bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II study of MEK162 (binimetinib [BINI]) in combination with imatinib in patients with untreated advanced gastrointestinal stromal tumor (GIST).
Authors: Chi Ping , Qin Li-Xuan , Kelly Ciara Marie , D'Angelo Sandra P. , Dickson Mark Andrew , Gounder Mrinal M. , Keohan Mary Louise , Movva Sujana , Nacev Benjamin , Crago Aimee Marie , Yoon Sam S. , Ulaner Gary A. , Martindale Moriah , Condy Mercedes M. , Phelan Haley , Biniakewitz Matthew , Singer Samuel , Hwang Sinchun , Antonescu Cristina R. , Tap William D.
Published: May 2020

11508

Background: ETV1 and KIT are lineage-specific master transcriptional and signaling survival factors in GIST. In preclinical models, dual lineage targeting of ETV1 by MEK inhibition with BINI and KIT by imatinib are synergistic in suppressing GIST tumorigenesis and progression. This single-arm phase II study is designed to test the efficacy of the BINI+imatinib as a first-line treatment in patients (pts) with advanced GIST. Methods: Adult pts with untreated advanced GIST received imatinib (400mg daily) plus BINI (30mg twice daily), 28-day cycles. The primary endpoint (EP) was RECIST1.1 objective response rate (ORR) (complete response [CR]+partial response [PR]). The study was designed to detect a 20% improvement in the ORR of imatinib alone (unacceptable rate of 45%; acceptable rate of 65%). A sample size of 44 patients was required, using an exact binomial test, one-sided type I error of 0.08 and type II error of 0.1. Confirmed PR in > 24 pts would be considered positive. Secondary EPs included RR by Choi and EORTC criteria, resectability conversion rate (RCR), progression free survival (PFS), overall survival (OS) and long-term AEs. Correlatives included characterization of tumor genomics by MSK-IMPACT, cfDNA by MSK-ACCESS, ETV1 protein levels and transcriptomes and signaling inhibition. Results: At data cutoff of Jan 31, 2020, 38/39 pts with advanced GIST of all genotypes, including 3 KIT/PDGFRA-wild type GIST pts, were evaluable for primary EP. Median age 60 (range 29-78), 29% female. 26/38 pts with confirmed PR; Best ORR was 68.4% (two-sided 95% CI, 51-83%; one-sided 90% CI, 57-100%). 8/9 pts became resectable after treatment; RCR was 88.9% (95% CI, 52-100%). 13 pts remain on trial (2-159 weeks [wks]). 9 pts discontinued trial due to disease progression (11-159 wks); one pt progressed within 3 months, indicating primary resistance. Grade 3/4 toxicity included CPK elevation (asymptomatic, 61%), neutrophil decrease (11%), maculopapular rash (8%), anemia (8%). No unexpected toxicities observed. Correlation of outcome with MSK-IMPACT, MSK-Access and paired tumor biopsies will be presented. Conclusions: This study met its primary endpoint. BINI plus imatinib is highly effective in treatment-naive advanced GIST, with expected and manageable long-term treatment-associated toxicities. The combination strategy warrants further evaluation in direct comparison with imatinib in the frontline treatment of GIST. Clinical trial information: NCT01991379 .
A multicenter phase II study of nivolumab +/- ipilimumab for patients with metastatic sarcoma (Alliance A091401): Results of expansion cohorts.
Authors: Chen James Lin , Mahoney Michelle R. , George Suzanne , Antonescu Cristina R. , Liebner David A. , Van Tine Brian Andrew , Milhem Mohammed M. , Tap William D. , Streicher Howard , Schwartz Gary K. , D'Angelo Sandra P.
Published: May 2020

11511

Background: In the open-label multicenter phase II study, A091401, nivolumab (N) and nivolumab+ipilimumab (N+I) demonstrated a confirmed response rate (RR) of 5% and 16%, respectively in patients (pts) with advanced sarcoma (D’Angelo SP et al Lancet Oncology 2018). Responses occurred in undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma, leiomyosarcoma, sarcoma not otherwise specified and alveolar soft part sarcoma. Here, we report efficacy of N and N+I, in each of 3 expansion cohorts [gastrointestinal stromal tumor (GIST), UPS and dedifferentiated liposarcoma (DDLS)]. Methods: Pts refractory to ≥ 1 regimen(s) were randomized (non-comparative) to receive either N [N (3 mg/kg q2W)] or N+I [N (3 mg/kg Q3W x4, then Q2W) plus I (3 mg/kg q3W x4)]. The primary endpoint was 6 month confirmed RR (RECIST v1.1). For UPS and DDLS, 2 confirmed responses in the 1st 12 evaluable pts was needed (85% power, 1-sided alpha=0.15, 5 v 25% RR). For GIST, a confirmed response in the 1st 9 evaluable pts expanded enrollment to 24 (80% power, 1-sided alpha=0.10, 5 v 20% RR). Other endpoints: adverse events (AEs, TRAEs), progression-free and overall survival (PFS, OS), and correlatives. Results: See table. Clinical trial information: NCT02500797 . Conclusions: Neither N or N+I lead to confirmed responses in GIST. In DDLS and UPS, the primary response endpoint was met with N+I but not with N alone (RR 14% for N+I vs. 7% and 8% for N alone). For the GIST cohort TRAE was higher with N+I, holding enrollment as required per protocol. There remains a pressing need to determine genomic and clinical biomarkers of response, resistance and toxicity. Correlative analyses (whole exome sequencing, multiplex IHC and RNAseq) are in progress. Support: U10CA180821, U10CA180882; ClinicalTrials.gov Identifier: NCT02500797. [Table: see text]
Trabectedin and radiotherapy in soft-tissue sarcoma (TRASTS) study: An international, prospective, phase II trial in localized myxoid liposarcoma—A collaborative Spanish (GEIS), Italian (ISG) and French (FSG) group study.
Authors: Gronchi Alessandro , Hindi Nadia , Blay Jean-Yves , Redondo Andres , Sanfilippo Roberta , Morosi Carlo , Cruz Jurado Josefina , Luna Fra Pablo , Martinez-Trufero Javier , Valverde Morales Claudia Maria , Romero Jesus , Peinado Javier , Sangalli Claudia , Sunyach Marie Pierre , Romagosa Cleofe , Ranchère-Vince Dominique , Gutierrez Antonio , De Tos Paolo , Martin Broto Javier
Published: May 2020

11514

Background: Myxoid liposarcoma (ML) exhibits especial sensitivity to trabectedin (T). In prospective series, T showed responses in 44% of patients (pts) with ML. ML is also sensitive to radiation therapy (RT) and preclinical data suggested radiosensitizing properties of T. Preoperative short-course of T with concurrent low-dose RT was conducted in a multicenter, European, phase I/II trial. We present here the data from the phase II part in pts with centralized diagnosis of locally advanced, resectable ML. Methods: Pts received 3 cycles (C) of T in combination with RT (45 Gy) in 25 fractions (1.8Gy/fraction). The phase I part of the study had the classic 3+3 design. Dose Levels for T were: -1 (1.1 mg/m2), 1 (1.3 mg/m2) and 2 (1.5 mg/m2) Results were already reported (EClincalMedicine 2019;9:35-43) and the dose selected for the phase 2 part was 1.5 mg/m2. RECIST responses were evaluated preoperatively at week 10. Surgical specimens were processed for histologic changes and residual tumor. Results: From July 2016 to September 2019, 47 pts (M/F 31/16) with median age 43y (18-77) and median tumor size 11 cm (3-25 cm), 20 low and 24 high grade (3 not available) were enrolled in the phase II part of the study. The major grade 3/4 toxicities were neutropenia (21.3%), ALT (14.9%), GGT (8.5%) and AST (8.5%) elevation. There were no deaths due to toxicity. 43/47 patients received the planned 3 pre-operative T cycles. All pts completed RT. 1 patient started RT before the first cycle of T and was excluded from the analysis. All pts were evaluable for response: 14 achieved PR (30%), 32 SD (70%). All pts underwent surgery (37 [86%] R0/ 5 [12%] R1/ 1 [2%] R2/ 3 not available). Median viable residual tumor was 10% (0-90) with 23/43 pts (53%) with ≤ 10% viable remaining tumor. Of them 6/43 (14%) had complete responses. At a median FU of 18 months (3-41) one pt developed local recurrence and 2 distant metastases. No deaths were observed. The corresponding 2-yr disease-free survival and overall survival were 97% (95% confidence interval 95-100) and 100%. Conclusions: T in combination with RT was feasible and well tolerated in the preoperative setting. The activity of the combination compares favorably with the administration of T/RT alone. This regimen could potentially become an alternative to anthracycline+ifosfamide concurrent to RT in high risk localized ML. Clinical trial information: NCT02275286 .
A phase II single-arm study of nivolumab and ipilimumab (Nivo/Ipi) in previously treated classical Kaposi sarcoma (CKS).
Authors: Zer Alona , Icht Oded , Joseph Lilach , Avram Dana , Jacobi Oded , Fenig Eyal , Kurman Noga , Peretz Idit , Shamai Sivan , Merimsky Ofer , Ben-Ami Eitan , Shapira Roni , Schwarzbach Anna Ewa , Bernstine Hanna , Weitzen Rony , Vornicova Olga , Bar-Sela Gil , Stemmer Salomon M. , Lotem Michal
Published: May 2020

11518

Background: CKS is a mesenchymal neoplasm associated with HHV8 infection. Though recombinant INFa is approved for treatment of AIDS-related KS, data is limited regarding the role of immune modulation in CKS therapy. Based on favorable responses in viral-induced cancers, we hypothesized that CTLA-4 and PD-1 blockade can induce tumor regression in CKS. We present pre-planned interim analysis of a phase II study of Nivo/Ipi in previously treated progressive CKS. Methods: CKS pts with progressive disease after > 1 line of systemic therapy and measurable disease received nivolumab 240mg d1,15,28 and ipilimumab 1mg/kg d1 q42 days until progression or toxicity. The primary endpoint was overall response rate (ORR) evaluated clinically, radiologically (RECIST) and metabolically (FDG-PET). Secondary endpoints include 6-months progression free survival rate (PFS) and safety. Exploratory endpoints included PD-L1/MMR by IHC, DNAseq (596 genes)/RNAseq (whole transcriptome) of tumor and matched blood specimens to explore CKS genomic traits and IO correlates: TMB and MSI status, MMR and PD-L1 protein expression, and immune gene transcript expression (PD-1, PD-L1, CTLA-4, and others) (Tempus Labs, Chicago, IL, USA). Results: Fifteen patients were enrolled and evaluable (Apr18-Jan20). Median age 72.5 (61-81), all male. At a median FU of 15.7 mo ORR as per RECIST was 66% (9 pts PR, 1 pt CR, 2 pts SD, 3 pts NE). Clinical ORR was 87% and metabolic ORR was 60%. Median PFS was not reached, 6mo PFS rate was 85% and 1y PFS rate was 75%. The safety profile was as expected with all pts experiencing G1 toxicity, 3 pts with G2 toxicity (1 hepatic, 2 asymptomatic lipase increase) and 2 pts with G3 toxicity (1 colitis, 1 asymptomatic lipase increase). One SAE was reported (TIA considered not related to therapy) and treatment was discontinued in 3 pts. Correlative results are available for 8 pts showing a trend for copy number loss in genes with tumor-suppressive activity (FOXA1, ELF3), no PDL1 expression, low TMB, microsatellite stability, but marked overexpression of CTLA-4, PD-1, PDL-1, CD40, OX40 and LAG3 RNA immune transcripts. Conclusions: The interim analysis of this prospective phase II study of nivolumab and low-dose ipilimumab demonstrates promising activity in progressive CKS, with 66% ORR and a 6mo PFS rate of 85%. Toxicity profile is as expected in this class of drugs. Correlative studies are preliminary, but warrant further investigation into genomic traits and immune gene expression profiles. Clinical trial information: NCT03219671. Clinical trial information: NCT03219671 .
A phase II study of anlotinib in treating patients with relapsed or metastatic primary malignant bone tumor.
Authors: Tang Lina , Niu Xiaohui , Wang Zhen , Cai Qiqing , Tu Chongqi , Fan Zhengfu , Yao Yang
Published: May 2020

11525

Background: Primary malignant bone tumors are rare forms of cancer and include mainly bone sarcomas, which are categorized into 3 common types based on tissue origin: osteosarcoma, chondrosarcoma and Ewing sarcoma. A phase II trial was designed to explore the anlotinib activity in patients with relapsed or metastatic primary malignant bone tumor. Methods: Eligible pts were received 12mg of anlotinib once daily, 2 weeks on and 1 week off until progression or unacceptable toxicity. Key-eligibility criteria were aged 14-70 years, histologically confirmed diagnosis of osteosarcoma, chondrosarcoma, bone derived malignant fibrous histiocytoma, giant cell tumor, Ewing sarcoma and PNET, confirmed previous chemotherapy failure, ECOG 0-1(0-2 for amputation pts), required at least one measurable lesion. We observed PFS, OS, ORR, DCR and AE in this study. Results: From August 2018 to April 2019, 42 pts were included. Of 42 efficacy-evaluable pts, 25 were man, median age was 28 (14-68) years. There were 29 pts of osteosarcoma, 9 pts of chondrosarcoma, 3pts of Ewing sarcoma and 1 pt of bone derived malignant fibrous histiocytoma. The progression-free rate at 12 weeks (PFR12weeks), ORR and DCR were 71.3%, 9.52% and 78.57%. Median PFS was 5.26 months (95%CI = 3.48-8.44). Median OS was 11.40 months (95%CI = 10.09, [ ). Median PFS of osteosarcoma and chondrosarcoma was 4.83 months (95%CI = 3.48, 7.13 ) and 2.76 months (95%CI = 1.31, [ ) respectively. The most common Gr 3-5 anlotinib-related AEs were hypertension (19.05%), hypertriglyceridemia (9.52%), hand-foot syndrome (7.14%), and proteinuria (4.76%). Conclusions: The phase II study shows a promising activity of anlotinib in patients with relapsed or metastatic primary malignant bone tumor and an acceptable toxicity. Clinical trial information: NCT03527888 .
Maximum tumor dimension and tumor volume as prognostic factors in patients with newly diagnosed localized Ewing sarcoma (ES)- a report from the Children’s Oncology Group (COG).
Authors: Mascarenhas Leo , Buxton Allen , DuBois Steven G. , Wang Dian , Laack Nadia N. , Brown Kenneth L.B. , Pawel Bruce , Nadel Helen Ruth , Davis Justin , Hawkins Douglas S. , Grier Holcombe E. , Womer Richard B. , Stringham Del , Reed Damon R. , Janeway Katherine A. , Gorlick Richard Greg , Marina Neyssa , Bernstein Mark L. , Krailo Mark D. , Leavey Patrick ,   Bone Sarcoma Committee, Children's Oncology Group
Published: May 2020

11529

Background: Maximum tumor dimension > 8 cm. and large tumor volume have been reported to be adverse prognostic factors in patients with ES but have not been prospectively evaluated in the context of a phase 3 clinical trial with interval compressed chemotherapy. Methods: COG AEWS1031 (NCT01231906) was a randomized phase 3 clinical trial comparing interval compressed chemotherapy regimens in patients with newly diagnosed localized ES of bone and soft tissue. A correlative objective of AEWS1031 was to evaluate tumor size and volume as prognostic factors. Institution-reported dimensions of the primary tumor from baseline imaging were prospectively collected. For inclusion in this analysis, patients had to have at least 1 tumor dimension reported for tumor size analyses and dimensions in 3 axes for tumor volume analyses. Maximum dimension was dichotomized as less than vs. > / = 8cm. Tumor volume was dichotomized as less than vs. > / = 200 mL. Event-free (EFS) and overall survival (OS) from enrollment were calculated using Kaplan-Meier methods and compared between groups using a two-sided log-rank test. Hazard ratios (HR) and confidence intervals (CI) were calculated using the Cox model. Results: The 5-year EFS and OS of the 629 eligible patients was 78% (95% CI: 75-81%) and 87% (95% CI: 84-90%) respectively and there was no significant difference in both EFS and OS between the randomized interval compressed chemotherapy arms of AEWS1031. 590 of 629 (94%) patients were evaluable for maximum tumor dimension and 307 (52%) had tumors > / = 8 cm. Patients with tumors > / = 8 cm were at significantly increased risk for EFS events (p = 0.016) with estimated 5-year EFS of 73.7% (95% CI: 68.1 vs.78.4%) vs. 82.9% (95% CI 77.7-87.1%) for patients with tumors < 8 cm [HR: 1.53 (1.08-2.17)]. For tumor volume, 586 of 629 patients (93%) were evaluable and 180 (31%) had tumors > / = 200 mL. Patients with tumor volume > / = 200 mL were at significantly increased risk for EFS events (p = 0.003) with estimated 5-year EFS of 70% (95% CI: 62.3-76.4%) vs. 81.6% (95% CI: 77.2-85.2%) for patients with tumors < 200 mL [HR: 1.69 (1.2-2.39)]. Conclusions: Maximum tumor dimension and tumor volume as defined are both prognostic in patients with newly diagnosed localized ES treated with interval compressed chemotherapy. Clinical trial information: NCT01231906 .
Quality of life (QoL) and self-reported function with ripretinib in ≥4th-line therapy for patients with gastrointestinal stromal tumors (GIST): Analyses from INVICTUS.
Authors: Heinrich Michael C. , George Suzanne , Zalcberg John Raymond , Bauer Sebastian , Gelderblom Hans , Schoffski Patrick , Serrano Cesar , Jones Robin L. , Attia Steven , D'Amato Gina Z. , Chi Ping , Reichardt Peter , Becker Claus C. , Meade Julie Nicole , Ruiz-Soto Rodrigo , von Mehren Margaret , Blay Jean-Yves
Published: May 2020

11535

Background: Ripretinib is a novel switch-control tyrosine kinase inhibitor (TKI) that broadly inhibits KIT and PDGFRA kinase signaling through a dual mechanism of action. In INVICTUS (NCT03353753), a randomized, double-blind, placebo-controlled trial of ripretinib in ≥4th-line advanced GIST, ripretinib reduced the risk of disease progression or death by 85% vs placebo and had a favorable overall safety profile in patients previously treated with ≥3 prior TKIs. Methods: As part of the INVICTUS trial, patient reported outcome (PRO) measures were collected using EQ-5D-5L (EQ5D) and EORTC QLQ-C30 (C30). In prespecified and additional analyses, ANCOVA models were built to compare changes from baseline to cycle 2 day 1 (C2D1) for PRO measures within the ripretinib and placebo arms and determine the difference between treatment arms. PRO measures included the EQ5D visual analogue scale (VAS) and the C30 physical functioning (PF) and role functioning (RF) scales (all scores range from 0–100; higher scores are better). The C30 overall health and overall QoL questions were also assessed (scores range from 1–7; higher scores are better). Fixed effects included treatment arm, number of previous anticancer treatments (3 vs ≥4), and ECOG score at baseline (0 vs 1/2). Results: Overall, 129 patients were randomized and 128 received treatment (85 to ripretinib 150 mg QD; 43 to placebo). All PRO p-values are nominal, and no statistical significance is being claimed. VAS scores improved an average 3.7 points from baseline to C2D1 with ripretinib vs an average decline of 8.9 with placebo (P = 0.004; improvement or no change, 67% vs 41% of patients, respectively). Similarly, the average PF score improved 1.6 points with ripretinib and decreased 8.9 with placebo (P = 0.004; improvement or no change, 68% vs 44%). RF scores also improved an average of 3.5 points with ripretinib vs a decrease of 17.1 with placebo (P = 0.001; improvement or no change, 77% vs 50%). For the overall health and overall QoL questions, scores increased with ripretinib an average of 0.20 and 0.28, respectively, and decreased 0.78 and 0.76 with placebo (both P = 0.001; improvement or no change, 74% vs 47% and 79% vs 59%, respectively). Conclusions: Based on the 5 PRO measures assessed, when compared with placebo and best supportive care, ripretinib provided patient-benefit in advanced GIST with PRO measures of role and physical function, VAS, overall health, and overall QoL remaining stable. Clinical trial information: NCT03353753 .
A randomized trial of a palliative care intervention for patients on phase I studies.
Authors: Smith Thomas J. , Chung Vincent , Hughes Mark T. , Koczywas Marianna , Azad Nilofer Saba , Knight Louise , Cooper Rhonda , Ruel Nora , Ferrell Betty R.
Published: May 2020

12001

Background: The purpose of this study was to test a Palliative Care Intervention for patients with solid tumors enrolled in phase I therapeutic trials. Methods: This randomized trial compared patients accrued to phase I Clinical Trials in groups of Usual Care compared to a Palliative Care Intervention (PCI) in two comprehensive cancer centers. The PCI included assessment of quality of life (QOL) and symptoms, an interdisciplinary meeting to discuss the care plan, including goals of care, and two nurse-delivered teaching sessions. Subjects (n=479) were followed for 24 weeks, with 12 weeks as the primary outcome point. Results: Outcomes revealed that relative to Usual Care, PCI subjects showed less Psychological Distress (1.9 in Intervention and 1.2 in Control pts, p=0.03) and a trend toward improved QOL (3.7 versus 1.6, p=0.07), with differences between sites. We observed high rates of symptom-management admissions (41.3%) and low rates of Advance Directive completion (39%), and use of supportive care services including hospice (30.7%, for only1.2 months duration), despite a median survival for all patients in both groups of 10.1 months from initiating a phase 1 study until death. Patient satisfaction with oncology care was already high at baseline, and we did not see clinically significant changes in those scores by week 12. Conclusions: Palliative care interventions can improve QOL outcomes and distress for patients participating in phase 1 trials. Greater integration of PC is needed to provide quality care to these patients and to support transitions from treatment to supportive care, especially at the end of life. Clinical trial information: NCT01828775 .
A geriatric assessment (GA) intervention to reduce treatment toxicity in older patients with advanced cancer: A University of Rochester Cancer Center NCI community oncology research program cluster randomized clinical trial (CRCT).
Authors: Mohile Supriya Gupta , Mohamed Mostafa Refaat , Culakova Eva , Xu Huiwen , Loh Kah Poh , Magnuson Allison , Flannery Marie Anne , Ramsdale Erika E. , Dunne Richard Francis , Gilmore Nikesha , Obrecht Spencer , Patil Amita , Plumb Sandy , Lowenstein Lisa M , Janelsins Michelle Christine , Mustian Karen Michelle , Hopkins Judith O. , Berenberg Jeffrey L. , Gaur Rakesh , Dale William
Published: May 2020

12009

Background: GA evaluates aging-related domains (e.g., function) known to be associated with cancer treatment toxicity. In this CRCT, we evaluated if providing a GA summary with management recommendations to oncologists can reduce toxicity in older patients (pts) with advanced cancer receiving chemotherapy and/or other agents with a high reported prevalence of grade 3-5 toxicity. Methods: Pts aged > 70 with incurable solid tumors or lymphoma and > 1 impaired GA domain starting a new treatment regimen were enrolled. Community oncology practices were randomized to intervention (oncologists received GA summary/recommendations for impairments) or usual care (none given). The primary outcome was proportion of pts who experienced any grade 3-5 toxicity (CTCAE v.4) within 3 months. Practice staff prospectively captured toxicities; blinded oncology clinicians reviewed medical records to verify. Secondary outcomes included 6 month overall survival (OS) and treatment intensity (standard vs reduced). Outcomes were analyzed using generalized linear mixed/Cox models with Arm as a fixed effect, controlling for practice. Results: From 2013-19, 718 pts were enrolled from 41 practices. Age (mean 77 yrs), sex (43% women), number of impaired GA domains (median 4/8), and treatment type (chemotherapy 88%) were not different by Arm. More pts in intervention were Black (12% vs 3%, p<0.01), had GI cancer (38% vs 31%, p<0.01), and had prior chemotherapy (31% vs 23%, p=0.02). Pts in intervention experienced a lower proportion of grade 3-5 toxicity (175/349; 50%) than pts in usual care (262/369; 71%). The relative risk (RR: intervention vs usual care) of grade 3-5 toxicity was 0.74 (95% CI: 0.63-0.87; p=0.0002); the difference was mostly driven by non-heme toxicities (RR 0.73; 95% CI: 0.53-1.0, p<0.05). OS was not significantly different (71% vs 74%, p=0.3). More pts in intervention received reduced intensity treatment at cycle 1 (49% vs 35%, RR 0.81, p=0.01). Dose modifications due to toxicity were lower in intervention (42% vs 58%, p<0.0001), but results were not significant after controlling for practice (RR 0.85; 95% CI: 0.67-1.08, p=0.2). Conclusions: Providing GA information to oncologists reduces the proportion of older pts who experience grade 3-5 toxicity from high-risk palliative cancer treatment, without compromising OS. Reduced treatment intensity at cycle 1 may explain these results. Funding: R01CA177592, U01CA233167, UG1CA189961. Clinical trial information: NCT02054741 .
Impact of baseline symptom burden as assessed by patient-reported outcomes (PROs) on overall survival (OS) of patients with metastatic cancer.
Authors: Batra Atul , Cuthbert Colleen Ann , Harper Andrew , Yang Lin , Boyne Devon J. , Rigo Rodrigo , Cheung Winson Y.
Published: May 2020

12020

Background: Patients with metastatic cancer experience variable symptom burden, but serial symptom assessments using PROs may be challenging to implement in routine clinical practices. We aimed to determine if a single measurement of symptom burden at the time of metastatic diagnosis is associated with survival. Methods: We examined prospectively collected baseline PROs of patients newly diagnosed with metastatic breast, lung, colorectal, or prostate cancer using the revised Edmonton Symptom Assessment System (ESASr) questionnaire from a large province (Alberta, Canada) between 2016 and 2019. The ESASr was categorized into physical (PH), psychosocial (PS), and total symptom (TS) domains whereby scores were classified as mild (0-3), moderate (4-6), or severe (7-10). Multivariable Cox proportional hazards models were constructed to evaluate the effect of baseline symptom scores on OS. Results: We identified 1,315 patients, of whom 57% were men and median age was 66 (IQR, 27-93) years. There were 180, 601, 240, and 294 patients with breast, lung, colorectal, and prostate cancer, respectively. Approximately one-quarter of all patients reported moderate to severe PH, PS, and TS scores, with lung cancer patients experiencing the highest symptom intensity across all domains ( P<0.0001). While age did not affect symptom scores, women were more likely to report severe PH, PS, and TS scores as compared to men ( P=0.02, 0.002, and 0.007, respectively). On multivariable Cox regression analysis, older age (HR 1.02, 95% CI, 1.02-1.03, P<0.0001) and female sex (HR 1.67, 95% CI, 1.39-1.99, P<0.0001) were predictive of worse OS as were severe baseline PH and TS scores (see Table) . However, baseline PS scores were not related to OS. Conclusions: A single assessment of baseline symptom burden using the ESASr in patients with metastatic cancer has significant prognostic value. This may represent a feasible first step toward routine collection of PROs in real-world settings where serial symptom measurements can be challenging to implement. [Table: see text]
Effect of evidence-based nutrition educational intervention on adherence to dietary guidelines (ADG) and weight management among early-stage breast cancer (EBC) patients (pts): A prospective trial.
Authors: Trestini Ilaria , Sperduti Isabella , Caldart Alberto , Bonaiuto Clelia , Fiorio Elena , Parolin Veronica , Tregnago Daniela , Avancini Alice , Pilotto Sara , Lanza Massimo , Scambia Giovanni , Tortora Giampaolo , Milella Michele , Bria Emilio , Carbognin Luisa
Published: May 2020

12056

Background: Excess adiposity is linked to an increased risk of worse outcome among EBC pts. Pts undergoing EBC treatment are susceptible to change in nutrition status. However, implementation and assessment of the adherence to lifestyle interventions have been limited. This prospective trial aimed to evaluate the impact of an evidence-based nutrition intervention, according to the ADG, in terms of body composition changes in EBC pts. Methods: Entry criteria: EBC pts candidate to neoadjuvant/adjuvant therapy. At study entry, pts received a nutrition evidence-based tailored intervention. Dietary and anthropometric assessments were evaluated at baseline and after 12-months nutritional intervention. Waist circumference (WC) was assessed as a surrogate measure of fat distribution. ADG was estimated by Med-Diet 14-item questionnaire. Health-Related Quality of Life was analysed with EORTC QLQ-C30. Descriptive statistics was adopted. Associations between variables and groups according to nutritional variables were analysed (Chi-square test). Results: From February 2016 to December 2019, 243 pts were enrolled (median age 49 years): 27.6%/48.6% neoadjuvant/adjuvant treatment. At baseline, 38.3% of pts were overweight and 23.9% were obese. Notably, tumor size was significantly correlated with WC in the whole population (p = 0.003). Moreover, pts with central obesity were more likely to present HER2-negative tumors (57.4% vs. 42.5%, p = 0.03). Most pts reported relevant nutrition impact symptoms and symptoms affected QoL. Particularly, dyspepsia and constipation were more prevalent in overweight and obese pts (p < 0.0001 and p = 0.009, respectively), as well as in pts who gained ≥5% of weight (p = 0.04 and p = 0.02, respectively). At baseline, there was low ADG. After the 12-months intervention, ADG significantly increased (median Med-Diet score: 6 vs.12, p < 0.0001). A high ADG (defines as a Med-Diet score ≥10) significantly correlated with: 1) loss of weight ≥5% from the baseline weight (p = 0.003); 2) change in terms of BMI; 3) prevalence of central obesity. Conclusions: A tailored evidence-based nutritional intervention for EBC pts represents a tool to improve their ADG, weight management and, thus, to potentially influence the disease outcome. [Table: see text]
Lifelong disease burden of chemotherapy in Hodgkin lymphoma (HL): A simulation study from the St. Jude Lifetime (SJLIFE) Cohort and HL International Study for Individual Care (HoLISTIC).
Authors: Parsons Susan K. , Bhakta Nickhill , Rodday Angie Mae , Scharman Carlton , André Marc , Federico Massimo , Friedberg Jonathan W. , Friedman Debra L. , Gallamini Andrea , Hay Annette E. , Kahl Brad S. , Keller Frank G. , Kelly Kara M. , Meyer Ralph M. , Raemaekers John , Robison Leslie L. , Hudson Melissa M. , Cohen Joshua T. , Evens Andrew M. , Wong F. Lennie ,   on behalf of the HoLISTIC Consortium
Published: May 2020

12068

Background: Current emphasis for childhood and young adults with HL is to maintain high cure rates while concurrently identifying regimens to reduce excess long-term mortality/morbidity. Thus, understanding the late effects (LE) of contemporary clinical trials (CCT) for HL is critical. Methods: We used simulation to estimate the projected life expectancy (LExp), quality adjusted life-expectancy (QALE) & cause of death (COD) in a large cohort of HL CCT patients (pts) in the recently established HoLISTIC consortium by linking long-term risk models from the SJLIFE cohort. Individual patient data (IPD) on bleomycin, alkylating agents and anthracycline were extracted & harmonized for 982 HL pts in 5 prospective CCT (mean diagnosis age 19y, range 3-30y; 51% male; all treated with chemotherapy only; progression-free survival [PFS] >5y) in the HoLISTIC database. LExp, QALE & COD were projected using a previously developed microsimulation model (Bhakta, Blood [Supplement], 2019) that incorporated mortality & incidence of LEs by diagnosis age, sex, race, treatment exposures & attained age estimated from 5,522 adult 10-y survivors of childhood cancers in the SJLIFE cohort (56% male; mean age at last follow-up 35y, range 19-68). Microsimulation was applied to 10,000 randomly selected survivors of HL CCT cohort, from 10y after HL diagnosis until death to project the LExp, QALE & COD. Results: Assuming 10-y PFS, LExp and QALEs projected for the HL CCT cohort using adjusted US general population rates linked with the SJLIFE microsimulation model, COD and trial-specific exposures are shown in the Table. Conclusions: A novel lifetime simulation approach was used to project LExp, QALE & COD by linking together IPD from CCTs with the long-term risk model of the SJLIFE survivorship cohort. Despite differences in PFS, reflecting in part the variation in risk/stage status, the projected long-term outcomes were similar. Our approach highlights a new opportunity to inform future clinical trial design and aid provider & patient decision-making. [Table: see text]
Assessing the roles of inflammation and blood brain barrier permeability in cognitive impairment: A nationwide longitudinal study of patients receiving chemotherapy and non-cancer controls.
Authors: Belcher Elizabeth , Gilmore Nikesha , Kleckner Amber , Kleckner Ian , Culakova Eva , Lotta Louis , Thompson Bryan , Geer Jodi , Hopkins Judith O. , Long Joan , Janelsins Michelle Christine
Published: May 2020

12070

Background: Cognitive impairment is a prevalent side effect of chemotherapy. We have previously shown that chemotherapy treatment is associated with worse performance on the Rapid Visual Processing test (RVP), an objective measure of sustained attention, over time compared to non-cancer controls. Better understanding of the biologic mechanisms underlying cognitive impairment in cancer patients is needed. The pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) has been implicated in increasing blood brain barrier (BBB) permeability, which in turn is associated with cognitive impairment. This study assessed the relationships of TNFα and S100β, a biomarker of BBB permeability, to each other and to RVP performance over time. Methods: We analyzed a subset of participants (n = 89 patients, n = 52 controls, mean age = 60) from a prospective longitudinal study of women with breast cancer receiving chemotherapy and non-cancer controls. TNFα and S100β were measured in serum pre-chemotherapy (T1, ≤7 days before first treatment) and post-chemotherapy (T2, ≤1 month after last treatment) and at corresponding times for controls. Sustained attention was assessed by total correct rejections on the RVP test at T1 and T2. Separate linear regression models including all participants were used to relate 1) baseline TNFα and S100β levels to change in RVP performance over time, 2) change in TNFα and S100β to change in RVP performance over time, and 3) change in TNFα to change in S100β. Models were adjusted for age. 4) T-tests were used to compare the TNFα and S100β change scores (T1 to T2) of patients vs controls. Results: Greater increase (T1 to T2) in the pro-inflammatory cytokine TNFα was associated with worse cognition, measured by performance on RVP over time (p = 0.02). Higher baseline S100β, a biomarker of BBB permeability, was associated with worse performance on RVP over time (p = 0.09). Increase in TNFα was associated with increase in S100β (p = 0.11). S100β increased from T1 to T2 in patients relative to controls (p = 0.09). Conclusions: These results suggest that higher TNFα may be related to increases in blood brain barrier permeability and worse cognition. Future studies will further define the link between inflammation, blood brain barrier permeability and chemotherapy-related cognitive decline, with the goal of informing the development of new interventions. Funding: R01CA231014, T32CA102618, DP2CA195765, UG1CA189961.
Using digital engagement to proactively manage symptoms in patients on capecitabine.
Authors: Sohal Mandeep , McLarty Sarah , Friend Kayla E , Johnson Kathryn D , Johlie Melissa , Sawicki Christine , Johnson Kjel Andrew
Published: May 2020

12079

Background: Adherence to oral chemotherapy is a challenge due to the toxic adverse events (AEs) patients’ experience. Capecitabine (CAP) may cause patients to experience AEs such as diarrhea and hand and foot syndrome (HFS), leading to therapy non-adherence. Digital patient engagement has successfully improved patient adherence and has been used to monitor AEs in a variety of cancer types. We used proprietary secure messaging to engage specialty patients receiving CAP and to message them at the expected onset of diarrhea and HFS; nurse care management was deployed for patients reporting an AE. The objective of this study was to determine whether nurse engagement using digital tools to manage oncology AEs resulted in improved medication adherence. Methods: CAP patients were sent outgoing SMS branching logic messages during November 2019, and respondents reporting AEs were engaged by nurses using a proprietary secure messaging platform. Nurses made clinical interventions in these patients by either making a pharmacologic or non-pharmacologic recommendation or referring the patient to an oncologist. The number of patients responding to outgoing SMS and secure messaging, nurse interventions, and medication fill history were measured. We compared 30-day post-intervention proportion of days covered (PDC) in the intervention group (those that engaged with nurses and received digital adherence and clinical messages) to standard of care (those who received digital adherence and clinical messages but did not engage) using the Student’s t-test. Results: 1,421 outgoing messages were sent to utilizers of CAP; 95 patients replied indicating the occurrence of either diarrhea or HFS. Nurse care managers reached 49 (52%) unique patients resulting in 54 interventions where care coordination was provided. The majority of engaged patients reached (74%) had symptom resolution as a result of nurse intervention. PDC was 79.3% in the intervention group and 68.8% (p = 0.038) in the standard of care group. Conclusions: SMS and secure messaging patients with AEs on CAP resulted in clinical interventions by nurse care managers. Nurse intervention resulted in the majority of patients having symptomatic resolution and therapy continuation. PDC indicated greater medication adherence in the engaged group. These results for one drug suggest that nurse digital engagement can be effective in increasing adherence for patients treated with oral oncolytics suffering from AEs. Proactive symptom tracking supports the early identification of potential AEs and effective nurse care coordination.
Quality of life in patients with locally advanced head and neck cancer undergoing chemoradiation with once-a-week versus once-every-three-weeks cisplatin.
Authors: Menon Nandini Sharrel , Noronha Vanita , Joshi Amit , Patil Vijay Maruti , Bhattacharjee Atanu , Kalra Devanshi , Mathrudev Vijayalakshmi , Bhelekar Arti , Prabhash Kumar
Published: May 2020

12092

Background: This trial was conducted to compare the efficacy of low dose once-a-week cisplatin with once-every-3-weeks cisplatin with radiation in locally advanced head and neck squamous cell carcinoma (LAHNSCC). The current analysis focuses on the quality of life (QoL) of patients in this trial. Methods: In this phase III randomized trial, patients with stage III or IV non-metastatic LAHNSCC were randomized to receive cisplatin 30 mg/m2 once a week or cisplatin 100 mg/m2 once every 3 weeks concurrently with curative intent radiotherapy. The primary endpoint was locoregional control. QoL was a key secondary endpoint. QoL was assessed using the EORTC QLQ-C30 (v.3) and EORTC QLQ-H&N35 (v.1). QoL data were assessed at baseline and days 22 and 43 during treatment; at the end of chemoradiation and at each follow-up. The linear mixed effects model was used for longitudinal analysis of QoL domains to determine the impact of treatment (arm) and time on QoL scores. Results: Three hundred patients were enrolled, 150 in each arm. QoL data from 283 patients with at least one assessable questionnaire were analyzed. The pretreatment QoL scores were similar in both the arms in all domains. There was no significant difference in the global health status/QoL with respect to the treatment arm ( P =0.608) or time ( P=0.0544 ). There was no significant difference in the longitudinal QoL scores between the two treatment arms in all domains except the physical function ( P= .0074), constipation ( P= .0326), trouble with social contact ( P= .0321) and sexuality ( P= .0004). There was a decline in the QoL scores in all domains in both arms during treatment. After completion of treatment, the QoL scores started improving steadily up to 1 year and plateaued thereafter in both arms. Conclusions: The use of once-every-three weeks cisplatin significantly improved the locoregional control without adversely impacting the quality of life as compared to once-a-week cisplatin in combination with radical radiotherapy in locally advanced HNSCC. Clinical trial information: CTRI/2012/10/ 003062. .
CIFeR: A novel Clinician-lead Intervention to address Fear of cancer Recurrence (FCR) in breast cancer survivors.
Authors: Liu Jia , Bui Kim Tam , Serafimovska Anastasia , Kiely Belinda Emma , Hui Mun Ngah , Goodwin Annabel , McNeil Catriona M. , Costa Daniel SJ , Butow Phyllis , Beith Jane McNeil
Published: May 2020

12115

Background: FCR affects 50-70% of cancer survivors. There are no validated oncologist-delivered FCR interventions. This multicentre, single-arm study sought to determine the helpfulness, feasibility and efficacy of an oncologist-delivered FCR intervention. Methods: Women were invited to participate if they had completed local treatment, chemotherapy and/or HER2 targeted therapy for early stage breast cancer and had a FCR score >0 on the 42-item FCR Inventory. The brief intervention, delivered by their medical oncologist at routine follow-up, entailed 1) FCR normalisation; 2) provision of personalised prognostic information; 3) take-home education sheet on recurrence symptoms; and 4) advice on managing worry. Consultations were audio-recorded. FCR, need for help, depression and anxiety were assessed before the intervention (T0), and at one week (T1) and three months (T2) after the intervention. Satisfaction with the intervention was assessed at T1. The primary outcome was participant-rated helpfulness. Secondary outcomes included feasibility (response rate, time taken for intervention) and efficacy. Results: Five oncologists delivered the intervention to 61 women (255 women invited; response rate 24%). The mean age was 57 ± 13 years. The mean time since breast cancer diagnosis was 2.5 ± 1.3 years. Forty-three (72%) were on adjuvant hormonal therapy. Overall, 58 women (95%) found the intervention helpful and 59 (98%) would recommend it to others. FCR severity, and the proportion of women with clinically significant FCR decreased significantly over time. There were no significant changes in unmet need, depression, or anxiety. Forty (66%) of consultations were recorded. Mean consultation length was 22 minutes (range 12-37 minutes) and mean intervention length was 9 minutes (3-20 minutes). The intervention was perceived as useful and feasible by oncologists, all of whom have used components of the intervention to help manage FCR in other breast cancer patients. Conclusions: A brief oncologist-delivered intervention to address FCR is helpful and feasible, and has shown preliminary efficacy in reducing FCR. Plans for an implementation study amongst oncologists in Australia are underway. Clinical trial information: ACTRN12618001615279 . [Table: see text]
Video conference intervention for distance caregivers (DCGs) of patients with cancer: Improving psychological outcomes.
Authors: Douglas Sara L , Mazanec Polly , Lipson Amy R , Blackstone Eric , Day Kim , Bajor David Lawrence , Krishnamurthi Smitha S.
Published: May 2020

12123

Background: Family caregivers are increasingly involved in providing care and support for patients with cancer. Approximately 20% of caregivers live > 1 hour away from the patient and are considered DCGs. DCGs report higher distress and anxiety than local caregivers—often due to lack of first hand information and a high degree of uncertainty regarding the patient’s condition. Methods: This RCT was conducted at a large, urban comprehensive cancer center. Patients of all cancer types were eligible if they had monthly oncologist appointments and were receiving treatment. DCGs were randomized to one of three arms. Arm 1 received 4 monthly videoconference coaching sessions with a nurse practitioner or social worker focused upon information and support, participated in patient’s appointments with the oncologist via videoconference over the 4 month study period, and had access to a website designed for DCGs. Arm 2 did not receive the coaching sessions but received the other 2 components of Arm 1. Arm 3 received access to the DCG website only. Primary variables of interest were DCG distress and anxiety. DCGs completed online surveys prior to randomization and at the completion of the intervention period. PROMIS Anxiety and the NCCN distress thermometer were used. Results: Between November, 2016 and October, 2019, 441 patient-dyads were enrolled. Mean DCG age was 47 years; 71% were female, 65% Caucasian, 63% were the child of the patient and 81% were employed. Mean patient age was 65 years, 60% were female, 30% had GI cancer and 18% had hematologic cancer. For patients with solid tumor cancers, 59% were Stage IV. RMANOVA was used to examine the change in anxiety t-scores over time by arms of the intervention, controlling for DCG age, race, and gender. There was a significant anxiety by group interaction (p = .03) with Arm 1 being the only group that showed a significant reduction in anxiety over time (21.2% improved, ES = .57). Distress followed a similar pattern with a significant distress by group interaction (p = .02) with Arm 1 demonstrating the greatest improvement in distress over time (54.3%). Conclusions: These data suggest that the use of a coaching videoconference intervention made significant and clinically meaningful differences in anxiety and distress for these important members of the family caregiving team. Clinical trial information: NCT02666183 .
Discovery of a core-panel of markers for a blood-assay for cancer detection utilizing cfDNA methylation changes.
Authors: Seneviratne Lasika , Evans Steven , Pulicharam Juvairiya , Arber Nadir , Kuint Jacob
Published: May 2020

1522

Background: Cancer screening is limited to several cancers despite improved outcome A screening test should be acceptable, safe, and relatively inexpensive1 Tumors shed cfDNA to the blood where abundant tumor-specific methylation changes can be detected 1https://www.who.int/cancer/detection/variouscancer/en/. Methods: This is a prospective, multicenter, observational study under two protocols NCT04264767, NCT04264754. Plasma was collected from 1,255 subjects: 586 treatment-naïve cancer patients and 639 controls, in 21 sites and biobanks. Training set I (211 cases/99 controls) was used to select the 6 final markers for the core panel, training set II (200 controls) was used to lock the algorithm, and set the threshold to a score yielding specificity of 95%. The validation set (342 cases/310 controls) was performed utilizing the pre-specified algorithm and threshold. Plasma was separated from a single EDTA tube within 4 hours of blood draw. EpiCheck’s reagents and methylation-sensitive enzymes (Nucleix, Israel) were used for DNA extraction, digestion, and amplification in real-time PCR (ABI 7500 Fast Dx, Applied Biosystems). Results: Age was comparable but sex and smoking history were different (more women in cases, more smokers in controls). In the validation cohort twelve cancer types were included, with prominent representation of major cancer types (19% Breast, 14% colorectal and 21% lung) and stages I&II (56%). Specificity and sensitivity were maintained high at 94% and 62%. Highest sensitivity was demonstrated in GI cancers (77% colorectal, 83% esophageal, 100% gastric) and non-solid malignancies (83%). Sensitivity in early stage cancers (stages I, II & IIIA) was 71%, led by Sarcoma (83%) esophageal (76%) and colorectal (61%). Conclusions: This 6-marker blood-based methylation assay is a promising initial component in a future cancer screening test, generating significant signal in early cancers and utilizing simple and inexpensive PCR technology. Clinical trial information: NCT04264767, NCT04264754. [Table: see text]