bluuebunny/crossref_metadata_2025 huggingface dataset:
PD-1 blockade alone for mismatch repair deficient (dMMR) locally advanced rectal cancer.
Authors: Lumish Melissa Amy , Cohen Jenna L. , Stadler Zsofia Kinga , Weiss Jill A , Lamendola-Essel Michelle F. , Yaeger Rona , Segal Neil Howard , El Dika Imane H. , Saltz Leonard B. , Shcherba Marina , Sugarman Ryan , Desai Avni Mukund , Smith Jesse Joshua , Widmar Maria , Pappou Emmanouil , Paty Philip , Garcia-Aguilar Julio , Weiser Martin R. , Diaz Luis A. , Cercek Andrea
Published: January 2022

16

Background: Total neoadjuvant therapy with induction chemotherapy and chemoradiation (chemoRT) is the standard treatment for locally advanced rectal adenocarcinomas. Mismatch repair deficient (dMMR) rectal tumors respond poorly to neoadjuvant chemotherapy. PD-1 blockade is effective in patients with metastatic dMMR colorectal cancers, but its efficacy has not been established in the neoadjuvant setting. The purpose of this study is to evaluate the clinical benefit of neoadjuvant PD-1 blockade in dMMR locally advanced rectal cancer. Methods: We designed a prospective, single-arm, phase II study in which patients with stage II and III dMMR rectal cancer receive neoadjuvant dostarlimab (anti-PD-1) for a total of 6 months. The co-primary objectives are to determine the overall response rate (ORR) and pathologic complete response (pCR) or clinical complete response rate (cCR) with or without chemoRT. Tumor assessment with endoscopic evaluation is performed at baseline, 6 weeks, 3 months and 6 months; imaging is performed at pretreatment baseline, 3 months and 6 months. Patients with cCR by previously established criteria are eligible for non-operative management without chemoRT. Those with residual disease after neoadjuvant dostarlimab receive standard chemoRT. Following chemoRT, any patient failing to achieve a cCR is then managed surgically. Results: A total of 13 patients have been enrolled, with median age 52 years (range 26-78), 77% female, and 92% with node-positive disease by rectal MRI. The ORR is 100% in the 12 patients who have undergone at least a 3-month evaluation. Seven patients have completed induction therapy and all 7 (100%) have achieved a cCR and are undergoing observation without chemoRT or surgery. The rate of progressive disease thus far is 0%. No patients have required chemoRT or surgery. There have been no serious adverse events. Conclusions: Single agent neoadjuvant PD-1 blockade with dostarlimab is effective and well-tolerated in locally advanced dMMR rectal adenocarcinoma and allows patients to avoid chemoradiation and surgery. This suggests a potential new paradigm for treatment of dMMR locally advanced rectal cancer. Follow up and further patient accrual is ongoing. Clinical trial information: NCT04165772.
Racial disparities in colon cancer management in the National Cancer Database.
Authors: Greenberg Anya , Brand Nathan R , Chiou Sy Han , Rhoads Kim , Adam Mohamed , Sarin Ankit
Published: January 2022

18

Background: Racial and ethnic minorities in the US are at increased risk of developing and dying from colorectal cancer. Reasons for these disparities are multifactorial, among which are delayed presentation and initial disease management. We aimed to identify groups at highest risk to help address these disparities. Methods: Using the 2010-2017 National Cancer Database (NCDB), we analyzed clinical tumor stage at presentation and pathologic stage for adult patients (age≥18) diagnosed with primary colon cancer. We also examined trends in upstaging, downstaging, and delays >42 days between presentation and surgical intervention. We compared these outcomes by race/ethnicity using multivariable logistic or median regression, with select demographics, facility factors, and treatment details as covariates. Results: Fifty-one percent of patients with known clinical tumor stage (122,452/239,939) were diagnosed with stage III/IV at presentation, and 41% of those with known pathologic stage (123,009/298,716) had stage III/IV disease. In multivariable analysis, Black (OR 1.18, p<0.01) and Southeast Asian (OR 1.12, p=0.02) patients were significantly more likely than White patients to present with clinical stage III/IV. Black (OR 1.08, p<0.01), Hispanic (OR 1.07, p<0.01), East Asian (OR 1.28, p<0.01), and Southeast Asian (OR 1.40, p<0.01) patients were significantly more likely than White patients to have pathologic stage III/IV. Both clinical and pathological stage were available for 96,959 patients. Among those with clinical stage 0/I/II, Hispanic (OR 1.08, p=0.04), East Asian (OR 1.38, p<0.01) and Southeast Asian (OR 1.27, p=0.01) patients had significantly higher odds than White patients of being upstaged to pathologic stage III/IV. Among those with clinical stage III/IV, Black patients (OR 0.85, p=0.02) had significantly lower odds than White patients of being downstaged to pathologic stage 0/I/II. Black (OR 1.42, p<0.01), Hispanic (OR 1.33, p<0.01) and Southeast Asian (OR 1.23, p=0.05) patients had higher odds than White patients of waiting >42 days between presentation and surgery. Conclusions: Upstaging of colon cancer between diagnosis and surgery is disproportionately experienced by non-white patients. Surgical delays may partly explain this finding. Targeted interventions to avoid surgical delays as well as further research on the reasons (e.g., differences in tumor characteristics) for upstaging are needed to address this disparity.[Table: see text]
Incomplete preoperative staging results in suboptimal treatment in rectal cancer patients: A population-based study.
Authors: Patel Sunil , McClintock Chad , Merchant Shaila , Booth Christopher M. , Caycedo Marulanda Antonio , Bankhead Carl , Heneghan Carl
Published: January 2022

20

Background: Individuals with rectal cancer require a number of pre-treatment investigations to determine the local-regional and overall stage of disease. Stage of rectal cancer determines treatment plan; therefore incomplete or inadequate staging may result in sub-optimal care and outcomes. Methods: This is a population based study of all individuals undergoing surgical resection for rectal cancer in Ontario, Canada (population 14.6 million) between 2010 and 2019. Individuals were identified using the Ontario Cancer Registry which includes approximately 95% of all incident cases of rectal cancer in the province. “Complete Staging” in Rectal Cancer has previously been defined and includes assessments of distant metastasis, local-regional stage and an attempt at colonic assessment for synchronous lesions. Patient and care provider characteristics, staging investigations, stage of disease, treatments and long-term outcomes were determined using linked administrative databases. Results: The study cohort included 10,957 individuals with rectal cancer; 24% Stage I, 21% Stage II, 40% Stage III, 7% Stage IV, 8% Missing Stage. The average age was 65 (STD 12.6) and males accounted for 63% of the study population. Incomplete staging occurred in 26%, with incomplete local regional staging being the most common deficiency (21%). Increasing patient age (< 0.001), low volume surgeons (P < 0.001) and low volume hospitals (P < 0.001) were associated with incomplete staging. There was significant regional variation in the completeness of staging (low 68% - High 84%). In those with locally advanced rectal cancer (Stage II and Stage III), incomplete staging was associated with lower rates of preoperative radiation oncology assessments (27% vs. 80%, P < 0.001) and medical oncology assessments (12% vs. 39%, P < 0.001). In addition, incomplete staging was associated with lower rates of any radiation (pre or postoperative) (45% vs. 82%, P < 0.001), lower rates of preoperative neoadjuvant therapy (22% vs. 74%, P < 0.001) and higher rates of post operative radiation (23% vs. 8.3%, P < 0.001). Those with incomplete staging had a lower 5 year overall survival (73% vs. 81%, P < 0.001). Conclusions: In this study, we identified several modifiable risk factors for incomplete staging prior to treatment for rectal cancer. Incomplete staging likely results in suboptimal care in this population, as demonstrated by less oncology referrals and less use of appropriate neoadjuvant therapy.
Quality of life among colorectal cancer (CRC) survivors participating in a pilot trial of a web-based dietary intervention with text messages.
Authors: Wang Lufan , Kenfield Stacey , Langlais Crystal , Van Loon Katherine , Laffan Angela , Atreya Chloe Evelyn , Chan June M. , Zhang Li , Miaskowski Christine , Fukuoka Yoshimi , Meyerhardt Jeffrey A. , Venook Alan P. , Van Blarigan Erin
Published: January 2022

42

Background: Diet may be associated with survival and health-related quality of life (HRQOL) among CRC survivors. Behavioral interventions using web and mobile technology are feasible and acceptable approaches to modify dietary behavior. Little is known about the effect of web-based dietary interventions on HRQOL among CRC survivors. Methods: The Survivor Choices for Eating and Drinking study (SUCCEED) was a pilot randomized wait-list controlled trial designed to determine the feasibility and acceptability of a 12-week (wk) web-based dietary intervention with daily text messages. In this secondary analysis, we estimated the effect of the intervention on HRQOL. Between 2017-2018, 50 CRC survivors were randomized (1:1) to intervention or control. Participants in the intervention arm received the intervention in wk 1-12 and were followed from wks 12-24. Participants assigned to the control arm for 1-12 wks had the option to receive the intervention in wks 13-24. In both arms, HRQOL and sleep quality were assessed using the EORTC QLQ–C30 and CR29 and the Pittsburgh Sleep Quality Index at 0, 12, and 24 wks. Within- and between-group mean changes in HRQOL from enrollment to 12 and 24 wks were evaluated using independent t-test and paired t-test. Results: Follow-up was 88% complete at 12 and 24 wks in the intervention arm and 92% and 80% complete at 12 and 24 wks in controls. Participants mean age was 56 ± 9 y; 34% were men, 70% identified as non-Latinx White, 12% identified as Latinx, and 70% had stage III cancer. Between 0 and 12 wks, an increase in emotional functioning was observed in the intervention arm [mean change: 9.1; 95% confidence interval (CI): 2.2,16.0], while a decrease in emotional functioning was observed in controls (mean change: -5.1; 95%CI: -14.5,4.1; between-group mean difference: 14.3; 95%CI: 3.0,25.6). Between 0 and 24 wks, an increase in social functioning (mean change in intervention: 12.1; 95%CI: 2.1,22.1; between-group mean difference: 13.8; 95%CI: 2.1,25.5) and a decrease in fatigue (mean change in intervention: -9.1; 95%CI: -17.1,-1.1; between-group mean difference: -4.1; 95% CI: -15.8,7.6) was observed in the intervention arm. No other measures of HRQOL or sleep quality differed within or between arms. Conclusions: A web-based dietary intervention with daily text messages may improve emotional and social functioning among CRC survivors. Further study to evaluate the effect of web-based interventions on HRQOL among CRC survivors in larger studies may be merited. Clinical trial information: NCT02965521.
Survival outcome and treatment response of patients with young-onset locally advanced rectal cancer (YO-LARC) receiving total neoadjuvant therapy (TNT).
Authors: McKenna Edward , Oxencis Carolyn , Parish Marie , Eastwood Daniel , Miller James , Shreenivas Aditya V. , Kamgar Mandana , George Ben , Hall William A. , Erickson Beth , Ludwig Kirk A. , Szabo Aniko , Thomas James P. , Chakrabarti Sakti
Published: January 2022

44

Background: Despite an alarming rise in incidence, data on survival outcome and treatment response of young-onset (age < 50 years) locally advanced rectal cancer (YO-LARC) patients receiving total neoadjuvant therapy (TNT) are sparse. We retrospectively compared the outcome between YO-LARC and later-onset (aged 50 years or older) LARC (LO-LARC) patients treated with TNT. Methods: After the institutional review board approval, electronic medical records of the LARC (T3/T4 or node-positive) patients treated with TNT at a tertiary care cancer center between January 1, 2015, and June 30, 2020, were reviewed for data collection. TNT consisted of systemic chemotherapy with oxaliplatin-based regimens for 16 weeks followed by long-course radiation with concurrent capecitabine or 5-fluorouracil (CRT). Patients receiving only preoperative CRT were excluded. Most patients underwent surgical resection following the TNT. Non-operative management was offered to patients if TNT resulted in clinical complete response (cCR). The following comparisons between the YO-LARC and the LO-LARC patients were performed: patient characteristics, pathological complete response (pCR) rate, combined pCR + cCR rate, disease-free survival (DFS), and overall survival (OS). Results: Of 72 patients included in the analysis, 44(61%) were male, 49 (68%) were Caucasian, and 62 (86%) had clinical stage III disease. The study included 26 (36%) patients with YO-LARC (median age, 43 years) and 46 (64%) patients with LO-LARC (median age, 64 years). The comparison of patient characteristics that included gender, clinical stage, baseline carcinoembryonic antigen level, the distance of the tumor from the anal verge, presence of high-risk features, and histologic grade did not differ significantly between the groups. There were no statistically significant differences in pCR and combined pCR+cCR rates (p = 0.16) between the groups: YO-LARC, 12 % (3/26) and 15 % (4/26), respectively; LO-LARC, 22% (10/46) and 30% (14/46), respectively. Either group did not reach median DFS and OS after a median follow-up of 38 months for survivors. The estimated 5-year OS rates in patients with YO-LARC and LO-LARC were 86 % (95% confidence interval [CI], 69% to 100%) and 84% (95% CI, 68% to 100%), respectively (p = 0.92). The estimated 3-year DFS rates in patients with YO-LARC and LO-LARC were 67 % (95% CI, 50% to 89%) and 83% (95% CI, 72% to 95%), respectively (p = 0.19). Conclusions: The current retrospective analysis did not demonstrate significant differences in the pCR rates, combined pCR +cCR rates, DFS, or OS between the YO-LARC and LO-LARC patients treated with TNT.
Age-related trends in the incidence of metastatic colorectal cancer over the last 10 years: A retrospective analysis in commercially-insured population in the United States.
Authors: Vassilev Zdravko , Guo Helen , Lin Wenlong , Xu Julie , Khan Nasreen
Published: January 2022

46

Background: Previous studies have suggested age-related shifts in the incidence of metastatic colorectal cancer (mCRC). However, more contemporary data is needed to further understand the continuous changes in the distribution of mCRC and patient characteristics across different age groups. Methods: A retrospective observational study was conducted using the Optum Clinformatics database to estimate the incidence rates (IRs) and temporal trends of newly diagnosed mCRC during 2010-2019, stratified by age categories (18-49; 50-64; and 65+). IRs were calculated as the actual patient number of newly diagnosed mCRC divided by the overall enrollment number. The IRs were standardized to the 2010 US population and trends over time were characterized using annual percentage changes (APCs). Results: Total of 23,970 newly diagnosed patients with mCRC were identified during 2010-2019. Median age was 71 years, 65% of patients were white, and 68% of patients had commercial Medicare insurance. Most patients (69%) were 65 years of age or older at the time of mCRC diagnosis. Patients characteristics were similar across age groups, except for race and geographic region. The proportion of Hispanic (12.6%) and Asian (4.7%) mCRC patients was higher in the younger 18-49 group than in the 50-64 (respectively 9.4% and 3%) and 65+ groups (respectively 9.5% and 2.9%). Higher proportions in the 18-49 (44.4%) and 50-64 (47.5%) groups than in the 65+ group (37.6%) were from the South, while higher proportions in the 65+ group were from the West and Northeast (24.4% and 14%). Standardized IRs of mCRC decreased by 22% from 64.4 in 2010 to 50.5 per 100,000 in 2019 among patients 65+, with an APC of -2,11. Standardized IRs increased over the same period by 15% in the 50-64 group, APC = 2.33 and by 22% in the 18-49 age group, APC = 2.8. Conclusions: Temporal changes in mCRC incidence in a large commercially insured population during 2010-2019, showed an increasing trend in younger patients and a decreasing trend in patients 65+. The highest increase in IRs from 2010 to 2019 occurred in the 18-49 age group. Hispanic and Asian patients were more present among the 18-49 than among the older patient groups, and there were geographic differences among the age groups. The changes in age- distribution and evolving patient characteristics need to be considered in the delivery of treatments and care for mCRC.
Clinical utility of microsatellite instability (MSI-H) identified on liquid biopsy in advanced gastrointestinal cancers (aGI).
Authors: Kasi Pashtoon Murtaza , Klempner Samuel J , Starr Jason S. , Shergill Ardaman , Bucheit Leslie A. , Weipert Caroline , Liao Jiemin , Zhao Jing , Hardin Aaron , Zhang Nicole , Lang Kathryn
Published: January 2022

56

Background: Identification of MSI-H is clinically meaningful in patients with aGI given the associated approval of multiple immune checkpoint inhibitors. MSI-H has long been assessed via tissue analysis; and insights from plasma-based approaches are limited to small validation studies. We sought to assess prevalence of initial and acquired MSI-H status across aGI and report real-world outcomes of colorectal (CRC) patients who received ICI after MSI-H identification by a commercially available liquid biopsy (LBx) assay. Methods: Genomic results from a well-validated LBx assay (Guardant360) completed as part of usual clinical care between 10/1/2018-9/7/2021 in patients with aGI were queried to assess MSI-H prevalence and identify cases of potential acquired MSI-H. Real-world evidence (RWE) was sourced from the GuardantINFORM database comprised of aggregated payer claims and de-identified records from 11/1/2018-3/31/2021. Patients with plasma-identified MSI-H who started new therapy < 60 days after assay report date were sorted into treatment groups: chemotherapy +/- biologic therapy (“chemo”) or immunotherapy via pembrolizumab or nivolumab (“ICI”). Real-world time to discontinuation (rwTTD) and real-world time to next treatment (rwTTNT) were assessed as proxies for progression free survival. Log-rank tests were used to assess differences in rwTTD, rwTTNT and overall survival. Results: Prevalence of MSI-H was ̃2% across aGI (Table). Five cases were observed to have potential acquired MSI not attributable to tumor shed identified on serial LBx tests. Of 222 MSI-H CRC patients eligible for RWE analysis, 89(40%) started new therapy within 60 days of results: 42(48%) received ICI, 39(44%) received chemo, 8(9%) received other/mixed regimens. Patients who received ICI had significantly longer rwTTD and rwTTNT compared to patients who received chemo [median months to discontinuation = 7.5 (95% CI 3.4-12.3) vs. 2 (95% 1.4-3.3) p<0.001; median months to next treatment = 23.8 (95% 10.6-NA) vs. 4.5 (95% CI 2.9-NA) p=0.006]; no overall survival difference was observed (p=0.559). Conclusions: This LBx assay detected MSI-H at similar frequencies to published tissue cohorts and may identify acquired MSI-H following early lines of therapy. Patients who received ICI following LBx identification of MSI-H achieved responses in line with published data in previously treated aGI. Well-validated LBx is a viable tool to identify initial and acquired MSI-H in aGI and may expand the number of patients who could benefit from ICI therapy, particularly in cases where access to tissue specimens is not feasible. [Table: see text]
Colorectal cancer screening results in the regions of Kazakhstan with different levels of cancer prevalence.
Authors: Kaidarova Dilyara , Jumanov Abay , Zhylkaidarova Alma , Shayakhmetova Dinara
Published: January 2022

62

Background: In Kazakhstan colorectal cancer (CRC) occupies the third position in the structure of total oncological incidence and mortality. Kazakhstan is a country with a large territory, with different geographical, industrial characteristics and dietary habits of the population. So CRC prevalence levels vary from region to region: in 2013 the highest regional incidence rate is 6 times higher than the lowest. CRC population screening among men and women aged 50-70 years was started in 2011 in Kazakhstan. Methods: Within 10 years of the screening, 9 532 927 men and women were examined, 3419 CRC cases were detected. Coverage of target population ranged from 78.4% in 2012 to 53.1% in 2020. The analysis of screening indicators was carried out: cancer detection rate, the proportion of 0-1 stages, the ratio to the underlying incidence, the relationship with the dynamics of CRC incidence and mortality. According to the incidence rate in 2011-2020 regions of the country are conditionally divided into three groups: group A – high level (31.04-23.5 per 100 thousand population), group B – medium level (20.5-15.0%ooo), C - low level (11.6- 8.1%ooo). Results: The average annual CRC detection rate for 10 years of screening was 0.4% (4 cancer cases per 1000 examined), in groups A - 0.5%, B - 0.4% and C - 0.3%. The detection ratio of stage 0-I was 0.08%: in groups A - 0.10%, B - 0.09% and C - 0.05%. The average annual incidence rates were in groups A - 27.2 per 100 thousand population, B - 18.7%ooo and C - 9.8%ooo. During time of g-FOBT applying (2011-2013), the average annual incidence rates in the groups were in groups: A - 25.8%ooo, B - 16.4%ooo, C - 8.2%ooo. During time of using FIT (i-FOBT, 2014-2020), the average annual incidence rates increased to 27.0%ooo, 20.0%ooo and 9.9%ooo respectively. The greatest increase in the incidence was noted in groups B and C (22.7% and 22.2%), the smallest in group A (4.7%). Screening increased the CRC incidence from 15.5%ooo in 2011 to 16.5%ooo in 2020 and reduced mortality from 9.3%ooo (2011) to 8.0%ooo (2020). Conclusions: Screening increased the incidence (6.5%) and decreased the mortality from CRC (14%) for 10 years in Kazakhstan. There is a particularly significant effect of screening on the growth of some indicators (incidence and mortality rates, cancer detection rate and early cancer detection) in regions with a low CRC prevalence.
Adjuvant oxaliplatin and fall-related injury in patients with colorectal cancer.
Authors: Sue-Chue-Lam Colin , Brezden Christine , Sutradhar Rinku , Yu Amy YX , Baxter Nancy N.
Published: January 2022

78

Background: Adjuvant oxaliplatin improves colorectal cancer (CRC) survival but causes dose-dependent peripheral neuropathy, possibly increasing the risk of fall-related injuries (FRI) such as fractures. In this retrospective cohort study, we examined the impact of adjuvant oxaliplatin cycles on FRIs. Methods: All data were ascertained from linked health administrative and population databases. We included Ontarians aged 18-85 years at CRC diagnosis between January 1 2007 to December 31 2018 who underwent curative resection and received adjuvant oxaliplatin. We excluded those with a prior cancer diagnosis within 5 years, prior CRC diagnosis ever, non-adenocarcinoma histology, prior oxaliplatin, and <2 years of Ontario health insurance prior to CRC diagnosis. Oxaliplatin dose was determined in the 382 days after resection and dichotomized (1-6 vs. 7-12 cycles). The outcome was FRI, defined by ICD10 codes W00-W19 for any injury caused by a fall requiring emergency or inpatient care. Follow-up began at the end of the treatment window and terminated at the first of FRI, death, loss of Ontario health insurance, or March 31 2020. To account for differences between groups, clinical and demographic characteristics at diagnosis (Table) were used to estimate propensity scores for treatment and calculate inverse probability of treatment weights. These weights were applied to a Fine & Gray regression model to determine the subdistribution hazard ratio (sHR) estimating the association between FRI and 1-6 versus 7-12 cycles of oxaliplatin, with death as a competing risk. Standardized differences <0.1 indicated negligible imbalance. An interaction term tested for effect modification by age at diagnosis. Results: 9,324 patients were included in the study; 1,870 received 1-6 cycles and 7,454 received 7-12 cycles of oxaliplatin. Those exposed to 1-6 cycles were older (61.0 vs. 59.1 years), had higher comorbidity scores (13.5 vs 12.3), and more often had rectal cancer (27.5 vs. 22.2%). Negligible imbalance remained after weighting. Median follow-up was 50.2 months. Total follow-up was 44,472 person-years. There were 1,223 FRIs and 1,913 deaths. The sHR for FRIs comparing 7-12 cycles against 1-6 cycles of oxaliplatin was 0.98 (95% CI 0.85-1.14). The interaction p-value for age and oxaliplatin dose was 0.24. Conclusions: In this population-based retrospective cohort study of 9,324 patients with CRC, the risk of FRIs was similar for 7-12 cycles compared with 1-6 cycles of adjuvant oxaliplatin. This finding was consistent across age at diagnosis. Future research should examine the relationship between oxaliplatin dose and falls not resulting in injury. [Table: see text]
Survival outcomes associated with chemotherapy-induced neutropenia in the adjuvant treatment of colorectal cancer with FOLFOX.
Authors: Trincao-Batra Sara , Goodwin Rachel Anne , Marginean Horia , Maroun Jean Alfred , Vickers Michael M. , Asmis Timothy R. , Gotfrit Joanna
Published: January 2022

81

Background: Patients undergoing adjuvant treatment with FOLFOX for colorectal cancer (CRC) are at risk of developing chemotherapy-induced neutropenia (CIN). We assessed survival outcomes in patients who develop CIN in this setting. Methods: We performed a retrospective chart review of patients with CRC treated with FOLFOX at our institution in Canada from 2013 to 2015. The survival follow-up cut-off date was August 2021. Demographic, treatment, and outcome data were collected. CIN was defined as ANC <1.5, and all episodes of neutropenia were assumed to be the result of chemotherapy. Median OS was calculated using Kaplan-Meier product limit estimates. Results: A total of 302 patients were included (baseline demographics in the table). Median follow-up was 110 months. In the overall cohort, 174 patients (58%) had at least one episode of CIN. CIN occurred in 56% of those with stage II cancer, 43% of those with low risk stage III cancer (T1-3 and N1), and 45% of those with high risk stage III cancer (T4 or N2). Median time to first CIN event was 4.3 months. Among patients with at least one episode of CIN, the first CIN event occurred during the first 3 months of treatment in 110 (63%). Among patients with at least one episode of CIN, 79 (45%) received subsequent granulocyte colony-stimulating factor (GCSF). The median OS in the overall cohort was 171 months. For patients with and without CIN the median OS had not been reached, HR 0.84 (95% CI 0.55-1.29, p=0.43). The median OS for patients with CIN treated with and without GCSF had not been reached, HR 1.02 (95% CI 0.57-1.82, p=0.94). The 5-year survival rate for patients with and without CIN was 87% vs 77%. The 10-year survival rate for patients with and without CIN was 70% vs 64%. A trend toward improved survival in those with CIN remained when results were analyzed by cancer stage. Conclusions: Patients with CIN had a trend toward improved survival compared to those who did not have CIN. There was no indication that GCSF in the setting of CIN impacted survival. The causes for the potentially protective effect of CIN in the setting of adjuvant CRC treatment require further elucidation.[Table: see text]
Anti-HER2 therapy with pyrotinib and trastuzumab in refractory HER2-positive metastatic colorectal cancer: A preliminary report from HER2-FUSCC-G study.
Authors: Li Wenhua , Chang Jinjia , Xu Midie , Zhu Xiaodong
Published: January 2022

97

Background: Dual-targeted HER2 therapy has led to a promising antitumor effect in HER2 positive metastatic colorectal cancer. The current study was aimed to evaluate the therapeutic efficacy of pyrotinib and trastuzumab in patients with HER2 positive colorectal cancer. Methods: HER2-FUSCC-G is an ongoing, open-label, non-randomised, phase 2a study. Patients in this subset were diagnosed as HER2 positive metastatic colorectal cancer refractory to standard chemotherapies. All the enrolled patients were treated with a loading dose of trastuzumab at 8 mg/kg followed by 6mg/kg once every three weeks, and oral pyrotinib at 400 mg per day until progression. ORR was set as the primary endpoint. Estimates of PFS (progression free survival) and OS (overall survival) were obtained with the Kaplan-Meier method and compared with log-rank test. Results: Between January 2020 to June 2021, 11 patients were enrolled in this study. The ORR was 45.5% in whole population, and 55.6% in RAS wild-type patients. At a median follow-up of 17.73 months, median PFS and OS were 7.80 and 14.97 months, respectively. The KRAS wild-type group of patients had prolonged survival (PFS: 9.97 vs. 7.73 months, P = 0.19; OS: 20.67 vs. 12.43 months, P = 0.021) compared with KRAS mutant group. Nine of 11 (81.8%) patients reported≥1 grade treatment-emergent adverse events (TATEs), while 4 (36.4%) patients reported grade 3/4 TATEs. Conclusions: The combination of trastuzumab and pyrotinib showed a promising anti-tumor response and prolonged long-term survival benefit in RAS wild-type and HER2 positive mCRC with acceptable tolerance. Clinical trial information: NCT04960943.
Open-label phase 1/2 study evaluating the tolerability and antitumor activity of selinexor and pembrolizumab in colorectal cancer.
Authors: Golan Talia , Shentzer Kutiel Talia , Gottfried Maya , Zer Alona , Zick Aviad , Shai Ayelet , Ryvo Larissa , Dudnik Julia , Peled Nir , Oberkovitz Galia , Yang Fan , Sharoni Shmuel , Meng Changting , Michel Dayana , Sbar Eric , Shah Jatin J. , Kauffman Michael , Shacham Sharon , Geva Ravit
Published: January 2022

110

Background: Single agent selinexor, an oral selective inhibitor of nuclear export (SINE), showed activity against heavily pretreated CRC with RAS mutations (mut) or wildtype (wt) in 2 clinical studies. In preclinical studies, selinexor showed superior potency in KRAS mut over wt with improved activity in combination with PD-1/PD-L1 blockade. A phase 1b study (NCT02419495) showed the safety and antitumor activity of combined selinexor and a PD-1/PD-L1 inhibitor. This phase 1/2 open-label study is evaluating selinexor with pembrolizumab in patients with microsatellite instability (MSI)-stable CRC. Methods: The study enrolled patients with advanced/metastatic CRC who progressed after prior chemotherapy (1-3 lines for RAS wt, 1-2 for RAS mut) and are ineligible for anti-PD-1/PD-L1 therapy. Patients received weekly oral selinexor 80 mg and pembrolizumab 200 mg IV every 3 weeks. Antitumor activity, safety and tolerability were assessed. Results: Thirty-four patients, median age 57.5 years, male 59%, RAS mut 53%, median prior lines 2, are enrolled. At data cutoff (1-SEP-21) median treatment duration was 57 days (range: 1-246) and 25 patients were evaluable for response. Best response was stable disease in 8/13 patients with RAS mut CRC (62%) and in 3/12 patients with RAS wt CRC (25%). Median overall survival (months) has not been reached for the overall population (95% CI: 6.3, NE), for RAS mut (95% CI: 7.6, NE), and for the RAS wt (95% CI: 6.1, NE). Median progression-free survival is 3.0 and 1.4 months for patients with CRC with RAS mut and wt, respectively (p=0.04; HR: 0.43 [959% CI: 0.18, 1.01]). Thirty patients (88%) discontinued therapy, mostly due to progressive disease (44%). The most common treatment-emergent adverse events (TEAEs) (total; Grade ≥3) were nausea (77%; 3%), vomiting (41%; 0%), fatigue (41%; 12%), decreased appetite (35%; 0%), diarrhea (32%; 0%). Nine patients (26%) had serious treatment-emergent adverse events. Conclusions: Combined selinexor with pembrolizumab demonstrated higher disease control rates and prolonged overall survival in patients with chemotherapy-refractory advanced/metastatic CRC with RAS mut vs RAS wt tumors. These patients would not have been eligible for anti-PD-1 mAb therapy because their tumors were not MSI-high, suggesting that the combination may be active in RAS mut CRC. Therapy was well tolerated with no unanticipated adverse events. Further investigation of this combined treatment is warranted, particularly in patients with CRC with RAS mut. Clinical trial information: NCT04256707.
Colonic endoscopic submucosal dissection using a novel robotic system.
Authors: Kim Sang Hyun , Choi Hyuk Soon , Lee Jae Min , Kim Eun Sun , Keum Bora , Jeen Yoon Tae , Lee Hong Sik , Chun Hoon Jai , Im Junghyun , Hong Daehie , Kim Byung Gon ,   Korea University College of Medicine
Published: January 2022

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Background: Appropriate tissue tension and clear visibility of the dissection area using traction are essential for effective and safe endoscopic submucosal dissection (ESD). We developed a robotic assistive traction device for colonoscopy.This is a preclinical animal study to evaluate the performance of colorectal ESD using novel robotic system. Methods: Experienced endoscopist performed ESD on ex vivo porcine colon ten times using a robot and ten times by the conventional method. The outcome measures were operating time (from starting incision to finishing dissection), completeness of resection, procedure-related adverse events, and limitations of arm manipulation in a narrow working space as assessed by counting the frequency of blind cutting.We also conducted an in vivo feasibility study on live pig. Results: Total of twenty colonic lesions were resected from ex vivo porcine colon. The submucosal dissection speed was significantly faster in robotic ESD than in conventional ESD (P = 0.002). Adverse events such as perforation were also significantly higher in the conventional group. In the in vivo feasibility study, robot was attached to the colonoscope and inserted into the proximal colon. ESD was performed successfully. Conclusions: When the robot was assisting in the ESD procedure, the dissection speed improved significantly. Our robotic device can thus provide simple, effective, and safe multidirectional traction during colonic ESD.
Frequency, molecular characteristics, and therapeutic targeting of ROS1 oncogenic fusions in colorectal cancer.
Authors: Hussung Saskia , Akhoundova Dilara , Sivakumar Smruthy , Kahraman Abdullah , Zoche Martin , Rechsteiner Markus , Angst Florian , Britschgi Christian , Töpfer Antonia , Moch Holger , Weber Achim , Sokol Ethan , Fritsch Ralph M
Published: January 2022

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Background: c-Ros oncogene 1, receptor tyrosine kinase ( ROS1) rearrangements have been reported in colorectal cancer (CRC), but little is known about the molecular and clinical features of ROS1-driven CRC and the response to ROS1-targeted treatment in CRC patients. Methods: We report disease course and treatment response of an index patient with chemotherapy-refractory right-sided metastatic CRC, harboring an activating ROS1 fusion ( GOPC-ROS1). Moreover, we examined 40,589 patients with CRC who underwent comprehensive genomic profiling as part of routine clinical care at Foundation Medicine (Cambridge, MA); all classes of alterations in at least 324 genes were assessed, including ROS1. Results: The index patient experienced a rapid and sustained partial response to molecularly targeted treatment with crizotinib. After 15 months on crizotinib, disseminated tumor progression occurred, with KRAS Q61H emerging in tumor tissue (53.7% variant allele frequency (VAF)) and liquid biopsy (13.5% VAF). Within the clinical cohort, ROS1 genomic rearrangements ( ROS1 RE (+)) were identified in 34 out of 40,589 (0.08%) CRC samples. GOPC-ROS1 was the most commonly identified ROS1 fusion (11/34 samples), followed by TTC28-ROS1 (3/34 samples). All ROS1-alterations were found in microsatellite-stable (MSS) CRCs, and ROS1 genomic alterations were significantly enriched in KRAS wild type tumors ( KRAS mutations in 23.5% of ROS1 RE(+) vs. 49.8% of ROS1 RE(-), p=0.003). Conclusions: ROS1 rearrangements represent rare but clinically actionable molecular driver alterations in MSS CRCs. The detection of ROS1 fusion oncogenes in CRC can pose diagnostic challenges since intrachromosomal ROS1 fusions including GOPC-ROS1 and non-canonical ROS1 fusions such as TTC28-ROS1 can remain negative on fluorescence in situ hybridization and immunohistochemistry assays, respectively. NGS-based comprehensive molecular profiling may be a useful tool to screen for rare fusion oncogenes.
Mismatch repair proteins (MMR) expression as predictive factor in locally advanced rectal cancer.
Authors: Pretta Andrea , Donisi Clelia , Persano Mara , Pinna Giovanna , Cimbro Erika , Parrino Alissa , Aimola Valentina , Spanu Dario , Cerrone Giulia , Deidda Simona , Deidda Maria Assunta , Lai Eleonora , Pusceddu Valeria , Puzzoni Marco , Ziranu Pina , Barbara Raffaele , Restivo Angelo , Zorcolo Luigi , Faa Gavino , Scartozzi Mario
Published: January 2022

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Background: Only few data on microsatellite instability in rectal cancer are available in literature, and dMMR role in pre-operative chemoradiotherapy response is under debate. The aim of our study was to evaluate the frequency and therapeutic implications of dMMR status in patients (pts) with locally advanced rectal cancer belonging to our Center. Methods: Data were retrospectively collected from 231 patients belonging to the Medical Oncology Unit of the University Hospital of Cagliari from 2011 to 2021. All patients were affected by locally advanced rectal adenocarcinoma (cT3-4 +/- N1-2). All patients included in the study underwent neoadjuvant chemoradiotherapy treatment with capecitabine and RT long course (total dose of Gy 50.4) and subsequently underwent total mesorectal excision (TME) followed by adjuvant chemotherapy. Mismatch repair (MMR) expression was evaluated through immunohistochemistry on surgical samples. Results: Of the 231 patients, 213 were suitable for final analyzes. Patients median age was 68 years (range 34-89). 145/201 were male and 68 were female. 66 (31%) had stage II disease and 147 (69%) had stage III disease. Considering MMR, 205/213 (96%) patients had proficient mismatch repair (pMMR), while 8/213 (4%) had dMMR. In dMMR patients defective proteins were: MSH2 in 4 patients, MLH1 and PMS2 combined in 2 patients and MSH6 in 2 patient. dMMR patients showed, unlike pMMR patients, poor or no response to chemoradiotherapy. Responses were assessed through TRG evaluation (Ryan and Dworak scoring systems) on the primary tumour. 5 patients presented a TRG-3 and 3 patients showed a TRG-4, according to Ryan score. All of them had a grade 1 regression, according to Dworak. Conclusions: The results of our study, albeit with limitations related to the retrospective nature and the limited number of dMMR cases, might indicate a correlation between microsatellite instability and little or no response to preoperative chemo-radiotherapy. It would be useful to analyze the data prospectively and further evaluate MMR as a predictor of response to combined chemo-radiotherapy.[Table: see text]
High immunoscore as a predictor of outcome in patients who underwent chemoimmuno-therapy in locally advanced rectal cancer: A post-hoc analysis of the correlation between immunoscore and pCR in the Averectal study.
Authors: Shamseddine Ali , Khalifeh Ibrahim Moustafa , Elias Charbel , Turfa Rim , Kattan Joseph Gergi , Mukherji Deborah , Temraz Sally Naji , Alqasem Kholoud , Amarin Rula , Alawabdeh Tala , Deeba Samer , Mohamad Issa , Daoud Faiez , Al Masri Mahmoud , Dabous Ali , Hushki Ahmad , Jaber Omar , Charafeddine Maya , Farhat Lama , Tawil Ayman
Published: January 2022

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Background: The immunoscore (IS), a prognostic score, was first validated in early colon cancer reflecting the immune response against the tumor. It showed potential in its ability to downstage patients with pathologic complete response (pCR) who would potentially benefit from organ-sparing therapies in locally advanced rectal cancer (LARC). We first presented our initial outcome with 37.8% pCR in patients with LARC treated with short course radiation therapy (SCRT) followed by 6 cycles of mFOLFOX plus Avelumab followed by total mesorectal excision (TME) in the ESMO 23rd World Congress on Gastrointestinal Cancer 2021 Conference (presentation # SO-30). Here we are reporting the post-hoc analysis of the correlation between pCR and pre-treatment biopsy IS to further establish the IS as a prognostic score in patients with LARC. Methods: In this Phase II study, 44 patients were accrued from three centers, of whom 40 completed radiotherapy followed by chemoimmunotherapy then TME. 39 patients with available tissue samples, containing tumor cells and its margins, were collected at baseline. CD3 and CD8 cells were counted, and the IS is then derived from the mean density percentiles of CD3 and CD8 positive T cells infiltrating the tumor and in the invasive margin of the tumor. Cutoff for a high IS was established at 62%. We then compared the tumor regression grade (TRG) with the means of IS, using the student t-test. Results: 15 patients with pCR had a mean IS of 68 +/- 22 SD as opposed to a mean IS of 52 +/- 22 SD in 24 patients without pCR (p = 0.036). Conclusions: High IS correlates with TRG as pCR and successfully predicted clinical outcome in LARC patients who underwent chemoimmuno-therapy. It is a promising potential prognostic tool in stratifying patients who would benefit from specific modalities to augment pCR and subsequent organ preservation strategy. Clinical trial information: NCT03503630.
Real-world immunotherapy biomarker testing patterns and results for patients with advanced gastroesophageal cancers in the United States.
Authors: Mehta Rutika , Liepa Astra M. , Zheng Shen , Chatterjee Anindya
Published: January 2022

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Background: With the advent of immunotherapy as an option for gastric, gastroesophageal junction (GEJ), or esophageal cancer, guidelines recommend testing for mismatch repair (MMR) or microsatellite instability (MSI) and programmed death-ligand 1 (PD-L1) at time of advanced cancer diagnosis. However, little real-world information is available on testing patterns and results for MMR/MSI and PD-L1. Methods: This study used the nationwide Flatiron Health electronic health record-derived de-identified database. Starting with a subset of 1594 patients (pts) from the Advanced Gastric/ Esophageal Cancer database who had initiated first-line (1L) treatment 01Jan2017-31Aug2020 and for whom additional abstraction for details on MMR/MSI and PD-L1 testing was conducted, adult pts with ≥3 months (mos) of follow-up were selected. 1L initiation was index date. For each biomarker, pts were classified as tested vs not. Pt and disease characteristics and test results were summarized. Testing relative to line of therapy and PD-1 inhibitor use were evaluated (data will be presented later). Results: Of 1142 eligible pts, 88% were initially diagnosed with advanced disease and 92% treated in community practice. 582 (51%) were tested for MMR/MSI and 571 (50%) for PD-L1; 451 pts were tested for both. MMR/MSI testing rates were 59% for gastric, 51% for GEJ, and 46% for esophageal. PD-L1 testing rates were similar across primary tumor sites (48-54%), but lower in those with squamous histology (38% for esophageal/GEJ). For both, testing increased over time with ̃40% in 2017 and 60% in 2020. For both, median number of tests per pt was 1 (range 1-6 for MMR/MSI, 1-4 for PD-L1). For both, mean time from initial diagnosis to first test was approximately 4 mos (> 5 mos in pts in 2017 and < 2 mos for those in 2020). Majority (> 68%) of all tests used tissue from primary tumor site. 46% of all MMR/MSI tests were performed with immunohistochemistry and 43% with next-generation sequencing; 5% were dMMR/MSI-H. 71% of all PD-L1 tests were performed using the commercial 22C3 assay. Reported composite positive score (CPS) results are summarized below. Conclusions: Rates of MMR/MSI and PD-L1 biomarker testing are increasing and time relative to initial diagnosis is shortening. A high proportion of pts tested positive for PD-L1 with CPS > 1. PD-L1 CPS varies by primary tumor site, histology, and tissue collection site. In the new era of 1L immunotherapy, increased rates of testing and reduced time to testing are likely to make more meaningful impact on treatment decisions.[Table: see text]
Beyond median overall survival: Estimating multiple survival scenarios in patients with metastatic esophagogastric cancer.
Authors: Pape Marieke , Kuijper Steven , Vissers Pauline A.J. , Creemers Geert-Jan , Van Laarhoven Hanneke W.M. , Verhoeven Rob
Published: January 2022

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Background: Recent clinical trials of novel systemic therapies showed improved survival of patients with metastatic esophageal cancer (EC) and gastric cancer (GC). Survival improvements observed in clinical trials might be unrepresentative for the total population as the percentage of patients whom participate in clinical trials is limited and more than half of all patients receive best supportive care (BSC). The aim of our study is to assess the best-case, typical and worst-case survival scenarios in patients with metastatic esophagogastric cancer. Methods: We selected patients with metastatic EC (including junction) or GC diagnosed in 2006-2019 from the Netherlands Cancer Registry. Survival scenarios were calculated based on percentiles of the survival curve stratified by tumor location and treatment (tumor-directed therapy or BSC). Survival scenarios were calculated for the 10th (best-case), 25th (upper-typical), 75th (lower-typical) and 90th (worst-case) percentiles. Linear trend analysis was performed to test if changes in survival over the diagnosis years were significant. Results: We identified 12739 patients with EC and 6833 patients with GC. Percentage of patients receiving tumor-directed therapy increased from 34% to 47% and 30% to 45% for patients with EC and GC, respectively. The median survival remained unchanged for patients with EC (5.0 months) and improved slightly for patients with GC (3.1 to 3.7 months; P=0.006). For patients with EC survival of the best-case scenario improved (17.4 to 22.8 months; P=0.001), whereas the other scenarios remained unchanged: upper-typical 11.2 to 11.7 (P=0.11), lower-typical 2.1 to 2.0 (P=0.10) and worst-case 0.9 to 0.8 months (P=0.22). For patients with GC survival improved for the best-case (13.1 to 19.5; P=0.005) and upper-typical scenario (6.7 to 10.6 months; P=0.002), whereas the lower-typical (1.2 to 1.4 months; P=0.87) and worst-case (0.6 to 0.6 months; P=0.60) remained unchanged. For patients with EC receiving tumor-directed therapy survival in all scenarios remained unchanged while for patients receiving BSC survival decreased: best-case 11.8 to 9.8 (P=0.005), upper-typical 6.0 to 5.0 (P=0.002), lower-typical 1.4 to 1.0 (P=0.003) and worst-case 0.7 to 0.5 months (P=0.03). For patients with GC receiving tumor-directed therapy survival improved for all scenarios: best-case 19.8 to 30.4 (P=0.005), upper-typical 6.4 to 10.3 (P=0.002), lower-typical 3.6 to 5.4 (P<0.001) and worst-case 1.4 to 2.6 months (P<0.001), and for patients receiving BSC survival for all scenarios remained unchanged. Conclusions: The proportion of patients with EC and GC receiving tumor-directed therapy increased over time. Despite the fact that survival improvements were not observed across all scenarios, at least an increase in survival was observed in certain subgroups of patients.