STS, rendering checkpoint inhibitors (CPI) of interest in STS. Immune cell infiltrates are thought as a prerequisite for CPI efficacy and its role remains vague in STS. We analyzed whether the immune profile differed for STS treated within the phase II EPAZ study (NCT01861951). Methods RNA samples were measured using the PanCancer Immune Profiling Panel from the nCounter® Analysis System. FCF1, HDAC3, ZKSCAN5, MRPS5 and EIF2B4 were used as housekeeping genes. Samples were categorized in three groups based on their overall mRNA expression via unsupervised random forest analysis. Differences in gene expression were tested by T-tests or ANOVA, with correction for multiple testing. Ingenuity Pathway Analysis (IPA) were performed for activity prediction. K-M plots were used for survival estimates and log-rank analyses for comparisons. Results Specimens were available in 70/120 patients and 31 were assessable by immune profiling. 12 pts. received doxorubicin (DOX) and 18 pazopanib (PAZ). Median progression free survival (PFS) and median overall survival (OS) for the total cohort were 2.6 mo. and 11.6 mo., respectively. Patients were clustered in high (n = 4)/mixed (n = 20)/low (n = 7) mRNA profile expressions. While OS varied numerically between clusters (11.1/9.0/28.9 mo.), values were not significant (P = 0.5573). A similar pattern was detected for PFS (4.2/1.5/8.9 mo.; P = 0.4127). Conclusions Our study indicates that STS express a differential mRNA immune profile. However, clusters were not associated with outcome measures. A major limitation is the small sample size. Clinical trial identification NCT01861951. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure V. Grunwald: Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self): PharmaMar. M. Schuler: Research grant / Funding (institution): Novartis. P. Schoeffski: Honoraria (institution), Advisory / Consultancy: Daiichi; Honoraria (institution), Advisory / Consultancy: Eisai; Honoraria (institution), Advisory / Consultancy: Lilly; Honoraria (institution), Advisory / Consultancy: Medpace; Honoraria (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (institution): Biovitrium; Honoraria (institution): 6th element capital; Advisory / Consultancy, Travel / Accommodation / Expenses: Adaptimmune; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Blueprint; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: BoBoehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: Cristal Therapeutics; Advisory / Consultancy, Travel / Accommodation / Expenses: Epizyme; Advisory / Consultancy, Travel / Accommodation / Expenses: Genzyme; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Loxo Oncology; Advisory / Consultancy, Travel / Accommodation / Expenses: Nektar; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis. H. Kopp: Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Speaker Bureau / Expert testimony: LeoPharma; Speaker Bureau / Expert testimony: Pfizer; Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Amgen. B. Kasper: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Eisai ; Honoraria (self), Research grant / Funding (institution): PharmaMar. L. Lindner: Advisory / Consultancy: Novartis; Honoraria (self): Lilly; Honoraria (self): Eisai; Honoraria (self): EZ Medconsultant; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): Sennewald. J.M. Chemnitz: Honoraria (self): Ablynx; Advisory / Consultancy: Amgen; Advisory / Consultancy: Ablynx; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: PharmaMar. G. Egerer: Honoraria (self): MSD; Advisory / Consultancy: MSD; Honoraria (self): PharmaMar; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Astellas. All other authors have declared no conflicts of interest.

Background: The choice of drug treatment in advanced soft tissue sarcoma (STS) continues to be a challenge considering efficacy, QoL and toxicity. Unlike other cancer types, where integrating patient reported outcomes (PRO) has proven to be beneficial for QoL, there is no such evidence in patients with STS yet. Methods: This multi-center study explored the effect of a comprehensive intervention on QoL in patients with STS undergoing treatment with trabectedin (Yondelis®). Seven hospitals were cluster-randomized into control cluster (CC with electronic [e] assessment of PRO) or interventional cluster (IC including ePRO and expert-consensus based treatment suggestions). The center, where the multidisciplinary treatment suggestions were created, served as a reference center (RC). Outcomes included QoL (measured with FACT-G), symptoms (MDASI), anxiety and depression (HADS) and pain intensity and interference (BPI). The explorative primary endpoint was change of FACT-G total score (range 0-108) after nine weeks. Results: 80 patients (50% male; mean age: 58.1 years, range: 22-87 years) were included. After nine weeks, decrease in QoL was smaller in IC (-2.04) than in the CC (-5.5) and RC (-4.75). Nevertheless, this trend failed to reach statistical significance (p = 0.235). Improved, but not significant (p = 0.247) median progression free survival was observed in IC (277 days) and CC (279 days) than in RC (126 days). Other PRO showed non-significant, but yet medium to large effects. Conclusions: This is the first study to include ePRO in patients with STS. The clinically important benefit in QoL observed in the IC could serve as a proof of principle to strengthen patient care. Beyond proofing statistical significance of the clinically meaningful effects, this study is an important prerequisite for future research in this area. Clinical trial identification: NCT02204111. Legal entity responsible for the study: GWT-TUD GmbH. Funding: PharmaMar, Spain. Disclosure: B. Kasper: Consultancy: Bayer, Clinigen, Eisai, Lilly; Honoraria: Bayer, Eisai, Lilly, Novartis, PharmaMar, Pfizer; Financing of research: PharmaMar. M. Schuler: Research Grant: PharmaMar. All other authors have declared no conflicts of interest.Table: 1606PDSociodemographic data at baselineInterventional cluster (IC), n = 39Control cluster (CC), n = 29Reference center (RC), n = 12p-valueAge, mean (SD) Range (years)58.39 (11.68), 38-8755.80 (14.92), 22-8063.00 (15.63), 34 - 820.440Tumor entity Leiomyosarcoma Liposarcoma Others18 10 159 10 155 3 7ECOG 0 1 220 15 314 13 05 7 00.300Patient Reported OutcomesIC, n = 3CC, n = 18RC, n = 8Cohens dp-valueFACT-G total Mean change after 9 weeks-2.04-5.50-4.750.720.235HADS depression Mean change after 9 weeks0.651.44-0.250.910.181HADS anxiety Mean change after 9 weeks0.000.78-0.880.720.235BPI pain severity Mean change after 9 weeks0.480.01-0.470.720.235BPI pain interference Mean change after 9 weeks0.620.15-0.230.700.241MDASI, symptom severity Mean change after 9 weeks0.600.29-0.230.680.247MDASI, symptom interference Mean change after 9 weeks1.031.000.210.040.482 Open table in a new tab

11507 Background: DOX is still the standard in metastatic STS. We assessed the efficacy and safety of oral TRO. Methods: This is a randomized phase 2 trial at 15 german and 1 french centers. We included pts with metastatic high-grade STS, older than 60 yrs of age, with an ECOG of 0-1. They were randomly (1:2) assigned to either (A) DOX (60 or 75 mg/sqm i.v., on day 1, q 22 d for 6 cycles) or arm B (oral TRO, 300 mg, d1-7, then 150mg daily continuously p.o.) as first-line tx. Randomisation was stratified by presence of liver mets, and PS (0 vs 1). Pts were treated until PD or unacceptable toxicity. Primary aim was a 6-months (mos) PFS rate of at least 20 % in Arm B; secondary: safety, ORR, survival. Results: Between 8/04 and 10/12 40 pts were randomly assigned to arm A and 80 to Arm B, median age 70 yrs (60-89). Median duration of f/u of surviving patients was 18.4 mos (range, 3.8-94.7). Median treatment duration was 2.8 mos (0-4.6) in A and 2.8 mos (0.4-41.4) in B. No difference in terms of ORR with 7.7% (1.6-20.9) in arm A and 6.7% (2.2-14.9%) in arm B (p = 0.99); disease control rate (including disease stabilization) (53.8% (95%-CI, 37.2-69.9%) vs. 41.3% (95%-CI, 30.1-53.3%), p = 0.23), PFS (4.3 mos; 95%-CI, 2.2-5.9 vs. 2.8 mos; 95%-CI, 1.6-3.5), p = 0.99) and OS (9.6 mos; 95%-CI, 6.4-11.6 vs. 12.1mos; 95%-CI, 9.5-16.0), p = 0.59) were seen, without difference in ITT- and per-protocol populations. Duration of response lasted 5.0 mos in arm A (range, 1.3-8.0) and 4.0 mos (0-46.6) in arm B; however, in pts achieving a CR or PR duration was longer in favor of cohort B (0 vs. 27.7 mos resp. 4.3 vs. 8.2 mos). Primary study endpoint (6-mos PFR) was 27.6% in Arm B (95%-CI, 18.0-39.1). Safety analyses in 115 pts showed at least one side effect in 97.4% vs. 96.1% pts (p = 0.99); of note, side effects G3-4 were lower in favor of Arm B (59% vs. 30.3%; p = 0.005). TRO caused more often dyspnoe, fatigue (but only minor degree); DOX leukocyto- and neutropenia as well as mucositis, G1-4. Discontinuation rate other than PD was 15.4% vs. 7.9%. Conclusions: In an elderly population of pts who received either standard Dox or oral TRO for metastatic STS, equal median PFS and OS have been achieved. TRO associated with a more favorable toxicity profile. Clinical trial information: 00204568.

11506 Background: The systemic treatment standard of advanced, inoperable STS in elderly pts is single agent DOX. We tested the hypothesis whether PAZ has comparable efficacy to DOX in elderly STS pts, while offering better tolerability. Methods: Key inclusion criteria: age ³60 years, no prior systemic treatment for STS, progressive disease, ECOG 0-2, adequate organ function. DOX 75 mg/m2 q3wks for a total of 6 cycles or PAZ 800 mg OD continuously were given after 1:2 randomization. ECOG 2 and liposarcoma histology were used for stratification. The primary endpoint was progression free survival (PFS) in the per protocol (PP) population. A non-inferiority design was applied with an upper limit of the 95% confidence interval (CI) of less than 1.8. Key secondary endpoints were neutropenia and febrile neutropenia in hierarchical order. EORTC QLQ-C30 was utilized to measure quality of life. Cox regression analysis, ANCOVA and Kaplan-Meier curves were applied (NCT01861951). Results: Between 10/2012 and 03/2016, 39 pts were randomly assigned to DOX and 81 to PAZ. The median follow-up was 11.8 months (mo). The median age was 71 years (range: 60-88). In the PP population, DOX vs. PAZ achieved a PFS of 5.3 vs. 4.4 mo (HR 1.00; 95%CI 0.65-1.53; P = .993), respectively. The incidence of neutropenia CTC grade 4 and neutropenic fever in patients were 56% and 10% for DOX and 0% and 0% for PAZ, respectively. OS was 14.3 vs. 12.3 mo. (HR 1.083; 95%CI 0.68-1.72; P = .735) for the intention to treat population. Most frequent AEs for DOX were fatigue (64.9%), alopecia (56.8%) and nausea (48.6%), and for PAZ fatigue (58.0%), nausea (43.2%) and diarrhea (43.2%). Similar outcome was reported for global EORTC QLQ-C30 measures. Conclusions: This study showed that PAZ was non-inferior compared to DOX, rendering PAZ a putative therapeutic option in the first line treatment of STS of pts above 60 years of age. The distinct AE profile may be used to council pts and tailor therapy to individual needs. Clinical trial information: NCT01861951.Outcome of primary and key secondary endpoints DOX PAZ HR 95%CI P value PFS 5.3 mo 4.4 mo 0.998 0.650-1.533 0.993 Neutropenia grade 4 56% 0% - - < 0.0001 Febrile neutropenia 10% 0% - - 0.003

Clonal hematopoiesis of indeterminate potential (CHIP) occurs in an age-related manner and associates with an increased risk of hematologic cancer, atherosclerotic disease, and shorter overall survival. Little is known about the cell of origin, repartition patterns of clonal mutations within the hematopoietic differentiation tree, and its dynamics under evolutionary pressure. Using targeted sequencing, CHIP was identified in 121 out of 437 elderly individuals (27.7%). Variant allele frequencies (VAFs) of 91 mutations were studied in six peripheral blood cell fractions. VAFs were significantly higher in monocytes, granulocytes, and NK-cells compared to B- or T cells. In all cases with available bone marrow material, mutations could be identified in Lin−CD34+CD38− HSCs with subsequent expansion to myeloid primed progenitors. In 22 patients with solid cancer receiving (radio-)chemotherapy, longitudinal study of 32 mutations at 121 time points identified relative VAF changes of at least 50% in 13/32 mutations. VAFs of DNMT3A, were stable in 12/13 cases (P < .001). Cancer patients with a clonal mutation other than DNMT3A required more often red blood cell transfusions and dose reductions. Our results provide novel insights into cellular distribution of clonal mutations, their dynamics under chemotherapy, and advocate for systematic analyses for CHIP in cancer patients.

Background: The EPAZ study (NCT01861951) showed that pazopanib was non-inferior to doxorubicin in advanced, inoperable STS in elderly pts. We report an analysis on HR-QoL of EPAZ. Methods: STS patients ³60 years were randomly assigned to receive either DOX 75 mg/m2 q3wks for a total of 6 cycles or PAZ 800 mg OD continuously in a 1:2 fashion. EORTC QLQ C30 and elderly minimal comprehensive geriatric assessment (consisting of G8 screening tool, Charlson Comorbidity Index (CCI), instrumental activities of daily living (IADL) and social situation) were utilized for HR-QoL evaluation. All tools were applied at baseline and end of treatment. Subsequent measures were as follows: QLQ C30 weeks 3, 6, 9, 12, 15, 19, and 26; geriatric assessment weeks 12, 26 and then every 12 weeks thereafter. Results: A total of 39 pts were randomly assigned to DOX and 81 to PAZ and PFS was 5.3 vs. 4.4 mo (HR 1.00; 95%CI 0.65-1.53; P=.993), respectively. The median age was 71 years (range: 60-88). Frequent AEs for DOX were fatigue (64.9%), alopecia (56.8%), nausea (48.6%) and constipation (13.5%), and for PAZ fatigue (58.0%), nausea (43.2%) and diarrhea (43.2%). QLQ C30 global scale and geriatric assessment were not significantly different at baseline nor at time points during the study. For DOX and PAZ 9 (25.0%) and 25 (32.5%) pts. were dependent (P=.4200) and 36 (100%) and 71 (97.3%) pts. remained at home (P=.6018), respectively. Overall the CCI was low for DOX 0 (IQR 0-1) and PAZ 0 (IQR 0-1) (P=.7244). However, differences were detected in QLQ C30 symptom scales at week 9, indicating more symptoms from diarrhea for PAZ (P = 0.0274) and more symptoms from constipation for DOX (P = 0.0409). The remaining functional and symptom scales remained without significant difference between treatment groups. Conclusions: EPAZ recruited mainly independent and fit elderly patients with STS. While achieving non-inferior PFS, no apparent difference in HR-QoL measures was seen between treatment groups, except for symptom scales addressing specific adverse events of DOX (constipation) and PAZ (diarrhea). Clinical trial identification: NCT01861951. EudraCT: 2011-004168-30 Legal entity responsible for the study: Medical School Hannover. Funding: Novartis. Disclosure: V. Grünwald: Consulting: BMS, MSD, Merck Kga, AstraZeneca, Novartis, Pfizer, Ipsen, Cerulean, EUSA-Pharma, Roche; Shares: BMS, MSD, AstraZeneca; Honoraria: BMS, MSD, Merck Kga, AstraZeneca, Novartis, Pfizer, Ipsen, Eisai, Roche; Research funding: AstraZeneca, BMS, MSD, Pfizer; Travel: MSD, BMS, Roche. M. Schuler: Research funding: Novartis. P. Schöffski: Honoraria: Daiichi, Eisai, Lilly, Medscape, Novartis, Swedish Orphan Biovitrium; Consulting: 6th Element capital, Adaptimmune, Amcure, AstraZeneca, Bayer, Blueprint, BMS, Boehringer Ingelheim, Cristal Therapeutics, Daiichi, Lilly, Epizyme, Genzyme, Ipsen, Loxo Oncology, Medscape, Nektar, Novartis, Philogen, Piquir Ther., Plexxikon; Speaker's bureau: Bayer, Eisai, Lilly, GSK, Novartis, PharmaMar, Swedich Orphan Biovitum; Research: Bayer, Blueprint, Cobiores. H-G. Kopp: Consulting: MSD, BMS, Sanofi; Expert testimony: Novartis, Pfizer, IcoPharma; Travel: Sanofi, Lilly, Amgen, Novartis, MSD. B. Kasper: Honoraria: Bayer, Lilly, Novartis, PharmaMar; Consulting: Bayer, Lilly, Eisai; Rsearch funding: PharmaMar. L.H. Lindner: Reasearch funding: Sennewald Medizintechnik; Travel: PharmaMar; Consulting: Novartis, Lilly, Eisai, EZ Medconsult; Speaker Bureau: PharmaMar. J.M. Chemnitz: Honoraria: Ablynx; Consulting: Amgen, Ablynx; Travel: Amgen, PharmaMar. G. Egerer: Consulting: MSD; Speaker Bureau: MSD, PharmaMar; Travel: MSD, Astellas. All other authors have declared no conflicts of interest.