bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase1b study of navicixizumab plus FOLFIRI in second-line treatment of patients with metastatic colorectal cancer.
Authors: Lim Kian-Huat , Iglesia Michael , Culm Kerry , Koustenis Andrew G. , Mockbee Colleen M. , Mathew Lynn , Fakih Marwan , Garrido-Laguna Ignacio , Krauss John C.
Published: January 2023

111

Background: Navicixizumab is an anti-delta-like ligand 4 (DLL4)/vascular endothelial growth factor bispecific antibody which has shown promising preclinical and clinical activity in multiple tumor types. The blockade of DLL4, a transmembrane protein acting as a ligand for Notch receptors 1 and 4, causes tumor differentiation and reduction in cancer stem cells, as well as repolarization of the tumor microenvironment. Methods: We conducted a phase 1b single-arm dose escalation study combining navicixizumab with FOLFIRI or FOLFOX as second line treatment for patients with metastatic colorectal cancer (CRC). Patients were dosed either at 3 or 4 mg/kg intravenously once every 2 weeks (Q2W). The primary endpoint was the maximum tolerated dose of navicixizumab in combination with FOLFOX or FOLFIRI. Results: Between December 2016 and August 2018, 15 patients received navicixizumab plus FOLFIRI. Median patient age was 55 years, and nine of 15 patients were female (60%). Three patients were enrolled in the 3 mg/kg dose-escalation cohort, 2 patients were enrolled in the 4-mg/kg dose-escalation cohort, and 10 patients were enrolled in the 3 mg/kg dose expansion cohort. No DLTs were observed in this study. The median duration of navicixizumab therapy was 127 days. Hypertension was the most frequent all-grade treatment-related adverse event reported (12 of 15 patients, 80%), followed by fatigue (8 of 15 patients, 53.3%). Grade 3 hypertension was reported in 3 patients (20%). Eight of the 15 patients (53.3%) experienced at least one serious adverse event, resulting in discontinuation of study for 6 (40%) patients. One patient had a bowel perforation. One patient (3 mg/kg cohort) experienced a treatment-related grade 5 cardiopulmonary arrest resulting in death. The best overall response was partial response in three patients (20%). Eleven patients (73.3%) had stable disease and one (6.7%) experienced disease progression. Conclusions: This study was stopped early to focus on the development of navicixizumab in ovarian cancer. Although the disease control rate was promising, further evaluation is needed to determine whether navicixizumab delivers efficacy greater than chemotherapy alone and assess tolerability of this regimen. [Table: see text]
Efficacy of adjuvant fluoropyrimidine with or without oxaliplatin therapy in older adults with mismatch repair deficient stage III colorectal cancer.
Authors: Sears Jerod J , Hu Zishuo Ian , Liu Jingxia , Ballentine Samuel
Published: January 2023

112

Background: Standard adjuvant chemotherapy regimens for Stage III colorectal cancer (CRC) include FOLFOX/CAPOX, 5-FU/capecitabine, or observation alone. There is uncertainty around the therapeutic benefit of adding oxaliplatin to fluorouracil in older adults over the age of 70 with Stage III CRC, including in those with mismatch repair–deficient (MMR-D) CRC. In this single institutional study, we evaluate progression free survival (PFS) across a 12-year period in patients who receive FOLFOX/CAPOX or 5-FU/capecitabine compared to active surveillance in older adults with MMR-D Stage III CRC. Methods: We identified patients diagnosed with MMR-D Stage III CRC after the age of 70 who received care at our institution and affiliates between 2005-2019. We performed a retrospective chart review of patient outcomes during the 12-year follow up period based on chemotherapy regimen to determine PFS. Patients without MMR-D staining performed at initial time of diagnosis had MMR protein immunohistochemistry performed currently and included in the analysis. Results: Among patients with MMR-D stage III CRC, 50%, 62.5%, and 76% of patients were alive at the end of year 12 with no disease progression in the observation, 5-FU/capecitabine, and FOLFOX/CAPOX groups. The PFS probabilities at one year are 69.6%, 87.5%, and 87.0%, and at five years are 41.8%, 62.5%, and 87.0% in these groups, respectively. Finally, there was a statistically significant difference (P=0.039) in PFS across all chemotherapy regimens in the MMR-D cohort. Conclusions: Based on this study, older adult patients with stage III MMR-D colorectal cancer have an improved progression free survival when treated with oxaliplatin containing chemotherapy compared to active surveillance alone. [Table: see text]
Final analysis of a prospective controlled trial of the efficacy of uracil and tegafur/leucovorin for stage II colon cancer with risk factors for recurrence using propensity score-based methods (JFMC46-1201).
Authors: Kondo Ken , Sadahiro Sotaro , Sakamoto Kazuhiro , Tsuchiya Takashi , Takahashi Takao , Ohge Hiroki , Sato Toshihiko , Ogata Yukata , Baba Hideo , Itabashi Michio , Ikeda Masataka , Hamada Madoka , Maeda Kiyoshi , Masuko Hiroyuki , Takahashi Keiichi , Sakamoto Junichi , Kusano Mitsuo , Hyodo Ichinosuke , Taguri Masataka , Morita Satoshi
Published: January 2023

117

Background: The usefulness of adjuvant chemotherapy for stage II colon cancer with high-risk factors for recurrence has not been established. Methods: This was a prospective, non-randomized controlled study based on patients’ selection of treatment options, including randomized therapeutic decision-making. High-risk factors were defined as having at least one of the following factors: T4, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, and < 12 dissected lymph nodes. UFT (300 mg/m2/day) plus LV (75 mg/day) were orally administered for 6 months after surgery. The primary endpoint was disease-free survival (DFS) after adjusting for risk factors using propensity sore matching (1:2) and inverse probability of treatment weighting (IPTW) in the non-randomized arm. The secondary endpoints were overall survival (OS) and safety. Results: 1902 (98%) and 36 (2%) patients were enrolled in the non-randomized and randomized arms, respectively between May 2012 and April 2016. There were too few patients in the randomized arm and these were therefore excluded from the analysis. Eligible patients were divided into two groups: A, patients who selected surgery alone (n = 641); B, patients who selected UFT/LV treatment (n = 1239). Of the eligible patients, 402 in group A and 804 in group B were propensity score-matched. The 5-year DFS rate (95% confidence interval) was significantly higher in group B (76.3% [73.1-79.1]) than in group A (68.8% [63.9-73.2]) {hazard ratio [HR] 0.66 [0.51–0.84, P = 0.0008]}. The 5-year OS rates were not significantly different between group B and group A [HR 0.74 (95% CI 0.50–1.10, P = 0.1391)]. Using IPTW, significantly higher 5-year DFS [HR 0.71 (95% CI 0.59–0.86, P = 0.0006)] and overall survival [HR 0.66 (95% CI 0.49–0.90, P = 0.0122)] rates were observed in group B compared with group A. Multivariate analysis revealed that male sex, over 70 years old, T4, < 12 dissected lymph nodes, and no adjuvant chemotherapy were significant risk factors for recurrence. Conclusions: Adjuvant chemotherapy with UFT/LV significantly improves DFS. Oral UFT/LV as adjuvant chemotherapy shows efficacy with an acceptable safety profile for stage II colon cancer with risk factors. Clinical trial information: UMIN000007783 .
Modified (m)-FOLFOXIRI plus cetuximab versus m-FOLFOXIRI plus bevacizumab as initial treatment of patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer: Survival analysis of the phase II randomized DEEPER trial by JACCRO.
Authors: Sunakawa Yu , Shiozawa Manabu , Watanabe Takanori , Ota Hirofumi , Yasui Hisateru , Yabuno Taichi , Tei Mitsuyoshi , Kochi Mitsugu , Manaka Dai , Ohori Hisatsugu , Yamaguchi Tatsuro , Sagawa Tamotsu , Kotaka Masahito , Kubota Yutaro , Sekikawa Takashi , Nakamura Masato , Takeuchi Masahiro , Ichikawa Wataru , Fujii Masashi , Tsuji Akihito
Published: January 2023

120

Background: Triplet regimen, FOLFOXIRI, plus bevacizumab is considered as one of standard first-line treatments in metastatic colorectal cancer (mCRC). On the contrary, FOLFOXIRI plus anti-EGFR antibody has been shown to be a promising regimen with greater depth of response (DpR) in patients with RAS wild-type mCRC from the VOLFI and MACBETH trials (J Clin Oncol 2019, JAMA Oncol 2018). We therefore performed a randomized phase II study, DEEPER trial (JACCRO CC-13) [NCT02515734], to investigate the efficacy and safety of cetuximab (cet) vs. bevacizumab (bev) in combination with modified (m)-FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. We have reported a significantly better DpR of m-FOLFOXIRI plus cet compared to bev as the primary endpoint (Tsuji A, et al. ASCO 2021). Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) plus cet vs. bev as initial treatment in terms of DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC. The aim of the trial was to show that median DpR of cet arm was more than 12.5% higher than bev arm, with a power of 85% at a significance level of 0.05, in per protocol set (PPS) consisted of patients evaluable for the DpR. Secondary endpoints included progression-free survival, overall survival, overall response rate, early tumor shrinkage rate, secondary resection rate, and toxicity. A total of 359 patients were enrolled between July 2015 and June 2019. For the PPS (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 84%/16%), 159 and 162 patients were randomly assigned to the cet and bev arms, respectively. Clinical outcomes will be analyzed according to primary tumor sidedness which is included in the stratification factor. Additionally, we will collect data of BRAF status, and analyze the clinical outcomes in mCRC patients with RAS/ BRAF wild-type tumors and/or left-sided tumors. Pre-planned survival analysis will be performed to compare the two treatment arms at the time of 3 years after last patients’ enrollment using a log-rank test. All statistical tests are two-sided, and P values ≤ 0.05 are deemed significant. Statistical analyses will be performed using SAS version 9.4. Clinical trial information: NCT02515734 .
Prognostic and predictive impact of metastatic organ involvement on maintenance therapy in advanced metastatic CRC: Analysis of patients treated within the PanaMa trial (AIO KRK 0212).
Authors: Karthaus Meinolf , Sommerhäuser Greta , Kurreck Annika , Beck Alexander , Fehrenbach Uli , Fruehauf Stefan , Graeven Ullrich , Müller Lothar , Koenig Alexander , Fischer von Weikersthal Ludwig , Goekkurt Eray , Haas Siegfried , Stahler Arndt , Heinemann Volker , Held Swantje , Alig Annabel Helga Sophie , Kasper Stefan , Stintzing Sebastian , Trarbach Tanja , Modest Dominik Paul
Published: January 2023

127

Background: Despite molecular selection, patients with RAS wildtype mCRC represent a heterogeneous population, including different metastatic patterns and number of organs involved. We investigated metastatic patterns for their prognostic and predictive impact on maintenance therapy with (FU/FA plus Pmab or FU/FA alone) in patients treated within the PanaMa trial. Methods: The study population was stratified according to number of organs involved and also to different patterns including liver metastases alone or in combination with additional organs. Kaplan-Meier method and Cox regressions were used to correlate efficacy endpoints (i.e. progression-free survival (PFS) and overall survival (OS) of maintenance therapy) in the aforementioned populations. Results: Of 248 patients (pts) receiving maintenance therapy, 133 pts had a one-metastatic site disease (53.6%). Of those, 102 pts had liver-only metastases. Furthermore, liver metastases plus one additional involved organ was observed in 61/248 patients (24.6%), and liver metastases plus two or more organs in 40/248 patients (16.1%). In general, one organ disease was associated with favourable PFS of maintenance therapy compared to patients with ≥2 organs involved (HR 0.68, 95% CI 0.52–0.88; P = 0.004). A predictive impact of disease spread in terms of pmab-containing maintenance therapy was present for the PFS of maintenance therapy in patients with ≥ 2 organ disease (HR 0.58, 95% CI 0.39–0.86; P = 0.006) unlike in patients with only one-organ disease (HR 0.83, 95% CI, 0.57-1.21; P = 0.332) and also specifically in patients with a 2-organ disease including the liver (HR 0.57, 95% CI 0.33–0.99; P = 0.046). Conclusions: Consistent with previous reports, organ spread has prognostic impact in mCRC. The efficacy of more intensive maintenance therapy (including pmab and 5-FU/FA) is predominantly seen in patients with more than one organ involved in the metastatic spread, while less striking effects were seen in patients with only one organ disease. These data may support clinical decisions when EGFR-based maintenance therapy is considered. Clinical trial information: NCT01991873 .
The EPOCH trial: Identifying key patient subgroups to optimize treatment planning.
Authors: Harris William P. , Salem Riad ,   on behalf of the EPOCH Investigators
Published: January 2023

130

Background: The primary objective of the original EPOCH trial was to evaluate the potential benefit of adding transarterial radioembolization (TARE) with yttrium-90 glass microspheres to second-line chemotherapy (chemo) versus chemo alone in patients with liver-dominant metastatic colorectal cancer (mCRC). Randomization was stratified by key prognostic factors, including KRAS status; however, it did not account for ECOG status and baseline CEA levels. We present post-hoc analyses investigating the impact of prognostic factors on primary and secondary endpoints to help optimize patient selection. Methods: EPOCH was a 1:1 randomized, open-label, global, multicenter Phase 3 trial. Primary endpoints were progression-free survival (PFS) and hepatic PFS (hPFS). Overall survival (OS) and time to deterioration of quality of life (TTDQOL) were secondary. Post-hoc analyses of the following subgroups were performed: Subgroup A (excluding patients with both ECOG=1 and CEA≥35ng/mL) and Subgroup B (patients with KRAS wild-type and either ECOG=0 or CEA<35ng/mL). Kaplan-Meier analyses, hazard ratios (HRs) and log-rank tests were used to compare outcomes between TARE plus chemo and chemo only groups. Results: In Subgroup A, 160 (75.1%) patients were randomized to chemo only, versus 143 (66.5%) to the TARE arm. In Subgroup B, 91 (42.7%) patients were randomized to chemo only, versus 77 (35.8%) to the TARE arm. Results are shown for PFS, hPFS, OS, and TTDQOL in the intent-to-treat population. In both subgroups A and B, PFS, hPFS, and TTDQOL were significantly improved for the TARE plus chemo arm as compared to the chemo only arm; no OS difference was found. Conclusions: Careful patient selection using multiple prognostic factors is necessary to identify those who will benefit most from TARE with second-line chemo. Prognostic factors were important in identifying the level of benefit seen in patients treated with TARE and chemo versus chemo alone. Clinical trial information: NCT01483027 . [Table: see text]
SOX plus bevacizumab versus SOX plus cetuximab as initial treatment of recurrent advanced colorectal cancer with wild-type KRAS (MCSGO-1107 study): A phase II randomized study.
Authors: Okamura Shu , Nishizawa Yujiro , Kagawa Yoshinori , Imasato Mitsunobu , Miyake Masakazu , Ohara Nobuyoshi , Ide Yoshihito , Nonaka Ryoji , Tamai Koki , Konishi Ken , Kato Takeshi , Sawada Genta , Tei Mitsuyoshi , Satoh Taroh , Miyoshi Norikatsu , Uemura Mamoru , Takahashi Hidekazu , Murata Kohei , Doki Yuichiro , Eguchi Hidetoshi
Published: January 2023

136

Background: Although clinical outcomes of chemotherapy in patients with locally advanced or metastatic colorectal cancer (CRC) have improved over the last decade, the standard-of-care chemotherapy regimens for patients with unresectable RAS wild-type CRC remain to be discussed. The aim of this study was to compare S-1 and oxaliplatin (SOX) + bevacizumab (B-mab) with SOX + cetuximab (C-mab) in patients with previously untreated, unresectable, locally advanced, or metastatic CRC with wild-type KRAS. Methods: This phase II, randomized, open-label, multicenter study compared the efficacy and safety of SOX+B-mab with SOX+C-mab in patients with previously untreated, unresectable, locally advanced, or metastatic CRC with wild-type KRAS. Forty-five patients were enrolled in this study between February 2012 and October 2016. Results: The overall response rate (ORR) for the SOX+B-mab group was 59.1%, whereas that for the SOX+C-mab group was 43.5% (p = 0.29). The disease control rate (DCR) for the SOX+B-mab group was 90.9%, whereas that of the SOX+C-mab group was 91.3% (p = 0.96). For all patients, median OS were 25.3 months (95% CI: 16.5–39.4 months) in the SOX+B-mab group and 15.5 months (95% CI: 7.30–30.4 months, p = 0.167) in the SOX+C-mab group. Median PFS were 11.7 months (95% CI: 7.37–18.2 months) in the SOX+B-mab group and 5.5 months (95% CI: 3.36–10.1 months, p = 0.077) in the SOX+C-mab group. In the SOX+B-mab group, OS and PFS were not significantly different with and without early tumor shrinkage (ETS). However, in the SOX+C-mab group, patients with ETS had significantly better OS (30.4 months [95% CI: 8.0–44.3 months, p = 0.032]) and PFS (12.0 months [95% CI: 5.1–19.7 months, p = 0.003]) than those without ETS. Conclusions: The safety and efficacy of SOX+B-mab and SOX+C-mab as initial treatment for unresectable CRC with wild-type KRAS were almost the same. ETS was more correlated with PFS in the SOX+C-mab group than in the SOX+B-mab group, suggesting consideration of treatment strategy based on ETS may improve patient prognosis, especially in patients receiving the SOX+C-mab regimen. Clinical trial information: UMIN000006706 .
Updated results from ALTER-C001 study: Efficacy and safety of anlotinib plus XELOX regimen as first-line treatment followed by maintenance monotherapy of anlotinib for patients with mCRC.
Authors: Yan Jin , Han Yunwei , Zhang Li , Jin Yongdong , Sun Hao
Published: January 2023

137

Background: The standard first-line therapy followed by maintenance treatment is an optional approach to balance the efficacy and toxicity for metastatic colorectal cancer (mCRC). In general, this approach had been seen PFS benefit in some trials, but probably lack of OS benefit, which indicating that new regimens needed to be explored. Anlotinib, a novel multi-targeted TKI, significantly prolonged the PFS of refractory mCRC in a phase III clinical trial (NCT02332499). Previous results of this study exhibited antitumor efficacy and manageable toxicity for mCRC. Here we report an update results with a longer follow up. Methods: 29 patients with unresectable mCRC, aged 18-75, without prior systemic treatment and ECOG performance status 0-1 would be prospectively included. Anlotinib 10mg and capecitabine 1000mg/m2 was given orally for 14 days in 3-week cycles; oxaliplatin 130mg/m2 was given by intravenous infusion on day 1 in 3-week cycles. After 6 cycles of induction therapy, patients would receive anlotinib (12mg, po, d1~14, q3w) until disease progression or intolerable adverse events. The primary endpoint was PFS. Secondary endpoints included ORR, DCR, DOR and safety. Results: At data cut-off date (June 30, 2022), a total of 31 patients were enrolled, the median age was 57 years, 23 (74%) were males, ECOG PS 0/1 was 18 (58%)/13 (42%), 28 (90%) had more than one metastatic tumor. Among them, 24 patients were available for efficacy assessment. The median PFS was 8.28 months (95% CI: 6.29-10.27) and the median DOR was 6.01 months (95% CI: 4.59-7.43). The ORR was 62.5% (95% CI: 40.6-81.2) and DCR was 91.7% (95% CI: 73.0-99.0) in best overall response assessment, of which the longest duration of treatment was 17.5 months. The treatment-related adverse events (TRAEs) occurred in 31 pts (100.0%) including nausea (58.1%), vomiting (51.6%), neutropenia (51.6%), leukopenia (35.5%), hypertension (35.5%). The Grade 3/4 TRAEs were neutropenia (12.9%), hypertension (12.9%), lipase elevated (9.7%), hypertriglyceridemia (6.5%), and leukopenia (3.2%). Conclusions: The updated results suggested that anlotinib combined with XELOX as first line regimen followed by anlotinib monotherapy as maintenance therapy showed a promising clinical benefit and favorable safety profile for mCRC, and the results needed to be confirmed in trials continued subsequently. Clinical trial information: ChiCTR1900028417 .
Racial and regional disparities in the management of locally advanced rectal cancer.
Authors: Luo William Yu , Agala Chris B , Shetty Pragna , Kapadia Muneera Rehana , Stem Jonathan Michael , Guillem Jose G.
Published: January 2023

14

Background: Surgical margins following rectal cancer resection impact oncologic outcomes and may reflect adequacy of care. We examined the relationship between race, ethnicity, or region of care with margin positivity following rectal cancer resection. Methods: We queried the National Cancer Database (NCDB) for patients diagnosed with stage II-IV rectal cancer between 2004-2018 who underwent surgical resection and excluded patients with missing data for race/ethnicity and radiation therapy/surgery status, and/or who had local excision only. We performed a propensity-score analysis via inverse probability of treatment weighting (IPTW) of margin positivity rate as outcome and race/ethnicity and region as predictors of interest. We controlled for age, sex, Charlson-Deyo Score, pathologic stage, pathologic grade, time from diagnosis to surgical resection, surgery type, sequence of radiation and surgery, facility type, insurance type, level of education, distance between patient and facility, and region of the United States. Results: Our query yielded 73,269 patients. Median patient age was 63 (IQR: 54-72) years and 40% were female. 81%,8%, 6%, and 5% were non-Hispanic White, non-Hispanic Black, Hispanic, and non-Hispanic Other, respectively. After IPTW adjustment, non-Hispanic Black patients had 19% higher odds of margin positivity relative to non-Hispanic White patients (OR: 1.185, 95% CI: 1.094-1.284; p<.0001) Patients in the Northeast United States had a 10% lower odds of margin positivity compared to those in the South (OR: 0.900, 95% CI: 0.842-0.962; p=0.0019). Conclusions: Being non-Hispanic Black was significantly associated with a higher likelihood of positive margin following rectal cancer resection when compared to their non-Hispanic White counterparts. Patients in the South also experienced significantly higher rates of positive margin when compared to Northeast patients. Further investigation into potential interactions between racial and regional disparities and other contributors is warranted.[Table: see text]
A randomized phase 2 study of trastuzumab and pertuzumab (TP) compared to cetuximab and irinotecan (CETIRI) in advanced/metastatic colorectal cancer (mCRC) with HER2 amplification: SWOG S1613.
Authors: Raghav Kanwal Pratap Singh , Guthrie Katherine A , Kopetz Scott , Tan Benjamin R. , Denlinger Crystal S. , Fakih Marwan , Overman Michael J. , Dasari Arvind , Corum Larry R. , Hicks Lee G. , Patel Mital , Esparaz Benjamin T , Kazmi Syed Mohammad Ali , Alluri Nitya , Colby Sarah , Gholami Sepideh , Gold Philip Jordan , Chiorean E. Gabriela , Hochster Howard S. , Philip Philip Agop
Published: January 2023

140

Background: HER2 ( ERBB2) over-expression and amplification (HER2+) is seen in a small but distinct subset (2-3%) of mCRC and is enriched in RAS/BRAF wild type (WT) tumors. This subset is characterized by a limited response to anti-epidermal growth factor receptor monoclonal antibody-based (anti-EGFR) therapy and a promising response to dual-HER2 inhibition. Methods: In this multicenter, open label, randomized, phase 2 trial, we enrolled 54 patients with RAS/BRAF WT HER2+ mCRC who had had disease progression after 1 or 2 previous therapies. HER2 status was confirmed centrally with immunohistochemistry (IHC) and in-situ hybridization (ISH). HER2+ was defined as IHC 3+ or 2+ and ISH amplified (dual-probe HER2/CEP17 ratio > 2.0). Patients were then randomly assigned in a 1:1 ratio to receive either TP (trastuzumab [loading 8 mg/kg then 6 mg/kg] + pertuzumab [loading 840 mg then 420 mg] every 3 weeks) or CETIRI (cetuximab 500 mg/m2 + irinotecan 180 mg/m2 every 2 weeks). Crossover was allowed for patients on CETIRI arm to TP (cTP) after progression. Restaging (per RECIST v1.1) was performed at 6 and 12 weeks and then every 8 weeks until progression. The primary endpoint was progression-free survival (PFS). Key secondary endpoints were overall response rate (ORR), overall survival (OS) and safety. Results: A total of 54 (out of planned 62 due to low accrual) patients were randomized to TP (26) and CETIRI (28) between 10/2017 and 12/2021. By 8/18/2022, 20 patients had crossed over to cTP arm. One CETIRI patient was not analyzable. The results for key endpoints by protocol defined stratification factors, prior irinotecan (Piri) (yes or no) and HER2/CEP17 ratio (HCR) (>5 or ≤5), are summarized as of data cut-off of 9/6/2022. PFS did not vary significantly by treatment: medians 4.4 (95%CI: 1.9 – 7.6) months in TP group and 3.7 (95%CI: 1.6 – 6.7) months in CETIRI group (p = 0.35). Grade ≥3 adverse events occurred in 23%, 46% and 40% of patients in TP, CETIRI and cTP groups. Conclusions: Dual-HER2 inhibition with TP appears to be a safe and effective treatment option for patients with RAS/BRAF WT HER2+ mCRC with a promising response rate of 31%. Higher level of HER2 amplification may provide a greater degree of clinical benefit from TP compared to CETIRI. Future correlative efforts will explore biomarkers of response/resistance with this strategy. Clinical trial information: NCT03365882 . [Table: see text]
Identification and external validation of clinical-molecular features to predict benefit from oxaliplatin reintroduction/rechallenge in patients with refractory metastatic colorectal cancer (mCRC).
Authors: Salva Francesc , Paes Rafael , Costa e Silva Matheus , Cruz Heloisa , Saoudi Gonzalez Nadia , Baraibar Iosune , Ros Montañá Javier , Comas Raquel , Ruiz-Pace Fiorella , Garcia Ariadna , Dalpino Renata , Jácome Alexandre A. , Tabernero Josep , Elez Elena , Dienstmann Rodrigo
Published: January 2023

153

Background: Oxaliplatin is a backbone cytotoxic treatment for mCRC patients, particularly in the front-line setting. In the refractory disease, current treatment options are scarce and with limited efficacy. Several retrospective studies have explored the efficacy of oxaliplatin reintroduction/rechallenge (OxRe) in this scenario. However, more evidence is still needed to determine which patients do benefit from this treatment strategy. Methods: The discovery cohort includes all patients treated with oxaliplatin in a third- or fourth-line setting at VHIO between 2015 and 2021 (N = 102). Results were externally validated in a real-world cohort of patients treated at community oncology practices from Oncoclínicas Group in Brazil (N = 157). We analyzed the impact of clinical-molecular features in uni- and multivariable prognostic models in terms of median progression free survival (mPFS) (discovery cohort) and median time to treatment discontinuation (mTTD) (validation cohort). For both cohorts separately, data was extracted from EHRs in structured formats (demographics, tumor characteristics, pharmacy records) and combined with elements from unstructured sources (physician notes on progression and survival status) using technology-based abstraction techniques. Results: In the discovery cohort, 102 out of 735 mCRC patients (13,9%) were eligible. Median oxaliplatin-free interval (from Oxl stop to OxRe) was 17 months (CI95% 13.0-23.2). In OxRe setting, mPFS was 4.0 months (CI95% 3.29-5.03). In PFS multivariate analysis, determinants of favorable outcome were left tumor location (p = 0.01), oxaliplatin-free interval (p = 0.03), administration of Bev in refractory setting (p = 0.001), and not receiving Bev in first-line treatment (p = 0.008). Overall, 27% of all patients had a mPFS > 6 months with OxRe. In the validation cohort, out of 4,317 patients with mCRC, 157 (4%) were treated with OxRe. Median oxaliplatin-free interval was 15 months. Median time to treatment discontinuation (mTTD) of the OxRe was 3.4 months (CI95% 2.8-4.2). In multivariable model, the only independent prognostic factor was addition of Bev to OxRe (p = 0.036). Interestingly, 31% of all patients had mTTD > 6 months, largely enriched (65%) in patients with first Bev exposure at the time of OxRe. Conclusions: This study suggests that in refractory mCRC patients re-exposed to oxaliplatin-based chemotherapy, the addition of Bev is associated with improved outcomes. One-third of the patients are long-term responders (PFS/TTD > 6 months), reinforcing the value of this strategy in selected populations and the relevance of anti-angiogenic agents in refractory mCRC.
Total neoadjuvant oxaliplatin-based therapy (TNT) before (induction) and after (consolidation) chemoradiation for advanced rectal cancer: MRI correlation on complete response and outcome.
Authors: Cen Putao , Chan Kok Hoe , Van Eps Jeffrey , Rowe Julie Haewon , Wray Curtis Jackson
Published: January 2023

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Background: Preoperative chemoradiation with fluoropyrimidine, followed by total mesorectal excision (TME) and adjuvant chemotherapy is the standard care for locally advanced rectal cancer (LARC). Studies have shown the potential benefit of oxaliplatin based TNT approach. The benefits of using of both induction and consolidation chemotherapy with chemoradiation prior of TME is not well studied. We investigate whether the use of oxaliplatin based before (induction) and after (consolidation) neoadjuvant chemoradiation will increase the pCR and clinical Complete response (cCR), improve survival and MRI correlation. Methods: Patients treated with curative intent surgery for LARC who received oxaliplatin based induction and consolidation chemotherapy with neoadjuvant capecitabine chemoradiation were identified. Demographics and clinicopathologic data were analyzed. Multiparametric MRI was used for initial staging and restaging before surgery. The primary endpoint will be the complete response (pathological and clinical), recurrent-free survival (RFS), and overall survival (OS). Results: A total of 21 patients have been identified, all patient has T3/T4 and positive nodes N1/N2 on initial MRI staging, 2 (10%) patients had Stage IV disease with abdominal para-aortic nodes. Median age was 63 (range: 26-76); 14 (67%) male. As for the induction regimen, 9 (43%) had CAPOX/FOLFOX, 7 (33%) had short-course capecitabine, 5 (24%) had FOLFIRINOX. All patient received neoadjuvant chemoradiation with capecitabine. As for consolidation, 19 (90%) had CAPOX/FOLFOX, 1 (5%) had capecitabine and 1 (5%) had FOLFIRINOX. Median time for induction and consolidation chemotherapy was 8.5 weeks (range: 1-24) and 8 weeks (range: 2-16) respectively. Median time from starting induction chemotherapy to surgery was 6.8 months (range: 3.2-11). Eight (38%) patients had cCR and pCR. Post-treatment restaging MRI prior of resection has 100% concordant rate with pCR. All (100%) pateints had tumor downstaged after treated with TNT and chemoradiation. The sensitivity of MRI in detecting the residual lymph node post TNT/neoadjuvant chemoradiation was 55% (95% CI: 26-81%), and the negative predictive value was 75% (51-90%); the specificity was 100% (76-100%) and the positive predictive value was 100% (57-100%). There is no death and one patient had recurrence after recurrence free for 2 years. Median RFS and OS are not meet. Median follow up time is 25.7 months (range: 9.1-76.8). Conclusions: Neoadjuvant oxaliplatin based therapy before and after chemoradiation for rectal cancer potentially improves CR rate, and accurately predicted by post-treatment MRI. The use of MRI can potentially help to select candidates who desire organ preservation.
Clinical development and evaluation of plasma angiogenesis factors from phase II study of FOLFIRI plus ramucirumab with recurrent colorectal cancer refractory to adjuvant chemotherapy with oxaliplatin/fluoropyrimidine (RAINCLOUD): RAINCLOUD-TR.
Authors: Hata Tsuyoshi , Sugimoto Naotoshi , Ohara Nobuyoshi , Miyo Masaaki , Yoshioka Shinichi , Kagawa Yoshinori , Naito Atsushi , Tei Mitsuyoshi , Tamagawa Hiroshi , Konishi Ken , Sawada Genta , Danno Katsuki , Shimokawa Toshio , Satoh Taroh , Miyoshi Norikatsu , Takahashi Hidekazu , Uemura Mamoru , Murata Kohei , Doki Yuichiro , Eguchi Hidetoshi
Published: January 2023

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Background: Higher levels of vascular endothelial growth factor-D (VEGF-D) is a potential predictive biomarker for ramucirumab (Ram) efficacy on overall survival and progression-free survival (PFS) in Ram+FOLFIRI vs Placebo+FOLFIRI for bevacizumab (Bev) refractory metastatic colorectal cancer (mCRC). However, it is not clear whether VEGF-D acts as a predictive biomarker in pts who pretreated without Bev. RAINCLOUD showed the clinical benefit of FOLFIRI+ plus Ram for pts with recurrent CRC refractory to adjuvant chemotherapy (median PFS was 6.2 months (M); ESMO-GI 2022). RAINCLOUD-TR was designed as a prospective biomarker study estimating the association of biomarkers with Ram efficacy. Methods: Plasma sample collections were done at time points of pre-/ post-treatments in pts receiving FOLFIRI+Ram. Measurements of 17 factors (including VEGF-A, VEGF-D and PlGF) were performed by multiplex assay with Luminex technology. The high/ low groups were defined bases on the median plasma level at the baseline. Results: From September 2017 to September 2021, 81 plasma samples were collected from 48 pts and 32 pts in both pre/ and post treatment. Level of VEGF-A, VEGF-D, PlGF and TSP-2 were all significantly higher in post vs pre-treatment [Table]. The ORR analyses were as follows; VEGF-A, VEGF-D and PlGF in low vs high were 50.0%/33.3% (p=0.35, HR 1.97), 55.0% /33.3% (p=0.22, HR 2.39), and 60.0%/28.6% (p=0.35, HR 1.95). The PFS analyses were as follows; VEGF-A, VEGF-D, and PlGF in low vs high were 6.1M/6.0M (p=0.815, HR 0.92), 7.6M /5.6M (p=0.095, HR 0.56), and 8.0M/4.2M (p=0.014, HR 0.40). In other factors, low TSP-2 were better ORR (low vs high: 66.7%/20.0% (p=0.004, HR 7.54) and PFS 7.5M/4.3M (p=0.022, HR 0.45). Conclusions: In this exploratory study, PFS was numerically greater for pts with low vs high VEGF-D for Ram in pts with mCRC pretreated without Bev. VEGF-D may not be predictive biomarker, but TSP-2 may be a potential prognostic biomarker, further studies in larger cohorts are needed to confirm our results. Clinical trial information: UMIN000028678 . [Table: see text]
Circulating tumor cells (CTCs) as liquid biopsies in patients with metastatic colorectal cancer versus other GI malignancies.
Authors: Kasi Pashtoon Murtaza , Malkawi Walla I , Salem Aliasger K
Published: January 2023

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Background: Most of the focus on liquid biopsies for patients with colorectal cancers and other solid tumors has been on circulating tumor DNA (ctDNA). Circulating Tumor Cells (CTCs) are the other less talked about liquid biopsies. This is due to need for real-time processing and handling of CTCs, and is less conducive on previously banked samples. We took this prospective discovery endeavor to report in real-time CTC analyses using 2 very different platforms in patients with colorectal and other GI cancers. Methods: CTCs were evaluated using 2 platforms: RareCyte, which is simplistically based on density of CTCs and unbiased selection/identification for enumeration/biomarker analyses, and Parsortix, which is based on size/compressibility of CTCs. All patients signed written informed consent. Up to 4 serial draws were done for each patient (Total = 150 draws; 281 test results). CTCs were identified using standard definitions of nuclear/epithelial markers. À la carte we selected PD-L1, HER2, EGFR, Ki-67, and where adequate, confirmation with panel based single cell sequencing was also performed. Cell cultures were attempted for the Parsortix collections. Results: Patients with colorectal cancer (CRC) had the highest number of CTCs (Mean: 15.8; Median: 7.5). This was in sharp contrast to the number of CTCs in patients with pancreatic cancer (PC) (Mean: 4.2; Median: 3). At least a third of patients with CRC had at least 3 CTCs. Another 17.4% and 11.4% had at least 10, and at least 20 CTCs in CRC; while no patients with PC had more than 20 CTCs. CTCs in clusters were also common at baseline. In addition, we detected a significantly lower number of CTCs from patients receiving treatment versus those were not (Median 2.7 versus 0.7). Striking differences were also observed in CTCs for those with untreated/progressive disease versus those who had responding/stable disease (Median of 2.7 versus 0). Biomarker analyses on HER2/PD-L1/Ki-67/EGFR were feasible when CTCs were detected. There was overall agreement on CTCs detected on either platform. Where available, single cell sequencing data was concordant with clonal aberrations on sequencing. Conclusions: This is one of the largest prospective real-time endeavors in patients with colorectal and other GI cancers providing data on CTCs as liquid biopsies using 2 very different platforms. The descriptive insights gained from processing, enumeration, kinetics, timing of collection, biomarker analysis, costs, comparison across tumor types, attempts at cell culture, and single cell sequencing are of value for studies and investigators considering the use of CTCs in patients with colorectal and other GI cancers. While most of the focus is on ctDNA-based platforms, CTCs offer a different lens from a liquid biopsy standpoint that is complimentary and worth developing further.
A retrospective study of circulating tumor DNA for minimal residual disease detection in the management of colorectal cancer.
Authors: Storandt Michael H. , Emiloju Oluwadunni Eunice , Zemla Tyler J. , McWilliams Robert R. , Sinicrope Frank A. , Mitchell Jessica L. , Shi Qian , Jin Zhaohui
Published: January 2023

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Background: Circulating tumor DNA (ctDNA) consists of small fragments of DNA released into the plasma from cancer cells. Tumor informed ctDNA testing by whole exome sequencing of the primary tumor coupled with multiplex polymerase chain reaction (PCR)-based next generation sequencing of cell free DNA in serum, can detect and quantify ctDNA, allowing for detection of minimal residual disease (MRD). Methods: We conducted a retrospective analysis of 120 patients with colorectal cancer who had at least one tumor-informed ctDNA MRD assay completed between May 6, 2019, and July 1, 2022, at Mayo Clinic, Rochester. Disease recurrence was defined as radiographic evidence consistent with recurrence with or without biopsy confirmation. Data are presented descriptively, including number of ctDNA assays completed, ctDNA positivity prior to disease recurrence, and ctDNA concordance with carcinoembryonic antigen (CEA). The study protocol was exempt after review by the Mayo Clinic Institutional Review Board. Results: One-hundred twenty patients were included in the study with median age at initial disease diagnosis of 67.0 years. Sixty-four percent were male and 94% were white. At time of initial diagnosis, 10 had stage I, 23 stage II, 60 stage III, and 25 stage IV disease. In 120 patients, 476 ctDNA assays were performed, and 110 recurrences were observed among 62 patients. There were 39 instances in which ctDNA was obtained prior to clinical detection of recurrence and of these, at least one ctDNA assay was positive in 28 cases (72%). CEA was obtained prior to recurrence in 88 instances and was elevated in only 39 cases (44%). Among 37 instances where both ctDNA and CEA testing were obtained prior to recurrence, ctDNA was positive in 27 cases (73%) while CEA was positive in 14 cases (38%). ctDNA was positive in 83% of recurrences involving liver and 62.5% of recurrences involving only the lungs. ctDNA and CEA positivity are shown by location of recurrence. ctDNA and CEA were discordant in 44% of instances in which the assays were completed within 2-weeks of each other. Results of a ctDNA assay impacted management decisions in 16% of cases. Conclusions: ctDNA detected 72% of recurrences with higher rates of detection in liver versus lung metastasis. ctDNA performed superiorly to serum CEA in detection of recurrence, suggesting a role in disease surveillance. However, ctDNA impacted disease management in only 16% of patients, suggesting need for better patient selection and further study for ctDNA-based disease management strategy (more details will be reported). [Table: see text]
The prediction of pathological complete response after total neoadjuvant therapy for locally advanced rectal cancer using versatile liquid biopsy.
Authors: Matsuda Akihisa , Yamada Takeshi , Sonoda Hiromichi , Shinji Seiichi , Iwai Takuma , Takeda Kohki , Yonaga Kazuhide , Ueda Kohji , Kuriyama Sho , Miyasaka Toshimitsu , Kanaka Shintaro , Yoshida Hiroshi
Published: January 2023

230

Background: Total neoadjuvant therapy (TNT) has conferred a dramatic paradigm shift in the treatment for locally advanced rectal cancer (LARC), which can prolong the survival associated with high pathological complete response (pCR) rate and introduce non-operative management (NOM). However, useful biomarkers predicting the treatment efficacy of TNT and the prognosis has not been developed. Our previous study demonstrated that volume of blood long- and short-fragments DNA ( > 300 bp and < 180 bp) in LINE-1 gene are derived from tumor cell necrosis, and normal cell apoptosis, and the ratio (LSR) could reflect tumor growth or shrinkage, and minimal residual disease. Methods: A total of 17 LARC patients receiving consolidation TNT consisting of short-course radiation (5Gy x 5days) and 4 courses of CapOX, followed by total mesorectal excision were included. Blood concentrations of long-, short-fragment DNA and LSR in neoadjuvant phase were serially measured at pre-treatment, every treatment cycle, and pre-operation by real-time PCR. Results: Median age of patients were 64 years old and 65% were female. Clinical stage (IIa/IIc/IIIb/IIIc) were 2/1/8/6, respectively. Down staging was shown in 88% of patients. Tumor regression grade (0/1a/1b/2/3(pCR)) were 1/2/3/34/7(41%), respectively. Only 44% of patients had elevated CEA levels before TNT, which indicates less usefulness as the biomarker. The dynamics of the LSR in the entire cohort showed the gradual decrease until pre-operative phase (decrease to 77.8%). The LSR change from pre-treatment (or just after SCRT) to early preoperative treatment phase (1 or 2 course after CapOX) was significantly greater in the pCR(+)(n = 7) than the pCR(-)(n = 10) groups (66.8% vs. 101%, p = 0.03). The AUC of ROC analysis was 0.72 (cut off: 66.8%). Conclusions: NGS based liquid biopsy is the gold standard for the cancer prediction and monitoring, but limitations such as unsatisfied sensitivity and high cost are still involved. However, LSR measurement has great benefits on those points. Early phase LSR measurement could be a good predictive marker for the response of TNT and might be clinically useful for optimizing the preoperative therapy.
Neutrophil-to-lymphocyte ratio and clinical outcomes in liver resection for metastatic colorectal cancer.
Authors: Reddy Sarah , El Hajj Joanna , Karagkounis Georgios , Polanco Patricio M. , Porembka Matthew R. , Sanjeevaiah Aravind , Jones Amy Little , Al Mutar Salwan , Kainthla Radhika , Huang Emina , Kazmi Syed Mohammad Ali
Published: January 2023

233

Background: The neutrophil-to-lymphocyte ratio (NLR) has been shown to correlate with overall and disease-free survival in patients with colorectal cancer. The data about prognostic value of the NLR in patients undergoing liver resection for colorectal liver metastases (CRLM) is limited. We aimed to describe the relationship between the NLR, overall survival and disease progression in patients who underwent liver resection for CRLM in a safety-net hospital. Methods: We identified patients who underwent liver resection with curative intent for metastatic colorectal cancer at a large safety net hospital between 2008 and 2020. All patients had a complete blood count with differential available within three months prior to resection. We compared patients who had a pre-operative NLR ≤3 with those who had a NLR > 3, a cut-off based on ROC analysis. We used the Chi-squared statistic and t-test to compare the frequencies of categorical variables and the means of continuous variables, respectively. Multivariate survival analyses were performed using the Cox-regression model after adjusting for sex, age at liver resection, race/ethnicity, body mass index, insurance status, initial presentation of colorectal cancer (emergency room vs outpatient), primary malignancy (colon vs. rectal), temporality of CRLM (synchronous vs metachronous presentation with primary), staged vs simultaneous removal of primary mass and CRLM, number and size of liver CRLM, other metastatic sites at the time of liver resection, carcinoembryonic antigen (at initial diagnosis, before and after resection), and receipt of at least six months of peri-liver resection chemotherapy. Results: We identified 76 patients who underwent liver resection with curative intent for CRLM with a median follow up of 40.7 months. The population had a mean age of 56.2 (SD 9.9), was 50% female, and predominantly non-White (73.7%). Compared with patients who had a NLR ≤3 (N = 50), patients with a NLR > 3 (N = 26) were more likely to be white (46.2% vs 16.0%) and have rectal cancer (61.5% vs 28.0%). In unadjusted analysis, patients with NLR > 3 had 1.87 times (95% CI 1.01-3.47) increased risk of mortality, compared with patients who had an NLR ≤3. In adjusted analysis, patients with NLR > 3 had 6.88 times (95% CI 1.61-29.42), increased risk of mortality, compared with patients who had an NLR ≤ 3. There was no significant difference in risk of CRLM recurrence or overall disease progression among patients with NLR ≤3 vs patients with NLR > 3. Conclusions: An elevated pre-operative NLR > 3 is a potential predictor of overall survival among patients undergoing liver resection for metastatic colorectal cancer. This widely available test may aid clinicians in pre-operative risk stratification.
Effect of CXCL1 on the NF-κB/P300 signaling pathway and colon cancer progression.
Authors: Zhuo Changhua , Ruan Qiang , Zhao Xiangqian , Shen Yangkun , Lin Ruirong
Published: January 2023

236

Background: The upregulated expression of CXCL1 has been validated in colorectal cancer patients. As a potential biotherapeutic target for colorectal cancer, the mechanism by which CXCL1 affects the development of colorectal cancer is not clear. Methods: Expression data of CXCL1 in colorectal cancer were obtained from the GEO database and verified using the GEPIA database and the TIMER 2.0 database. Knockout and overexpression of CXCL1 in colorectal cancer cells by CRISPR/Cas and "Sleeping Beauty" transposon-mediated gene editing techniques. Cell biological function was demonstrated by CCK-8, transwell chamber and Colony formation assay. RT-qPCR and Western Blot assays measured RNA and protein expression. Protein localization and expression were measured by immunohistochemistry and immunofluorescence. Results: Bioinformatics analysis showed significant overexpression of CXCL1 in the colorectal cancer tissues compared to normal human tissues, and identified CXCL1 as a potential therapeutic target for colorectal cancer. We demonstrate that CXCL1 promotes the proliferation and migration of colon cancer cells and has a facilitative effect on tumor angiogenesis. Furthermore, CXCL1 elevation promoted the migration of M2-tumor associated macrophages (TAMs) while disrupting the aggregation of CD4+ and CD8+ T cells at tumor sites. Mechanistic studies suggested that CXCL1 activates the NF-κB pathway. In the in vivo colon cancer transplantation tumor model, treatment with the P300 inhibitor C646 significantly inhibited the growth of CXCL1-overexpressing colon cancer. Conclusions: CXCL1 promotes colon cancer development through activation of NF-κB/P300, and that CXCL1-based therapy is a potential novel strategy to prevent colon cancer development.