Clinical colorectal cancer最新文献

Background: This study evaluated the safety, tolerability and preliminary efficacy of pembrolizumab in combination with capecitabine and bevacizumab in microsatellite stable (MSS) metastatic colorectal cancer (mCRC).

Patients and methods: Patients with MSS/pMMR mCRC with stable or progressive disease on at least 1 prior fluoropyrimidine-based therapy received capecitabine 1000 mg/m² by mouth twice daily days 1 to 14, bevacizumab 7.5 mg/kg day 1, and pembrolizumab 200 mg day 1 every 3 weeks. The primary endpoint was overall response rate by RECIST 1.1. Secondary endpoints were safety, duration of response, progression-free survival (PFS), and overall survival (OS).

Results: Forty-four patients were enrolled between April 2018 and October 2021. Median follow up time was 9.3 months, while median time on treatment was 6 months. Overall response rate for 40 evaluable patients was 5% with median duration of response of 13.5 months. Median PFS was 4.1 months, and median OS was 10.1 months. Grade ≥ 3 treatment related adverse events occurred in 13 patients (30%); none were classified as immune-related. Grade 1 to 2 immune-related adverse events occurred in 8 patients (18%). Dose modifications occurred in 27 patients (61%), most commonly for palmar-plantar erythrodysesthesia. Single cell RNA sequencing on a subset of tumor biopsies demonstrated that the frequency of dendritic cells and tumor-infiltrating activated T cells correlated with time on treatment.

Conclusions: The combination of pembrolizumab with capecitabine and bevacizumab was tolerable with an expected toxicity profile in MSS/pMMR mCRC patients. The overall response rate of 5% did not meet the prespecified target of ≥ 15%; however, 55% patients remained on treatment > 6 months.

Clinicaltrials: gov Identifier: clinicaltrials.gov: NCT03396926.

Background: Recent studies have shown an increased incidence of early-onset CRC (EO-CRC), particularly in advanced stages and with metastatic disease. Our study aimed to evaluate the role of metastasectomies related to the clinical and molecular characteristics of EO-CRC patients with liver metastases compared to average-onset CRC (AO-CRC) patients.

Methods: We retrospectively collected data from 1123 stage IV colorectal cancers, including 782 with liver metastases, from 5 different Italian institutions. The main objective of the study was to compare the overall survival of liver metastatic EO-CRC and AO-CRC patients who underwent metastasectomy versus those who were not resected.

Results: Liver resected EO-CRCs patients showed a statistically significant lower mOS than liver resected AO-CRCs (44.0 vs. 64.0 months, P < .0001). mPFS was also statistically significant lower in EO-CRCs (13.0 vs. 17.0, P < .0001). Same outcomes were found in RAS mut subgroup (37.0 vs. 52.0 months, P < .0001) and in RAS/BRAF wild-type subgroup (50.0 vs. 81.0 months, P < .0001). EO-CRC patients showed a higher prevalence of TP53 alterations (56.2%) and a lower of APC mutation (29.9%). EO-CRCs presented a higher frequency of ARID1A (4.4%) and CTNNB1 (3.0%) alterations.

Conclusion: The results indicate a worse overall prognosis for EO-CRC patients undergoing metastasectomy compared to average-onset patients. This outcome appears to occur independently of the molecular status. These observations could have a considerable impact on clinical practice and research.

Background: Reproducibility and accuracy of radiological classification with CT imaging is crucial for selecting patients with resectable, nonmetastatic colon cancer (CC) who may benefit from neoadjuvant strategies.

Methods: We evaluated interobserver agreement among 4 independent radiology equipes in classifying patients with resectable, nonmetastatic, mismatch repair proficient CC with available preoperative CT imaging. Radiology equipes were blinded to clinical and pathological data, and categorized tumors according to FOxTROT and Node-RADS criteria, classifying T (T1/2, T3, T4, including stratification by extramural invasion [EMI]) and N status. The primary endpoint was interobserver agreement (Cohen's κw); secondary endpoints included concordance with pathological staging and diagnostic performance metrics. Bayesian and cross-validation analyses assessed robustness.

Results: Among 109 patients (32.1% pT2, 33.9% pT3, 33.9% pT4; 45.9% pN0/1c, 54.1% pN1-2), overall interobserver agreement indicated inadequate concordance for both cT (κw = 0.56; 95% CI, 0.43-0.68) and cN category (κw = 0.51; 95% CI, 0.36-0.66). Of 109 patients, 38 (35%) were classified identically for T stage by all 4 Radiology groups, while 74 (68%) showed some disagreement. When considering risk stratification into high risk (cT3 with EMI ≥5 mm or cT4) versus low risk (cT1/cT2 or cT3 with EMI <5 mm) 56 patients (51%) received the same classification all 4 groups, and 95 patients (87%) were classified consistently by at least 3 groups. Overall concordance between radiology and pathological staging was inadequate for both T (κw = 0.47; 95% CI, 0.35-0.57) and N staging (κw = 0.16; 95% CI, 0.07-0.33). The mean sensitivity and specificity of CT scan for pT3/T4 and pT4 were 72%/78% and 33%/93%.

Conclusions: Identification of high-risk features in resectable CC by CT scan should be implemented to guide patients' selection for neoadjuvant therapies.

Background: Trifluridine has demonstrated superior radio-sensitizing ability in vitro, and trifluridine/tipiracil (FTD/TPI) confers clinical benefit in metastatic colorectal cancer. The FIERCE trial (NCT04104139) sought to assess the safety of FTD/TPI as total neoadjuvant therapy (TNT) for rectal cancer.

Methods: Patients with stage II/III rectal adenocarcinoma at a single institution underwent chemo-radiation with FTD/TPI followed by oxaliplatin-based chemotherapy for 4 months. FTD/TPI was examined in cohorts of 3 patients at 3 dose levels (25 mg/m², 30 mg/m², and 35 mg/m²) until 18 were reached per Bayesian Optimal Interval design (BOIN). FTD/TPI was taken orally twice-daily for 5 days/week on weeks 1, 3, and 5 of radiation. Dose-limiting toxicity (DLT) was defined by relevant adverse events related to FTD/TPI. The primary endpoint was the proportion of DLT during chemo-radiation.

Results: Eighteen of 22 screened patients were evaluable after completing TNT. All patients had proficient mismatch repair and staged as cT3, of which 8 (44%) were node-negative and 10 (56%) were node-positive. Grade 3 neutropenia was observed in 4 (22%) patients during chemo-radiation, with 1 DLT occurring at 25 mg/m² and 1 at 35 mg/m². Using isotonic estimate of observed toxicity probability, the maximum tolerated dose of FTD/TPI was 35 mg/m² (PO, BID). At data cutoff, 10 (56%) patients entered into watch-and-wait surveillance, with 9 (50%) achieving clinical complete response.

Conclusion: FTD/TPI at 35 mg/m² on days 1 to 5, 15 to 19, and 29 to 33, is safe and feasible with concurrent radiation as TNT for rectal cancer and should be further studied to evaluate promising efficacy signal including organ preservation.

Colorectal liver metastases (CRLM) remain a leading cause of cancer-related mortality, with recurrence rates of 50 to 70% following curative-intent hepatic resection. Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for minimal residual disease (MRD) detection, yet its prognostic value in resected CRLM has not been systematically quantified. A systematic review and meta-analysis was conducted following PRISMA 2020 guidelines (PROSPERO: CRD420251177140). MEDLINE, Embase, Web of Science, Cochrane CENTRAL, and Scopus were searched through October 2025. Studies evaluating ctDNA as a prognostic biomarker in adults with resected CRLM were included. Hazard ratios (HRs) for recurrence-free survival (RFS) and overall survival (OS) were pooled using random-effects models. Evidence certainty was assessed using GRADE methodology. Ten studies (1034 patients) were included. Postoperative ctDNA positivity was significantly associated with inferior RFS in the MRD window (HR 3.28, 995% CI, 2.58-4.17; I² = 10%) and after adjuvant chemotherapy (HR 8.69, 995% CI, 5.43-13.90; I² = 0%). ctDNA positivity was also associated with reduced OS (HR 7.11, 995% CI, 3.87-13.09). ctDNA detection preceded radiological recurrence by 3.5 to 6.1 months. Preoperative ctDNA was not a statistically significant predictor. ctDNA is a promising prognostic biomarker in resected CRLM, strongly associated with recurrence and mortality. However, prospective randomized trials are needed before routine clinical implementation.

Background: Current treatments for patients with previously treated metastatic colorectal cancer (CRC) have poor outcomes. LEAP-005 (ClinicalTrials.gov, NCT03797326) was a multicohort, open-label phase II study evaluating the efficacy and safety of lenvatinib plus pembrolizumab in participants with previously treated selected solid tumors. We report findings from the LEAP-005 CRC cohort.

Patients and methods: Participants aged ≥ 18 years with advanced (metastatic and/or unresectable) CRC with 2 prior lines of systemic therapy were eligible for the CRC cohort of LEAP-005. Participants received oral lenvatinib (20 mg/day) plus intravenous pembrolizumab (200 mg Q3W) combination therapy (Arm 1) or lenvatinib (24 mg/day) monotherapy (Arm 2). Dual primary endpoints were objective response rate (ORR) per RECIST version 1.1 and safety. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

Results: 135 participants were enrolled in the CRC cohort (Arm 1, n = 105; Arm 2, n = 35). In Arm 1, ORR was 14% (95% CI, 8-23), median PFS was 3.4 (95% CI, 2.1-4.1) months, and OS was 8.7 (95% CI, 7.0-10.0) months. In Arm 2, ORR was 7% (95% CI, 1-22), median PFS was 3.4 (95% CI, 2.1-4.2) months, and OS was 7.7 (95% CI, 5.6-14.8) months. Treatment-related AEs occurred in 96% of participants (grade 3/4, 63%) in Arm 1 and 97% (grade 3/4, 63%) in Arm 2. One participant in Arm 1 died due to treatment-related intestinal perforation.

Conclusion: Lenvatinib plus pembrolizumab demonstrated antitumor activity in participants with advanced CRC with 2 prior lines of treatment. No new safety signals were identified.

Anal canal squamous cell carcinoma (ACSCC) is a rare malignancy, accounting for approximately 2% of all colorectal cancers. Brain metastases originating from this primary site are exceedingly uncommon and scarcely documented. The aim of this study is to review the literature-reported cases of brain metastases from ACSCC and to supplement this analysis with the description of a clinical case. A systematic review of the literature was conducted in accordance with PRISMA guidelines to identify published cases of brain metastases from ACSCC. The clinical and therapeutic features of these cases were analyzed. In addition, we present a rare case of a 74-year-old woman with a primary diagnosis of HPV-negative ACSCC with an isolated brain metastasis occurring 20 months after completion of definitive chemoradiotherapy. She underwent craniotomy with gross total resection of the mass and adjuvant stereotactic radiotherapy to the tumor bed. Overall, 4 papers were included. Prognosis following cerebral dissemination is generally poor, ranged from 3 months to 8 years. Management is predominantly palliative, with the goal of symptom relief. But recent advances in therapeutic strategies are contributing to improved long-term survival in these patients. Concerning our case report, a personalized approach was adopted. Six months after neurosurgery and adjuvant stereotactic radiotherapy, the patient was in good general condition with no new or progressive neurological symptoms, indicating effective control of cerebral disease. The patient is currently alive and receiving active treatment. This systematic review highlights the importance of prompt brain metastasis diagnosis and of a multimodal treatment approach--including surgery, radiotherapy and systemic therapy--to significantly enhance both prognosis and quality of life in affected patients. Clarifying biological pathways is essential for developing targeted therapies and advancing precision oncology in ACSCC. A multinational approach could help address this issue and potentially determine if treatment intensification is necessary.

Purpose: In our pilot study adding paclitaxel to chemoradiotherapy (CRT) with capecitabine and mitomycin C (MMC) showed promising efficacy and we aimed to determine whether it could improve progression-free survival (PFS) in a randomized clinical trial setting.

Methods: We performed a randomized phase III trial at 2 centers. Enrolled patients with stage I-IIIB SCAC were randomly (1:1) allocated to either CRT with capecitabine and MMC (CRT-CM arm) or CRT with capecitabine, MMC and paclitaxel (CRT-CMP arm). The CRT-CMP regimen comprised 52 to 58 Gy IMRT, paclitaxel 45 mg/m² on days 3, 10, 17, 24, 31, capecitabine 625 mg/m² bid on treatment days and mitomycin C 10 g/m² on day 1. The primary endpoint was PFS. Secondary endpoints were toxicity, overall survival (OS), complete clinical response (cCR) at 12 and 26 weeks.

Results: Between January 2016 and February 2020, 87 patients were enrolled in the CRT-CMP arm and 86 patients in the CRT-CM arm. The trial was stopped prematurely because MMC was no longer available in the country. Median follow-up was 50.3 months. Three-year PFS was 84.8% in the CRT-CMP arm and 66.9% in the CRM-CM arm (P = .009). Grade 3 or worse adverse events were observed in 45 (51.7%) patients in the CRT-CMP arm and in 20 (23.3%) patients in the CRT-CM arm (P < .0001). Seventy seven (89.5%) patients in the CRT-CMP arm and 63 (75.9%) patients in the CRM-CM arm had a cCR at 26 weeks (P = .024).

Conclusion: Adding paclitaxel to CRT with capecitabine and MMC improves cCR rate and long-term outcomes in SCAC at the cost of higher toxicity.

Background: Appendiceal cancer frequently presents with peritoneal metastases. Cytoreductive surgery combined (CRS) with heated intraperitoneal chemotherapy (HIPEC) is currently standard practice for metastatic appendiceal cancer, particularly mucinous subtypes. However, the specific benefit of adding standard postoperative systemic chemotherapy, either alone or in addition to HIPEC, remains unclear.

Methods: Using the National Cancer Database (NCDB) from 2018 to 2022, we identified 888 patients with appendiceal cancer (goblet cell/composite, signet-ring/diffuse, or adenocarcinoma) characterized by peritoneal metastases. Mucinous subtypes were excluded. All patients underwent cytoreductive surgery, and many underwent primary tumor resection concurrently. Patients were stratified based on initial systemic treatment received: no chemotherapy (n = 181), standard adjuvant chemotherapy (n = 415), perioperative chemotherapy (n = 62), HIPEC with additional systemic therapy (n = 122) or without additional systemic chemotherapy (n = 124). Survival outcomes were compared using Kaplan-Meier analysis and multivariable Cox regression, adjusting for age, sex, Charlson-Deyo comorbidity index and histologic subtype.

Results: With a median follow-up of 41 months, the 3-year overall survival was 20.2% for no chemotherapy, 25.3% for adjuvant chemotherapy, 39.3% for perioperative chemotherapy, and 58.4% for HIPEC without additional systemic therapy and 46.3% for HIPEC with additional systemic therapy. Compared to surgery alone, standard adjuvant chemotherapy reduced mortality risk by approximately 20% (HR 0.80; 95% CI, 0.60-1.07; P = .13), and HIPEC-based therapy reduced mortality risk by approximately 43% (HR 0.57; 95% CI, 0.40-0.81; P = .002), regardless of whether additional systemic therapy was received. Neither age, sex, nor specific histologic subtype independently influenced survival. A higher comorbidity burden (Charlson-Deyo ≥ 2) trended towards worse survival (HR 1.81; P = .05).

Conclusions: While prior literature suggests a role of systemic therapy in addition to cytoreductive surgery and HIPEC in treating peritoneal metastases from appendiceal cancers, our findings demonstrate that additional systemic chemotherapy, whether standard adjuvant or perioperative, is not associated with significantly improved survival outcomes compared to surgery and HIPEC alone. These results do not support the routine consideration of postoperative or perioperative systemic therapy for all patients undergoing cytoreductive surgery and HIPEC, irrespective of histologic subtype.