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Yu Tian, Elham Kharazmi, Hermann Brenner, Xing Xu, Kristina Sundquist, Jan Sundquist, and Mahdi Fallah

Background: The aim of this study was to explore the risk of invasive colorectal cancer (CRC) in relatives of patients with colorectal carcinoma in situ (CCIS), which is lacking in the literature. Patients and Methods: We collected data from Swedish family-cancer datasets and calculated standardized incidence ratio (SIR) and cumulative risk of CRC in family histories of CCIS in first- and second-degree relatives. Family history was defined as a dynamic (time-dependent) variable allowing for changes during the follow-up period from 1958 to 2015. Of 12,829,251 individuals with available genealogical data, 173,796 were diagnosed with CRC and 40,558 with CCIS. Results: The lifetime (0–79 years) cumulative risk of CRC in first-degree relatives of patients with CCIS was 6.5%, which represents a 1.6-fold (95% CI, 1.5–1.7; n=752) increased risk. A similarly increased lifetime cumulative risk (6.7%) was found among first-degree relatives of patients with CRC (SIR, 1.6; 95% CI, 1.6–1.7; n=6,965). An increased risk of CRC was also found in half-siblings of patients with CCIS (SIR, 1.9; 95% CI, 1.1–3.0; n=18) and also in half-siblings of patients with CRC (SIR, 1.7; 95% CI, 1.3–2.1; n=78). Moreover, the increased risk of CRC was higher for younger age at diagnosis of CCIS in the affected first-degree relative and for younger age at diagnosis of CRC in the index person. Conclusions: Results of this study show that first-degree relatives and half-siblings of patients with CCIS have an increased risk of CRC, which is comparable in magnitude to the risk of those with a family history of invasive CRC. These findings extend available evidence on familial risk of CRC and may help to refine guidelines and recommendations for CRC screening.

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Camilla Zimmermann, Ashley Pope, Breffni Hannon, Monika K. Krzyzanowska, Gary Rodin, Madeline Li, Doris Howell, Jennifer J. Knox, Natasha B. Leighl, Srikala Sridhar, Amit M. Oza, Rebecca Prince, Stephanie Lheureux, Aaron R. Hansen, Anne Rydall, Brittany Chow, Leonie Herx, Christopher M. Booth, Deborah Dudgeon, Neesha Dhani, Geoffrey Liu, Philippe L. Bedard, Jean Mathews, Nadia Swami, and Lisa W. Le

Background: Routine early palliative care (EPC) improves quality of life (QoL) for patients with advanced cancer, but it may not be necessary for all patients. We assessed the feasibility of Symptom screening with Targeted Early Palliative care (STEP) in a phase II trial. Methods: Patients with advanced cancer were recruited from medical oncology clinics. Symptoms were screened at each visit using the Edmonton Symptom Assessment System-revised (ESAS-r); moderate to severe scores (screen-positive) triggered an email to a palliative care nurse, who called the patient and offered EPC. Patient-reported outcomes of QoL, depression, symptom control, and satisfaction with care were measured at baseline and at 2, 4, and 6 months. The primary aim was to determine feasibility, according to predefined criteria. Secondary aims were to assess whether STEP identified patients with worse patient-reported outcomes and whether screen-positive patients who accepted and received EPC had better outcomes over time than those who did not receive EPC. Results: In total, 116 patients were enrolled, of which 89 (77%) completed screening for ≥70% of visits. Of the 70 screen-positive patients, 39 (56%) received EPC during the 6-month study and 4 (6%) received EPC after the study end. Measure completion was 76% at 2 months, 68% at 4 months, and 63% at 6 months. Among screen-negative patients, QoL, depression, and symptom control were substantially better than for screen-positive patients at baseline (all P<.0001) and remained stable over time. Among screen-positive patients, mood and symptom control improved over time for those who accepted and received EPC and worsened for those who did not receive EPC (P<.01 for trend over time), with no difference in QoL or satisfaction with care. Conclusions: STEP is feasible in ambulatory patients with advanced cancer and distinguishes between patients who remain stable without EPC and those who benefit from targeted EPC. Acceptance of the triggered EPC visit should be encouraged. identifier: NCT04044040.

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Chetna Malhotra, Rahul Malhotra, Filipinas Bundoc, Irene Teo, Semra Ozdemir, Noreen Chan, and Eric Finkelstein

Background: Reducing suffering at the end of life is important. Doing so requires a comprehensive understanding of the course of suffering for patients with cancer during their last year of life. This study describes trajectories of psychological, spiritual, physical, and functional suffering in the last year of life among patients with a solid metastatic cancer. Patients and Methods: We conducted a prospective cohort study of 600 patients with a solid metastatic cancer between July 2016 and December 2019 in Singapore. We assessed patients’ psychological, spiritual, physical, and functional suffering every 3 months until death. Data from the last year of life of 345 decedents were analyzed. We used group-based multitrajectory modeling to delineate trajectories of suffering during the last year of a patient’s life. Results: We identified 5 trajectories representing suffering: (1) persistently low (47% of the sample); (2) slowly increasing (14%); (3) predominantly spiritual (21%); (4) rapidly increasing (12%); and (5) persistently high (6%). Compared with patients with primary or less education, those with secondary (high school) (odds ratio [OR], 3.49; 95% CI, 1.05–11.59) education were more likely to have rapidly increasing versus persistently low suffering. In multivariable models adjusting for potential confounders, compared with patients with persistently low suffering, those with rapidly increasing suffering had more hospital admissions (β=0.24; 95% CI, 0.00–0.47) and hospital days (β=0.40; 95% CI, 0.04–0.75) during the last year of life. Those with persistently high suffering had more hospital days (β=0.70; 95% CI, 0.23–1.17). Conclusions: The course of suffering during the last year of life among patients with cancer is variable and related to patients’ hospitalizations. Understanding this variation can facilitate clinical decisions to minimize suffering and reduce healthcare costs at the end of life.

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Brooke E. Wilson, Michelle B. Nadler, Alexandra Desnoyers, and Eitan Amir

Background: Censoring due to early drug discontinuation (EDD) or withdrawal of consent or loss to follow-up (WCLFU) can result in postrandomization bias. In oncology, censoring rules vary with no defined standards. In this study, we sought to describe the planned handling and transparency of censoring data in oncology trials supporting FDA approval and to compare EDD and WCLFU in experimental and control arms. Methods: We searched FDA archives to identify solid tumor drug approvals and their associated trials between 2015 and 2019, and extracted the planned handling and reporting of censored data. We compared the proportion of WCLFU and EDD between the experimental and control arms by using generalized estimating equations, and performed logistic regression to identify trial characteristics associated with WCLFU occurring more frequently in the control group. Results: Censoring rules were defined adequately in 48 (59%) of 81 included studies. Only 14 (17%) reported proportions of censored participants clearly. The proportion of WCLFU was higher in the control group than in the experimental group (mean, 3.9% vs 2.5%; β-coefficient, −2.2; 95% CI, −3.1 to −1.3; P<.001). EDD was numerically higher in the experimental arm in 61% of studies, but there was no statistically significant difference in the proportion of EDD between the experimental and control groups (mean, 21.6% vs 19.9%, respectively; β-coefficient, 0.27; 95% CI, −0.32 to 0.87; P=.37). The proportion of EDD due to adverse effects (AEs) was higher in the experimental group (mean, 13.2% vs 8.5%; β-coefficient, 1.5; 95% CI, 0.57–2.45; P=.002). WCLFU was higher in the control group in studies with an active control group (odds ratio [OR], 10.1; P<.001) and in open label studies (OR, 3.00; P=.08). Conclusions: There are significant differences in WCLFU and EDD for AEs between the experimental and control arms in oncology trials. This may introduce postrandomization bias. Trials should improve the reporting and handling of censored data so that clinicians and patients are fully informed regarding the expected benefits of a treatment.

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Esther N. Pijnappel, Willemieke P.M. Dijksterhuis, Lydia G. van der Geest, Judith de Vos-Geelen, Jan Willem B. de Groot, Marjolein Y.V. Homs, Geert-jan Creemers, Nadia Haj Mohammad, Marc G. Besselink, Hanneke W.M. van Laarhoven, Johanna W. Wilmink, and for the Dutch Pancreatic Cancer Group

Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor survival rate, which can be improved by systemic treatment. Consensus on the most optimal first- and second-line palliative systemic treatment is lacking. The aim of this study was to describe the use of first- and second-line systemic treatment, overall survival (OS), and time to failure (TTF) of first- and second-line treatment in metastatic PDAC in a real-world setting. Patients and Methods: Patients with synchronous metastatic PDAC diagnosed between 2015 and 2018 who received systemic treatment were selected from the nationwide Netherlands Cancer Registry. OS and TTF were evaluated using Kaplan-Meier curves with log-rank test and multivariable Cox proportional hazard analyses. Results: The majority of 1,586 included patients received FOLFIRINOX (65%), followed by gemcitabine (18%), and gemcitabine + nab-paclitaxel (13%) in the first line. Median OS for first-line FOLFIRINOX, gemcitabine + nab-paclitaxel, and gemcitabine monotherapy was 6.6, 4.7, and 2.9 months, respectively. Compared to FOLFIRINOX, gemcitabine + nab-paclitaxel showed significantly inferior OS after adjustment for confounders (hazard ratio [HR], 1.20; 95% CI, 1.02–1.41), and gemcitabine monotherapy was independently associated with a shorter OS and TTF (HR, 1.98; 95% CI, 1.71–2.30 and HR, 2.31; 95% CI, 1.88–2.83, respectively). Of the 121 patients who received second-line systemic treatment, 33% received gemcitabine + nab-paclitaxel, followed by gemcitabine (31%) and FOLFIRINOX (10%). Conclusions: Based on population-based data in patients with metastatic PDAC, treatment predominantly consists of FOLFIRINOX in the first line and gemcitabine with or without nab-paclitaxel in the second line. FOLFIRINOX in the first line shows superior OS compared with gemcitabine with or without nab-paclitaxel.

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Jason H. Lee, Tariq Mohamed, Celia Ramsey, Jihoon Kim, Shelly Kane, Kathryn A. Gold, Farhoud Faraji, and Joseph A. Califano III

Background: Accurate oncologic staging meeting clinical practice guidelines is essential for guideline adherence, quality assessment, and survival outcomes. However, timely and uniform documentation in the electronic health record (EHR) at the time of diagnosis is a challenge for providers. This quality improvement project aimed to increase provider compliance of timely clinical TNM (cTNM) or pathologic TNM (pTNM) staging for newly diagnosed oncologic patients. Methods: Providers in the following site-specific oncologic teams were included: head and neck, skin, breast, genitourinary, gastrointestinal, lung and thoracic, gynecologic, colorectal, and bone marrow transplant. Interventions to facilitate timely cTNM and pTNM staging included standardized EHR-based workflows, learning modules, stakeholder meetings, and individualized provider training sessions. For most teams, staging was considered compliant if it was completed in the EHR within the first 7 days of the calendar month after the date of the patient visit. Factors associated with staging compliance were analyzed using logistic regression models. Results: From January 1, 2014, to December 31, 2018, 7,787 preintervention and 5,152 postintervention new patient visits occurred. During the preintervention period, staging was compliant in 5.6% of patients compared with 67.4% of patients after intervention (P<.001). In the final month of the postintervention period, the overall staging compliance rate was 78.1%. At most recent tracking, staging compliance was 95%, 97%, and 93% in December 2019, January 2020, and February 2020, respectively. Logistic regression found that increasing years of provider experience was associated with decreased staging compliance. Conclusions: High rates of staging compliance in complex multidisciplinary academic oncologic practice models can be achieved via comprehensive quality improvement and structured initiatives. This approach serves as a model for improving oncologic documentation systems to facilitate clinical decision-making and multidisciplinary coordination of care.

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Taymeyah Al-Toubah, Eleonora Pelle, Tiffany Valone, Mintallah Haider, and Jonathan R. Strosberg

Background: The capecitabine/temozolomide (CAPTEM) regimen has significant activity in advanced neuroendocrine tumors (NETs). Questions exist regarding activity in pancreatic versus nonpancreatic NETs, risk of opportunistic infections, long-term myelotoxicity, and safety of prolonged treatment duration. Analysis of large patient cohorts is needed for the evaluation of rare toxicities and assessment of risk factors. Methods: We conducted a retrospective study of all patients with advanced NETs seen at Moffitt Cancer Center between January 2008 and June 2019 who received treatment with CAPTEM. Results: A total of 462 patients were eligible. The objective radiographic response rate was 46%, and the disease control rate was 81%. Median progression-free survival (PFS) was 18 months (95% CI, 14.0–21.9 months) and median overall survival was 51 months (95% CI, 42.8–59.2 months): 62 months in well-differentiated NETs versus 14 months in poorly differentiated neuroendocrine carcinomas (P<.0001). Patients with primary pancreatic tumors had the highest partial response rates and longest median PFS. Incidences of grade 4 thrombocytopenia and neutropenia were 7% and 3%, respectively, and substantially higher in women than men (P=.02 and P=.004, respectively). Only 1 case (0.2%) of suspected Pneumocystis pneumonia (PCP) was observed in a patient receiving corticosteroids. Three patients developed myelodysplastic disease, all of whom had received prior peptide receptor radiotherapy (PRRT). There were no acute treatment-related deaths; 1 patient died 2 months after a thrombocytopenic bleed. Conclusions: The CAPTEM regimen is exceptionally safe. Efficacy is particularly robust in well-differentiated pancreatic NETs. Severe myelotoxicity is rare; the risk of grade 4 cytopenias is significantly increased in women, and therefore sex-based dosing should be considered. There were no cases of myelodysplastic syndromes, except among patients who had received PRRT, a known risk factor. The risk of PCP is negligible.

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Marcus J. Geer, Charles E. Foucar, Sumana Devata, Lydia Benitez, Anthony J. Perissinotti, Bernard L. Marini, and Dale Bixby

Background: All-trans retinoic acid (ATRA) serves as the backbone of the management of patients with acute promyelocytic leukemia (APL), with guidelines recommending the initiation of ATRA as soon as APL is suspected. As a regional referral center for patients with acute leukemia, those who are suspected of having APL are often transferred to our facility. However, many referring centers are unable to initiate treatment using ATRA. We conducted an exploratory analysis of the clinical availability of ATRA and the factors limiting access to this critical drug. Patients and Methods: The United States was divided into 6 geographic regions: Northwest, Southwest, Central, Southeast, Northeast, and the Great Lakes. Twenty hospitals were randomly selected from states within each of these regions and were surveyed as to whether they typically treated patients with acute leukemia, the availability of ATRA at their institution, and reported reasons for not stocking ATRA (if not available). Results: Less than one-third of hospitals queried (31%) had ATRA in stock. Neither the size of the hospital nor the hospital’s status as academic versus nonacademic (53% vs 31%; P=.08) influenced ATRA availability. Of the hospitals that referred patients with APL, only 14% (7/49) had ATRA readily available. Hospitals that treated patients with APL were more likely to have ATRA available than referring centers (58% vs 14%; P=.000002). Conclusions: Nearly two-thirds of the hospitals surveyed that cared for patients with acute leukemia do not have ATRA immediately available. Moreover, the vast majority of hospitals that refer patients to other centers do not have ATRA. These findings should spur investigation into the impact of immediate ATRA availability on the morbidity and mortality of patients with APL. A call by hematologists nationwide to their formulary committees is warranted to ensure that this lifesaving medication is available to patients suspected of having APL.

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Sapho X. Roodbeen, Marta Penna, Susan van Dieren, Brendan Moran, Paris Tekkis, Pieter J. Tanis, Roel Hompes, and on behalf of the International TaTME Registry Collaborative

Background: The oncologic safety of transanal total mesorectal excision (TaTME) for rectal cancer has recently been questioned, with high local recurrence (LR) rates reported in Dutch and Norwegian experiences. The objective of this study was to evaluate the oncologic safety of TaTME in a large cohort of patients with primary rectal cancer, primarily in terms of LR, disease-free survival (DFS), and overall survival (OS). Patients and Methods: This was a prospective international registry cohort study, including all patients who underwent TaTME for primary rectal adenocarcinoma from February 2010 through December 2018. The main endpoints were 2-year LR rate, pattern of LR, and independent risk factors for LR. Secondary endpoints included 2-year DFS and OS rates. Kaplan-Meier survival analysis was used to calculate actuarial LR, DFS, and OS rates. Results: A total of 2,803 patients receiving primary TaTME were included, predominantly men (71%) with a median age of 65 years (interquartile ratio, 57–73 years). After a median follow-up of 24 months (interquartile ratio, 12–38 months), the 2-year LR rate was 4.8% (95% CI, 3.8%–5.8%) with a unifocal LR pattern in 99 of 103 patients (96%). Independent risk factors for LR were male sex, threatened resection margin on baseline MRI, pathologic stage III cancer, and a positive circumferential resection margin on final histopathology. The 2-year DFS and OS rates were 77% (95% CI, 75%–79%) and 92% (95% CI, 91%–93%), respectively. Conclusions: This largest TaTME cohort to date supports the oncologic safety of the TaTME technique for rectal cancer in patients treated in units that contributed to an international registry, with an acceptable 2-year LR rate and a predominantly unifocal LR pattern.

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Pamala A. Pawloski, Cara L. McDermott, James H. Marshall, Vanita Pindolia, Catherine M. Lockhart, Catherine A. Panozzo, Jeffrey S. Brown, and Bernadette Eichelberger

Background: Chemotherapy-induced febrile neutropenia (FN) is prevented or minimized with granulocyte colony-stimulating factors (G-CSFs). Several G-CSF biosimilars are approved in the United States. The Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) is a nonprofit initiative whose objective is to provide scientific evidence on real-world use and comparative safety and effectiveness of biologics and biosimilars using the BBCIC distributed research network (DRN). Patients and Methods: We describe real-world G-CSF use in patients with breast or lung cancer receiving first-cycle chemotherapy associated with high FN risk. We assessed hospitalizations for FN, availability of absolute neutrophil counts, and G-CSF–induced adverse events to inform future observational comparative effectiveness studies of G-CSF reference products and their biosimilars. A descriptive analysis of 5 participating national health insurance plans was conducted within the BBCIC DRN. Results: A total of 57,725 patients who received at least one G-CSF dose were included. Most (92.5%) patients received pegfilgrastim. FN hospitalization rates were evaluated by narrow (<0.5%), intermediate (1.91%), and broad (2.99%) definitions. Anaphylaxis and hyperleukocytosis were identified in 1.15% and 2.28% of patients, respectively. This analysis provides real-world evidence extracted from a large, readily available database of diverse patients, characterizing G-CSF reference product use to inform the feasibility of future observational comparative safety and effectiveness analyses of G-CSF biosimilars. We showed that the rates of FN and adverse events in our research network are consistent with those reported by previous small studies. Conclusions: Readily available BBCIC DRN data can be used to assess G-CSF use with the incidence of FN hospitalizations. Insufficient laboratory result data were available to report absolute neutrophil counts; however, other safety data are available for assessment that provide valuable baseline data regarding the effectiveness and safety of G-CSFs in preparation for comparative effectiveness studies of reference G-CSFs and their biosimilars.