bluuebunny/crossref_metadata_2025 huggingface dataset:
Burnout among oncology physician assistants (PAs) from 2015 to 2019.
Authors: Tetzlaff Eric Daniel , Hylton Heather Marie , Ruth Karen , Hasse Zachary , Hall Michael J.
Published: May 2020

11009

Background: Changes in the demand and delivery of healthcare have led to a significant increase in employment of PAs in Oncology (Onc). These changes may also increase PAs risk of burnout, a syndrome characterized by a high level of emotional exhaustion (EE) and/or depersonalization (DP). This study was initiated to explore temporal changes in burnout & the PA workforce. Methods: Using the same methods from 2015, a national survey of Onc PAs was conducted in 2019. Survey items (n = 74) examined personal and professional characteristics, collaborative practice (CP), team structure, organizational context (OC), and burnout. OC was assessed using Areas of Worklife Survey (AWS) domains: workload, control, reward, community, fairness, & values. Low AWS domain score indicated a workplace mismatch (WM). Burnout was assessed with the Maslach Burnout Inventory. Change in burnout was examined with repeated measures logistic regression. Results: 234 out of 917 PAs (25.5%) completed the full survey. Respondents were mostly female (86%), married/partnered (78%), in Med Onc (71%), and practicing in the outpatient setting (67%). Burnout increased from 34.8% in 2015 to 48.7% in 2019 [odds ratio for burnout, 2019 vs 2015 = 1.92 (95%CI 1.40-2.65), p < .001]. Adjustment for workforce variables did not explain the increase in burnout. Among 2019 respondents, increased hours worked (p = .003), sub-specialty (P = .018), less time (%) spent on direct patient care (p = .007), practicing below full extent of education and training (p = .048), dissatisfaction with CP (p < .001), and perceptions of poor collaborative physician leadership (p < .001) were associated with higher rates of burnout. No difference in burnout was seen for personal or team characteristics, practice setting, years in onc, or # of patient visits. AWS scores were lower for PAs with burnout vs. without burnout (p < .001). PAs with a WM had a higher rate of burnout for each AWS domain (p < .001); most common WMs were fairness (44%) and workload (43%). Conclusions: The rate of burnout for Onc PAs has significantly increased and is now at levels of nearly 50%. Burnout in Onc PAs related to WM in workload is common, significant, & not explained by patient volume alone. The causes of burnout are multifactorial and additional research is needed in this at risk group. [Table: see text]
Identifying burnout in young oncologists: The sooner the better.
Authors: Elez Elena , Cebria Annabel , Bosch-Barrera Joaquim , Almudena Cotes , Montosa Fernando Gálvez , Paez David , Quintanar Verduguez Maria Teresa , Vaswani Avinash Ramchandani , Rogado Revuelta Jacobo , Sánchez Cánovas Manuel , Sanz-Garcia Enrique , Miquel Josep M , González Flores Encarnación , Rodríguez-Lescure Álvaro , Vera Ruth
Published: May 2020

11010

Background: Professional burnout is an important issue for the healthcare systems with potentially relevant consequences in the quality of patient care. Young oncologists are a special risk population, due to high workload, academic pressure and other specific factors related to cancer care. Work life and lifestyle factors are related with burnout levels and may define specific interventions to reduce and prevent burnout. Methods: A survey based on the validated Maslach Burnout Inventory Human Services Survey for Medical Personnel (MBI-HSS MP) was conducted. Additional questions to explore work life and lifestyle factors were included. We studied potential burnout amongst young Spanish oncologists (residents and oncologist in the first 5 years of professional performance). Statistical analyses, including linear regression, were carried out to test the relations between overall burnout score and work and lifestyle factors. Results: We obtained 243 responses to the survey. The sample was representative in terms of age, sex, geographic region, professional profile (residents and young oncologists) and a homogeneous distribution per year of residence (final participation rate was of 26.6%). Regarding 5 Burnout profiles, 32.1% of the participants were classified as Ineffective, 25.1% as Burnout, 21% as Engaged, 17.3% as Overextended and 4.5% as Disengaged. Percentage of Burnout profile is higher in medical oncology residents (28.24%) than in young oncologists (19.79%). The highest percentage of burnout profile was observed in the second-year residents (35,71%) and gradually decreases, in parallel to an increase in the engaged profile. The multivariable linear regression analysis showed a significant correlation between not having a good work life balance and adequate vacation time and the burnout score. Conclusions: Burnout affects a significant number of young oncologists with significantly different profiles and differences across regions. Adapted interventions to the most frequent profiles and at different stages of the training and professional career may be necessary particularly at the early beginning. Actions towards achieving a better work and personal life balance and stress management could be effective. These results are the basis for the prospective part of our study that aims to design an intervention and to assess its efficacy in this population.
Results of emotional burnout study among oncologists in Russia.
Authors: Semiglazova Tatiana , Safina Sufia , Tsimafeyeu Ilya , Karaseva Vera V. , Mukhamediarova Gulnara , Fairushina Aigul , Tjulandin Sergey
Published: May 2020

11011

Background: Emotional burnout (EB) is a syndrome caused by chronic work-related stress. This is a non-adaptive reaction to chronic stress resulting from professional activities and leading to the depletion of emotional and personal resources. Oncologists have high burnout risk, because involuntarily involved in the negative experiences of patients and get emotional stress. So it is important to develop measures to prevent EB for medical oncologists. Aim: The aim is to study the prevalence and severity of EB among oncologists and to develop preventive measures. Methods: A screening survey of the Russian Society of Clinical Oncology (RUSSCO) was conducted among 389 oncologists in various regions of Russia. The Maslach Burnout Inventory and online self-administered questionnaire were used. The questionnaire was sent out in November 2019. The questionnaire was based on a multi-factor model, which includes the following components: emotional exhaustion, depersonalization, reduction of professional achievements. Results: The average age of the respondents was 49.5 years, 61% of them were female. Chemotherapists made up 47.5%, 28% were surgeons, 8.5% were radiotherapists, 7% were diagnostic profile specialists, administrators made up 3%, 14.5% of the respondents had related specialties: clinical psychologists, pathologists, palliative care doctors. 30% of respondents had scientific degree. The results of the study were the following. 71.6% of specialists have expressed EB syndrome; 28% at EB formation stage, 1% have no signs of EB. There wasn’t a significant difference in EB rates across oncologists of various specialties. All stages of EB were identified. Female specialists are more likely to have manifestations of EB. EB severity was the same for doctors of inpatient and outpatient care. The extreme mode of work did not show significant differences of EB among both male and female specialists. First 5 years and more than 15 years of professional activity are most vulnerable to development of EB. EB was least affected by specialists over 65 years old with extensive experience. Conclusions: Hight level of EB was revealed among oncologists. Study results should be used during EB prevention, development of psychotherapeutic assistance and in educational programs.
Exploring glocalization in the construction and implementation of global curricula.
Authors: Giuliani Meredith Elana , Frambach Janneke , Driessen Erik , Martimianakis Maria Athina (Tina)
Published: May 2020

11020

Background: Despite proposed advantages of global oncology curricular harmonization including physician mobility and improving the quality of care the challenges and unintended consequences require greater study. The aim of this study was to problematize the concept and implementation of global oncology curricula and their relationship to local contexts of power and culture. Methods: Fourteen international participants involved in the development and implementation of global oncology curricula completed in-depth, one-on-one semi-structured interviews lasting 40-60 minutes. Snowball sampling was employed. The participant sample was representative of different geographic regions, genders and professional scopes of practice to ensure diverse perspectives were sought. Through iterative analyses, using an abductive approach, the study team discussed and reviewed the data and made revisions through collaborative analysis to enhance comprehensiveness and to improve credibility. In the final analysis the meaning and implication of the themes were discussed yielding a conceptual analysis. Results: Our data have articulated 5 key challenges for global curricula including 1) Ambiguous or conflicting perspectives on the purpose and scope of Global Oncology Curricula 2) Insufficient representation of diverse perspectives and realities in the creation of the final curricula 3) A rigid conceptualization of competency requirements 4) A mismatch between the curricular requirements and local context and 5) The influence of power relationships and decision makers. Leveraging the strengths of diversity including fostering representation, addressing power differentials and factoring local contexts may be an approach to mitigating these challenges. Conclusions: Global oncology curricula may serve important advocacy roles within the healthcare system. Leveraging diversity may positively impact the common challenges in the construction and implementation of global oncology curricula.
Setting focus on oncology in a German undergraduate medical training program: Our experience with a longitudinal elective Interdisciplinary Oncology.
Authors: Zschaebitz Stefanie , Jaeger Dirk , Winkler Eva Caroline , Halama Niels
Published: May 2020

11034

Background: Compared to other academic disciplines such as social sciences and humanities, medical school curricula leave limited opportunities to meet individual interests of students. Methods: To allow students to set an individual focus in their MD education, and to promote a sound scientific basis, n = 11 longitudinal electives (“tracks”) were introduced within the Heidelberg Curriculum Medicinale (HeiCuMed) in 2017. The volume of additional training consists of 2 weekly lectures hours for at least 1.5 years of training. Participation in the program has been on a voluntary basis until 2019 and now is obligatory for every student. Results: n = 141 students are currently enrolled within the track “Interdisciplinary Oncology (IO)”. More than n = 50 optional courses are offered each semester covering oncologic subjects such as scientific methods in cancer research, ethical issues in research and clinical practice, communication and clinical skills training. The modular system of the IO elective allows for a wide selection of topics for participating students but also poses a challenge for graded assessments. Conclusions: Conducting a modular elective including graded assessments is feasible. The longitudinal track IO has a high voluntary participation rate and very positive feedback from students. This indicates that our teaching concept is very well suited to address the call for increased choice and specialization in medical curricula in Germany.
Results of the second interim assessment of rEECur, an international randomized controlled trial of chemotherapy for the treatment of recurrent and primary refractory Ewing sarcoma (RR-ES).
Authors: McCabe Martin G. , Kirton Laura , Khan Maria , Fenwick Nicola , Dirksen Uta , Gaspar Nathalie , Kanerva Jukka , Kuehne Thomas , Longhi Alessandra , Luksch Roberto , Mata Cristina , Phillips Marianne , Safwat Akmal , Strauss Sandra J. , Sundby Hall Kirsten , Valverde Morales Claudia Maria , Westwood Andrew J. , Winstanley Mark , Whelan Jeremy , Wheatley Keith
Published: May 2020

11502

Background: Five-year survival of RR-ES is about 15%. Several chemotherapy regimens are used, but without robust evidence. rEECur, the first randomised controlled trial in this setting, is defining a standard of care, balancing efficacy and toxicity. Methods: Patients aged 4 to 50 with RR-ES and fit to receive chemotherapy were randomised between topotecan & cyclophosphamide (TC), irinotecan & temolozomide (IT), gemcitabine & docetaxel (GD) or high-dose ifosfamide (IFOS). Primary outcome measure was objective response (OR) after 4 cycles by RECIST 1.1. Secondary outcomes included PFS, OS and toxicity. A probability-based Bayesian approach was used with multiple pairwise comparisons. At the first interim analysis patients allocated to GD had worse OR and PFS than the other arms and accrual to the GD arm was halted. The second interim assessment was planned to determine which arm should be closed when at least 75 evaluable patients had been recruited to the remaining arms and evaluated for the primary outcome measure. Results: 366 patients (87% RECIST-evaluable), recruited between 18/12/14 and 17/12/19, were randomised to TC (n=124), IT (118), GD (72) and IFOS (53). Median age was 20 years (range 4-49). Patients had: refractory disease (19%), first recurrence (66%), > first recurrence (14%). Initial disease site was bone in (66%). Sites of progression were: primary site only (16%) pleuropulmonary only (32%), other metastatic (52%). At median follow up of 9.2 months, outcome in the IT arm was: response rate 20%, median PFS 4.7 months (95% CI: 3.4 to 5.7), median OS 13.9 months (95% CI: 10.6 to 18.1). The table shows, for each pairwise comparison of IT with the other open arms (randomly labelled A and B to maintain blinding), the probabilities that OR, PFS and OS were better for X than for each other arm (RR = risk ratio, HR = hazard ratio). For OR, PFS and OS, all comparisons favoured arms A and B. The main grade 3/4 adverse events (% patients with an event) for IT (left hand values) compared with A and B pooled were: vomiting (6% v 1%), nausea (6% v 0%), diarrhoea (17% v 0%), fatigue (3% v 1%) and febrile neutropenia (3% v 24%). Conclusions: The first randomised trial in RR-ES has shown that IT, used as a control arm in planned and ongoing randomised phase II studies in RR-ES, is less effective than A and B in achieving tumour shrinkage or prolonging PFS and OS. The remaining two arms are continuing to recruit patients. Clinical trial information: ISRCTN36453794 . [Table: see text]
A pilot study evaluating the safety, tolerability, and efficacy of doxorubicin and pembrolizumab in patients with metastatic or unresectable soft tissue sarcoma.
Authors: Livingston Michael B. , Jagosky Megan , Robinson Myra M. , Ahrens William , Benbow Jennifer H , Farhangfar Carol J. , Foureau David , Maxwell Deirdre , Baldrige Emily , Steuerwald Nury , Anderson Colin J , Patt Joshua , Kneisl Jeffrey , Kim Edward S.
Published: May 2020

11519

Background: Doxorubicin has been the traditional standard therapy for treatment of advanced soft tissue sarcoma (STS). The addition of cytotoxic agents leads to increased toxicity with minimal improvement in efficacy. Pembrolizumab monotherapy has demonstrated activity and tolerability in previous study of advanced STS. This study combined pembrolizumab with doxorubicin to determine safety and efficacy in the frontline setting. Methods: This single-center, single-arm, phase 2 trial enrolled subjects with unresectable or metastatic STS and no prior anthracycline therapy. Subjects were treated with pembrolizumab 200 mg IV and doxorubicin 60 mg/m2 (75 mg/m2 dose escalation per investigator discretion) IV every 3 weeks. The primary endpoint of safety, based on Bayesian stopping rules, evaluated if the severe or life-threatening treatment emergent adverse event (TEAE) rate exceeded 0.55. Secondary endpoints included overall survival (OS), objective response rate (ORR), and progression free survival (PFS). Efficacy and safety were based on RECIST 1.1 and CTCAE v 4.0, respectively. Kaplan-Meier methods evaluated time to event outcomes. Results: From 4/2017 to 12/2019, 30 subjects (53% female, median age 61.5 years, 10 patients > 70 years (33%)) were enrolled in the study with 6 (20%) patients still on treatment and 27 evaluable for response. The most common histologic subtypes were leiomyosarcoma (33%) and liposarcoma (23%), and a majority of patients demonstrated high grade disease (60%). Current analysis shows a median follow-up of 9.9 months. One subject experienced a stopping rule event (grade 3 autoimmune disorder). ORR was 33% (95% CI 17-54%), with documented disease control in 78% (95% CI 57.7-91.4%) of patients. Eight (30%) patients achieved a partial response, one (4%) patient achieved a complete response and 12 (44%) patients had stable disease. Preliminary results demonstrate median PFS of 6.9 months (PFS-6 mo: 52%) and median OS of 15 months (OS-6 mo: 81%) compared to historical PFS-6mo of 4.6 months and OS of 12.8 months with doxorubicin alone.1 Most common grade 3+ TEAEs included neutropenia (11 [37%]), febrile neutropenia (6 [20%]), anemia (5 [17%]), and nausea (4 [13%]). Molecular and biomarker analysis is currently in progress. Conclusions: The combination of pembrolizumab with doxorubicin has manageable toxicity and preliminary promising activity in the treatment of anthracycline-naive advanced soft tissue sarcomas. Ref: 1. Lancet Oncol. 2014 Apr; 15(4):415-23. Clinical trial information: NCT03056001 .
Preliminary evaluate the safety and efficacy of anlotinib in advanced sarcoma patients in multi-line therapy.
Authors: Weitao Yao , Wang Jiaqiang , Zhang Peng , Wang Xin , Du Xinhui , Tian Zhichao , Niu Xiaoying
Published: May 2020

11526

Background: Patients with advanced bone and soft tissue sarcoma are mostly treated with chemotherapy, but the effect is poor. Anlotinib hydrochloride is a multi-targeted receptor of tyrosine kinase inhibitors (TKI), which has demonstrated therapeutic effects on a variety of sarcoma subtypes, and is approved for the treatment of advanced soft tissue sarcomas in China. Methods: This is a single-arm, prospective, single-center clinical study. The included criteria were patients with pathological diagnose of bone and soft tissue sarcoma, at least one measurable lesion (according to RECIST 1.1), failed of more than first-line therapy (except for alveolar soft tissue sarcoma) in the last 6 months, with the normal function of main organs. All patients received anlotinib for more than 1 month. The primary study endpoint was objective response rate (ORR). Disease control rate (DCR) and side effects was also calculated. Results: At the latest follow up in Jan. 20th, 2020, a total of 31 patients were enrolled. The median age of the patients was 38 (8-79) years. The main subtypes included osteosarcoma (25.8%), undifferentiated pleomorphic sarcoma (19.4%), synovial sarcoma (16.1%), fibrosarcoma (12.9%). 83.9% of patients received for at least third-line therapy of anlotinib. The oral administration time was 1.5-15 months, with the average of 4.34 months. The ORR was 29%. The DCR was 77.4%. Patients who had received other TKI drugs had an ORR of 20% and a DCR of 70% in 10 cases (32.2%) in this group. mPFS and mOS have not been reached. Adverse events were mainly in grades I and II, including 6 (19.4%) of anorexia or diarrhea, 5 (16.1%) of pain, 4 (12.9%) of hand-foot syndrome, 3 (9.7%)of hypertension, fatigue and mucosa ulcer each. One case had hypertension in grades III. Conclusions: Anlotinib has shown a definite effect in the treatment of advanced sarcomas. Effectiveness can also be observed in patients who have failed in other targeted therapy. The adverse events are minor and can be tolerated. Clinical trial information: NCT04223583 .
Laparoscopic versus open surgery for gastrointestinal stromal tumor in esophagogastric junction: A multi-center, retrospective cohort analysis with propensity score matching.
Authors: Xiong Wenjun , Chen Tao , Feng Xingyu , Xu Yuting , Wan Jin , Zhou Rui , Li Yong , Li Guoxin , Wang Wei
Published: May 2020

11534

Background: Laparoscopic resection is increasingly performed for Gastrointestinal stromal tumor (GIST). Nevertheless, laparoscopic approach for the GIST located in the esophagogastric junction (EGJ-GIST) represent a surgical challenge. This study aims to investigate the efficacy of laparoscopic surgery and open procedure for EGJ-GIST through the propensity score matching (PSM) method. Methods: Between April 2006 and April 2018, 1824 patients underwent surgery were finally diagnosed with primary gastric GIST at four medical centers in South China. EGJ-GIST was defined as a GIST with an upper border of less than 5 cm from the EG line. Among them, 228 patients were identified and retrospectively reviewed with regard to clinicopathological characteristics, operative information and long-term outcomes. The PSM methods was used to eliminate the selection bias. Results: After PSM, 102 cases, consisted of 51 laparoscopic (LA) and 51 open surgery (OP), were enrolled. The match factors contained year of surgery, gender, age, BMI, tumor size, mitotic rate, recurrence risk and adjuvant tyrosine kinase inhibitors treatment. The LA group was superior to the OP group in operative time (108.5±56.5 vs. 169.3±79.0 min, P <0.001), blood loss (54.6±81.9 vs. 104.9±156.4 ml, P = 0.042), time to liquid intake (3.1±1.8 vs. 4.3±2.2 d, P = 0.003), hospital stay (6.0±2.3 vs. 9.9±8.1, P = 0.001), and postoperative complication (5.9% vs. 25.5%, P = 0.006). The median follow-up was 55 (range, 2-153) months in the entire cohort. No significant differences were detected in either the relapse-free survival (RFS, P = 0.109) or overall survival (OS, P = 0.113) between two groups. The 1-, 3-, and 5-year RFS in the LA and OP groups were 100.0%, 95.5%, 91.0% and 100.0%, 90.8%, 85.7%, respectively. The 1-, 3-, and 5-year OS in the LA and OP group were 100%, 95.6%, 91.3% and 100.0%, 91.1%, 85.4%, respectively. Conclusions: Laparoscopic surgery for EGJ-GIST is associated with the advantages of shorter operative time, reduced blood loss, shorter time to liquid intake and shorter length of stay, all without compromising post-operative outcomes and long-term survival.
A phase II trial of the DNA methyl transferase inhibitor, SGI-110 (Guadecitabine), in children and adults with SDH-deficient GIST, pheochromocytoma, and paraganglioma, and HLRCC-associated kidney cancer.
Authors: Wedekind Mary Frances , Del Rivero Jaydira , Arnaldez Fernanda Irene , Srinivasan Ramaprasad , Spencer Melissa , Steinberg Seth M. , Peer Cody J. , Figg William Douglas , Killian Jonathan Keith , Meltzer Paul S. , Linehan W. Marston , Widemann Brigitte C. , Glod John
Published: May 2020

11540

Background: Loss of activity of the Krebs cycle component succinate dehydrogenase (SDH) complex is a mechanism of tumorigenesis in SDH-deficient cancers. Accumulation of the metabolite succinate inhibits α-ketoglutarate-dependent dioxygenases leading to DNA hypermethylation. Guadecitabine is a small molecule DNA methyltransferase inhibitor. We conducted a Phase II study to test the hypothesis that guadecitabine will impact tumor growth by reversing DNA hypermethylation in tumors with Krebs cycle abnormalities (NCT03165721). Study Objectives: Our primary objective was to assess the clinical activity of guadecitabine in patients with SDH-deficient GIST, PHEO/PGL, and HLRCC-associated renal cell carcinoma. Secondarily, we desired to evaluate the toxicities of patients on treatment with guadecitabine. Methods: We conducted a single site, open label, phase II study using a small optimal two-stage design to evaluate response in SDH-deficient GIST, PHEO/PGL, and HLRCC-associated renal cell carcinoma. Patients >12 years of age received guadecitabine subcutaneously at 45mg/m2/day for 5 consecutive days on a 28-day cycle. Activity via imaging response was assessed utilizing RECISTv1.1. Toxicities were graded using version 4.0 of the NCI Common Toxicity Criteria. All patients were included in analysis. Results: We enrolled nine patients (6F:3M) with an age range of 18-57 years. Seven patients had SDH-deficient GIST (78%), one patient with paraganglioma (11%), and one with HLRCC-associated renal cell carcinoma (11%). No patients had a complete or partial response. Five patients came off study due to progression (56%) with one death due to disease progression in the patient with HLRCC-associated renal cell carcinoma (11%). Three patients (33%) withdrew due to lack of response with stable disease. One patient was withdrawn due to investigator’s discretion (11%). Toxicities possibly, probably, or definitely related to drug included grade 3 leukopenia (11%) febrile neutropenia (11%), grade 3-4 neutropenia (22%) requiring dose reductions, grade 3 hypertension (11%), grade 2 lung infection requiring hospitalization (11%). Conclusions: In this single site, open label, phase II study in patients with SDH-deficient GIST, PHEO/PGL, and HLRCC-associated renal cell cancer guadecitabine was tolerated by the majority of patients. No complete or partial responses were observed. Clinical trial information: NCT03165721 .
Immune-checkpoint genes as predictive biomarkers of trabectedin in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) translational study.
Authors: Moura David Silva , Hindi Nadia , Lopez-Alvarez Maria , Sanchez-Bustos Paloma , Carrasco-Garcia Irene , Santos-Fernandez Paloma , Martinez-Delgado Paula , Lacerenza Serena , Blanco-Alcaina Elena , Mondaza-Hernandez Jose Lucinio , Gutierrez Antonio , Alvarez Rosa Maria , Cordeiro Magda , De Sande González Luis Miguel , Marquina Gloria , Cano Juana Maria , Cruz Jurado Josefina , Valverde Morales Claudia Maria , Martinez-Trufero Javier , Martin Broto Javier
Published: May 2020

11546

Background: Despite several second-line options are accessible for the treatment of advanced STS, there is a lack of predictive biomarkers available to support the rational selection of these drugs. Trabectedin specifically targets mononuclear cell lineage (macrophages and monocytes) that ultimately could inhibit tumor angiogenesis. Moreover, trabectedin seems to induce the expression of immune-checkpoint proteins (e.g. PD-L1); however, the predictive value of these factors remains unknown. We present the analyses of immune-checkpoint genes ( CD274, CD86, CTLA4, HAVCR2, LAG3 and PDCD1) and CD163, CD4, CD68 and CD8A expression as potential predictive factors of response to trabectedin in a subset of STS patients of the GEIS registry. Methods: Selection criteria included patients with STS, pretreated with at least 2 lines in the advanced setting (one line being trabectedin), with paraffin block available and ethic committee’s approval. Direct transcriptomics was performed using HTG Molecular Oncology Biomarker Pathway panel (HTG Molecular Diagnostics, Inc.; Tucson, AZ, USA), following manufacturers’ instructions. Data analyses were performed taking into account the median Log2 of expression of each gene and by correlating it with progression-free survival (PFS) for trabectedin, and overall survival measured from the starting date of trabectedin treatment (OS). Results: Among 387 registered patients, fitting with the inclusions criteria, 139 cases were used for gene expression analyses, as the discovery set. Patients had median age of 52 years, 54% were females and had a median follow-up from diagnosis of 44 months. High expression of CD274 (PD-L1) was significantly associated with better PFS of trabectedin (5.4 vs. 3.0 months; p= 0.006). Similar results were obtained with high expression of CTLA4 and LAG3: 6.0 vs 3.1 months; p = 0.005 and 5.4 vs 2.7 months; p = 0.042, respectively. Expression of CTLA4 and LAG3 showed no significant impact in OS; whereas CD274 high expression showed a trend towards better OS (17.9 vs 10.2 months; p = 0.077). Also, no significant correlation was achieved for CD163, CD4, CD68, CD8A, CD86 and HAVCR2; PDCD1 (PD-1) showed a trend towards better PFS of trabectedin, p = 0.114. Conclusions: The expression of selected immune-checkpoint genes exhibited a potential predictive value for trabectedin in advanced STS. Validation studies (at the transcriptional and protein level) are currently ongoing to confirm their potential predictive role.
Comparison of different systemic therapeutic regimes in resectable high-risk soft tissue sarcoma: Results of a network meta-analysis.
Authors: Haussmann Jan , Budach Wilfried , Boelke Edwin , Tamaskovics Balint , Djiepmo Njanang Freddy Joel , Corradini Stefanie , Kammers Kai , Wessalowski Ruediger , Matuschek Christiane
Published: May 2020

11549

Background: The treatment of high-risk soft tissue sarcoma of the trunk or the extremities consists of surgical resection with risk-adapted radiation therapy. Further treatment options which can significantly improve local and systemic tumor control including chemotherapy are not well established. Due to the heterogeneity of disease different systemic approaches as well as their application during different time points have been attempted. Methods: We conducted a literature search for randomized clinical trials in the treatment of localized, resectable high-risk soft tissue sarcoma comparing different treatment modalities according to the PRISMA guidelines. We extracted published hazard ratios and number of events for the endpoints of overall and disease-free survival (OS; DFS) as well as local and distant recurrence-free interval (LRFI; DRFI). The different modalities were compared in a network meta-analysis against the defined standard treatment surgery ± radiotherapy using the inverse-variance heterogeneity model (ivhet) with the help of the Microsoft Excel add-in Meta-XL V5.3. Results: The literature search identified 25 studies including 3489 patients. The network analysis showed that adjuvant chemotherapy (adjCTx) results in a significant improvement in overall survival (HR = 0.86; CI-95%: 0.75-0.97; p = 0.017) compared to the standard treatment of surgery ± radiatherapy alone. Combined treatment with regional hyperthermia and neoadjuvant chemotherapy (HTx+nadjCTx) also improves OS (HR = 0.45; CI-95%: 0.20-1.00; p = 0.049). Preoperative chemotherapy alone (nadjCTx) as well as perioperative chemotherapy (periopCTx) resulted both in non-statistically significant improvements in OS (HR = 0.61; CI-95%: 0.29-1.29; p = 0.195) and (HR = 0.48; CI-95%: 0.15-1.55; p = 0.218). Histology-tailored neoadjuvant chemotherapy (tNaCTx) also showed no effect on overall survival (HR = 1.08; CI-95%: 0.45-2.61; p = 0.868). The analysis of DFS, LRFI and DRFI disclosed a similar pattern between the different treatment regimens. Conclusions: The addition of cytotoxic chemotherapy in resectable high-risk soft tissue sarcomas provides a measurable benefit in overall survival. Shifting of systemic therapy to the neoadjuvant setting and combination with regional hyperthermia might be favored. Predictive clinical and molecular markers are needed to evaluate and limit potentional risks prospectively going forward.
Phase Ib study of decitabine in combination with gemcitabine in treatment of advanced soft tissue and bone sarcomas.
Authors: Monga Varun , Dodd Rebecca , Scherer Amanda , Gutierrez Wade Robert , Tanas Munir , Mott Sarah L. , Milhem Mohammed M.
Published: May 2020

11550

Background: Sarcomas are a heterogeneous group of tumors and are associated with high rates of metastases leading to poor prognosis. Numerous epigenetic changes including hypermethylation have been identified in several sarcoma subtypes. Restoration of normal methylation patterns using DNA hypomethylating agent when combined with chemotherapy has shown to slow tumor growth in preclinical studies. Low continuous dosing of hypomethylating agent has epigenetic modulating effect with less toxicity. We conducted a Phase 1b study evaluating safety & tolerability and identifying the recommended phase 2 dose (RP2D) of subcutaneous (SQ) decitabine (DEC) given with fixed dose infusion gemcitabine (GEM) in patients with advanced soft tissue sarcomas (STS) and bone sarcomas. Methods: Eligible patients at least age 18 yrs with metastatic histologically confirmed STS or bone sarcoma after progression on one line or if refused adriamycin for STS were included. Prior GEM use was permitted. A modified 3+3 dose escalation design was used exploring two dose cohorts of DEC, 0.1 and 0.2 mg/kg SQ administered on a twice weekly schedule for three weeks and GEM given as 900 mg/m2, IV over 90 min on days 1, 8 & 15 of a 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity. Dose limiting toxicity (DLT) was defined as any drug related non-hematological grade 3 or 4 toxicity per CTCAE v4.0. Disease assessment was performed every 8 weeks using RECIST v1.1. Results: 31 patients (25 STS & 6 bone sarcomas) were enrolled of which 7 were non-evaluable. There were 12 evaluable patients in each dosing cohort. Of the total 744 adverse events (AE) 17.2% were grade 3/4 and most were neutropenia without neutropenic fever. 45.7% AEs were possibly (44.6%) or probably (1.1%) attributed to DEC use. The toxicities were not significantly different between DEC doses. No DLTs were observed. One patient died due to progressive disease. Conclusions: Combination of fixed dose infusion GEM with low dose subcutaneous DEC is moderately toxic. Most toxicities were hematological. While there were few responses, the RP2D of DEC selected was 0.1 mg/kg as it showed prolonged disease stabilization. Clinical trial information: NCT02959164 . [Table: see text]
Effect of integrating machine learning mortality estimates with behavioral nudges to increase serious illness conversions among patients with cancer: A stepped-wedge cluster randomized trial.
Authors: Manz Chris , Parikh Ravi Bharat , Evans Chalanda N. , Chivers Corey , Regli Susan B , Changolkar Sujatha , Bekelman Justin E. , Small Dylan , Rareshide Charles A.L. , O'Connor Nina , Schuchter Lynn Mara , Shulman Lawrence N. , Patel Mitesh S.
Published: May 2020

12002

Background: Most patients with cancer die without a documented serious illness conversation (SIC) about prognosis and goals. Interventions that increase SICs between oncology clinicians and patients may improve goal-concordant care and end-of-life outcomes. Methods: In this stepped-wedge cluster randomized trial (NCT03984773), we tested the effect of an intervention delivering machine learning-based mortality estimates with behavioral nudges to oncologists to increase SICs among patients with cancer. The clinician-focused intervention consisted of 1) weekly emails providing individual SIC performance feedback (number of SICs in the past month) and peer comparisons; 2) a list of patients scheduled for the next week with a ≥10% predicted risk of 6 month mortality by a validated machine learning prognostic algorithm, and 3) automated opt-out text prompts on the patient’s appointment day to consider an SIC. Eight medical oncology clinics were randomized to receive the intervention in a stepped-wedge fashion every four weeks for a total of 16 weeks. Medical oncology clinicians were included if they were trained to use the SIC Guide (Ariadne Labs, Boston MA). Patients were included if they had an outpatient encounter with an eligible clinician between June 17 and November 1, 2019. The primary outcome was the percent of patient encounters with a documented SIC. Intention to treat analyses adjusted for clinic and wedge fixed effects and clustered at the oncologist level. Results: The sample consisted of 78 clinicians and 14,607 patients. The mean age of patients was 61.7 years, 55.7% were female, 70.4% were white, and 19.6% were black. The percent of patient encounters with an SIC was 1.2% (106/8536) during the pre-intervention period and 4.0% (401/10,152) during the intervention period. In intention to treat adjusted analyses, the intervention led to a significant increase in SICs (adjusted odds ratio, 3.7; 95% CI, 2.5 to 5.4, P value < 0.0001). Conclusions: An intervention consisting of machine learning mortality estimates and behavioral nudges to oncology clinicians increased SICs by three-fold over 16 weeks, a significant difference.This is one of the first studies evaluating a machine learning-based behavioral intervention to improve serious illness communication in oncology. Secondary analyses (completed April 2020) will clarify whether this intervention leads to a sustained increase in SIC rates and improves goal-concordant care and end-of-life outcomes. Clinical trial information: NCT03984773 .
Risk of cardiovascular disease in women with and without a history of breast cancer: The Pathways Heart Study.
Authors: Greenlee Heather , Iribarren Carlos , Neugebauer Romain , Rana Jamal S , Nguyen-Huynh Mai , Cheng Richard , Shi Zaixing , Izano Monika , Laurent Cecile , Lee Valerie S. , Roh Janise M. , Shen Hanjie , Santiago-Torres Margarita , Hershman Dawn L. , Kushi Lawrence H. , Kwan Marilyn L.
Published: May 2020

12016

Background: Breast cancer (BC) survivors are at increased risk of cardiovascular disease (CVD) following diagnosis, as compared to women without BC. To provide a population-based estimate of CVD risk in BC survivors, we compared risk of CVD events in women with and without BC history enrolled in the Kaiser Permanente Northern California (KPNC) integrated health system. Methods: Data were extracted from KPNC electronic health records. All invasive BC cases diagnosed between 2005-2013 were identified and matched 1:5 with non-BC controls on birth year, race/ethnicity and KPNC membership at date of BC diagnosis. Cox regression models were used to assess differences in the hazard of four major CVD events (ischemic heart disease (IHD), heart failure (HF), cardiomyopathy, and stroke). Models were adjusted for factors known to influence risk of breast cancer or CVD.Other CVD events included arrhythmia, cardiac arrest, carotid disease, myocarditis/pericarditis, transient ischemic attack, valvular disease, and venous thromboembolism (VTE). We additionally examined subgroups of cases who received chemotherapy, radiation, and endocrine therapy, and their controls. Results: A total of 14,942 women with a new diagnosis of invasive BC were identified and matched to 74,702 women without BC history. On average, women were 62.0 years, 28.3 kg/m2BMI, 64.9% non-Hispanic white. Among all cases and controls, there were no significant differences in hazard of developing IHD, cardiomyopathy, and stroke; there was a borderline difference in HF (HR: 1.08, 95% CI: 0.99, 1.19). Cases were more likely to have a cardiac arrest (HR: 1.39, 95% CI: 1.09, 1.78) and develop VTE (HR: 1.97, 95% CI: 1.74, 2.23). Women treated with chemotherapy were more likely than controls to develop HF (HR: 1.44, 95% CI: 1.21, 1.72), cardiomyopathy (HR: 2.01, 95% CI: 1.02, 3.98), and VTE (HR: 3.15, 95% CI: 2.62, 3.79). Women who received radiation therapy were more likely to develop carotid disease (HR: 5.49, 95% CI: 1.22, 24.66) and VTE (HR: 1.65, 95% CI: 1.35, 2.03) than controls. Women who received endocrine therapy were more likely to experience a cardiac arrest (HR: 1.49, 95% CI: 1.07, 2.09) and develop VTE (HR: 1.70, 95% CI: 1.42, 2.03) than controls. Conclusions: Women with BC were at increased risk of heart failure, cardiomyopathy, cardiac arrest, VTE and carotid disease. These risks varied by cancer treatment, with higher risk in those who received chemotherapy. Future studies should explore the effects of chemotherapy class and radiation dose exposure on diverse CVD endpoints in BC survivors.
Temporal trends in opioid prescribing patterns among oncologists in the Medicare population.
Authors: Jairam Vikram , Yang Daniel X. , Pasha Saamir , Soulos Pamela R. , Gross Cary Philip , Yu James B. , Park Henry Soo-Min
Published: May 2020

12022

Background: In the wake of the United States (U.S.) opioid epidemic, there have been significant governmental and societal efforts to curb opioid prescribing. However, it is unknown whether these efforts have affected prescribing among oncologists, whose patient population often requires narcotics for symptom management. We investigated temporal patterns in opioid prescribing for Medicare patients among oncologists. Methods: We queried the Centers for Medicare and Medicaid Services Part D prescriber dataset to identify independently practicing physicians between January 1, 2013 and December 31, 2017. We used population-averaged multivariable negative binomial regression to estimate the association between time and per-provider opioid prescribing rate, defined as number of opioid claims (original prescriptions and refills) per 100 patients, among oncologists and non-oncologists on both a national and statewide level. All models were adjusted for provider characteristics and annual total patient count per provider. Results: The final study sample included 20,513 oncologists and 711,636 non-oncologists. From 2013 to 2017, the national opioid prescribing rate declined by 19.3% (68.8 to 55.5 opioid prescriptions per 100 patients; P< 0.001) among oncologists and 20.4% (50.7 to 40.3 prescriptions per 100 patients; P< 0.001) among non-oncologists. During this timeframe, 40 U.S. states experienced a significant ( P< 0.05) decrease in opioid prescribing among oncologists, most notably in Vermont (-43.2%), Idaho (-34.5%), and Maine (-32.8%). In comparison, all 50 states exhibited a significant decline ( P< 0.05) in opioid prescribing among non-oncologists. In 5 states, opioid prescribing decreased more among oncologists than non-oncologists, including Oklahoma (-24.6% vs. -7.1%), Idaho (-34.5% vs. -17.8%), Utah (-31.7% vs. -18.7%), Texas (-19.9% vs. -14.7%), and New York (-24.0% vs. -19.7%) (all P< 0.05). Conclusions: Between 2013 and 2017, the opioid prescribing rate decreased by approximately 20% nationwide among both oncologists and non-oncologists. These findings raise concerns about whether opioid prescribing legislation and guidelines intended for the non-cancer population are being applied inappropriately to patients with cancer and survivors.
FDA analysis of ECOG performance status and safety outcomes.
Authors: Singh Harpreet , Gong Yutao , Roy Pourab , King-Kallimanis Bellinda , Bhatnagar Vishal , Pazdur Richard , Kluetz Paul Gustav
Published: May 2020

12024

Background: Patients with poor performance status are often excluded from clinical trials. The FDA has published several guidances on modernizing oncology clinical trial eligibility criteria to more accurately reflect the patient population. Many patients receiving novel oncology therapeutics are heavily pretreated, and often have comorbidities, organ dysfunction, and frailty syndromes. Little is known about the safety of novel therapeutics in patients with poor performance status. Methods: Data from six randomized trials (n=4465) leading to registration for several solid tumor and malignant hematologic cancers, including multiple therapeutic mechanisms of action, such as EGFR TKI’s, immune checkpoint inhibitors (ICI), and chemotherapy, were pooled. Cumulative incidence of Grade 3-5 adverse events and serious adverse events at Days 30, 90, and 180 were evaluated based on ECOG 0-2. Rates of treatment discontinuation by ECOG was also examined. Results: Cumulative incidence of toxicity events at days 30, 90, and 180 are shown in Table. Patient dropout rates due to death were 3.9%, 6.7%, and 10.9%; dropout rates due to disease progression were 66.5%, 66.6% and 56.9%; and dropout rates due to reasons other than progression or death were 29.7%, 26.7% and 32.1% for ECOG PS 0, 1 and 2, respectively. Conclusions: This FDA exploratory analysis of safety outcomes in registration trials based on ECOG suggests increasing rates of adverse events and rates of treatment discontinuation due to death with worsening performance status. Discontinuation rates due to disease progression and other reasons did not appear to be worse for ECOG 2 compared to 0-1. These findings were consistent across therapies (targeted therapy, ICI, chemotherapy). All trials in the analysis led to FDA approval, thus inclusion of patients with ECOG 2 did not adversely affect the trial outcome for this set of FDA approved agents. ECOG performance status eligibility criteria should be evaluated and modified on a frequent basis during drug development. Additional analysis of trials which enroll patients with ECOG 2 is needed. [Table: see text]
Omission of adjuvant chemotherapy in elderly patients with early stage breast cancer.
Authors: Ma Sung Jun , Oladeru Oluwadamilola Temilade , Singh Anurag K
Published: May 2020

12032

Background: Breast cancer incidence in elderly population over 70 years is anticipated to grow up to 35% by 2030. However, this elderly population is under-represented in the TAILORx (Trial Assigning Individualized Options for Treatment) with less than 5% of the entire study cohort. As the omission of radiation therapy among the elderly with favorable prognosis is a reasonable alternative option, omission of chemotherapy has not been prospectively investigated. To address this knowledge gap, we conducted an observational cohort study to evaluate the omission of chemotherapy in elderly patients with early breast cancer. Methods: The National Cancer Database (NCDB) was queried for patients above the age of 70 diagnosed with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, pT1-2N0 breast cancer who underwent hormone therapy with or without chemotherapy (2010-2015). Kaplan-Meier method and Cox multivariable analysis (MVA) were performed for survival analysis. Propensity score matching in a 1:1 ratio without any replacement was used to address selection bias. Sensitivity analysis was performed on a subgroup of those with a high 21-gene recurrence score (RS) > 25. Results: A total of 12004 patients were identified, including 10802 and 1202 patients with and without adjuvant chemotherapy, respectively. The median follow up was 38.2 months (IQR 22.5-57.2). On univariate analysis, chemotherapy was not associated with improved overall survival (HR 0.96, p = 0.71), ineligible for inclusion in the final MVA model. On interaction analysis, the use of chemotherapy had no interaction with RS (p = 0.46), age (p = 0.08), tumor size (p = 0.23), tumor grade (p = 0.42), and comorbidity score (p = 0.22). On 1030 and 689 matched pairs for all RS and RS > 25, respectively, there was no association of overall survival with chemotherapy (all RS: HR 0.76, p = 0.08; RS > 25: HR 0.74, p = 0.10). Conclusions: For elderly patients with early stage breast cancer, the addition of adjuvant chemotherapy may not be associated with improved survival even in the setting of high RS > 25. Given the toxicity profile of systemic therapy, shared decision making between clinicians and elderly patients is needed to individualize treatment options.