bluuebunny/crossref_metadata_2025_split huggingface dataset:
Severe enterocolitis with capecitabine (CAPE) is not a predictor of gastrointestinal (GI) toxicity with infusional 5-fluorouracil (5-FU)–based regimens: An institutional analysis.
Authors: Parish Marie , Cox Ronald , Shreenivas Aditya V. , Mahipal Amit , Chakrabarti Sakti 
Published: January 2023

89 Background: Enterocolitis is a potentially fatal toxicity of CAPE. The safety of infusional 5-FU-based regimens in patients developing severe enterocolitis with CAPE is not well established in the literature. Methods: After institutional review board approval, a database search identified patients who received infusional 5-FU-based regimens between January 2015 and July 2022 in a tertiary care cancer center after experiencing severe CAPE-induced enterocolitis, defined as the presence of grade 3 or higher diarrhea and features of enterocolitis on computed tomography (CT) scan. Data on patient characteristics, grade of CAPE-induced diarrhea, clinical course, details of 5-FU-based regimens administered after recovery, and outcomes were collected by retrospective electronic chart review. Results: Among the 791 patients treated with CAPE during the study period, 27 (3.4%) developed grade 3 or higher diarrhea, and 15 of these 27 patients (1.9%) had evidence of enterocolitis on CT scan. All patients were treated with supportive measures. All but 1 patient recovered fully; 1 patient died due to a condition unrelated to CAPE toxicity. After complete recovery, 7 patients aged 46 to 69 years (median, 68 years) received FOLFOX (oxaliplatin and infusional 5-FU). The time interval between recovery from CAPE-induced enterocolitis and the start of infusional 5-FU ranged from 4 to 20 weeks (median, 12 weeks), with 3 patients starting 5-FU within 4-5 weeks of recovery. Standard dose 5-FU (2400 mg/m2 over 46 hours) was given to 2 of the 7 patients; the remaining 5 patients received 50% to 80% of the standard dose at the beginning of treatment, but eventually tolerated the standard dose. All patients tolerated 5-FU infusion without experiencing any grade 2 or higher 5-FU induced GI toxicity. Conclusions: Most patients developing severe enterocolitis with CAPE recover fully with appropriate supportive measures. Infusional 5-FU-based regimens appear to be safe in this patient group. Severe CAPE-induced enterocolitis should not preclude the use of infusional 5-FU-based regimens, especially in curative-intent settings such as adjuvant therapy.
Toxicities and outcomes of neoadjuvant treatment in elderly patients with locally advanced rectal cancer: A scoping review.
Authors: Hamed Ruba Ahmed Mohammed , Korpanty Greg , Kella Dervla 
Published: January 2023

91 Background: Neoadjuvant treatment (NAT) followed by surgery has become the standard treatment for locally advanced rectal cancer (LARC). This scoping review aims to assess the toxicity and outcomes of the currently available NAT of rectal cancer in elderly patients with age-associated frailty. Methods: Six thousand seventy-nine records were identified on Ovid Medline, Embase, Cochrane database, and CINAHL. Two independent reviewers screened the articles. Fifteen articles were identified through a hand search. Articles on NAT in LARC in elderly patients were included. Results: Thirty-three studies from 2005 to 2022 met inclusion criteria, including 27 retrospective reviews, 4 clinical trials (Phase 1 and 2) and 2 prospective studies; 5 were multicentred. The median age of the sample was 70-75 in 24 studies and 76-83 in 11 studies. One study examined only patients above 80. Twenty-four studies examined NAT with long course concurrent chemoradiotherapy (LCCRT), 5 examined both LCCRT and RT alone, 3 examined short-course radiotherapy (SCRT), one examined SCRT with sequential chemotherapy (CT), and one study examined neoadjuvant CT followed by LCCRT. Concurrent CT with 5 FU-based treatments was given in 23 studies with either intravenous or oral, and oxaliplatin was added to 5 FU in 10 studies. Interruption of concurrent treatment was reported with dose reduction, delay or discontinuation in 26 studies. Diarrhea, nausea/vomiting and radiation dermatitis were reported as significant side effects (G3 -4), with G3-4 diarrhea reported in 18 studies. Haematological toxicities were very frequent, with a 20-60% rate in the studies. No dose interruption of RT was required in the three studies that included only SCRT, except for one patient. The study on CT followed by LCCRT showed that CT was completed in 82% and LCCRT in 76% of patients. A preliminary result of PRODIGE 42-GERICO 12 NACRE, a randomised trial comparing SCRT with chemoradiotherapy (CRT), showed that 14% of patients in the CRT arm did not receive all of the planned treatment compared to 0% in SCRT arm, and the 6 months death rate was 10.0% in CRT arm and 3.92% in SCRT. Conclusions: Toxicities are frequently reported with Neoadjuvant LCCRT in the elderly and lead to treatment interruption. SCRT is well tolerated and probably associated with better survival (pending final results of the NACRE trial). Studies in this scoping review are over-represented by retrospective studies, and we suggest that future clinical trials focus on elderly patients to investigate treatment strategies with fewer toxicities.
LEANOX: Lean body mass normalization of oxaliplatin-based chemotherapy for patients with stage III colon cancer treated in adjuvant setting: Impact on oxaliplatin-induced sensitive neurotoxicity—A multicenter phase II randomized trial.
Authors: Assenat Eric , BEN Abdelghani Meher , Monnier Maeva , Perrier Herve , Khemissa Faiza , Desgrippes Romain , Galais Marie-Pierre , Rinaldi Yves , Lepage Come , Tetreau Raphael , Senesse Pierre 
Published: January 2023

92 Background: Adjuvant chemotherapy is the current worldwide standard of care for stage III colorectal cancer (CRC) but it leads to significant neurotoxicity. We have shown in 2 cohorts of CRC patients treated with Oxaliplatin (Ox) that Ox-due neuropathy occurred in patients receiving an excess of 3.09 mg Ox/ kg Lean Body Mass (LBM). The aim of this trial was to determine whether the Ox dose adaptation based on the LBM index can reduce neurotoxicity, in patients treated for a stage III CRC. Methods: LEANOX is a randomized phase II multicentre study in patients eligible for an Ox regimen as adjuvant chemotherapy for CRC. Patients without sarcopenia (LBM index <3.09mg/kg, group 1) received a dosage of Ox according to Body Surface Area (BSA) (85 mg/m²).Patients with sarcopenia (LBM index ≥3.09mg/kg) were randomized in 2 groups, group 2: dosage of Ox according to BSA (similar to group 1) and group 3: a dosage of Ox according to LBM (3.09 mg Ox/ kg LBM). Randomization (1:1) was stratified by center, age and weight loss. The primary endpoint was the percentage of patients without grade ≥2 neurotoxicity during the first 6 cycles of adjuvant Ox-based chemotherapy. The study required 108 randomized patients (bilateral α=0.05, 80% power) to compare the primary endpoint between groups 2 and 3 with P2=55% and P3=80%. Secondary endpoints included time to onset of grade≥2 chronic cumulative neurotoxicity, duration of the chronic cumulative neurotoxicity, cumulative Ox doses that can be delivered without reaching the dose-limiting chronic neurotoxicity, tolerance, disease free survival, overall survival and quality of life. Results: A total of 160 patients were included in 18 french centers: 33 in group 1, 64 in group 2 and 63 in group 3. Median age was 63 years, 52.5 % male, 89.3 % OMS 0 and tumoral stage was T3 (57.5%), T4 (33.8%), N1 (60.6%) and N2 (38.1%). Grade 3-4 AE events occurred in 58.0% in group 2 and 59.7% in group 3. The percentage of patients without experiencing grade ≥ 2 of neurotoxicity during the first 6 cycles of adjuvant Ox-based chemotherapy was 43.9% in group 2 vs 67.2% in group 3 (p=0.01). Conclusions: We wish to avoid severe adverse reactions to Ox regimen by personalization of cancer chemotherapy. Clinical trial information: NCT03255434 .
Impact of dose adjustment of fluoropyrimidines on toxicity in patients with DPD-deficient colorectal cancer: A single-center experience.
Authors: Martinez-Perez Daniel , Ghanem Ismael , Rosas-Alonso Rocio , Arias Pedro , Rodriguez-Novoa Sonia , Borobia Alberto , Viñal David , Ruiz-Gutierrez Iciar , Jiménez-Bou Diego , Rodriguez Salas Nuria , Feliu Batlle Jaime 
Published: January 2023

94 Background: Fluoropyrimidines (FPs) are the chemotherapy backbone for most patients with CRC. FPs are metabolized by dihydropyrimidine dehydrogenase (DPD). Current guidelines recommend measuring DPD activity before chemotherapy administration to adjust the initial dose and thus prevent high-grade toxicity. However, the clinical impact of this strategy is still understudied. We aim to study the efficacy and toxicity of FPs dose modifications according to DPD activity in patients with CRC. Methods: We retrospectively identified all the CRC cancer patients treated with FPs between January 2017 and July 2021 and with DPD activity assessment at Hospital Universitario La Paz, Madrid, Spain. Clinical characteristics and tolerability were collected. Two cohorts were stablished according to its DPD activity, patients with a normal DPD metabolism (DPD wild-type patients) and patients with a diminished metabolism of FPs (DPD deficient patients). Results: A total of 249 CRC patients were included in this study. Sixteen patients (6,4%) were DPD deficient, and 15 of them (94%) received initially 50% of the recommended standard dosing of FPs (increasing to 75% in following cycles if well tolerated) according to guidelines. Forty percent of non-DPD deficiency started FPs at 75% of the standard initial dose due to frailty. Two toxic deaths were observed in the DPD-wild-type cohort, none in the DPD deficient cohort. Clinico-pathological characteristics of patients and their toxicity according to each cohort are depicted in the table. No significant differences in G3/4 toxicity between both groups (40% and 37% in the DPD-wild-type and DPD-deficient cohort, respectively). Diarrhea G3/4 was numerically more present in the DPD-deficient group (25% vs 12%, respectively). Conclusions: Overall, DPD genotype-guided FP treatment in DPD deficient patients with CRC may prevent high-grade toxicity. Diarrhea might still be higher in this group despite dose modifications, so careful surveillance and early treatment should be considered in these patients. [Table: see text]
Updated analysis: Effect of biweekly dosing schedule of trifluridine-tipiracil (TAS-102) on rates of myelosuppression and maintenance of therapeutic efficacy in patients (pts) with previously treated metastatic colorectal cancer (mCRC).
Authors: Cann Christopher G , LaPelusa Michael Brian , Cimino Sarah , Grieb Brian , Ciombor Kristen Keon , Agarwal Rajiv , Das Satya , Goff Laura Williams , Cardin Dana Backlund , Davis Shemeka , Berlin Jordan , Eng Cathy 
Published: January 2023

95 Background: For surgically unresectable metastatic colorectal cancer pts, a continuum of treatment is required to improve the OS of our pts. Oral trifluridine-tipiracil (TAS-102) is FDA approved in refractory mCRC per the RECOURSE trial. As per the FDA insert, the recommended dose is 35 mg/m2 twice daily (maximum = 80 mg/day) on Days 1-5 and Days 8-12 of 28-day cycles commonly resulting in Grade 3-4 neutropenia (38%), dose delays (53%), dose reductions (14%) and requiring G-CSF support (9%). To maintain efficacy and to potentially reduce toxicity, we analyzed an alternative biweekly dosing (Days 1-5 and Days 15-19 q28 days). Methods: A retrospective analysis was completed (2019-2022) at Vanderbilt-Ingram Cancer Center in pts with refractory mCRC and appendiceal cancer (CA) who completed ≥ 12 days of TAS-102 therapy and underwent surveillance imaging every 8-12 weeks. Patient data was assessed for ECOG performance status (PS), prior lines of therapy, the use of bevacizumab and CTCAE grade of treatment-related myelotoxicity. Evaluation of progression-free survival (PFS) was completed in mCRC pts. Results: Forty-three patients met the inclusion criteria, with a mCRC:appendiceal CA ratio of 39:4. The median age = 50 y/o (range 30-80); male:female 23:20; median ECOG PS = 1; median number of prior therapies = 3; and median duration of therapy = 97 days (range: 12-396). Associated grade 3/4 hematologic toxicities included: Neutropenia 39% [Grade 3 (12.2%), Grade 4 (2.4%)]; anemia 36.5% [Grade 3 (12.2%)]. No pts required G-CSF. No incidences of neutropenic fever were reported. Five pts (11.6%) required a dose delay and 3 pts (7%) required a dose reduction due to myelosuppression. In mCRC pts, the median PFS was 2.53 months. To date, 6 pts remain on treatment (range: 97-331). Conclusions: In our updated analysis, biweekly dosing of TAS-102 (35 mg/m2 twice daily; Days 1-5 and Days 15-19 of 28-day cycles) for pts with refractory mCRC and appendiceal CA demonstrated tolerable myelosuppression, while preserving PFS in pts with mCRC. With an improved toxicity profile, this alternative TAS -102 dosing schedule may potentially broaden utilization of TAS-102 in patients with borderline PS and may be a more favorable option for future combination studies. Additional prospective data are needed to validate these findings. To our knowledge, this remains the first analysis of biweekly TAS-102 in a US patient population.
NAPOLI-3: A randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Wainberg Zev A. , Melisi Davide , Macarulla Teresa , Pazo-Cid Roberto , Chandana Sreenivasa R , De La Fouchardiere Christelle , Dean Andrew Peter , Kiss Igor , Lee Woojin , Goetze Thorsten Oliver , Van Cutsem Eric , Paulson Andrew Scott , Bekaii-Saab Tanios S. , Pant Shubham , Hubner Richard , Xiao Zhimin , Chen Huanyu , Benzaghou Fawzi , O'Reilly Eileen Mary 
Published: January 2023

LBA661 Background: Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA and Europe for mPDAC following progression with gemcitabine-based therapy. A phase 1/2 study (Wainberg et al. Eur J Cancer 2021;151:14–24; NCT02551991) demonstrated promising anti-tumor activity in patients with mPDAC who received first-line liposomal irinotecan 50 mg/m2 + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin 60 mg/m2 (NALIRIFOX). Herein, we present results from NAPOLI-3 (NCT04083235), a randomized, open-label, phase 3 study investigating the efficacy and safety of NALIRIFOX compared with nab-paclitaxel + gemcitabine as first-line therapy in patients with mPDAC. Methods: Eligible patients with histopathologically/cytologically confirmed untreated metastatic PDAC were randomized (1:1) to receive NALIRIFOX on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 (Gem+NabP) on days 1, 8 and 15 of a 28-day cycle. Randomization was stratified by ECOG performance status, geographic region and presence or absence of liver metastases. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), overall response rate (ORR) and safety. OS was evaluated when ≥ 543 events were observed using a stratified log-rank test with an overall 1-sided significance level of 0.025. Results: Overall, 770 patients (NALIRIFOX, n = 383; Gem+NabP, n = 387) were included. Baseline characteristics were well balanced between arms. At a median follow-up of 16.1 months, 544 events had occurred. The median OS was 11.1 months in the NALIFIROX arm as compared with 9.2 months in the Gem+NabP arm (HR 0.84 [95% CI 0.71–0.99]; p = 0.04); PFS was also significantly improved (7.4 months vs 5.6 months; HR 0.70 [0.59–0.84]; p = 0.0001). Grade 3/4 treatment-emergent adverse events (TEAEs) with ≥ 10% frequency in patients receiving NALIRIFOX versus Gem+NabP included diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), anemia (10.5% vs 17.4%) and neutropenia (14.1% vs 24.5%). Conclusions: First-line NALIRIFOX demonstrated clinically meaningful and statistically significant improvement in OS and PFS compared with Gem+NabP in treatment-naïve patients with mPDAC. The safety profile of NALIRIFOX was manageable and consistent with the profiles of the treatment components. Funding: Funded by Ipsen. Clinical trial information: NCT04083235 .[Table: see text]
Phase II/III study of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage II colon cancer: NRG-GI005 (COBRA).
Authors: Morris Van K. , Yothers Greg , Kopetz Scott , Jacobs Samuel A. , Lucas Peter C. , Iqbal Atif , Boland Patrick M , Deming Dustin A. , Scott Aaron James , Lim Howard John , Hong Theodore S. , Wolmark Norman , George Thomas J. 
Published: January 2023

TPS259 Background: Detection of circulating tumor DNA (ctDNA) shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells after surgical resection. For patients (pts) with colon cancer (CC), the detection of ctDNA is associated with persistent disease after resection and outperforms traditional clinical and pathological features in prognosticating risk for recurrence. However, for pts with stage II CC, there are currently no validated biomarkers predicting benefit in identifying pts whose residual disease cancer be cleared by adjuvant chemotherapy. We hypothesize that for pts whose stage II colon cancer has been resected and who have no traditional high-risk features, a positive ctDNA status may identify those who will benefit from adjuvant chemotherapy. Methods: In this prospective phase II/III clinical trial, pts (N=1,408) with resected stage II CC without traditional high-risk features and whom the evaluating oncologist deems suitable for active surveillance (i.e., not needing adjuvant chemotherapy) will be randomized 1:1 into 2 arms: standard-of-care/observation (Arm A), or prospective testing for ctDNA (Arm B). Postoperative blood will be analyzed for ctDNA with the Guardant Reveal assay, covering CC-relevant mutations and CC-specific methylation profiling. Pts in Arm B with ctDNA detected will be treated with 6 months of adjuvant (FOLFOX) chemotherapy. For all pts in Arm A, ctDNA status will be analyzed retrospectively at the time of endpoint analysis. The primary endpoints are clearance of ctDNA with adjuvant chemotherapy (phase II) and recurrence-free survival (RFS) for “ctDNA-detected” pts treated with or without adjuvant chemotherapy (phase III). Secondary endpoints will include time-to-event outcomes (OS, RFS, TTR) by ctDNA marker status and treatment, prevalence of detectable ctDNA in stage II CC, and rates of compliance with assigned intervention. Archived normal and matched tumor and blood samples will be collected for exploratory correlative research. Enrollment continues across North America to the 540-patient phase II endpoint. Support: U10CA180868, -180822; UG1CA189867; GuardantHealth. Clinical trial information: NCT04068103 .
NRG GI008: Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-US).
Authors: Lieu Christopher Hanyoung , Lin Yan , Kopetz Scott , Jacobs Samuel A. , Lucas Peter C. , Sahin Ibrahim Halil , Deming Dustin A. , Philip Philip Agop , Hong Theodore S. , Rojas-Khalil Yesenia , Loree Jonathan M. , Wolmark Norman , Yothers Greg , George Thomas J. , Dasari Arvind 
Published: January 2023

TPS260 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage III A, B (all pts) and stage II, IIIC (ctDNA+ only) CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera™, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP) + oxaliplatin (Ox) for 3-6 mos per established guidelines vs . serial ctDNA monitoring. Patients who are ctDNA+ post-operatively or with serial monitoring (Cohort B) will be randomized to FP+Ox vs . more intensive AC with addition of irinotecan (I) for 6 mos. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate vs . delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox vs FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June, 2022. Support: U10-CA-180868, -180822; UG1CA-189867; Natera, Inc. Clinical trial information: NCT05174169 .