bluuebunny/crossref_metadata_2025 huggingface dataset:
Perceptions of research training in a hematology/oncology fellowship program.
Authors: Pritzl Stephanie L , Lang Laura M , Lang Joshua Michael , Lubner Sam Joseph , Parkes Amanda Marie
Published: May 2020

11030

Background: Current research training in Hematology/Oncology (Heme/Onc) fellowship is typically limited to mentoring relationships, which are highly variable due to the absence of standardized training for mentors and different perceptions of successful mentor-mentee relationships. Formal research productivity assessment is challenging and lacking in our current educational framework. Methods: Electronic surveys were developed to assess research training during fellowship at the University of Wisconsin (UW). Surveys were sent to current Heme/Onc fellows (n = 9), members of fellowship leadership (n = 4), and core research faculty (n = 5) with prior successful mentorship to trainees. Results: Surveys were completed by 6 fellows, 3 fellowship leadership, and 5 core research faculty. Both faculty and trainees recognized the research mentor-mentee relationship to be critical, with 5/6 (83%) fellows and 3/5 (60%) core research faculty identifying research mentors as the most meaningful training source. However, despite 5/6 (83%) fellows having a research mentor identified, there were large variations in the perceived level of proficiency in core research topics. While 3 fellows felt only slightly prepared in basics of clinical trial design, 1 fellow felt very prepared and 2 felt somewhat prepared. Furthermore, 2 fellows each felt very prepared, somewhat prepared, or not at all prepared in assembling grant components. There was also variable confidence reported by core research faculty in the ability of trainees to obtain funding and conduct independent research after fellowship, with 1 extremely confident, 2 somewhat confident, and 2 only a little confident. All individuals surveyed recognized manuscript publication, abstract presentation, and grant acquisition as important measures of research productivity. Beyond that, however, only 1/5 (20%) core research faculty and 0/3 (0%) fellowship leadership noted using rubrics for critical review of trainee academic progress despite 3/6 (50%) fellows believing that such rubrics were being used for their evaluation. Conclusions: The divergent experiences identified among research mentors and mentees and the lack of clearly defined metrics of research productivity highlights the need for a more standardized educational framework and formative evaluation tools. These identified needs have led to a pilot program at UW that intends to create a professional learning community for research mentors, define competencies for research training, and design a research training portfolio and accompanying assessment rubric.
Assessing impact of inpatient rotations on resident interest in hematology-oncology.
Authors: Farooqi Bilal , Meyer Lynne , Close Julia Lee , Duff Jennifer Michelle
Published: May 2020

11031

Background: Working as a hematologist-oncologist is rewarding yet challenging. As cancer cases increase, there is a growing need to recruit more oncologists. It has been hypothesized that earlier exposure to oncology may improve resident interest in the field. This is often achieved by rotations on inpatient oncology wards, which represents only a small subset of the clinical work typical in hematology-oncology. We looked to assess whether early exposure to an inpatient oncology rotation impacts pursuit of this career path. Methods: Categorical interns in Internal Medicine at the University of Florida during year 2017-2018 were surveyed anonymously before and after their inpatient oncology rotation. Confidential identifiers were used to pair surveys. Similar surveys were used in the cardiology and gastroenterology rotations to allow for comparison. The survey included descriptor words to choose when describing the field. These words were categorized as either positive or negative. Results: Thirty-three interns were surveyed. Seventeen surveys were able to be paired (52% response rate) in oncology. Cardiology had 15 paired survey responses and gastroenterology had 13 paired responses. Using a 4-point Likert scale, interest in hematology-oncology decreased overall from 3.12 to 2.82 (p = 0.059) while interest in pursuing a fellowship remained the same. Stress levels were increased slightly from 2.30 to 2.05 (p = 0.564). Cardiology also saw a decrease in interest in the field from 3.53 to 2.93 (p = 0.007) but also an increase in pursuing fellowship from 2.20 to 2.60 (p = 0.014) and decreased stress from 3.13 to 2.67 (p = 0.020). Gastroenterology saw a decrease in interest in the field as well from 3.46 to 2.92 (p = 0.020). Interest in pursuing a fellowship and stress levels were not significantly different for gastroenterology. Field descriptors including “challenging,” “scared,” and “excited” decreased the most while “confident,” “inspired,” and “motivated” increased the most when describing hematology-oncology. Conclusions: While interest in this field was negatively impacted, stress levels associated with the field decreased. Furthermore, field descriptors were generally more positive and optimistic in the post-rotation setting. Though not statistically significant, these findings suggest that interns see oncology as less stressful and feel more capable after inpatient exposure during intern year. As much of hematology-oncology practice is outpatient, increasing intern exposure in this area may further improve perception and recruitment to the field.
Use of oncology electronic learning resources to learn about geriatric oncology.
Authors: Hsu Tina , LaDonna Kori , Touchie Claire
Published: May 2020

11033

Background: Despite the aging population driving cancer growth, oncology trainees receive little training in geriatrics. While electronic resources, such as ASCO University, may help meet this gap, use of available geriatric oncology (GO) modules is low. We sought to understand why by exploring how oncology trainees currently learn about GO, their preferred methods for learning about GO, and their attitudes towards e-learning and geriatrics. Methods: Canadian medical oncology residents and recent graduates were electronically surveyed about the following domains: demographics, self-directed learning practices, use of electronic resources, perceived facilitators and barriers to e-learning, and geriatric oncology teaching. Descriptive statistics were used to analyze the data. Results: Respondents (n = 47) were mostly aged < 35 (66%). Respondents felt that learning about older adults was important (mean 4.3±1.0 out of 5) and generally felt comfortable caring for them (mean 3.9±0.9 out of 5) despite minimal training in geriatrics.Almost half (48.9%) received 0-2 hours of teaching in GO during residency, with the majority (59.6%) receiving teaching in clinic, 36.2% through lectures and 21.3% via seminars. Respondents also learned about GO through reading journal articles (42.6%), modelling in clinic (36.2%), reading a textbook (19.2%) or attending a conference (19.2%). Respondents preferred to learn about GO through on-site lectures (46.8%), dinner meetings (42.6%), case discussion (42.6%) and attending conferences (38.3%). Although overall respondents highly valued electronic learning (mean 4.3±0.75 out of 5), only a minority (8.5%) had received GO teaching electronically using e-modules and only 23.4% respondents were aware of e-learning resources in GO. In contrast most respondents (83%) had used an e-learning resource to learn about oncology. The most common oncology e-resources used were ASCO University (61.7%), Oncology Education (61.7%), and ASCO meeting videos (44.7%). Conclusions: Although oncology trainees value and commonly use e-learning resources, e-learning is not a common or preferred way to learn about GO, potentially due to lack of awareness about these resources. Future research will explore whether the current methods of educating oncology learners about older adults are appropriate and sufficient, as well as how trainees value and prioritize learning about topics that are not included in the formal curricula.
Effect of live education targeted to genetic counselors on knowledge and competence.
Authors: Carranza Vanessa , Gitzinger Susan H. , Taylor Bryan Carson , Fowler Joan B.
Published: May 2020

11035

Background: Rapid advancements in genomics and sequencing technologies have presented a growing need for experts in the field of genetics to translate results and optimize patient care. As knowledge regarding DNA mutations and the technology to properly detect them continuously advances, it will be vital that genetic counselors play a larger role in the oncology healthcare team. Methods: These activities were designed to target genetic counselors involved in the diagnosis, management and genetic counseling of patients who have or are at risk for DDR-mutated cancers, attending live symposia at the 2018 & 2019 American College of Medical Genetics & Genomics Annual Meeting. Learning and knowledge was objectively assessed by analyzing pre- and post-test results before and after the educational activities. To determine retention of knowledge over time, follow-up assessments were sent to participants after each live activity. Assessment questions in the form of case studies were utilized to gauge whether participants translated knowledge into practice at follow-up. Statistical testing between pre- and post-tests and from pre-test to follow-up were conducted via chi square analysis with a priori significance set at 0.05. Results: Evaluations were collected from N = 275 (onsite) participants. Improved learners, as determined by significant ( P < 0.05) increases in correct responses, were observed in several specific topic areas: When to consider germline testing (2018 participants: 53.33% pre-test vs. 87.5% post-test; 2019 participants: 42.55% pre-test vs. 84.72% post-test). Patients most likely to benefit from a PARP inhibitor based on genetic testing results (2018 participants: 50% pre-test vs. 93.75% post-test; 2019 participants: 75.49% pre-test vs. 94.37% post-test). However not all improvement was sustained at follow-up: When it is appropriate to consider germline testing (2018 participants: 64.44% at follow-up – not significant ( P= 0.138); 2019 participants: 85% at follow-up ( P< 0.001). Patients most likely to benefit from a PARP inhibitor based on genetic testing results (2018 participants: 68.89% at follow-up – not significant ( P= 0.140); 2019 participants: 65% at follow-up – not significant ( P= 0.329). Conclusions: This analysis shows that live accredited education can significantly improve the knowledge and competence of genetic counselors in multiple areas surrounding the use of germline testing to guide treatment recommendations. Results also suggest that ongoing education in clinically appropriate scenarios is warranted.
Customized social media-based oncology education.
Authors: Punukollu Udaykumar , Jonnadula Jyothi , Rasheed Abdul , Parikh Purvish Mahendra , Srilanari Numburu , Chanakya Ajay , Thomas Joseph , Patlolla Rajkumar , Gundeti Sadashivudu , Bala Stalin J. , Chennamaneni Rachana , Konatam Meher Lakshmi , P Venkateswar Rao , Shrivastva Sarita ,   Team Abhaya
Published: May 2020

11038

Background: Social media has profoundly impacted our professional lives. Quick access to reliable sources of information and engaging with like-minded experts certainly aids in professional development. The purpose of this study is to assess the perception of oncology experts towards social media based education and to develop a platform based on their feedbacks for constructive engagement of the professionals and to improve educational outcomes. Methods: Based on Kirkpatrick 4 level model, 15 questions were designed for oncology experts. We collected responses through online surveys and by distributing the questionnaires at oncology events. Based on the results obtained, we developed a customised social media application for oncologists in android version. User experience design was done in InVision Studio and Model View Presenter (MVP) design pattern was used in software development. Beta testing of the application was done with 50 experts and questionnaire was given to them at the end of beta testing period to compare the technical advantages of our mobile application with their currently preferred social media platform for oncology based education. Results: Among 311 responders, medical oncologists, radiation oncologists, surgical oncologists, hemato oncologists and oncopathologists constituted 45%, 29%, 16%, 7% and 3% respectively. Only 14% clearly denied that social media has improved educational outcomes. Eighty seven percent felt that they lack adequate knowledge in other areas of expertise and 67% of the oncologists were not well informed about the latest oncology updates. Only 60% could actively engage in interdiscliplinary collaboration due to reasons unspecified. When asked about the best way to learn a topic of interest, majority opined it through peer discussion with experts pertaining to that topic of interest. The two major problems faced by experts while seeking social media based education is academic discussions being unorganised and non-academic discussions unwelcomed. After considering these feedbacks, a mobile application in android version was developed. At the end of beta testing, 96% reported a technical advantage of our customised application over their preferred social media based oncology education. Conclusions: A minimum viable product has been developed after considering the feedbacks received from oncologists of various sub-specialities. Such a customised social media application is more appealing when easily applicable across low and middle income countries and in a manner that allows addition of local language options without changing the application software.
Comparison of two chemotherapy regimens in Ewing sarcoma (ES): Overall and subgroup results of the Euro Ewing 2012 randomized trial (EE2012).
Authors: Brennan Bernadette , Kirton Laura , Marec-Berard Perrine , Martin -Broto Javier , Gelderblom Hans , Gaspar Nathalie , Strauss Sandra J , Sastre Urgelles Ana , Anderton Jennifer , Laurence Valerie , Whelan Jeremy , Wheatley Keith
Published: May 2020

11500

Background: In 2010, different chemotherapy regimens were standard in Europe and the USA for newly diagnosed ES. In the absence of novel agents to investigate, comparison of these two strategies was considered worthwhile. Methods: Newly diagnosed localised or metastatic ES patients aged 5-50 were eligible. Patients were randomized to receive either the European regimen (Arm A) of VIDE (vincristine [V], ifosfamide [I], doxorubicin [D] and etoposide [E]) induction and VAI or VAC (V, actinomycin D and I or cyclophosphamide [C]) consolidation or the USA regimen (Arm B) of compressed VDC/IE induction and IE/VC consolidation. The primary outcome measure was event-free survival (EFS); secondary outcomes included overall survival (OS) and toxicity. The design was Bayesian with interpretation based on posterior probabilities (with non-informative priors) – i.e. probability that true hazard ratio (HR) < 1.0 given the data [Pr(HR<1.0|data)], with 95% credible intervals (CrI) reported. HRs were obtained from Cox models adjusted for baseline stratification parameters. Heterogeneity tests (HT) were used to investigate whether the treatment effect differed according to baseline parameters. Analysis was intention-to-treat. Results: Between December 2013 and May 2019, 640 patients were randomised (320 to each arm) from 10 European countries. Baseline stratification factors were: sex (58% male; 42% female); age (41% <14 years; 59% 14+ years); disease type (74% localised, 17% lung/pleural metastasis, 9% other metastasis); tumour volume (56% <200 ml, 44% >200 ml); country (37% UK, 31% France, 32% other). Median follow-up was 1.7 years. The HRs (95% CrI) were 0.70 (0.51, 0.95) for EFS and 0.64 (0.42, 0.96) for OS in favour of Arm B, with posterior probabilities of 98% for both that Arm B was better. Subgroup analyses showed no evidence that this benefit differed depending the baseline features, with no HT being close to significance (table). There were no major differences in acute toxicity: 68% of patients in Arm A experienced serious adverse events and 67% in Arm B. Conclusions: VDC/IE chemotherapy is superior to VIDE for both EFS and OS, with no excess toxicity. This benefit is consistent across all baseline stratification parameters. Clinical trial information: ISRCTN92192408 . [Table: see text]
Efficacy of add-on treosulfan and melphalan high-dose therapy in patients with high-risk metastatic Ewing sarcoma: Report from the International Ewing 2008R3 trial.
Authors: Dirksen Uta , Bhadri Vivek , Brichard Bénédicte , Butterfass-Bahloul Trude , Cyprova Sona , Faldum Andreas , Gelderblom Hans , Hardes Jendrik , Hauser Peter , Havemann Lianne , Hjorth Lars , Juergens Heribert , Kanerva Jukka , Kuehne Thomas , Ladenstein Ruth Lydia , Raciborska Anna , Rascon Jelena , Timmermann Beate , Ranft Andreas , Koch Raphael ,   on behalf of the Cooperative Ewing Sarcoma Study Group Ewing 2008, Sponsor UKM
Published: May 2020

11501

Background: Ewing 2008R3 (EudraCT2008-003658-13) was conducted in 12 countries. It evaluated the effect of treosulfan and melphalan high dose chemotherapy followed by re-infusion of autologous hematopoietic stem cells (HDTreoMel) on event-free (EFS, primary endpoint) and overall survival (OS) in high-risk Ewing Sarcoma (EwS). Methods: Phase III, open label, prospective, multi-center, randomized controlled clinical trial. Eligible patients (pts) had disseminated EwS with metastases to bone and/or other sites, excluding pts with only pleuropulmonary metastases. Pts received 6 cycles of VIDE induction and 8 cycles of VAC consolidation therapy. Patients were randomized to receive additional HDTreoMel chemotherapy or no further treatment (control), They were further stratified by number of bone metastases (1, 2-5, > 5). One-sided adaptive inverse-normal 4-stage design, changed after the 1st interim analysis via Müller-Schäfer method. Initial sample size 185 pts, type I error rate 2.5%, power 80%. Results: 109 pts were randomized between 2009 and 2018: 55 were randomized to HDTreoMel. With a median follow-up of 3.3 years, the primary endpoint EFS was not significantly different between HDTreoMel and control in the adaptive design (HR 0.85, 95% CI 0.55-1.32, intention-to-treat). 3-year (3y) EFS was 20.9 % (95% CI 11.5-37.9%) in HDTreoMel and 19.2 % (95% CI 10.8-34.4%) in control pts. Results were similar in the per protocol collective. Subgroup analyses showed that independent of treatment, male patients had a worse outcome than female patients: 3y EFS 13.3% (95% CI 5.7-31.1%) vs 25.2% (95% CI 15.5-40.8%); p = 0.07. Patients aged < 14 had a better outcome when treated in the HDTreoMel group: 3y EFS 39.3% (95% CI 20.4-75.8%) vs 9% (95% CI 2.4-34%); p = 0.016; HR 0.40 (0.19-0.87). These effects were similar in the per protocol collective. Severe toxicities of hematology, gut, general condition and infection were more pronounced in the HDTreoMel group (p < 0.05). Conclusions: In patients with very high risk EwS, additional HDTreoMel was of no benefit for the entire cohort of patients. HDTreoMel may be of benefit for children age < 14. This observation is supported by comparable results from a non-randomized trial EE99 R3 (Ladenstein et al. JCO, 2010). Clinical trial information: NCT00987636 .
Preliminary results of a phase II study of neoadjuvant checkpoint blockade for surgically resectable undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS).
Authors: Roland Christina Lynn , Keung Emily Zhi-Yun , Lazar Alexander J. , Torres Keila E , Wang Wei-Lien , Guadagnolo Ashleigh , Bishop Andrew Justin , Lin Heather Y. , Hunt Kelly , Feig Barry W. , Bird Justin E. , Lewis Valerae O. , Tawbi Hussein Abdul-Hassan , Ratan Ravin , Patel Shreyaskumar , Wargo Jennifer Ann , Somaiah Neeta
Published: May 2020

11505

Background: is a randomized, phase II non-comparative trial evaluating the efficacy of neoadjuvant checkpoint blockade [nivolumab (N) or ipilimumab/ nivolumab (I/N)] in patients (pts) with surgically resectable retroperitoneal DDLPS or extremity/truncal UPS treated with concurrent neoadjuvant radiation therapy (RT, UPS only). Methods: Primary endpoint was pathologic (path) response. Secondary endpoints were safety, RECIST response, recurrence-free survival, overall survival and patient-reported outcomes. Biospecimens (tumor, blood, fecal microbiome) at baseline, on therapy, and at time of surgery were collected and will be assessed for immune-based prognostic biomarkers. We assessed correlation between radiographic and pathologic response by linear regression. Correlative analyses includes assessment of tumor PD-L1 expression, characterization of tumor immune infiltrates by multiplex immunohistochemistry, and transcriptomic and genomic analyses. Results: Of the 25 pts enrolled; 24 are evaluable for response (14 DDLPS, 9 UPS). Clinical activity was variable by histologic subtype and treatment with RT. Median path response in the UPS cohort was 95% [95% CI 85–99] and was similar between the N/RT and I/N/RT groups (Table). Median path response in the DDLPS cohort was 22.5% [95% CI 85–99; Table]. Median change in tumor size (radiographic response) was -4% and +9% in the UPS and DDLPS cohorts, respectively. There was no correlation between path response and radiographic response (R2 0.0309; p = 0.43). Of 8 pts with path response ≥ 85%, there was 1 partial response, 5 stable disease and 2 progressive disease by RECIST criteria. There was 1 delay to surgery due to grade 3 hyperbilirubinemia (Arm B). There was no difference in toxicity between N/RT and I/N/RT. Conclusions: N/RT and I/N/RT have significant clinical activity in UPS; more than expected compared to historic controls. Toxicity profiles were as expected and the majority of patients underwent resection without delay. Larger studies evaluating N/RT in UPS are warranted given the significant path response in this cohort. RECIST was not associated with path response and better markers of on-treatment clinical activity are needed. Correlative analyses that may guide combination strategies are ongoing and will be presented at the meeting. Clinical trial information: NCT03307616 .
Defining the role of neoadjuvant systemic therapy in high-risk retroperitoneal sarcoma: A multi-institutional TARPSWG study.
Authors: Tseng William W. , Barretta Francesco , Conti Lorenzo , Grignani Giovanni , Tolomeo Francesco , Albertsmeier Markus , Angele Martin K , Rutkowski Piotr , Skoczylas Jacek , De Paoli Antonino , Navarria Federico , Hu James S , Raut Chandrajit P , Fairweather Mark , Farma Jeffrey M. , Nessim Carolyn , Goel Neha , Subhawong Ty , Grignol Valerie Patrice , Gronchi Alessandro ,   on behalf of the Transatlantic Australasian Retroperitoneal Sarcoma Working Group
Published: May 2020

11513

Background: Surgery is the mainstay of treatment for patients with retroperitoneal sarcoma (RPS), but this can be challenging, and recurrence rates are high. Novel treatment approaches are needed. In this study, we sought to 1) determine the frequency and potential predictors of radiologic tumor response and 2) assess clinical outcomes in patients with primary high risk RPS who were treated at sarcoma referral centers with neoadjuvant systemic therapy followed by surgery. Methods: Clinicopathologic data was retrospectively collected for eligible patients treated from 2008-2018 at 13 institutions within the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG). For each patient, preoperative objective response (RECIST1.1) was reported by each institution. Univariable and multivariable logistic models were performed to determine predictors of response. Kaplan-Meier plots were constructed for overall survival (OS) and cumulative incidences of local recurrence (LR) and distant metastasis (DM). Results: In total, 158 RPS patients were included in this study. A median of 3 cycles (IQ range 2-4) of neoadjuvant systemic therapy were given. No complete responses were observed. Partial response (PR) was seen in 37 patients (23%), stable disease (SD) in 88 (56%) and progressive disease (PD) in 33 (21%). Subtype-specific differences were seen including PR in 5 out of 11 (45%) patients with undifferentiated pleomorphic sarcoma. Overall, higher number of cycles given was positively associated with PR (p = 0.005). No other factors including receipt of neoadjuvant radiation therapy were predictive of PR. All patients underwent complete (R0/R1) resection with a major complication (Clavien-Dindo ≥3) rate of 23%. Differences in OS were observed based on preoperative response type (p = 0.005). In grade 3 dedifferentiated liposarcoma, patients who received adriamycin-ifosfamide versus another regimen had decreased LR and improved OS. In leiomyosarcoma, patients who received adriamycin-DTIC versus another regimen had a higher PR rate (37% vs. 16%), decreased LR, DM and improved OS. Limited by low numbers, these subtype-specific data did not reach statistical significance. Conclusions: In patients with high risk RPS, response to neoadjuvant systemic therapy is overall modest and may be regarded as an indicator of disease biology to predict survival after surgery. Subtype-specific regimens should be further validated and incorporated into prospective trials of neoadjuvant systemic therapy in RPS (e.g. STRASS2).
A randomized phase II study of gemcitabine (G) alone or with pazopanib (P) in refractory soft tissue sarcoma (STS).
Authors: Ryan Christopher W. , Degnin Catherine , Cranmer Lee D. , Chen Yiyi , Pollack Seth , Tonkinson Jesse , Norr Phillip , Davis Lara E.
Published: May 2020

11515

Background: Both G and P are active single-agents in the treatment of STS. We hypothesized that the anti-VEGF-R activity of P could augment the efficacy of G and conducted this study of G+P vs G+placebo (0). Methods: In this multi-center, double-blind study, eligibility included metastatic STS with receipt of 1–3 prior systemic regimens inclusive of an anthracycline. Patients (pts) were stratified by sarcoma subtype (liposarcoma (LPS) vs. other) and study site, then randomly assigned 1:1 to receive G 1000 mg/m2 IV over 30 minutes on days 1 and 8 every 21 days plus either P 800 mg PO or matching 0 daily. The primary endpoint was progression-free survival (PFS). Results: 54 pts were accrued from 2012–2019, Accrual was halted prior to the planned N of 80 due to withdrawal of funding. There were no differences in pt characteristics between the two arms including age (median = 60), sex (M/F 52/48%), histology (LPS 30%, leiomyosarcoma 26%, UPS 15%, synovial 11%, other 17%) and number of prior systemic therapies (median = 1). With a median follow-up of 19.1 months, PFS favored G+P and was significant using the Gehan-Wilcoxon test which favorably weighs earlier events (table). The response rate was 6.9% on the G+P arm and 8.0% on the G+0 arm; response rate was 22% for LPS treated with G+P. The most common grade ≥3 AEs (G+P v G+0) were: neutropenia (41% vs 40), hypertension (17% v 4), anemia (7% v 12). One patient died of hepatic failure on the G+P arm. Conclusions: This study demonstrated improved PFS with G+P as compared with G alone. Early termination limited statistical power. G+P is active in LPS, although P regulatory labeling currently limits use for LPS. Clinical trial information: NCT01532687 . [Table: see text]
SAINT: Results of an expanded phase II study using safe amounts of ipilimumab (I), nivolumab (N), and trabectedin (T) as first-line treatment of advanced soft tissue sarcoma [NCT03138161].
Authors: Gordon Erlinda Maria , Chua-Alcala Victoria S. , Kim Katherine , Dy Paul Stendahl , Paz Micaela Kristina , Angel Nicole , Moradkhani Ania , Quon Doris , Wong Steven , Jafari Omid , Chawla Sant P.
Published: May 2020

11520

Background: Sarcoma cells are most immunogenic earlier in the disease. Hypothesis: Immune checkpoint inhibitors would be most effective when given as first-line therapy. Methods: Eligible patients include previously untreated male or female patients, ≥ 18 years of age with locally advanced unresectable or metastatic soft tissue sarcoma (STS), with measurable disease by RECIST v1.1. Immune checkpoint inhibitors I (1 mg/kg i.v. q 12 weeks) and N (3 mg/kg i.v. q 2 weeks) were given with T (1.2 mg/m2 i.v. q 3 weeks), a tumoricidal agent that depletes growth-promoting macrophages in the tumor microenvironment. Primary endpoint: Objective response rate by RECIST v1.1; Secondary endpoints: (1) Progression-free survival (PFS) at 6 months, (2) Overall survival (OS) at 6, 9, 12, 24, and 48 months, and (3) Incidence of adverse events. Results: Efficacy analysis: There were forty-one evaluable subjects. Best overall response rate was 19.5%; disease control rate 87.8%. The median OS was >12.5 months; median PFS was >6.0 months (6-month OS rate: 75%; 6-month PFS rate: 50%). Safety analysis: Grade 3 TRAEs include fatigue (n = 5), increased TSH (n = 3), decreased TSH (n = 1), adrenal insufficiency (n = 1), hyperglycemia (n = 1), dehydration (n = 1), hyponatremia (n = 2), bipedal edema (n = 2), increased AST (n = 8), increased ALT (n = 19), increased ALP (n = 2), increased CPK (n = 3), port site infection (n = 2), psoriasis exacerbation (n = 1), anemia (n = 6), thrombocytopenia (n = 2), and neutropenia (n = 2). Grade 4 TRAES include neutropenia (n = 1), thrombocytopenia (n = 2), and increased CPK (n = 2). Conclusions: These data suggest that combinatorial therapy with Ipilimumab, Nivolumab and Trabectedin (1) may have synergistic activity in achieving disease control, and (2) is safe with manageable toxicity for patients with previously untreated STS. Clinical trial information: NCT03138161 . [Table: see text]
IMMUNOSARC: a collaborative Spanish (GEIS) and Italian (ISG) sarcoma groups phase I/II trial of sunitinib and nivolumab in advanced soft tissue and bone sarcoma: Results from the phase II part, bone sarcoma cohort.
Authors: Palmerini Emanuela , Lopez-Pousa Antonio , Grignani Giovanni , Redondo Andres , Hindi Nadia , Stacchiotti Silvia , Sebio Ana , Lopez-Martin Jose A. , Valverde Morales Claudia Maria , Martinez-Trufero Javier , Gutierrez Antonio , de Alava Enrique , D'Ambrosio Lorenzo , Collini Paola , Picci Piero , Casali Paolo Giovanni , Martin Broto Javier
Published: May 2020

11522

Background: Herein, we present the results of the cohort on advanced bone sarcoma patients of the phase II part of the IMMUNOSARC study (NCT03277924), a European multicentre phase I-II trial aimed at investigating the activity of the combination of sunitinib (SU) and nivolumab (NI) in selected advanced sarcoma subtypes. Methods: Adult, pre-treated, progressing patients, ECOG 0-1, with a diagnosis of osteosarcoma, high-grade bone sarcoma, Ewing sarcoma, chondrosarcoma or dedifferentiated chondrosarcoma were eligible. SU 37.5 mg/day as induction was given days 1-14 and then reduced to 25mg/day continuously. NI was administered at 3 mg/Kg every 2 weeks from week 3. SU-NI was maintained up to progression or intolerance. Primary end-point was progression-free survival rate (PFSR) at 6 months (H1: PFSR 6-months: 15%). Secondary end-points: overall survival (OS), objective response rate (ORR) by RECIST v 1.1 and toxicity. Results: From Nov 2017 to Dec 2018, 40 eligible patients were included: (M/F = 27/13), median age 47 years (range 21-74), ECOG 0 in 11 (27%) cases, 36 (90%) were metastatic, 4 (10%) locally advanced. Histology: 17 osteosarcomas (43%), 14 chondrosarcomas (35%) (4 dedifferentiated), 8 Ewing sarcomas (20%), 1 bone undifferentiated pleomorphic sarcoma (2%). PFSR at 6 months based on local evaluation was 32%. At a median FU of 12.5 months (2-26), median PFS was 3.7 months (95% IC 3.4-4) while median OS was 14.2 months (95%CI: 7.1-21.3). OS rate at 3 and 6 months were 87% and 73%, respectively. ORR by RECIST: 1 CR (2.5%) (1 patient with dedifferentiated chondrosarcoma, lasting 22 months and on going), 1 PR (2.5%) (1 patient with osteosarcoma, lasting 5.7 months), 22 SD (55%, lasting > 6 months in 45% of the cases) and 16 PD (40%). G3/5 toxicities are detailed in Table. Conclusions: The trial met its primary endpoint in the cohort of patients with advanced bone sarcoma, with > 30% of patients free from progression at 6 months. Pre-planned tumor microenvironment genomic, exploratory analysis on pre and post-treatment tumor samples is on going. Clinical trial information: NCT03277924 . [Table: see text]
Efficacy of maintenance therapy with zoledronic acid in patients with localized Ewing sarcoma: Report from the international Ewing 2008 trial.
Authors: Dirksen Uta , Koch Raphael , Bhadri Vivek , Brichard Bénédicte , Butterfass-Bahloul Trude , Cyprova Sona , Gelderblom Hans , Hauser Peter , Havemann Lianne , Hjorth Lars , Juergens Heribert , Kanerva Jukka , Kuehne Thomas , Ladenstein Ruth Lydia , Raciborska Anna , Rascon Jelena , Streitbuerger Arne , Timmermann Beate , Ranft Andreas , Faldum Andreas ,   on behalf of the Cooperative Ewing Sarcoma Study Group Ewing 2008, Sponsor UKM
Published: May 2020

11523

Background: Ewing 2008R1 (EudraCT2008-003658-13, Sponsor UKM) was conducted in 12 countries. It evaluated the effect of zolendronic acid (ZOL) maintenance therapy on event-free (EFS, primary endpoint) and overall survival (OS) from randomization in standard risk Ewing Sarcoma (EwS). Methods: Phase III, open label, prospective, multi-center, randomized controlled clinical trial. Eligible patients (pts) had localized EwS with either good histological response to induction chemotherapy and/or small tumors ( < 200ml). Pts received 6 cycles VIDE induction and 8 VAI (male) or 8 VAC consolidation (female) and were randomized to receive either 9 cycles of maintenance ZOL or no further treatment (control;ctrl). ZOL cycles started parallel to the 6th consolidation cycle. Randomization was stratified by tumor site (pelvis/no pelvis). Two-sided adaptive inverse-normal 4-stage design, changed after the 1st interim analysis via Müller-Schäfer method. Initial sample size 448 pts, type I error rate 5%, power 80%. Results: 284 pts were randomized between 2009 and 2018 (142 ZOL / 142 ctrl). With a median follow-up of 3.9 years, the primary endpoint EFS was not significantly different between the ZOL and ctrl group in the adaptive design (HR 0.74, 95% CI 0.43-1.28, intention to treat). 3-year (3y) EFS rates were 84.0% (95% CI 77.7-90.8%) for ZOL vs 81.7% (95% CI 75.2-88.8%) for ctrl. Results were similar in the per protocol collective. Cause-specific HR for local recurrence in ZOL was csHR 0.30 (95% CI 0.08 -1.09; p = 0.07), for metastatic progress/new metastases csHR 1.0 (CI 0.5-2.2), for combined relapse/progress csHR 0.3 (95% CI 0.1-1.7), for second malignancies csHR 4.0 (95% CI 0.45-36.1) compared to ctrl. The 3y OS was 92.8% (95% CI 88.4-97.5%) for ZOL and 94.6% (95% CI 90.9-98.6%) for ctrl. For ZOL the 5y OS was 87.3% (95% CI 80.7-94.5%) and 89% (95% CI 83.7-95.9%) for ctrl. Noticeable more renal, neurological and gut toxicities were observed for ZOL (p < 0.05), with severe renal toxicities occurring more often in the ZOL arm (p = 0.003). Conclusions: In patients with standard risk localized Ewing Sarcoma there is no benefit from maintenance treatment with zoledronic acid, but significant side effects were observed. Clinical trial information: NCT00987636 .
A randomized, double-blind, phase II clinical trial of GI-6301 (yeast-brachyury vaccine) versus placebo in combination with standard of care definitive radiotherapy in locally advanced, unresectable, chordoma.
Authors: DeMaria Peter Joseph , Bilusic Marijo , Park Deric , Heery Christopher Ryan , Madan Ravi Amrit , Strauss Julius , Donahue Renee Nicole , Marte Jenn , Gilbert Mark R. , Steinberg Seth M. , Schlom Jeffrey , Gulley James L.
Published: May 2020

11527

Background: Chordoma is a rare neoplasm of the notochord that overexpresses brachyury, a transcription factor associated with epithelial-to-mesenchymal transition, metastasis, poor prognosis, and chemotherapy resistance. GI-6301 is a recombinant yeast-brachyury vaccine shown to demonstrate brachyury-specific immunogenicity, excellent safety profile, and some evidence of clinical activity in patients with chordoma in a previous phase I trial. Radiation therapy (RT) can modulate the tumor to become an immunostimulatory milieu. Preclinical studies have shown a synergistic effect combining RT with vaccine, thus prompting this clinical trial evaluating the combination of GI-6301 with RT in chordoma (NCT02383498). Methods: Adults with locally advanced, unresectable chordoma were treated on a randomized, double-blind, placebo controlled, phase 2 clinical trial. Patients received 3 doses of GI-6301 (80 x 107 yeast cells) vs placebo followed by photon or proton RT, followed by GI-6301 vs placebo until disease progression. Primary outcome was overall response rate (ORR) defined as a complete response or partial response in the irradiated tumor site at 24 months. Immune assays were conducted to evaluate immunogenicity. Due to slow accrual, an unplanned interim analysis was undertaken. Results: 24 pts were randomized and treated between May 2015 and September 2019. Vaccine was well tolerated with no dose reductions or treatment discontinuation. Treatment-related serious adverse events included: nausea/emesis (2); fatigue (2); dehydration (2); diarrhea (1); radiation necrosis (1); stroke (1); sepsis (1). There was no difference in ORR between the two arms. Pre-existing brachyury-specific T-cells were detected in the majority of patients but did not correlate with response to therapy. Most patients developed T-cell responses during therapy, regardless of treatment arm. Conclusions: There was no difference in ORR between the two arms. GI-6301 was well tolerated with toxicities related to RT, not vaccine. The trial was stopped early due to low conditional power for finding a statistical difference at the planned end of accrual, based on findings to date. Future studies will define utility of vaccines targeting brachyury in chordoma. Clinical trial information: NCT02383498 . [Table: see text]
Role of adjuvant imatinib dose in radically resected GIST harboring KIT exon 9 mutations.
Authors: Vincenzi Bruno , Napolitano Andrea , Nannini Margherita , Fumagalli Elena , Grignani Giovanni , Martin Broto Javier , Hindi Nadia , Italiano Antoine , Rutkowski Piotr , Hohenberger Peter , Brunello Antonella , Gasperoni Silvia , Joensuu Heikki , Badalamenti Giuseppe , Gennatas Spyridon , De Pas Tommaso Martino , Gronchi Alessandro , Dei Tos Angelo Paolo , Jones Robin Lewis , Bauer Sebastian
Published: May 2020

11533

Background: Gastrointestinal stromal tumors (GIST) with a driver mutation in KIT exon 9 (Ex9) represent about 10% of all newly diagnosed cases. In the metastatic setting, Ex9-mutated GIST patients benefit from higher doses of imatinib (800 mg/day vs standard 400 mg/day). The additional therapeutic benefit from a higher dose of imatinib in the adjuvant setting in this molecular subgroup has not been confirmed. Methods: We retrospectively identified 105 patients (pts) with resected Ex9-mutated GIST treated with adjuvant imatinib (800 mg/day or 400 mg/day) in 15 different European centers. Disease-Free Survival (DFS) and Imatinib Failure-Free Survival (IFFS) were calculated and analyzed according to the daily dose of imatinib and relevant clinical and pathological variables. Kaplan–Meier curves were used to estimate survival in univariate analyses, and the log-rank test was used to compare the groups. Hazard Ratios (HR) with 95% confidence intervals (CI) were calculated using a univariable Cox model. A multivariate Cox regression model was also performed. Results: Of the 105 pts who met the inclusion criteria, 69 (65.7%) were treated with 400 mg/day and 36 (34.3%) with 800 mg/day. The risk score (AFIP-Miettinen criteria) between the two dose groups was not statistically different (P = 0.29). Median DFS was 73.0 months (mo) in the 400 mg/day group and 61.9 mo in the 800 mg/day group (HR = 0.82, 95% CI: 0.47-1.47; P = 0.50). Median IFFS was 156.8 mo in the 400/day mg group and 117.4 mo in the 800 mg/day group (HR = 0.66, 95% CI: 0.34-1.29; P = 0.19). In a multivariable analysis, the variables statistically associated with DFS were mitotic count, the longest tumor diameter and the duration of adjuvant therapy. Mitotic count and the duration of adjuvant therapy were also associated with IFFS. Importantly, the daily imatinib dose was not associated with survival in either analysis (Table). Conclusions: This is the largest reported cohort of pts with Ex9-mutated GIST treated with either the 400 mg/day or the 800 mg/day dose of adjuvant imatinib. Although retrospective in nature, the data confirm the prognostic value of mitotic count and suggest that patients with Ex9-mutated GIST derive no additional survival benefit from the 800 mg/day dose. [Table: see text]
Lower-dosing ponatinib in pre-treated GIST: Results of the POETIG phase II trial.
Authors: Falkenhorst Johanna , Hamacher Rainer , Reichardt Peter , Ivanyi Philipp , Kasper Bernd , Hohenberger Peter , Hermes Barbara , Kostbade Karina , Pink Daniel , Sülberg Heiko , Metzenmacher Martin , Crysandt Martina , Bauer Sebastian
Published: May 2020

11536

Background: Despite long-lasting responses to imatinib most metastatic gastrointestinal stromal tumors (GIST) eventually progress and subsequent treatments are associated with limited duration of disease control. Ponatinib is a potent KIT inhibitor with a strong activity against secondary mutations in exon 17, including the highly resistant D816 mutations of KIT. Based on the dose-depending toxicity profile we sought to evaluate the safety and activity of lower dosing (30mg) ponatinib in pretreated patients with KIT-mutant GIST. We here report safety data for the whole cohort and first efficacy data for the last line cohort within a planned interim analysis. Methods: This multicenter phase 2 trial (NCT03171389) recruited patients with advanced, unresectable GIST progressing after imatinib (Cohort A/B: absence/presence of KIT Exon 13/14 mutations by plasma sequencing) or imatinib, sunitinib and regorafenib (Cohort C). Patients were treated with 30mg oral ponatinib daily in 4-week-cycles. The primary endpoint was the clinical benefit rate at 16 weeks as measured by mRECIST1.1 criteria. Results: At the cutoff date of 31st Jan 2020, 39 patients were evaluable for safety analysis (25 male, 14 female, median age 60 (38-86) years). Median duration of treatment was 65 (14-699) days. 66.7% of all patients observed Grade 3/4 adverse events (AEs), most common were pain (10/39), hypertension (6/39), GGT or lipase increase (both 5/39), and fever (3/39). One AE of special interest was observed (myocardial infarction, rated not related to study drug) and 20/39 patients experienced at least 1 severe AE (6/39 possibly related to ponatinib). Within the last line cohort, 20 patients were evaluable for efficacy. Clinical benefit rate was 35% (CI 15.4-59.2%). Median progression-free survival was 86 days with single patients yielding long-lasting responses (75% quartile 210 days, maximum: 420 days). Conclusions: Treatment with ponatinib was tolerable at a dose of 30mg qd with a toxicity profile comparable to other TKIs used in GIST. The majority of grade 3/4 AEs were hypertension or asymptomatic increases of laboratory values and thromboembolic events were rare. In a heavily pretreated patient population that lacks alternative treatment options the clinical activity was notable. An updated analysis including predictive biomarkers will be presented. Clinical trial information: NCT03171389 .
Prognostic role of MRP1 in localized high-risk soft tissue sarcoma (STS): Translational research associated to randomized phase III trial (ISG-STS 1001).
Authors: Martin Broto Javier , Moura David Silva , Ramos Rafael , Braglia Luca , Collini Paola , Renne Salvatore L , Romagosa Cleofe , Coindre Jean Michel , Velasco Valerie , Merlo Domenico F , Palmerini Emanuela , Stacchiotti Silvia , Quagliuolo Vittorio , Lopez-Pousa Antonio , Grignani Giovanni , Blay Jean-Yves , Brunello Antonella , Picci Piero , Casali Paolo Giovanni , Gronchi Alessandro
Published: May 2020

11543

Background: The ceiling-drug effect seen for most active drugs in STS could be related, partially, to multidrug resistance mechanisms (MDRM). We previously reported the independent prognostic role for RFS and OS of MRP1 in high-risk localized STS of limbs and trunk-wall treated with epirubicin and ifosfamide (Mol Cancer Ther.2014 13(1):249-59). A translational study was carried out within the randomized phase III trial of epirubicin plus ifosfamide vs histotype-tailored neoadjuvant chemotherapy (NCT01710176), to investigate MRP1 prognostic value using the trial population as validation set. Methods: Patients enrolled in the trial were invited to participate, through the informed consent, to this analysis. IHC used QCRL-1 (Santa Cruz biotechnology) MRP1 monoclonal antibody. TMAs were built on the highest-grade area of each tumor, being the procedure blinded for clinical data. MRP1 expression was grouped as low (≤ 25% positive cells) vs high ( > 25% positive cells) expression. For data analysis, patients were grouped as A) epirubicin plus ifosfamide control arm and B) histotype-tailored experimental arm. Drugs used in group B were: gemcitabine-docetaxel (UPS), gemcitabine-DTIC (LMS), trabectedin (High-grade (HG) myxoid LPS), ifosfamide-etoposide (MPNST) and high-dose ifosfamide (SS). Prognostic value of MRP1’s extension was analyzed using Cox’s proportional hazard regression. A p-value < 0.05 was considered statistically significant. Results: 175 patients were analyzed (median age 49; males 61%) with median follow-up of 4.66 y. Group A (n = 88) included HG-myxoid LPS (27%), SS (25%), UPS (24%), LMS (12%) MPNST (10%) and others (2%); group B (n = 87) included UPS (38%), SS (24%), HG-myxoid LPS (20%), LMS (10%) and MPNST (8%). MRP1 high extension was distributed as follows: 48% (A) and 57% (B). High MRP-1 expression showed significantly worse prognosis for disease-free survival (DFS) (HR 2.71 (1.31-5.62) p = 0.007) and a trend towards worse OS (HR = 2.75 (0.97-7.81) p = 0.058) in group A. No correlation was seen between MRP-1 expression and DFS (p = 0.384) or OS (p = 0.665), in group B. Conclusions: MRP1 overexpression was related to significant worse prognosis in 2 prospective randomized series of high-risk, localized, STS treated with neoadjuvant epirubicin and ifosfamide. These agents are both substrate of MRP1; this could add rationale for a possible predictive role, as MDRM, for the two most active drugs in STS. A trial combining epirubicin, ifosfamide and MRP1 inhibitor is currently under design.