Kaplan–Meier curves for survival outcomes in patients with MSS/pMMR mCRC receiving ICI-based therapies, stratified by liver metastasis status at the time of ICI initiation. A, PFS: Patients without liver metastases had significantly higher 12-month PFS rates (12.8% vs. 1.1%; P = 0.034). The median PFS was 2.1 months (95% CI, 1.59–2.62) in those with liver metastases and 2.5 months (95% CI, 2.22–2.71) in those without liver metastases (HR, 1.68; 95% CI, 1.13–2.5; P = 0.009). B, OS: Median OS was 11.53 months (95% CI, 3.01–20.06) in those without liver metastases and 6.17 months (95% CI, 2.87–9.46) in those with liver metastases (HR, 2.03; 95% CI, 1.35–3.06; P < 0.001).

Demographic and clinical characteristics of patients with MSS/pMMR mCRC by liver metastasis status.

Regimens of immune checkpoint inhibitor-based therapies

Immune checkpoint inhibitors (ICI) have limited efficacy in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), potentially because of immunosuppressive mechanisms associated with liver metastases. The impact of liver metastases on survival outcomes was evaluated in a retrospective cohort of patients with MSS mCRC treated with ICI-based therapies at Mass General Brigham between January 2015 and December 2022. Patients were stratified by liver metastasis status at ICI initiation. The primary endpoint was progression-free survival (PFS); the secondary endpoint was overall survival (OS). A total of 132 patients were included, of whom 93 (70.5%) had liver metastases at ICI initiation. Most patients in both groups had received ≥2 prior lines of therapy. No significant differences were observed between groups for RAS/BRAF mutation status or tumor mutational burden. Patients without liver metastases demonstrated higher clinical benefit rates (46.2% vs. 16.1%; P = 0.001), longer median PFS (2.5 vs. 2.1 months; HR, 1.68; P = 0.009), and higher 12-month PFS rates (12.8% vs. 1.1%; P = 0.034). The median OS was also prolonged in patients without liver metastases (11.5 vs. 6.2 months; HR, 2.03; P < 0.001). No history of liver metastases was an independent favorable risk factor for PFS and OS in univariable and multivariable analyses. These findings indicate that liver metastases are associated with inferior survival outcomes in patients with MSS mCRC treated with ICI-based therapies, supporting the immunosuppressive role of liver metastases and underscoring the importance of stratifying patients by liver metastasis status to guide patient selection and optimize therapeutic strategies. SIGNIFICANCE:The limited efficacy of ICIs in MSS mCRC remains a major challenge. The association between liver metastases and inferior outcomes supports the liver's immunosuppressive role and suggests that liver metastasis status may guide patient selection and treatment optimization.

Subsequent treatments after immune checkpoint inhibitor-based therapy

Univariable and multivariable Cox regression analysis for OS.

Kaplan-Meier curves for survival outcomes in MSS/pMMR mCRC patients receiving ICI-based therapies, stratified by liver metastases status at baseline

Details of molecular characteristics and tumor mutational burden by timing of treatment

Univariable and multivariable Cox regression analysis for PFS.

Purpose Chemoradiation-induced lymphopenia is common and associated with poorer survival in multiple solid malignancies. However, the association between chemoradiation-related lymphopenia and survival outcomes in rectal cancer is yet unclear. The objective of this study was to evaluate the prognostic impact of lymphopenia and its predictors in patients with rectal cancer undergoing neoadjuvant chemoradiation. Methods The inclusion criteria for this single-institution retrospective study were as follows: (1) biopsy-proven diagnosis of rectal adenocarcinoma, (2) receipt of neoadjuvant chemoradiation followed by surgery, and (3) absolute lymphocyte count available prior to and within 12 weeks of chemoradiation. In general, chemoradiation consisted of 5-fluorouracil or capecitabine and radiotherapy with 50.4 Gy over 28 fractions. Lymphopenia was graded according to the Common Terminology Criteria for Adverse Events version 5.0. The primary variable of interest was absolute lymphocyte count nadir within 12 weeks of chemoradiation, dichotomized by <500/μL (grade 3 or worse lymphopenia). The primary endpoint was overall survival. Cox modeling and Kaplan-Meier methods were used to perform survival analyses. Results A total of 193 patients were identified with a median follow-up of 68 months. Overall clinical stage was 2 in 21% and 3 in 76%. Median baseline lymphocyte count for the entire cohort was 1700/μL. One hundred ten patients (57%) experienced chemoradiation-related severe lymphopenia. Pathologic complete response rate was 21%; 83% received adjuvant chemotherapy. Lower baseline lymphocyte count was significantly associated with increased risk for chemoradiation-related severe lymphopenia (odds ratio, 1.71). On multivariable Cox regression analysis, chemoradiation-related severe lymphopenia was significantly associated with worse disease-free survival (hazard ratio, 2.64) and overall survival (hazard ratio, 4.32). Five-year overall survival was 79% versus 92%, and 5-year disease-free survival was 70% versus 86% in the cohort that experienced versus did not experience severe lymphopenia, respectively. Discussion Chemoradiation-induced lymphopenia is common and a prognostic marker of poorer survival in rectal cancer. Closer observation in high-risk patients and treatment modifications may be potential approaches to mitigating treatment-related lymphopenia. Our findings also suggest an important role of the host immunity in rectal cancer outcomes and support future studies investigating ways to reduce treatment-induced lymphopenia.

3554 Background: Approximately 30% of patients (pts) diagnosed with colorectal cancer (CRC) develop liver metastases (LM). Liver is the most common organ of metastasis of CRC. The ARCAD database contains individual patient data of randomized trials that included CRC pts with initially unresectable metastases treated with systemic therapy. The aim of this study was to assess the response and survival outcomes in non-LM (NLM) vs LM across different lines of treatment. Methods: We analyzed survival outcomes of mCRC pts with either single site (SS) or multiple sites (MS) according to LM status in the following treatment groups: A: chemotherapy (CT) alone, B: CT + VEGF-antibodies, C: CT + EGFR-antibodies in KRAS wild-type tumors, within first-line (1L) and second line (2L) of therapy and D: pts enrolled on third line (≥3L) trials treated with trifluridine/tipiracil or regorafenib and placebo. The primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS) which were assessed using Kaplan-Meier estimates and adjusted Cox models on ECOG PS, age, and gender. Results: We included 26 trials with 17924 pts. 14066 pts had LM. Pts with LM had a higher rate of colon vs rectum as primary tumor (72 vs 62%; P < .001) and less SS (31 vs 47%; P < .001) than those with NLM. OS and PFS results in subgroups are reported in the table. In groups A and B, we found better OS and PFS outcomes in NLM pts as either SS or MS in 1L and 2L. In group C from 1L, we found better survival outcomes in pts with SS LM. In pts with MS, NLM superiority was observed in OS but not in PFS. However, these results were influenced by primary tumor sidedness. In group D, better OS and PFS was observed in pts without LM than those with LM whether in pts with SS or MS. Response rates were higher in LM than in NLM in most 1L and 2L subgroups. Conclusions: LM is a poor prognostic factor for mCRC increasing from the 1L to ≥3L. Survival with CT alone and CT + anti-VEGF according to LM and NLM differs significantly in 1L and 2L but not with CT + anti-EGFR. This data justifies using LM as a stratification factor at least in ≥3L trials. [Table: see text]

Current guidelines recommend that clinically staged T1N0 esophageal cancers are to be referred to surgery or endoscopic resection. Using the National Cancer Database, we identified 733 individuals with clinically staged T1N0 esophageal carcinoma, who underwent upfront surgery and did not receive any prior treatment. We assessed upstaging, which was defined as & GE; T2 disease or positive lymph nodes. Poorly differentiated adenocarcinomas were associated with upstaging, whereas squamous cell carcinomas were not. Specifically, the percentage of upstaging among individuals with clinically staged T1b and poorly differentiated tumor was 33.8%. Therefore, clinically staged T1bN0 poorly differentiated esophageal adenocarcinomas are at high risk for upstaging following surgery.

Among patients with metastatic MSS CRC treated with ICIs and RT in two phase 2 studies, ORR, DCR, and OS are significantly higher in patients without liver metastases. Liver-directed RT may improve ICI efficacy and OS in patients with liver metastases. Further analysis of PFS and prospective study of ICIs with comprehensive liver-directed RT are warranted.

Purpose Colorectal cancer is the second leading cause of cancer mortality in the United States. Antiangiogenic therapy with bevacizumab combined with chemotherapy improves survival in previously untreated metastatic colorectal cancer. This study was conducted to determine the effect of bevacizumab (at 10 mg/kg) on survival duration for oxaliplatin-based chemotherapy in patients with previously treated metastatic colorectal cancer.Patients and Methods Eight hundred twenty-nine metastatic colorectal cancer patients previously treated with a fluoropyrimidine and irinotecan were randomly assigned to one of three treatment groups: oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) with bevacizumab; FOLFOX4 without bevacizumab; or bevacizumab alone. The primary end point was overall survival, with additional determinations of progression-free survival, response, and toxicity.Results The median duration of survival for the group treated with FOLFOX4 and bevacizumab was 12.9 months compared with 10.8 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for death = 0.75; P = .0011), and 10.2 months for those treated with bevacizumab alone. The median progression-free survival for the group treated with FOLFOX4 in combination with bevacizumab was 7.3 months, compared with 4.7 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for progression = 0.61; P < .0001), and 2.7 months for those treated with bevacizumab alone. The corresponding overall response rates were 22.7%, 8.6%, and 3.3%, respectively (P < .0001 for FOLFOX4 with bevacizumab v FOLFOX4 comparison). Bevacizumab was associated with hypertension, bleeding, and vomiting.Conclusion The addition of bevacizumab to oxaliplatin, fluorouracil, and leucovorin improves survival duration for patients with previously treated metastatic colorectal cancer.

PDF file - 37K, Comparison of study cases and overall patient population

Importance Patient-reported outcomes (PROs), such as quality of life (QOL) and symptoms, are often associated with clinical outcomes in patients with cancer. In practice, oncologists use serum tumor markers (TMs) (ie, carcinoembryonic antigen [CEA] and carbohydrate antigen 19-9 [CA 19-9]) and imaging to monitor clinical outcomes in patients with gastrointestinal cancer.Objective To examine associations of 1-month changes in PROs and TMs with treatment response and survival among patients with gastrointestinal cancer.Design, Setting, and Participants This cohort study enrolled patients at Massachusetts General Hospital Cancer Center with at least 1 month follow-up from May 2019 to December 2020. Included patients were beginning first-line systemic therapy, aged 18 years or older, and had been diagnosed with metastatic pancreaticobiliary, colorectal, or gastroesophageal cancer. Data analyses took place from January 2021 to January 2022.Intervention PROs were collected, including QOL (Functional Assessment of Cancer Therapy General [FACT-G]), physical symptoms (Edmonton Symptom Assessment System [ESAS]), and psychological symptoms (Patient Health Questionnaire-4 [PHQ4] total, PHQ4-depression, and PHQ4-anxiety), as well as TMs (CEA and CA 19-9), at the time of chemotherapy initiation and 1 month later.Main Outcomes and MeasuresAssociations of 1-month changes in PROs and TMs with treatment response (clinical benefit vs disease progression) at first scan, progression-free survival (PFS), and overall survival (OS), adjusted for baseline values using regression models.Results This study included 159 patients, with 134 patients (84.3%) evaluable for analysis. Patients had a median (range) age of 64.0 (28.0-84.0) years and 86 (64.2%) were male. One-month PRO changes (FACT-G: OR, 1.07; 95% CI, 1.03-1.11; P = .001; ESAS-total: OR, 0.97; 95% CI, 0.94-1.00; P = .02; ESAS-physical: OR, 0.96; 95% CI, 0.92-1.00; P = .03; PHQ4-depression: OR, 0.67; 95% CI, 0.49-0.92; P = .01) were significantly associated with treatment response, but PHQ4-total or TMs were not. Changes in FACT-G (HR, 0.97; 95% CI, 0.95-0.99; P = .003), ESAS-total (HR, 1.03; 95% CI, 1.01-1.05; P = .004), ESAS-physical (HR, 1.03; 95% CI, 1.00-1.05; P = .02), PHQ4-depression (HR, 1.22; 95% CI, 1.01-1.48; P = .04), and CEA (HR, 1.00; 95% CI, 1.001-1.004; P = .001) were associated with PFS, but changes in PHQ4-total or TMs were not. Changes in ESAS-total (HR, 1.03, 95% CI, 1.01-1.06; P = .006) and ESAS-physical (HR, 1.04, 95% CI, 1.01-1.06; P = .015) were associated with OS, but changes in TMs were not associated with OS.Conclusions and Relevance These findings suggest that 1-month changes in PROs can be associated with treatment response and survival in patients with advanced gastrointestinal cancer. Notably, 1-month changes in TMs were not consistently associated with these outcomes. These findings highlight the potential for monitoring early changes in PROs to associate with clinical outcomes while underscoring the need to address the QOL and symptom concerns of patients with advanced cancer.

PDF file - 260K, Scoring of immunohistochemically stained samples