bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gaps in caregiving for young-onset colorectal cancer patients.
Authors: Newcomer Kim Lynn , Yarden Ronit , Peterson Danielle ,   Never Too Young Advisory Board
Published: February 2020

82 Background: The rise of young-onset colorectal cancer (YO-CRC) is an alarming public health issue. Interestingly, the proportion of new cases diagnosed in young people (20-49) had increased from 6% in 1990 to 11% in 2013 and coincides with the declining CRC cases in older people. YO-CRC patients face unique clinical challenges as many are diagnosed at advanced stages of the disease and subjected to aggressive treatments. In addition, diagnosis often disrupts early family and career developmental tasks and goals, suggesting the need for additional psychosocial support. Caregivers are an important part of the patient journey. Caregivers serve as liaisons with the medical community and the patient’s social network. The goal of this study is to cast light and explore the experience of caregivers who were caring for YO-CRC patients. Methods: The online survey was completed by 208 caregivers, diverse in age, gender, and race/ethnicity. Participants indicated their relationship as either: spouse/partner, parents, siblings, children, and non-family members. Results: Caregivers self-report they do not understand the important aspects of patients' medical needs despite 79% of caregivers are college graduates and 43% had an advanced degree. Most of the respondents (76%) lack understanding about treatment options and 56% did not feel confident they understood healthcare decisions. Overall, caregivers needed more information and guidance for managing the side-effects of treatment, A majority of caregivers (93%) reported fatigue due to lack of sleep and 63% reporting they missed eight hours or more of work each month. Participants (73%) reported they needed help for panic and anxiety and employed different coping mechanisms to deal with the toll of caregiving. Conclusions: Our survey indicates we must recognize caregivers as the patient's healthcare partners and engage them in the entire plan of care. A growing population of YO-CRC patients means a growing population of caregivers who are navigating work, parenthood, impacts on sexual health, and role changes right along with that patient. Such understanding could help in developing appropriate interventions for caregivers aimed at reducing their burden and stress in caring for patients with YO-CRC.
Phase Ib trial of pembrolizumab and XL888 in patients with advanced gastrointestinal malignancies: Results of the dose-escalation phase.
Authors: Akce Mehmet , Alese Olatunji B. , Shaib Walid Labib , Wu Christina , Lesinski Gregory B. , El-Rayes Bassel F. 
Published: February 2020

830 Background: XL888 is a selective inhibitor of heat shock protein 90 (HSP90). It modulates several oncogenic signaling pathways, and the tumor microenvironment. In preclinical models, XL888 potentiates efficacy of PD-1 inhibition. We report the results of the dose escalation (DE) portion of a phase Ib trial of combined XL888 and pembrolizumab (P) in advanced gastrointestinal adenocarcinomas. Methods: XL888 was administered orally (PO) in three dose levels of 45 (DL1), 90 (DL2), 60 (only if DLT on DL2) mg twice weekly with P 200 mg IV on day 1, in 21-day cycles. Eligible patients included stage IV or locally advanced unresectable gastrointestinal adenocarcinomas with at least one prior therapy (patients with colorectal (CRC) adenocarcinoma must have received oxaliplatin, irinotecan, and fluoropyrimidine), age ≥18 years, ECOG PS 0-1, adequate organ function, no prior anti-PD-1 or anti-PD-L1 agent. The primary endpoint was recommended phase II dose (RP2D), while secondary endpoints included safety and tolerability. Pre-treatment and on-treatment correlative peripheral blood specimens were collected. Results: A total of 14 patients were enrolled in the DE phase. 9 male, median age 66.5. Diagnoses included CRC (6), pancreatic adenocarcinoma (5), biliary tract cancer (1), ampullary (1), and duodenal (1). Two patients were ineligible for assessing the primary endpoint (DL2) due to biliary stent obstruction and sepsis. One DLT (grade 3 autoimmune hepatitis) was observed on DL2. We enrolled three patients on DL3. Five additional patients were subsequently enrolled on DL2 with no additional DLT. Three patients (1 duodenal, 2 CRC) had prolonged stable disease (6, 9 and 15 cycles). The most common treatment-related toxicities included autoimmune hepatitis (G3; n = 1), retinopathy (G2; n = 2), nausea (G2; n = 1), constipation (G2; n = 1), and diarrhea (G2; n = 3). Conclusions: The XL888 and pembrolizumab combination had an acceptable safety profile and the RP2D of XL888 was 90 mg twice weekly combined with P 200 mg, every 3 weeks. The dose expansion portion and a robust series of immunologic correlative laboratory studies for this study is ongoing. Clinical trial information: NCT03095781.
Splenomegaly during oxaliplatin-based chemotherapy in colon cancer.
Authors: Ji Ruoyu , Huang Guanghua , Liu Lingshan , Chen Mengyin , Yu Xiaoduo , Zhou Aiping , Du Chun-Xia 
Published: February 2020

88 Background: Splenic enlargement has been reported in patients treated with oxaliplatin. However, the characteristics of oxaliplatin-induced splenomegaly were not well studied. Here we evaluated the change of splenic volume and its clinical significance in patients treated by oxaliplatin-based regimen. Methods: Patients with stage II-IV primary colon cancer treated with oxaliplatin and capecitabine in China National Cancer Center from January 2016 to December 2017 were screened for this retrospective study. Those with complete laboratory tests and computed tomographic data before, during and up to 1.5 years after the chemotherapy were selected. The splenic size was measured by AWVolumeshare5. Splenomegaly was defined as an over 30% increase of splenic size from baseline. Recovery of splenomegaly was defined as the splenic size fell back to a 0.9 to1.1-fold range of baseline. Results: Out of a total of 144 patients, 102 (70.8%) had over 30% increase, 72 (50.0%) had over 50% increase, and 22 (15.3%) had over 100% increase in splenic size after oxaliplatin-based regimen. Among the 102 splenomegaly patients, 5 (4.9%) develop splenomegaly within 3 chemotherapy cycles, 53 (53.0%) within 6 cycles, 73 (71.6%) within 9 cycles, and 102 (100.0%) within 3 months after the last administration of oxaliplatin. Compared to the group without splenomegaly, patients with splenomegaly received more cycles of oxaliplatin administrations (median 8 vs 6, p < 0.001) and greater dose intensity (total dose per square meter) (median 822.8mg/m2 vs 629.3mg/m2, p < 0.001). Patients with splenomegaly had higher incidence of thrombocytopenia (61.7% vs 38.1%, p = 0.009) and are more likely to undergo oxaliplatin dose reduction due to thrombocytopenia (21.6% vs 7.1%, p = 0.038). The recovery rates of splenic size within 0.5, 1 and 1.5 years after the end of oxaliplatin treatment were 23.2%, 50.6% and 74.3%, respectively. Conclusions: Splenomegaly are common in patients treated with oxaliplatin-based chemotherapy, and most would recover in 1.5 years after completion of therapy. Patients with splenomegaly are prone to experience thrombocytopenia and oxaliplatin dose reduction. Further studies are needed to reveal the mechanism how oxaliplatin induce splenomegaly.
Prospective DPYD testing and dose adjustment in colorectal cancer patients prior to fluoropyrimidine-based chemotherapy: Experience in a regional cancer center.
Authors: Graham Janet Shirley , Saunders Jocelyn , Naylor Gregory , Crearie Christine , Campbell Wendy , Abdullah Tareq , Dunn Mary G. , MacLeod Nicholas James , McDonald Alec , McGaffin Gillian , McKillop Anne Jane , Miller Laura , Mohammed Nazia , Othman Aqilah , Radford Liz , Smith Karen , Storey Dawn Jane , Williams Nicola , Westwood Paul , Wilson Richard H. 
Published: February 2020

93 Background: The fluoropyrimidines (FP), 5-Fluorouracil (5-FU) and capecitabine are a mainstay of colorectal cancer (CRC) treatment. Dihydropyrimidine dehydrogenase (DPYD), an enzyme encoded by the DPYD gene, is the initial and rate-limiting step in pyrimidine catabolism, deactivating over 80% of 5-FU. Approximately 5% of the population are deficient in DPYD and can develop severe or fatal FP toxicities. Currently, few national guidelines recommend routine prospective DPYD testing. In July 2019, we commenced a 6 month prospective pilot, testing DPYD status of all CRC patients undergoing first FP treatment in a large regional cancer centre. Methods: All CRC patients eligible for first exposure to FP are tested using a rapid molecular assay screening for five SNPs (detects 70% of DPYD mutations) and we will present data on prevalence of each. We will use electronic chemotherapy prescribing records (July 19-Jan 20) to collect information on dose modifications and toxicities. Once the pilot is completed we will perform a cost-effectiveness analysis. Results: Data from the first 3 months of this pilot have been reviewed and 201 patients have been tested with 15 heterozygotes identified, of which 2 had more than one mutation. No homozygotes were found. All heterozygote patients are started with a dose reduction (or have alternative therapy). One patient treated at 50% dose was hospitalised with several grade 3 toxicities despite dose reduction. Two patients have had subsequent dose escalation (by 25%). Nine patients have received one dose reduced cycle without complication. Three patients are due to start dose-reduced treatment. Conclusions: Routine prospective testing of DPYD status in a large regional cancer centre is feasible and with a sufficiently swift result turnaround to permit up-front dose modification. Detailed toxicity analysis and cost-effectiveness data will be presented.
Randomized phase II trial of CAPOX with continuous versus intermittent use of oxaliplatin as an adjuvant chemotherapy after curative resection of stage II/III colon cancer (CCOG-1302 study).
Authors: Nakamura Masanori , Nakayama Goro , Ishigure Kiyoshi , Mashita Naoki , Yokoyama Hiroyuki , Hattori Norifumi , Uehara Keisuke , Yamada Suguru , Koike Masahiko , Kodera Yasuhiro 
Published: February 2020

95 Background: The aim of this study was to evaluate the efficacy and safety of CAPOX with intermittent use of oxaliplatin compared to continuous use of oxaliplatin as an adjuvant setting for colon cancer. Methods: Patients with curative resection of stage II or III colon cancer were randomly assigned to receive either CAPOX with continuous use of oxaliplatin (continuous arm: 8 cycles of CAPOX) or CAPOX with intermittent use of oxaliplatin (intermittent arm: 2 cycles of CAPOX→4 cycles of capecitabine→2 cycles of CAPOX). The primary endpoints were frequency of disease-free survival (DFS) rate at 3-year after surgery and peripheral sensory neuropathy (PSN) at 1-year after surgery. The secondary end points included DFS, overall survival (OS), compliance and safety. Results: A total of 200 patients were enrolled. The intent-to-treat and safety population comprised 100 and 99 patients in the continuous arm, and 100 and 98 patients in the intermittent arm, respectively. After a median follow-up period of 39 months, disease recurrence and death occurred in 37 patients (19%) and 8 patients (4%) in the ITT population, respectively. The 3-year DFS was 78% (95% CI, 70-87%) in the continuous arm and 82% (95% CI, 74-90%) in the intermittent arm (HR, 0.80; 95% CI, 0.42-1.52; p = 0.49). In the patients with stage III disease, the 3-year DFS was 76% (95% CI, 66-86%)in the continuous arm and 80% (95% CI, 71-88) in the intermittent arm(HR, 0.75; 95% CI, 0.38-1.51; p = 0.43). The frequencies of PSF at 1-year after surgery were 58% (95% CI, 48-68%) in the continuous arm and 19% (95% CI, 11-26%) in the intermittent arm (p < 0.01), and those at 3-year after surgery were 37% (95% CI, 27-47%) and 9% (3-15%), respectively (p < 0.01). Conclusions: CAPOX with planned intermittent use of oxaliplatin could be equally effective as an adjuvant setting for colon cancer, and substantially reduce long-term PSN and potential improve patient quality of life. Clinical trial information: UMIN 000012535.
A phase III study of nivolumab (NIVO), NIVO + ipilimumab (IPI), or chemotherapy (CT) for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC): Checkmate 8HW.
Authors: Abdullaev Sandzhar , André Thierry , Lei Ming , Lenz Heinz-Josef , Novotny James , Paulson Andrew Scott , Tejpar Sabine , Yamazaki Kentaro , Ledeine Jean-Marie 
Published: February 2020

TPS266 Background: Patients (pts) with MSI-H/dMMR mCRC treated with CT have poorer outcomes than pts with microsatellite stable/MMR proficient mCRC. NIVO (anti–programmed death [PD]-1) and IPI (anti–cytotoxic T lymphocyte antigen-4 [CTLA-4]) are immune checkpoint inhibitors that act synergistically and promote antitumor immune response by complementary mechanisms. NIVO±IPI received accelerated US FDA approval for MSI-H/dMMR mCRC that progressed after fluoropyrimidine, oxaliplatin, and irinotecan treatment based on the phase 2, non-randomized, multicohort CheckMate 142 study. Indirect comparisons suggest that NIVO (3 mg/kg) + low-dose IPI (1 mg/kg) provides improved clinical benefit vs NIVO (investigator-assessed [INV] objective response rate [ORR] 55% vs 31%; 12-month [mo] INV progression-free survival [PFS] rate 71% vs 50%; 12-mo overall survival [OS] rate 85% vs 73%) with a favorable benefit-risk profile for previously treated MSI-H/dMMR mCRC (Overman et al. JCO 2018). NIVO+low-dose IPI also demonstrated robust and durable clinical benefit in first-line MSI-H/dMMR mCRC (INV ORR 64%; 12-mo INV PFS rate 77%; 12-mo OS rate 84%; Lenz et al. ASCO 2019, #3521). To date, no prospective phase 3 studies have reported results for anti–PD-1, anti–PD-1 + anti–CTLA-4, or CT in MSI-H/dMMR mCRC; these treatments will be evaluated in the international, multicenter, open-label, randomized, phase 3 CheckMate 8HW (NCT04008030) study. Methods: Approximately 494 pts aged ≥18 years with histologically confirmed recurrent or mCRC, irrespective of prior treatment with CT and/or targeted agents, not amenable to surgery, and with known tumor MSI-H or dMMR status, and Eastern Cooperative Oncology Group performance status ≤1 will be randomized to receive NIVO, NIVO+IPI, or investigator’s choice CT (pts in the CT arm can receive NIVO+IPI upon progression). The primary endpoint is PFS, assessed by blinded independent central review (BICR). Secondary endpoints include PFS by INV, ORR and disease control rate by BICR and INV, OS, time to and duration of response. Exploratory endpoints include safety. Clinical trial information: NCT04008030.
A phase II study to evaluate safety and efficacy of neoadjuvant pembrolizumab and radiotherapy in localized MSS rectal cancer.
Authors: Kossler Thibaud , Nicolas Buchs , Dutoit Valérie , Puppa Giacomo , Tsantoulis Petros , Frossard Jean-Louis , Bichard Philippe , Montet Xavier , McKee Thomas , Di Marco Mariagrazia , Dietrich Pierre-Yves , Roth Arnaud , Zilli Thomas , Ris Frédéric 
Published: February 2020

TPS272 Background: Locally advanced rectal cancer remains a clinical challenge with few improvements noted over the past few decades. Although immunotherapy has no current clinical role in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironment, and improve the likelihood of anti-tumor activity with checkpoint inhibitors use. This prospective phase II trial will test that hypothesis in addition to confirming safety of this approach using a “window-of-opportunity” study design with the anti-PD-1 agent Pembrolizumab. Methods: This monocentric phase II trial, will enroll patients (pts) with rectal cancer who are undergoing neoadjuvant short course RT (scRT) (25 Gy in 5 fractions). according to the standard of care. Eligible includes pts with MSS stage II-III rectal cancer with adequate organ function and availability of pre-treatment tumor, who are undergoing scRT with intention to proceed to surgical resection. Standard ineligibility criteria include active infections, systemic steroid use, or other conditions making immunotherapy use unsafe. Treatment includes 4 doses of Pembrolizumab (200mg IV, once every 3 wks), the first dose being given before the first scRT fraction. Surgery will be performed within 12-16 weeks of the final scRT dose. Primary endpoint is tumor regression grade (TRG) using the Mandard regression grade score targeting a 30% pathological complete response (pCR) compared to 10% in historical controls. Secondary endpoints include OS, DFS, toxicity, local and distant relapse-free survival, negative surgical margins, QoL, quality of surgery and exploratory assessments of tumor infiltrating lymphocytes, profiling of circulating immune cell populations, and molecular predictors of response. A safety stopping rule is planned based on Wald’s sequential probability ratio test for the occurrence of the safety outcome. Enrollment target is 25 pts. Support: MSD. Clinical trial information: NCT04109755 .
Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line therapy in patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.
Authors: Xu Rui-hua , Arkenau Hendrik-Tobias , Bang Yung-Jue , Denlinger Crystal S. , Kato Ken , Tabernero Josep , Wang Jin , Li Jiang , Castro Henry , Moehler Markus H. 
Published: February 2020

TPS458 Background: First-line standard of care in patients with locally advanced or metastatic G/GEJ adenocarcinoma is fluoropyrimidine- and platinum (plat)-based combination chemotherapy. Despite improved chemotherapy regimens, outcomes remain poor and survival is low. Tislelizumab, an investigational humanized IgG4 monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding of FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Previous reports from early phase studies suggested tislelizumab, as a single agent and combined with chemotherapy, was generally well tolerated and had antitumor activity in patients with advanced solid tumors, including G/GEJ cancer. Methods: This randomized, placebo-controlled phase 3 study (NCT03777657) is designed to evaluate plat/fluoropyrimidine + tislelizumab vs plat/fluoropyrimidine + placebo as first-line therapy for patients with locally advanced or metastatic G/GEJ adenocarcinoma. Adult patients (n≈720) from ~160 centers will be randomized 1:1 to receive tislelizumab (200 mg IV Q3W) or placebo in combination with chemotherapy. Oxaliplatin (130 mg/m² IV Q3W) + capecitabine (1000 mg/m2 orally BID for 2 weeks) or cisplatin (80 mg/m² IV Q3W) + 5-fluorouracil (800 mg/m2/day IV on Days 1-5 Q3W) will be used as backbone chemotherapy on an individual basis. Chemotherapy will be administered for up to 6 cycles; capecitabine maintenance therapy is optional for patients who received capecitabine and oxaliplatin. Progression-free and overall survival are primary endpoints of the study. Secondary endpoints will include overall response rate, quality-of-life outcomes, and the safety/tolerability profile of combination therapy. Exploratory endpoints include disease control rate, time to response, and an analysis of potential predictive biomarkers including PD-L1 expression; the VENTANA PD-L1 (SP263) assay will be used for PD-L1 expression analysis. This study is actively enrolling. Clinical trial information: NCT03777657.
A phase Ib study of alofanib, an allosteric FGFR2 inhibitor, in patients with advanced or metastatic gastric cancer.
Authors: Statsenko Galina , Fedyanin Mikhail , Moiseyenko Vladimir , Vladimirova Liubov Yu , Tsimafeyeu Ilya , Tjulandin Sergei 
Published: February 2020

TPS466 Background: Fibroblast growth factor receptor 2 (FGFR2) is amplified or overexpressed in 3% to 61% of patients with gastric cancer and associated with a poor prognosis. Acquired mutations in FGFR2 develop resistance to multikinase inhibitors. Besides, resistance to monoclonal antibodies depends on the type of FGFR2 isoforms IIIc or IIIb expressed by cancer cells. Alofanib (RPT835) is a novel selective allosteric inhibitor of FGFR2. Alofanib could bind to the non-active site of FGFR2 extracellular domain and had an inhibitory effect on FGF2-induced phosphorylation of FRS2α. On preclinical models no severe organ and function test changes were observed. Based on these results, alofanib has advanced into clinical evaluation. Methods: RPT835GC1B is a Phase 1b study, being conducted in at least four sites in Russia, evaluating the safety and preliminary efficacy of alofanib in patients with advanced and metastatic gastric adenocarcinoma pretreated with ≥ 1 previous lines of therapy. This trial consists of two parts. The standard dose-escalation part (design 3+3) aims to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (R2PD) as a primary endpoint. The first part of the study includes a 28-day period when alofanib is administered daily intravenously for 5-days followed by a 2-day interval (rest). There are five dose levels: 50, 100, 165, 250, and 350 mg/m2. The dose-expansion phase accrues additional 20 patients, where comprehensive information to be collected. Secondary endpoints include pharmacokinetic parameters, rate of adverse events, progression-free survival, overall survival, and objective response rate. All patients will receive alofanib until disease progression or unacceptable toxicity. FGFR2 amplification, fusion, and overexpression will be assessed as well. Clinical trial information: NCT04071184.