bluuebunny/crossref_metadata_2025 huggingface dataset:
Meta-analysis of phase II/III randomized controlled trials (RCTs) to determine the incidence of hypertension and proteinuria in patients with gastrointestinal (GI) cancers treated with fruquintinib.
Authors: Srinivasmurthy Ramaditya , Aboaid Hazem , Nguyen Kevin , Jones Daniel Thomas , Nanda Rishi Kumar , Ta Jason , Thein Kyaw Zin
Published: January 2025

119

Background:
Fruquintinib is a selective inhibitor of vascular endothelial growth factor receptors which impedes angiogenesis associated with tumor growth. On November 8th, 2023, the US FDA approved fruquintinib for use as a third-line treatment for metastatic colorectal cancer (mCRC). With the introduction of novel cancer therapies, monitoring for adverse events is critical. This meta-analysis aims to assess the risk of hypertension (HTN) and proteinuria in patients with GI cancers treated with fruquintinib.
Methods:
We conducted a comprehensive search of MEDLINE, EMBASE, and COCHRANE databases from inception through August 12th, 2024, identifying Phase II/III RCTs that employed fruquintinib in GI cancers and reported HTN and proteinuria as adverse effects. The Mantel-Haenszel method was used to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). Heterogeneity was assessed using Cochran’s Q-statistic, and a random effects model was applied.
Results:
Our analysis included 1872 patients, 1131 (60%) of whom received fruquintinib, from three Phase III RCTs (FRESCO, FRESCO-2, FRUTIGA) and one Phase II RCT. FRESCO, FRESCO-2, and the phase II trials compared fruquintinib to placebo in patients with mCRC. FRUTIGA trial involved patients with gastric or gastroesophageal junction adenocarcinoma, comparing fruquintinib + paclitaxel to placebo + paclitaxel. The incidence of any-grade HTN was higher in the fruquintinib group, 34.92% vs 7.55% (RR 3.96; 95% CI: 3.05-5.13; P<0.00001); the rate of high-grade HTN was 13.96% vs 1.21% (RR 9.01; 95% CI: 4.67-17.40; P<0.00001). In the mCRC subgroup, incidence of any-grade and high-grade HTN was 43.02% vs 10.45% (RR 3.97; 95% CI: 2.95-5.33; P<0.00001), and 17.28% vs. 1.27% (RR 12.06; 95% CI: 5.19-28.01; P<0.00001), respectively. Incidence of any-grade proteinuria was also found to be statistically significant and higher in the fruquintinib arm in both GI cancer cohort and mCRC subgroup: 27.3% vs 16.19% (RR 1.89; 95% CI: 1.30-2.74; P=0.0008), and 25.22% vs 11.73% (RR 2.29; 95% CI: 1.17-4.51; P=0.02). The rate of high-grade proteinuria was not statistically significant in both cohorts. In GI cancer group, 1.85% vs 0.53% (RR, 2.49; 95% CI: 0.86-7.16; P=0.09), and mCRC subgroup 2.17% vs 0.51% (RR, 2.87; 95% CI: 0.74-11.12; P=0.13).
Conclusions:
This meta-analysis revealed a higher incidence of any-grade and high-grade HTN with fruquintinib in GI cancer patients, with significant association in the mCRC subgroup. Fruquintinib was also noted to be associated with increased risk of any-grade proteinuria, however, incidence of high-grade proteinuria was not different in patients treated with fruquintinib compared to placebo. Prompt identification and early management of these adverse events are crucial.
Phase Ib/II study of fruquintinib plus 5-fluorouracil/leucovorin after progression on fruquintinib monotherapy in metastatic colorectal cancer.
Authors: Yang Wenwei , Liu Xiu , Wang Qi , Gao Lizhen , Ou Kai , Ma Xiaoting , Yang Lin
Published: January 2025

128

Background:
Fruquintinib is a standard third-line treatment in metastatic colorectal cancer (mCRC). However, no standard therapeutic regimen is available for mCRC patients who progressed on third-line therapy. Preclinical experiments supported a rationale for combining antiangiogenic therapy and 5-fluorouracil (5FU) in refractory mCRC with evidence for synergy. This open-label phase Ib/II study was designed to determine the safety and efficacy of fruquintinib plus 5-fluorouracil/leucovorin for mCRC patients who progressed on fruquintinib monotherapy.
Methods:
The enrolled patients would receive fruquintinib at a fixed dose of 4mg once daily (three weeks on, one week off) and 5FU at two dose levels (1800mg/m
2
and 2400mg/m
2
) CIV 46 hours on day one and day 15, with leucovorin 400mg/m
2
iv 2 hours before 5FU. Treatments were repeated every 28 days. The primary endpoint was determining the recommended phase II dose (R2PD) of 5FU in phase Ib and the six-month OS rate in phase II. Secondary endpoints for phase II included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and safety. Planned enrollment was 39 patients.
Results:
No dose-limiting toxicities occurred in the phase Ib dose-escalation study, and the R2PD of 5FU was 2400mg/m
2
. Between April 2020 and June 2024, 24 patients were enrolled in the phase II stage. The median age was 57.5 years old (from 35 to 68), and 58.33% were female. Left-sided colorectal cancer patients accounted for 75%. Sixteen (66.7%) patients harbored KRAS mutation, and one (4%) had BRAF V600E mutation. Regarding the number of lines of systemic therapy, 83.3% received this study regimen as fourth-line therapy and 16.7% as fifth-line or later therapy. As of June 30, 2024, efficacy was assessed in all 24 patients with a DCR of 62.5% (15 stable disease, nine progression disease). The median follow-up time was 16.5 months (95% CI:12.553-20.447). The primary endpoint six-month OS rate was 91.3%, the median PFS was 4.4 months (95% CI: 1.243-7.557), and the median OS was 17.3 months (95% CI: 12.892-21.708). The most common TRAEs were nausea (25%), hand-foot syndrome (16.7%), abnormal liver function (8.3%), and proteinuria (8.3%). One patient experienced grade 3 mucositis. No treatment-related death occurred.
Conclusions:
Fruquintinib plus 5-fluorouracil/leucovorin regimen preliminarily demonstrated promising efficacy with a tolerable safety profile for mCRC patients despite progression on prior fruquintinib monotherapy. Further investigation into this possible later-line regimen in mCRC is warranted.
Clinical trial information: ChiCTR2000032640
.
Pattern and predictors of D3 lymph node station positivity in patients undergoing curative surgery for adenocarcinoma of colon.
Authors: Mohan Anjaly , Muralee Madhu , Nair Chandramohan Krishnana , Wagh Mira
Published: January 2025

137

Background:
The prognosis and surgical management of colon cancer is intricately related to its lymphatic drainage. The oncological outcome of apical node positivity has been evaluated in different studies with varying results. There is no published regional data on the rate of apical node positivity in colon cancer. An insight into the probability of apical node metastases and the risk factors for the same may help us in prognosticating colon cancer patients better.
Methods:
This was a prospective observational study conducted at the Regional Cancer Centre Thiruvananthapuram from September 2022 to June 2024. Our primary objective was to determine the prevalence of apical lymph node positivity in patients undergoing surgery for colon cancer with D3 lymphadenectomy. The secondary objectives were to find out the factors associated with the risk of apical node metastasis, the incidence of skip metastases to apical nodes, the adequacy of lymph node harvest and the postoperative complications. Patients undergoing primary surgery for adenocarcinoma of the colon were included. Patients with metastatic disease, synchronous colon or rectal cancers, past history of colonic surgery were excluded. All patients underwent D3 lymphadenectomy along with colectomy depending upon the tumour location. Lymphatic tissue corresponding to the D3 station was retrieved and sent separately after grossing the fresh specimen on the side table in the operating room.
Results:
A total of 139 patients were included in the study. Fifty two (37.4%) patients had stage III disease, 38.9% had stage II disease and the rest had stage I colon cancer. The mean nodal harvest was 17.86 and mean apical node harvest was 2.04. Node harvest was adequate in 89.21% patients. The apical node positivity rate was 7.19% (10 patients). Skip metastasis to the apical nodes was found in 2 patients. Lymphovascular invasion, number of positive lymph nodes and young age (≤45 years) had a significant correlation with apical node positivity on multivariate analysis. Clavien Dindo grade 3 and above complications were seen in 5.03%.
Conclusions:
Our study showed an apical node positivity rate of 7.19%, with a skip metastasis rate of 1.4%. This is the first Indian data on apical node positivity rate in colon cancer and its predictors. The prognostic value of apical nodes and the occurrence of skip metastasis to the apical nodes are compelling reasons to advocate D3 dissection, even with relatively low prevalence of apical node positivity.
Neoadjuvant chemoradiotherapy with ipilimumab and nivolumab in rectal cancer (CHINOREC): A prospective randomized, open-label, multicenter, phase II clinical trial.
Authors: Laengle Johannes , Kuehrer Irene , Kulu Askin , Kabiljo Julijan , Ammon Daphni , Zirnbauer Rebecca , Stift Anton , Herbst Friedrich , Dauser Bernhard , Monschein Matthias , Razek Peter , Biebl Matthias , Geinitz Hans , Hulla Wolfgang , Muellauer Leonhard , Widder Joachim , Bittermann Clemens , Laengle Friedrich , Schmid Rainer , Bergmann Michael M ,   On behalf of the CHINOREC Study Group
Published: January 2025

139

Background:
Immune checkpoint inhibitors (ICIs) seem only effective in a primed tumor immune microenvironment (TIME). Neoadjuvant radiotherapy (RT) has been shown to induce an immunogenic cell death (ICD) and thereby restores the susceptibility to ICI. This study evaluates the safety of neoadjuvant chemoradiotherapy (CRT) with concomitant ipilimumab (IPI) and nivolumab (NIVO) in curative rectal cancer (RC) patients.
Methods:
The CHINOREC study (ClinicalTrials.gov identifier NCT04124601) is a prospective, randomized (ratio 50:30), open-label, multicenter, phase II investigator-initiated trial (IIT). Patients with RC received neoadjuvant CRT (50 Gy in 2 Gy fractions with concurrent capecitabine 1650 mg/m
2
/d) alone or in combination with IPI (1 mg/kg IV at day 7), following 3 cycles of NIVO (3 mg/kg IV Q2W, starting on day 14). Surgical resection was performed 10-12 weeks post CRT. The primary endpoint was surgical safety and feasibility (Clavien-Dindo Classification) of neoadjuvant CRT with sequential IPI and NIVO following surgical resection. Secondary outcome was complete response rate (clinical and pathological).
Results:
Between June 2020 and November 2023, 145 patients were screened and 80 randomly assigned to CRT (n=30) or CRT+IPI/NIVO (n=50). The primary endpoint (any surgical complication) did not differ between the 2 groups (78% vs. 77%). The reoperation rate (≥Grade IIIb) was comparable low in both groups (8% vs. 7%). No new safety signals were identified. The rate of major pathological response (MPR) and complete response (CR) was also comparable high in both arms (38% vs. 37% and 30% vs. 22%, respectively).
Conclusions:
Neoadjuvant IPI/NIVO can be safely applied concomitant with CRT in patients with RC, as it does not increase the rate of reoperation or surgical complications. The validity of the encouraging CR rate needs to be elucidated over time. Further translational analyses will elucidate mechanistic insight regarding improved fraction, dosing and timing of CRT and ICI.
Clinical trial information: NCT04124601
.
Phase I/II study of cabozantinib alone or in combination with panitumumab in patients with
MET
-amplified metastatic colorectal cancer.
Authors: Mishima Saori , Kawazoe Akihito , Ohta Takashi , Esaki Taito , Kato Takeshi , Shinozaki Eiji , Taniguchi Hiroya , Komatsu Yoshito , Fuse Nozomu , Wakabayashi Masashi , Takakusa Maiko , Matsuda Seiko , Tamura Hitomi , Nomura Shogo , Sato Akihiro , Fujii Satoshi , Nakamura Yoshiaki , Yoshino Takayuki
Published: January 2025

146

Background:
Despite the introduction of anti-EGFR therapies, resistance remains a significant challenge in metastatic colorectal cancer (mCRC). MET amplification is a recognized resistance mechanism. Cabozantinib, a multi-kinase inhibitor targeting MET, has shown promise in overcoming resistance to anti-EGFR therapy. This study aimed to evaluate the efficacy and safety of cabozantinib alone (Cabo) or in combination with panitumumab (Cabo+Pmab) in patients with MET-amplified mCRC. Patients and
Methods:
The study population included patients with RAS and BRAF wild-type mCRC who had progressed on anti-EGFR therapy and subsequently confirmed MET amplification by circulating tumor DNA. The phase I part aimed to establish the recommended cabozantinib dose in combination with panitumumab by assessing dose-limiting toxicity (DLT) within the first four weeks. The primary endpoint of phase II part was objective response rate (ORR) in patients receiving the study treatment as third-line therapy or later. In phase II part, patients were randomized to Cabo or Cabo+Pmab group. Based on a threshold ORR of 1.6% response rate and an expected efficacy of 30%, the planned sample size was 14 patients with one-sided alpha of 1.25% and power of 80% in each arm, Cabo and Cabo+Pmab. A tumor response of at least 3 out of 14 patients would warrant further investigation of these treatments.
Results:
A total of 35 patients were enrolled (6 in phase I and 29 in phase II, 28 for the primary analysis; 13 in Cabo and 15 in Cabo+Pmab). In phase I, no DLTs were observed. This allowed researchers to set the maximum tolerated dose and recommend a dosage of 60 mg/day of cabozantinib in combination with panitumumab for phase II. Of 28 pts for the primary analysis, ORR was 7.7% (1/13; 95%CI 0.2-36%) in Cabo group and 0% (0/15; 95%CI 0-21.8%) in Cabo+Pmab group, median progression-free survival was 3.1 months in both groups, and cumulative proportion of pts with grade ≥3 treatment-related adverse events was 38.5% (including hypertension [23.1%]) in Cabo and 60% (including hypomagnesaemia [20%]) in Cabo+Pmab group.
Conclusions:
The combination of cabozantinib 60 mg plus panitumumab had manageable safety profile. However, this treatment did not demonstrate significant clinical benefit in patients with MET-amplified mCRC. Further investigation is warranted to explore alternative therapeutic strategies for this patient population.
Clinical trial information: jRCT1080224637
.
Immunotherapy outcomes in dMMR/MSI-H and/or TMB-H metastatic colorectal cancer (CRC) with peritoneal metastases (PM).
Authors: Mosalem Osama M , Elhariri Ahmed , Wiest Nathaniel Edward , Kamatham Saivaishnavi , Abdel-Razeq Nayef Hikmat , Jones Jeremy Clifton , Sonbol Mohamad B. , Jin Zhaohui , Babiker Hani M. , Bekaii-Saab Tanios S. , Majeed Umair , Starr Jason S.
Published: January 2025

163

Background:
CRC with PM has a poor prognosis and limited treatment options. Immunotherapy has shown promise in improving outcomes for patients with microsatellite instability-high (MSI-H), mismatch repair-deficient (dMMR), and high tumor mutational burden (TMB-H) tumors. However the peritoneal niche has a unique microenvironment, which can influence the effectiveness of immune check point inhibitors (ICIs). We assessed the impact of ICI on progression-free survival (PFS) and overall survival (OS) in CRC patients (pts) and PM, considering key clinical and molecular characteristics.
Methods:
A retrospective review aiming to identify CRC pts with MSI-H/dMMR and PM treated with immunotherapy between 2015 and 2023 was performed. Data collected included pt demographics, tumor characteristics, and treatment details. Responses were evaluated using RECIST v1.1 criteria.
Results:
37 pts were included, 9 (24%) had Lynch syndrome. The median age of diagnosis was 61 years and most pts were females (65%). Most pts had MSI-H/dMMR tumors, while one pt was treated based on ultra-hypermutated phenotype (TMB 202) and POLE mutation. Among those with available TMB data, the median TMB was 52 mutations/Mb (0-202). Common mutations were
PMS2
(51%),
MLH1
(38%),
MSH6
(16.2%), and
MSH2
(16.2%). Right-sided tumors were in 54%, mucinous histology in 62%, and ascites in 54%. Pts received a median of 11 cycles of ICI (2-52). Pembrolizumab was the most frequently used ICI (78%), while Nivolumab was used either alone (11%) or in combination with Ipilimumab (11%). Median PFS in our cohort was 7.8 months and median OS was 29.9 months. The disease control rate (DCR) was 81%, with an objective response rate (ORR) of 51.3% (9 complete responses, 12 partial responses). At the time of data collection, 30% of pts were off systemic therapy and 5-FU-based chemotherapy combined with a biologic agent was the most common subsequent treatment in 32% who had PD. Univariate analysis showed no significant differences in PFS or OS based on tumor sidedness, isolated PM, liver metastases, mucinous vs. non mucinous histology or
BRAF
/
RAS
status (WT vs mutant). Malignant ascites was associated with worse OS(HR 0.3; p= 0.03).
Conclusions:
Treatment with ICIs in pts with MSI-H/dMMR and/or TMB-H CRC and PM improved disease control in CRC pts with PM, however, as compared to historical controls for patients with MSI-H/d-MMR disease treated with ICI, this group showed less favorable outcomes. Malignant ascites was associated with poorer overall survival. Further research of the immune response and tumor microenvironment in the peritoneal cavity is warranted.
A phase Ib study of immunotherapy with ex-vivo pre-activated and expanded CBNK cells in combination with cetuximab, in patients with colorectal cancer (CRC) with minimal residual disease (MRD): Final report.
Authors: Morelli Maria Pia , Basar Rafet , Marin David , Huey Ryan W , Banerjee Pinaki Prosad , Willis Jason , Morris Van K. , Rafei Hind , Dasari Arvind , Kee Bryan K. , Zeller Brittany E , Diao Stacy , Menter David , Shpall Elizabeth J. , Kopetz Scott , Rezvani Katy
Published: January 2025

176

Background:
Colorectal cancer (CRC) is the second most common type of cancer. Even following successful curative treatment, patients often relapse, likely because of undetected micro-metastatic foci. Tumor-informed ctDNA testing has helped to identify those patients before they developed radiographic evidence of disease, introducing the concept of minimal residual disease (MRD) in solid tumors. No standard-of-care treatment options are available for MRD patients. Therefore, we have designed a phase IB trial of the combination of
in vitro
pre-activated and pre-expanded cord blood natural killer (pre-A+E CBNK) cells with cetuximab. We hypothesized that we could achieve CAR-like efficacy without genetic engineering, by pre-activating NK cells with inflammatory cytokines and by using antibodies to redirect NK cell specificity and antibody-dependent cellular cytotoxicity. The highly immunosuppressive CRC tumor microenvironment is understudied, and novel NK-cell therapy could be highly effective in MRD clearance.
Methods:
15 patients with CRC-MRD were enrolled in this trial and completed treatment. All the patients received immunodepleting treatment prior to an infusion of pre-A+E CBNK cells, up to a dose of 1x10^8/kg. Patients were monitored inpatient for 24 hours after treatment for infusion-related reaction, and were then seen for toxicity follow-up in the outpatient clinic twice/week for 4 weeks (DLT window). Samples for correlative analysis were collected at different times.
Results:
8/15 patients enrolled were female and 7 were male, age range 26-69. They all had no measurable radiographic evidence of disease and a positive ctDNA Signatera test at baseline. 11/15 were previously treated for metastatic disease; 13 patients had a history of metastases (including 7 liver, 2 lymph nodal, 2 peritoneal). All of them received 5-FU-based chemotherapy. 7/15 were RAS/RAF WT, 4/10 were KRAS mut, 1/10 had BRAF mutation, 1/10 had HER2 amplification. They were all pMMR. No DLT was observed, only 1 patient had G2 CRS requiring tocilizumab. 9/15 patients treated so far had ctDNA clearance at some point. One patient had negative ctDNA at 3 and 6 months, 4/15 were negative at d28 and 7/15 at d14. 4/15 patients have not met the 90-day time point yet. 10/12 patients analyzed up to the primary endpoint had decreased ctDNA over baseline CBNK cells in blood peaked 3 hours post-infusion and persisted at 3 days. Phenotype analysis of CBNK pre-post, donor NK and other immune cells is ongoing.
Conclusions:
Cetuximab in combination with pre-A+E CBNK is safe and showed promising results for the treatment of MRD-CRC.
Clinical trial information: NCT050468
.
Effect of homologous recombination deficiency on survival in patients with metastatic colorectal cancer with KRAS mutations.
Authors: Kim Minsoo , Lee Jiwon , Kim Jwa Hoon , Choi Yoon Ji , Lee Soohyeon
Published: January 2025

252

Background:
Metastatic colorectal cancer (mCRC) patients exhibit intertumoral genetic heterogeneity, making it difficult to apply precision medicine. In the molecular genetic profile of mCRC, there are relatively few other gene alterations that significantly impact treatment decisions beyond KRAS and MSI status. We aim to investigate the prognostic impact of Homologous recombination deficiency (HRD)-related genetic alterations in mCRC patients, focusing on how mutation status influences on patient outcomes.
Methods:
The analysis included 364 mCRC patients who underwent comprehensive genomic profiling at Korea University Anam Hospital from Sep. 2016 to Dec. 2020. HRD was defined by the presence of pathogenic variants in genes including ATM, ATR, BARD1, BRCA1/2, BRIP1, CDK12, CHEK2, FANCA, MRE11A, PALB2, RAD50/51. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method. Multivariate Cox proportional hazards regression analyses were performed to assess the independent impact of HRD status.
Results:
Of the total cohort, 181 of patients (49.78%) harbored KRAS mutations. HRD gene mutations were identified in 38 of patients (10.4%) of patients, predominantly in ATM, BRCA 1/2, ARID1A genes. KRAS-HRD co-mutations were present in 18 of patients (4.7%). There is no significant difference in HRD status between the KRAS mutant and wild-type groups (p=0.73). While first-line treatment PFS was independent of KRAS mutational status (wt 10.8 vs. mut 9.6 months, p=0.31), it was significantly associated with HRD gene mutation status (16.2 vs. 10.6 months, p=0.001). OS was similar with KRAS mutations (34.7 vs. 32.9 months, p=0.72) and HRD mutations (34.7 vs. 39.1 months, p=0.73). However, patients with both KRAS and HRD mutations had significantly worse OS compared to those with either KRAS and HRD mutation (21.3 vs. 36.7 vs. 65.3 months, p=0.034, <0.001). A multivariate analysis was performed to evaluate factors affecting OS in mCRC patients. Among the variables, metastasectomy, which 44% of patients underwent, had a significantly low HR (=0.28) and would contributed to more favorable outcomes when evaluating OS. Neither KRAS nor HRD mutation alone was a significant prognostic factor, but their co-mutation was significantly associated with poor survival (HR=2.39, p=0.048).
Conclusions:
Poor OS in patients with KRAS-HRD co-mutations, despite metastasectomy, highlights the need for additional treatment strategies beyond surgery. Future studies with larger sample sizes and analyses stratified by metastasectomy status are necessary to strengthen these findings.

Variables
HR (95% CI)
p-value

Metastasis site

Liver
2.16 (1.60 – 2.92)
< 0.001

Peritoneum
1.52 (1.01 – 2.11)
0.013

Bone
1.69 (0.96 – 2.97)
0.067

Metastasectomy
0.28 (0.47 – 0.74)
< 0.001

KRAS
1.03 (0.77 – 1.37)
0.826

HRD
0.75 (0.40 – 1.41)
0.367

Co-mutation
2.39 (1.01 – 5.66)
0.048
Prognostic factors for thermo-ablation of liver metastases in colon cancer: A Maltese perspective.
Authors: Buhagiar Malcolm , Sapiano Angeline , Darmanin Amanda , Caruana David Karl , Cortis Kelvin , Cannataci Christine
Published: January 2025

267

Background:
Malta is a small Mediterranean archipelago with an annual colon cancer incidence of 300 patients per year and a cumulative 5-year overall survival of 58%. Despite major improvements in therapeutic strategies, colon cancer remains the third leading cause of cancer deaths locally with an annual mortality rate of circa 110 patients per year. Percutaneous thermal ablation of colorectal liver metastases involves exposure of metastatic deposits to temperature extremes using radiofrequency, microwave or cryotherapy. The role of this case series was to examine the prognostic value of clinico-pathological variables to provide insight into patient selection for ablative therapy.
Methods:
This retrospective analysis of 66 adult patients with colorectal liver oligometastatic disease who underwent thermal ablation between January 2014 and January 2022, reviews demographic and pathological criteria including tumour grade, presence of vascular invasion, mismatch repair and k-RAS & BRAF mutational status, CEA & Ca19.9 assay at time of treatment. Other parameters include metachronous versus synchronous disease, hepatic burden and concurrent chemotherapy. All these co-variables were analysed using the Cox Regression Hazard model to assess their impact on progression free- (PFS) and overall survival (OS).
Results:
For this patient cohort, the mean PFS and OS were 13.1 and 33.8 months. Our data indicates that most individuals experience progression within the first 10 months, with a gradual decline in PFS for the remaining individuals. A Ca19.9 level within normal limits (p=0.004, HR 0.157-0.700 95% CI) was related to an improved PFS but not OS. The presence of synchronous metastases (p=0.004, HR 0.168-0.715 95% CI) and ablation of one lesion (p=0.013 HR 0.191 (0.052-0.702 95 CI) were favourable prognostic markers for improved OS. k-RAS wt status was a prognostic adverse biomarker for PFS (p=0.002, HR 1.529, 6.686 95% CI). There was a paucity of data for BRAF and MMR status so these were excluded from the final analysis. No statistical survival benefit was noted for patients treated with chemotherapy, and other variables including gender, age, primary tumour sidedness, LVSI or CEA value.
Conclusions:
There are two surprising trends here- the paucity of survival benefit for the use of chemotherapy in conjunction with ablation and the worse outcome for k-ras wt tumours. We postulate that the absence of BRAF sub-stratification at the time of patient accrual, impacted statistical hazard. This case series suggests that the prognosis and survival of colorectal liver oligometastatic disease is multifactorial and complex, highlighting the need for further genomic and molecular insights.
Biological and therapeutic impact of tumor mutational burden in microsatellite instability/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICI).
Authors: Blanchet Deverly Sarah , Raffy Balthazar , Ratovomanana Toky , Nicolle Remy , Nay Paula , Andre Thierry , Duval Alex , Cohen Romain
Published: January 2025

272

Background:
Microsatellite instability (MSI) is linked to hypermutability and response to ICI(s), especially in colorectal cancer. The predictive impact of tumor mutational burden (TMB) in ICI-treated MSI/dMMR metastatic colorectal cancer remains controversial, with some studies suggesting low TMB as a potential biomarker of resistance to ICI(s). We aimed to investigate the biological relevance of TMB in MSI/dMMR mCRC and its impact on survival outcomes in ICI(s)-treated patients (pts).
Methods:
MSI/dMMR mCRC pts treated with ICI(s) from the NIPICOL trial (NCT03350126) and the immunoMSI prospective monocentric cohort with available data from whole exome sequencing (WES) and RNA-sequencing (RNA-seq) were included. All cases were centrally assessed for MSI and dMMR status. TMB was calculated as described (Dupain et al., BMC, 2024). The search for a cutpoint able to optimize the difference in survival between 2 groups of patients with low and high-TMB was applied. The main endpoint was progression free survival (PFS) by iRECIST criteria. The cohort (NIPICOL, immunoMSI) was included as a covariate in the analysis of differential gene expression and pathway enrichment, with various tumor mutational burden (TMB) thresholds evaluated, specifically 10 and 30 mutations per megabase (mut/Mb).
Results:
A total of 99 pts were analyzed, with 4 (4%) excluded after central MSI/dMMR status review. Of these, 52 received anti-PD1 plus anti-CTLA4 therapy, while 43 received anti-PD1 alone. Median follow-up was 25 months. Median TMB was 51.8 mut/Mb (IQR: 35.9-74.9). TMB was not predictive of patient PFS, whatever the TMB threshold applied, including cutpoints already reported in the literature, the 2-year PFS rates being 80% versus 80% for TMB ≤ 10 and > 10 mut/Mb, and 79% versus 82% for TMB ≤ 30 and > 30 mut/Mb, respectively. Multivariate analysis including treatment type confirmed no association between TMB and PFS (HR 1.00, 95% CI [0.97–1.04]). TMB levels were not linked with specific signalling pathways related to immune checkpoints or antigen presentation as evaluated by RNA-seq with Gene Set Enrichment Analysis (GSEA) at a TMB threshold of 10 or 30 mut/Mb. However pathways involved in cell proliferation (e.g., “cell cycle”, “DNA replication”) were increased in TMB high (adjusted p-value <0.05). RNA-seq signature quantification and deconvolution analysis revealed similar cell populations (e.g., fibroblasts, B cells, T cells) between high and low TMB groups at a TMB threshold of 10 and 30 mut/Mb.
Conclusions:
TMB has no survival impact for patients with ICI(s)-treated dMMR/MSI mCRC and does not discriminate two biologically distinct subpopulations. Other biomarkers should be developed for personalized medicine amongst these patients.
Development and validation of a deep learning–based pathomics signature for prognosis and chemotherapy benefits in colorectal cancer: A retrospective multicenter cohort study.
Authors: Lou Shenghan , Du Fenqi , Li Huiying , Huang Yanming , Yang Laishou , Li Gen , Song Wenjie , Xue Jingmin , Li Hao , Mo Genshen , Wang Hang , Wang Pai , Wang Zhuozhong , Han Peng
Published: January 2025

298

Background:
The current TNM staging system fails to provide adequate information for prognosis and adjuvant chemotherapy benefits in colorectal cancer (CRC). Pathomics, an emerging field, shows promise in improving prognosis estimation and decision-making. In this study, we developed and validated a pathomics signature (PS
CRC
) that directly analyzes hematoxylin and eosin–stained slides using deep learning to predict outcomes.
Methods:
A total of 883 whole slide images from two cohorts, Harbin Medical University Cancer Hospital and The Cancer Genome Atlas (TCGA), were retrospectively analyzed. An interpretable, multi-instance deep learning model was proposed to establish the PS
CRC
. Shapley additive explanations were employed to interpret the model's decisions, and gradient-weighted class activation mapping was applied to visualise the pathological phenotypes of the PS
CRC
. The transcriptomics data from TCGA cohort was used to explore the potential pathogenesis underlying the PS
CRC
.
Results:
The PS
CRC
was identified as an independent prognostic factor associated with both overall survival and disease-free survival. Incorporating the PS
CRC
into the TNM stage model resulted in a significant improvement in prognosis estimation, as evidenced by a notable increase in net reclassification improvement and integrated discrimination improvement. Moreover, among stage II and III CRC patients with low levels of PS
CRC
, satisfactory benefits from chemotherapy were observed. Notably, the main underlying features of PS
CRC
include tumor cell infiltration, adipocyte accumulation, fibrous tissue deposition, and stromal infiltration. Transcriptome analysis further support the relevance of PS
CRC
to tumor progression and immune suppression.
Conclusions:
Our finds highlight the significant potential of histopathology images-based deep learning in predicting prognosis and assess therapeutic response of CRC. The PS
CRC
could serve as an effective tool in clinical decision for CRC management, providing insights into the underlying pathogenic mechanisms. However, prospective studies are still necessary for further validation.
Differences in disease characteristics in young vs older adults with colorectal carcinoma.
Authors: Modi Shivani , Peshin Supriya , Moka Nagaishwarya , Gim Gahyun , Dharia Adit
Published: January 2025

34

Background:
Colorectal carcinoma (CRC) exhibits distinct disease characteristics between younger (≤50 years) and older (>50 years) adults, which may significantly influence treatment decisions and outcomes. This study aims to investigate differences in disease characteristics of colorectal carcinoma among patients aged ≤50 years compared to those aged >50 years, utilizing data from the Surveillance, Epidemiology, and End Results (SEER) database.
Methods:
A retrospective analysis was performed using the SEER database covering the years 2000 to 2020. A total of 150,000 diagnosed CRC cases were included. Key variables analyzed comprised stage at diagnosis, tumor grade, histological subtype, and 5-year survival rates. Rates of CRC diagnoses in various age brackets were calculated for three time periods: 2000-2010, 2010-2020, and overall from 2000-2020.
Results:
Within the total cohort, 12% (18,000 cases) were diagnosed in young adults, while 88% (132,000 cases) were in older adults. An analysis of age-specific rates showed: 2000-2010
:
Young adults (≤50 years) represented 10% of CRC cases, with 16% presenting at advanced stages (Stage III or IV). 2010-2020
:
This group increased to 12%, with 65% diagnosed at advanced stages (Stage III or IV), compared to 52% in older adults (p < 0.001). In terms of tumor characteristics, poorly differentiated tumors were more prevalent in young adults (28% vs. 18%, p < 0.001). The prevalence of microsatellite instability-high (MSI-H) tumors was significantly greater in young adults at 18%, compared to 12% in older adults (p < 0.05). The 5-year overall survival rate for young adults was 68%, notably higher than the 48% for older adults (p < 0.001).
Conclusions:
This study underscores significant differences in disease characteristics between young and older adults with colorectal carcinoma. Young patients are more likely to present with advanced disease but have better survival outcomes. These findings indicate the necessity for an age specific approach to screening and treatment strategies.

Differences in stage at diagnosis, tumor grade, presence of MSI-H, and survival outcomes between younger and older adults diagnosed with colorectal carcinoma.

Category
Young Adults (≤50 years)
Older Adults (>50 years)
p-value

Proportion of Total CRC Cases
12% (18,000 cases)
88% (132,000 cases)

Advanced Stage (Stage III or IV)
65% (2010-2020)
52% (2010-2020)
< 0.001

Poorly Differentiated Tumors
28%
18%
< 0.001

Microsatellite Instability-High (MSI-H)
18%
12%
< 0.05

5-Year Overall Survival Rate
68%
48%
< 0.001
Correlation between PD-L1 CPS and clinical outcomes in patients treated with first-line nivolumab plus chemotherapy for advanced gastric or gastroesophageal junction cancer: A multi-center retrospective study in Japan.
Authors: Onishi Misa , Ogura Nozomu , Inamoto Rin , Kito Yosuke , Nagashima Kengo , Takahashi Naoki , Furuta Mitsuhiro , Shoji Hirokazu , Machida Nozomu
Published: January 2025

364

Background:
The CheckMate 649 trial showed the superiority of first-line nivolumab plus chemotherapy (Nivo-CT) compared with chemotherapy alone for advanced gastric and gastroesophageal junction (GEJ) cancer with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) >5, while survival benefit was poor in PD-L1 CPS <1 and <5. However, there were few studies on correlation between PD-L1 CPS and efficacy of first-line Nivo-CT for advanced gastric or GEJ cancer in real world data.
Methods:
This multi-center retrospective study included patients with histologically confirmed advanced gastric or GEJ cancer who were started on first-line Nivo-CT between December 2021 and December 2023. PD-L1 CPS was assessed before the start of Nivo-CT by classified into three groups at each center: <1, 1~5 and >5, using the Dako PD-L1 immunohistochemistry 28-8 pharmDx assay. The efficacy was evaluated by overall survival (OS), progression-free survival (PFS) and objective response rate (ORR).
Results:
A total of 271 patients were included (median age, 70 [range 18–85] years; male/female, 64/36%; performance status (PS) 0/1/2, 47/49/4%; primary tumor site gastric/GEJ, 90/10%; status unresectable/recurrent, 81/19%; histology intestinal/diffuse, 30/70%). PD-L1 CPS status were evaluated 234 (86%) patients and PD-L1 CPS <1, 1~5 and >5 was found in 35 (15%), 76 (33%) and 123 (53%) patients, respectively. Median follow-up time was 11.3 (range 1-30) months. The median PFS was 9.7 (95%CI, 5.9-16.3), 8.8 (95%CI, 7.2-13.0) and 6.3 (95%CI, 5.3-9.0) months in the patient with PD-L1 CPS <1, 1~5 and >5, respectively. The median OS was 18.7 (95%CI, 17.4-NA), 23.4 (95%CI, 17.7-NA) and 18.3 (95%CI, 13.3-22.5) months, and the ORR were 30.8, 66.7 and 61.3% (p = 0.075) in the patient with PD-L1 CPS <1, 1~5 and >5, respectively. Liver metastases were found in 43 (35.0%) of the patients with PD-L1 CPS >5, significantly more than in the patients with PD-L1 CPS <5 (p < 0.001). Multivariate analysis indicated that PD-L1 CPS status was not associated with prognosis (PD-L1 CPS ≥5 vs. <1, HR 1.18 [95%CI, 0.75-1.86], p = 0.48). In the overall population, grade ≥3 adverse events were observed in 102 (37.6%) patients and grade ≥3 immune-related adverse events were observed in 26 (9.6%) patients.
Conclusions:
There were no significant differences in prognosis and response between PD-L1 CPS in first-line Nivo-CT for advanced gastric or GEJ cancer in real world data.
Envafolimab in combination with lenvatinib and albumin paclitaxel for previously treated advanced GEJ adenocarcinoma: Latest analysis of a phase II, two-cohort study.
Authors: Zhao Xiaoying , Guo Weijian , Zhu Xiaodong , Feng Wanjing , Huang Mingzhu , Geng Qirong , Zhang Zhe , Sheng Xuedan
Published: January 2025

375

Background:
The combination of first-line chemotherapy and PD-1 has emerged as a standard treatment, enhancing the efficacy in advanced gastric/gastroesophageal junction (GEJ) cancer. The efficacy of the combination of second-line chemotherapy and PD-1/PD-L1 remains unclear. This study aims to observe the efficacy of Envafolimab (PD-L1 inhibitor ) plus tyrosine kinase inhibitors (TKIs) and second-line chemotherapy in the treatment of patients (pts) with advanced GEJ adenocarcinoma.
Methods:
Eligible pts with HER2-negative, microsatellite stable (MSS), advanced GEJ adenocarcinoma were enrolled in this study. Pts who never received PD-1 or PD-L1 inhibitors before would assign into Group A. Pts in Group B have failed first-line PD-1 antibody combined chemotherapy, with optimal efficacy as or above stable disease (SD). Pts in both groups received Envafolimab (200mg, hypodermic injection, days 1, 15, Q4W) combined with Lenvatinib (8mg/12mg, po, once a day) and albumin paclitaxel (100mg/m2, IV, days 1, 8 and 15, Q4W, up to 6 cycles) until disease progression, unacceptable toxicity, or pts refusal to continue treatment. The primary endpoint was objective response rate(ORR) per iRECISTv1.1, and the secondary endpoints included disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety.
Results:
From Oct 2022 to Apr 2024, 32 pts were enrolled. Both groups enrolled 16 pts equally, and 15 pts of each group were evaluable for efficacy analysis. The average ages were 60.07 ± 11.73 y and 50.13 ± 12.18 y in group A and B respectively. In group A, 7 pts had been tested for PD-L1 status, of which 2 (13.3%) was positive and 5 (33.3%) were negative. PD-L1 status was negative in 5(33.3%) pts, positive in 9 (60.0%), and untested in 1(6.7%) in group B. As of Sep 14, 2024, The ORR was 60.0% (9/15) in group A and 46.7% (7/15) in group B. The DCR was 100.0% (15/15) in both groups. After a median follow-up of 17.0 mo (IQR: 8.0-18.8) in group A, the mPFS was 8.2 mo (95% CI = 6.1-10.4), and the mOS was 14.8 mo(95% CI = 7.4-22.2). With median follow-up of 9.0 mo (IQR: 6.1-16.2) in group B, the mPFS was 5.9 mo (95% CI= 3.8-8.1) and the mOS was 11.5 mo (95% CI = 3.1-19.9). Overall incidences of adverse events (AEs) of any grade was 100% (30/30), and 80.0% (24/30) pts had ≥ grade 3 AEs during treatment. Most treatment-related adverse events (TRAEs) of grade ≥3 included decreased neutrophil count (73.3%), decreased leukocyte count (63.33%), Anemia (10%), febrile neutropenia (6.67%).
Conclusions:
In pts of advanced gastric cancer who have previously received PD-1 inhibitors or not, this second-line combination therapy demonstrates promising preliminary effects. Pts who have not previously received ICIs might benefit more from this combination therapy.
Clinical trial information: NCT06030934
.
Outcome of radiation related esophageal stricture from endoscopic dilation.
Authors: Wang Yinghong , Baerman Elliot , Colli Cruz Carolina , Black Samuel , Gajagowni Saivaroon , Weston Brian
Published: January 2025

387

Background:
Esophageal strictures present a significant challenge, particularly in cases of radiation-induced strictures. Esophageal dilation is a commonly used intervention aimed at improving swallowing function and nutritional status. However, radiation-induced strictures are amongst the most refractory to dilation. Understanding the success and limitations of this procedure is crucial for optimizing patient outcomes in the cancer population.
Methods:
This was a single-center retrospective chart review of 736 patients who received radiation as well as an EGD between 2014 and 2024. Patients without a radiation-induced stricture that was dilated were excluded. All continuous data are summarized as medians with interquartile ranges (IQR). Independent t-test was used for comparison among different groups.
Results:
192 were eligible for this study. Our population was mostly male (58%) with a median age of 66 (IQR 67-74). The leading cancer diagnosis were esophageal (37%), head and neck (30.2%), and lung (17.1%). Radiation targets were head and neck (50.5%), lung (45.3%), both (1.6%), or other (1.6%). Patients were receiving active chemotherapy in 9.9% of cases. Mortality by the end of the study period was 51%. The median radiation dose was 5040 cGy (IQR 5040-6600) in a median of 28 fractions (IQR 26-33). Common indications for dilation were dysphagia (91.1%), weight loss (21.9%), and tube feed dependency (17.2%). Strictures were most often dilated 2 to 4 times (39.6%) to a median dilation size of 14 mm (IQR 12-15). Of note, 18.2% of patients needed 8 or more dilations. Dilation was associated with weight gain in 46.4% of patients, PEG tube removal in 3.1%, both forms of improvement in 9.9%, and no change in 40.6%. Complications included perforation (3.6%), aspiration pneumonia (3.6%), chest pain (0.5%), and hospitalization (0.5%). No significant differences were found in maximum dilation size, number of dilations, initial luminal diameter of the stricture, and initial length of the stricture between those who had clinical improvement as compared to those who did not.
Conclusions:
Our study reported 59.4% clinical improvement from esophageal dilation for radiation-induced strictures with nearly 20% of patients needing 8 or more dilations. The stricture dilation parameters did not appear to affect the success rate. This is the largest known single study of esophageal dilation for radiation-induced strictures.
Short- and long-term outcomes of conversion surgery for initially unresectable advanced gastric cancer: A Japanese multicenter retrospective cohort study.
Authors: Yasufuku Itaru , Terashima Masanori , Takahashi Naoki , Boku Narikazu , Kurokawa Yukinori , Fujibayashi Seito , Matsuhashi Nobuhisa , Omori Takeshi , Ito Yuichi , Ishida Michihiro , Yamagata Yukinori , Yamada Takanobu , Saito Takuro , Takeno Atsushi , Sato Sho , Sugimura Keijiro , Yoshikawa Takaki
Published: January 2025

402

Background:
The efficacy of conversion surgery in patients with unresectable advanced gastric cancer at the initial diagnosis who converted to be resectable due to remarkable response to chemotherapy is unclear. To evaluate short- and long-term outcomes of conversion surgery for initially unresectable cStage IVB/pStage IV gastric cancer as the basic data for the JCOG2301 trial, which is a randomized controlled trial comparing conversion surgery with continuation of chemotherapy, a multicenter retrospective cohort study was conducted in the Stomach Cancer Study Group of the Japan Clinical Oncology Group.
Methods:
Inclusion criteria were as follows; (1)gastric cancer with at least one of following distant metastasis at the initial diagnosis; (i) peritoneal metastasis (PER) diagnosed by imaging examination or P1b or P1c disease diagnosed by laparoscopy or laparotomy, (ii) multiple liver metastasis (HEP) more than three lesions, and (iii) distant lymph node metastasis (LYM) beyond paraaortic lymph node station 16a2/b1, (2) conversion to be resectable after systemic chemotherapy, (3) surgery aiming at an R0 resection of the primary and remaining lesions between April 2010 and September 2017. Clinical data were retrospectively obtained from electronic patient records of 58 institutions.
Results:
Atotal of 241 patients were included to the study. Initial unresectable factors were PER, HEP, and LYM in 132(55%), 37(15%), and 63(26%) patients, respectively, and 9(4%) patients had two or more factors. Conversion to be resectable obtained during the first and second/later line chemotherapy was in 209 (87%) patients and 32 (13%), respectively. 182(76%), 29(12%), and 30(12%) patients underwent R0, R1, and R2 resection, respectively. The incidence of postoperative complication of Clavien-Dindo Grade II or higher was 24% and no surgery-related death was observed. The median overall survival (mOS) from surgery was 45.4 (95%CI 30.9-61.4) months in R0 resection, 16.6 (11.5-18.5) months in R1, and 20.9 (11.3-35.6) months in R2. In case of R0 resection, the mOS from surgery was 34.4 (95%CI 26.5-59.2) months in PER, 55.9 (21.8-96.7) months in HEP, 54.6 (30.9-98.3) months in LYM, and not reached (19.7-NA) in two or more factors.
Conclusions:
Conversion surgery appears to be safe and a promising treatment strategy for patients who have initially unresectable advanced gastric cancer and presented remarkable response to systemic chemotherapy.
Factors and timing of decreased adherence to S-1 in postoperative docetaxel + S-1 therapy for gastric cancer.
Authors: Kawakami Kazuyoshi , Kimura Yuka , Nakamura Masashi , Yokokawa Takashi , Kobayashi Kazuo , Aoyama Takeshi , Suzuki Wataru , Hatori Masahiro , Shimizu Hisanori , Hiraide Makoto , Suzuki Kenichi , Takahari Daisuke , Yamaguchi Kensei , Yamaguchi Masakazu
Published: January 2025

403

Background:
The combination of docetaxel + S-1 (DS) therapy in postoperative adjuvant treatment for gastric cancer has proven to be effective and has become a standard therapy. Clarification of factors involved in and the timing of S-1 non-adherence is important to minimize non-adherence.
Methods:
Among 92 patients who started DS treatment as postoperative adjuvant chemotherapy for gastric cancer between November 1, 2015 and April 30, 2021 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 90 were eligible for this study. The S-1 adherence rate per cycle was defined as the number of times a patient took S-1 divided by 28. In this study, adherence to S-1 was assessed through pill counts and by asking patients about reasons for non-adherence in interviews at a pharmaceutical outpatient clinic. Elicited reasons for non-adherence were categorized and analyzed.
Results:
Percentage of remaining S-1 was 3.9% in the first cycle, 7.4% in the second cycle, and 2.0% in the seventh cycle. Median relative dose intensity of S-1 was 80.9%. As reasons for non-adherence, patients most commonly cited nausea/vomiting (18.9%), missed dose (17.6%), and diarrhea (9.9%). From the first to the seventh course, the highest percentage of remaining S-1 was in the second course.
Conclusions:
Nausea/vomiting, missed dose, and diarrhea were identified as the most common factors for decreased adherence to S-1 in postoperative DS therapy for gastric cancer. Between the first and seventh courses, S-1 adherence decreased the most during the second course, when docetaxel was started. Using this information, we intend to develop methods to improve S-1 adherence in the future.