Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

Long-term outcomes of intraoperative chemotherapy with 5-FU for colorectal cancer patients receiving curative resection (IOCCRC): a randomized, multicenter, prospective, phase III trial.

BACKGROUND: We aimed to compare combined intraoperative chemotherapy and surgical resection with curative surgical resection alone in colorectal cancer patients. METHODS: We performed a multicenter, open-label, randomized, phase III trial. All eligible patients were randomized and assigned to intraoperative chemotherapy and curative surgical resection or curative surgical resection alone (1:1). Survival actualization after long-term follow-up was performed in patients analyzed on an intention-to-treat basis. RESULTS: From January 2011 to January 2016, 696 colorectal cancer patients were enrolled and randomly assigned to intraoperative chemotherapy and radical surgical resection (n=341) or curative surgical resection alone (n=344). Intraoperative chemotherapy with surgical resection showed no significant survival benefit over surgical resection alone in colorectal cancer patients (3-year DFS: 91.1% vs. 90.0%, P=0.328; 3-year OS: 94.4% vs. 95.9%, P=0.756). However, colon cancer patients benefitted from intraoperative chemotherapy, with a relative 4% reduction in liver and peritoneal metastasis (HR=0.336, 95% CI: 0.148-0.759, P=0.015) and a 6.5% improvement in 3-year DFS (HR=0.579, 95% CI: 0.353-0.949, P=0.032). Meanwhile, patients with colon cancer and abnormal pretreatment CEA levels achieved significant survival benefits from intraoperative chemotherapy (DFS: HR=0.464, 95% CI: 0.233-0.921, P=0.029 and OS: (HR=0.476, 95% CI: 0.223-1.017, P=0.049). CONCLUSIONS: Intraoperative chemotherapy showed no significant extra prognostic benefit in total colorectal cancer patients who underwent radical surgical resection; however, in colon cancer patients with abnormal pretreatment serum CEA levels (> 5 ng/ml), intraoperative chemotherapy could improve long-term survival.

Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial.

OBJECTIVE: To compare neoadjuvant chemotherapy (nCT) with CAPOX alone versus neoadjuvant chemoradiotherapy (nCRT) with capecitabine in locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). BACKGROUND DATA: nCRT is associated with higher surgical complications, worse long-term functional outcomes, and questionable survival benefits. Comparatively, nCT alone seems a promising alternative treatment in lower-risk LARC patients with uninvolved MRF. METHODS: Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to nCT group with 4 cycles of CAPOX (Oxaliplatin 130 mg/m2 IV day 1 and Capecitabine 1000 mg/m2 twice daily for 14 d. Repeat every 3 wk) or nCRT group with Capecitabine 825 mg/m² twice daily administered orally and concurrently with radiation therapy (50 Gy/25 fractions) for 5 days per week. The primary end point is local-regional recurrence-free survival. Here we reported the results of secondary end points: histopathologic response, surgical events, and toxicity. RESULTS: Of the 663 initially enrolled patients, 589 received the allocated treatment (nCT, n=300; nCRT, n=289). Pathologic complete response rate was 11.0% (95% CI, 7.8-15.3%) in the nCT arm and 13.8% (95% CI, 10.1-18.5%) in the nCRT arm ( P =0.33). The downstaging (ypStage 0 to 1) rate was 40.8% (95% CI, 35.1-46.7%) in the nCT arm and 45.6% (95% CI, 39.7-51.7%) in the nCRT arm ( P =0.27). nCT was associated with lower perioperative distant metastases rate (0.7% vs. 3.1%, P =0.03) and preventive ileostomy rate (52.2% vs. 63.6%, P =0.008) compared with nCRT. Four patients in the nCT arm received salvage nCRT because of local disease progression after nCT. Two patients in the nCT arm and 5 in the nCRT arm achieved complete clinical response and were treated with a nonsurgical approach. Similar results were observed in subgroup analysis. CONCLUSIONS: nCT achieved similar pCR and downstaging rates with lower incidence of perioperative distant metastasis and preventive ileostomy compared with nCRT. CAPOX could be an effective alternative to neoadjuvant therapy in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results.

High dose chemoradiotherapy increases chance of organ preservation with satisfactory functional outcome for rectal cancer.

BACKGROUND: High dose chemoradiotherapy offers a curative chance for patients with rectal cancer that are unfit or unwilling to undergo surgical resection, yet its long-term survival and functional outcomes have been rarely investigated. METHODS: Patients with non-metastatic rectal adenocarcinoma who received pelvic radiation for curative intent from April 2006 to July 2017 were retrospectively investigated. Survival rates were analyzed using the Kaplan-Meier method. Quality of life and functional outcomes were evaluated using the EORTC quality of life questionnaire. RESULTS: A total of 57 patients were included, with a median age of 59.0 (range, 29-84) years. The numbers of patients who were diagnosed as stage I, II and III were 5 (8.8%), 16 (28.1%) and 36 (63.2%), respectively. 53 (93.0%) patients had tumor located within 5 cm from the anal verge. All patients received fluorouracil-based concurrent chemoradiotherapy with a median radiation dose of 80 (range, 60-86) Gy. All kinds of grade 3-4 adverse events occurred in 18 (31.6%) patients. 42 (73.7%) patients achieved a clinical complete response after chemoradiotherapy. After a median follow-up of 43.5 (range 14.9-163.2) months, 12 (21.1%) patients had local progression and 11 (19.3%) developed distant metastasis. The 3-year local recurrence-free survival and distant metastasis-free survival were 77.3% (95% CI, 65.7-88.8%) and 79.2% (95% CI, 68.2-90.2%), while the 3-year progression-free survival, cancer-specific survival, overall survival were 61.9% (95% CI, 48.8-75.0%), 93.1% (95% CI, 85.8-100.0%) and 91.4% (95% CI, 83.6-99.2%), respectively. For patients who had tumor located within 3 cm from the anal verge, the sphincter preservation rate was 85.3% at last follow-up. Long-term adverse events mainly were anal blood loss. 21 patients completed the quality-of-life questionnaire and had a score of the global health status of 78.57 ± 17.59. Of them, 95.2% reported no urinary incontinence and 85.7% reported no fecal incontinence. CONCLUSIONS: High dose chemoradiation demonstrated promising survival outcomes with acceptable short-term and long-term side effects, and satisfying long-term functional outcomes and quality of life. It could be considered as a non-invasive alternative for rectal cancer patients who refuse surgery.

Factors associated with adherence to colonoscopy among individuals who were positive in the preliminary screening for colorectal neoplasms.

OBJECTIVES: This study aimed to investigate the potential factors associated with adherence to colonoscopy among participants who were preliminarily screened positive in a community-based colorectal cancer screening program in China. METHODS: This study analyzed data from 1219 out of 6971 community residents who were identified as positive cases by the well-validated high-risk factor questionnaire (HRFQ) or fecal immunochemical test (FIT) in the preliminary screening stage for colorectal neoplasms. Patients showing adherence to colonoscopy were defined as those who received positive results in a preliminary screening for colorectal neoplasms and later received a colonoscopy examination as required. The associations of social-demographic factors, lifestyle behaviors, history of diabetes, body mass index (BMI), and risk factors in the HRFQ with adherence to colonoscopy were evaluated using logistic regression models. RESULTS: Among 1219 participants who preliminarily screened positive, the top five risk factors reported by the participants were chronic constipation (25.9%), hematochezia (23.5%), family history of CRC in first-degree relatives (22.1%), chronic diarrhea (21.8%), and history of polyps (16.6%). Around 14.2% of participants who preliminarily screened positive reported three or more risk factors, and the proportion was 26.2% among participants who were positive according to both HRFQ and FIT. Among all participants who were preliminarily screened positive, the multivariable results showed that those who were married (OR = 1.58, 95% CI: 1.12, 2.25, p = 0.01), had chronic diarrhea (OR = 1.34, 95% CI: 1.00, 1.78, p = 0.047), and had a positive FIT (OR = 1.60, 95% CI: 1.21, 2.10, p < 0.001 for patients who were negative according to HRFQ but positive according to FIT; OR = 2.12, 95% CI: 1.33, 2.78, p = 0.002 for patients who were positive for both HRFQ and FIT) were more likely to adhere to colonoscopy, while participants with a history of cancer (OR: 0.50, 95% CI: 0.31, 0.79, p = 0.003) were less likely to adhere to colonoscopy. The results among participants who were tested positive according to only HRFQ were similar to those among all participants who were tested positive according to HRFQ or FIT. However, among participants who were tested positive according to only FIT, we only found that those who were married (OR = 2.52, 95% CI: 1.08, 5.90, p = 0.033) had a higher odds of adhering to colonoscopy, while those with a history of diabetes (OR = 0.35, 95% CI: 0.13, 0.96, p = 0.042) were less likely to adhere to colonoscopy. CONCLUSION: Our findings provide evidence supporting the development of tailored interventional strategies that aim to improve adherence to colonoscopy for individuals with a high risk of colorectal neoplasms. Both barriers and facilitators associated with adherence to colonoscopy should be considered in supportive systems and health policies. However, further well-designed prospective studies are warranted to confirm our findings.

Programmed death-ligand 1 expression in the tumour stroma of colorectal liver oligometastases and its association with prognosis after liver resection.

BACKGROUND: The clinical value of programmed death-ligand 1 (PD-L1) expression in colorectal liver oligometastases (CLOs) remains undefined. This study aimed to detect PD-L1 in the microenvironment of CLOs and determine its association with patient prognosis. METHODS: We collected 126 liver-resection specimens from CLO patients who underwent curative liver resection between June 1999 and December 2016. Immunohistochemistry (IHC) was performed to assess PD-L1 expression in paraffin-embedded specimens. Overall survival (OS) and recurrence-free survival (RFS) were analysed using the Kaplan-Meier method and log-rank test. RESULTS: PD-L1 was mainly expressed in the stroma of liver oligometastases. Patients with high PD-L1 expression had a higher proportion of clinical-risk scores (CRSs) of 2-4 (67.7% vs 40.4%; P = 0.004). With a median 58-month follow-up, patients with high PD-L1 expression had a significantly lower 3-year OS rate (65.5% vs 92.7%; P = 0.001) and 3-year RFS rate (34.7% vs 83.8%; P < 0.001) than patients with low PD-L1 expression. Multivariate Cox analysis demonstrated that high PD-L1 expression (hazard ratio [HR] = 3.581; 95% confidence interval [CI] 2.301-9.972; P = 0.015), CRS 2-4 (HR = 6.960; 95% CI 1.135-42.689; P = 0.036) and increased preoperative CA19-9 (HR = 2.843; 95% CI 1.229-6.576; P = 0.015) were independent risk factors for OS. High PD-L1 expression (HR = 4.815; 95% CI 2.139-10.837; P < 0.001) and lymph-node metastasis (HR = 2.115; 95% CI 1.041-4.297; P = 0.038) were independent risk factors for RFS. CONCLUSION: This study found that PD-L1 was commonly expressed in the tumour stroma of CLOs and high PD-L1 expression was associated with poor prognosis.

Neoadjuvant chemoradiotherapy in patients with unresectable locally advanced sigmoid colon cancer: clinical feasibility and outcome.

BACKGROUND: Patients with locally advanced sigmoid colon cancer (LASCC) have limited treatment options and a dismal prognosis with poor quality of life. This retrospective study aimed to further evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy (NACRT) followed by surgery as treatment for select patients with unresectable LASCC. METHODS: We studied patients with unresectable LASCC who received NACRT between November 2010 and April 2019. The NACRT regimen consisted of intensity modulated radiotherapy (IMRT) of 50 Gy to the gross tumor and positive lymphoma node and 45 Gy to the clinical target volume. Capecitabine­based chemotherapy was administered every 2 (mFOLFOX6) or 3 weeks (CAPEOX). Surgery was scheduled 6-8 weeks after radiotherapy. RESULTS: Seventy­two patients were enrolled in this study. Patients had a regular follow-up (median, 41.1 months; range, 8.3-116.5 months). Seventy­one patients completed NACRT, and sixty-five completed surgery. Resection with microscopically negative margins (R0 resection) was achieved in 64 patients (88.9%). Pathologic complete response was observed in 15 patients (23.1%), and multivisceral resection was necessary in 38 patients (58.3%). The cumulative probability of 3-year overall survival (OS) and progression-free survival (PFS) were 75.8 and 70.7%, respectively. CONCLUSIONS: For patients with unresectable LASCC, neoadjuvant chemoradiotherapy is feasible, surgery can be performed safely and may result in increased survival and organ preservation rates.

Primary tumor immune score fails to predict the prognosis of colorectal cancer liver metastases after hepatectomy in Chinese populations.

BACKGROUND: Increasing evidence suggests that the immune score is significantly associated with cancer prognosis. However, the prognostic role of primary tumor immune score in colorectal cancer liver metastases (CRLM) after hepatectomy in Chinese patients has not been reported. The present study is designed to investigate whether the immune score of primary tumor can predict the postoperative survival of liver metastases in Chinese patients. METHODS: A total of 131 patients diagnosed with CRLM were included, and the corresponding primary tumor and liver metastasis specimens were acquired. An immune score ranging from 0 to 4 was established based on the counts and densities of CD3+ and CD8+ T cells in the core tumor (CT) and the invasive margin (IM). Relapse-free survival (RFS) and overall survival (OS) were analyzed by Kaplan-Meier curves to assess the prognostic role of primary tumor immune score. Furthermore, we conducted a comprehensive search of the Gene Expression Omnibus (GEO) and selected stage IV colorectal cancer (CRC) patients with liver metastasis to compare the tumor-infiltrating T cell profiles of the primary tumor and liver metastases by CIBERSORT. RESULTS: Patients with high immune scores in the primary tumor has no significantly better RFS and OS after hepatectomy than those with low immune scores [median RFS (95% CI): 19.13 (10.07-28.20) vs. 27.13 (15.97-38.29) months, P=0.604; median OS (95% CI): 64.37 (35.96-92.78) vs. 40.07 (32.54-47.59) months, P=0.652]. Data collected from the GEO indicates that the proportion of CD8+ T cells and total T cells in the primary tumor and liver metastatic lesion are also not significantly correlated (CD8+ T cells: r2 =0.030, P=0.468; total T cells: r2 =0.165, P=0.076). CONCLUSIONS: The immune score of the primary tumor fails to predict the prognosis of CRLM after hepatectomy in Chinese patients.

CMTM6 and PD-L1 coexpression is associated with an active immune microenvironment and a favorable prognosis in colorectal cancer.

BACKGROUND: CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6), a programmed death-ligand 1 (PD-L1) regulator, is widely expressed in various tumors and regulates the immune microenvironment. However, its prognostic value remains controversial, and the roles of CMTM6 in colorectal cancer (CRC) are still unknown. In this study, we aimed to elaborate the expression patterns of CMTM6 and PD-L1 in CRC and investigate their relationship with the infiltration of T cells and the prognosis of patients with CRC. METHODS: Analysis of CMTM6 mRNA levels, gene ontology enrichment analysis and single-sample gene set enrichment analysis were performed in a The Cancer Genome Atlas colon cancer cohort. The expression of CMTM6 and PD-L1 and the infiltration of T cells in tumor tissues from our cohort containing 156 patients with CRC receiving adjuvant chemotherapy and 77 patients with CRC without chemotherapy were examined by immunohistochemistry assay. RESULTS: CMTM6 expression was upregulated in CRC compared with normal colon tissues, and CMTM6 levels were lower in advanced tumors than in early-stage tumors. High expression of CMTM6 correlated with lower pT stage and more CD4+/CD8+ tumor-infiltrating lymphocytes (TILs) and predicted a favorable prognosis in CRC. PD-L1 was expressed in CRC tissues at a low level, and PD-L1 positivity in tumor stroma (PD-L1(TS)), but not PD-L1 positivity in cancer cells (PD-L1(CC)), was associated with an increased density of CD4+ TILs and a favorable prognosis. The coexpression status of CMTM6 and PD-L1(TS) divided patients with CRC into three groups with low, moderate and high risks of progression and death, and patients with CMTM6High/PD-L1(TS)+ status had the longest survival. Moreover, the prognostic value of CMTM6/PD-L1 expression was more significant in patients with CRC treated with adjuvant chemotherapy than in those not treated with chemotherapy. CONCLUSION: CMTM6 has a critical impact on the immune microenvironment and can be used as an independent prognostic factor for CRC. The coexpression status of CMTM6 and PD-L1 can be used as a new classification to stratify the risk of progression and death for patients with CRC, especially for patients receiving adjuvant chemotherapy. These findings may provide insights into improving responses to immunotherapy-included comprehensive treatment for CRC in the future.

Phase III randomized, placebo-controlled, double-blind study of monosialotetrahexosylganglioside for the prevention of oxaliplatin-induced peripheral neurotoxicity in stage II/III colorectal cancer.

BACKGROUND: Monosialotetrahexosylganglioside (GM1) is a neuroprotective glycosphingolipid that repairs nerves. Oxaliplatin-based chemotherapy is neurotoxic. This study assessed the efficacy of GM1 for preventing oxaliplatin-induced peripheral neurotoxicity (OIPN) in colorectal cancer (CRC) patients receiving oxaliplatin-based chemotherapy. METHODS: In total, 196 patients with stage II/III CRC undergoing adjuvant chemotherapy with mFOLFOX6 were randomly assigned to intravenous GM1 or a placebo. The primary endpoint was the rate of grade 2 or worse cumulative neurotoxicity (NCI-CTCAE). The secondary endpoints were chronic cumulative neurotoxicity (EORTC QLQ-CIPN20), time to grade 2 neurotoxicity (NCI-CTCAE or the oxaliplatin-specific neuropathy scale), acute neurotoxicity (analog scale), rates of dose reduction or withdrawal due to OIPN, 3-year disease-free survival (DFS) and adverse events. RESULTS: There were no significant differences between the arms in the rate of NCI-CTCAE grade 2 or worse neurotoxicity (GM1: 33.7% vs placebo: 31.6%; P = .76) or neuropathy measured by the EORTC QLQ-CIPN20 or time to grade 2 neurotoxicity using NCI-CTCAE and the oxaliplatin-specific neuropathy scale. GM1 substantially decreased participant-reported acute neurotoxicity (sensitivity to cold items [P < .01], discomfort swallowing cold liquids [P < .01], throat discomfort [P < .01], muscle cramps [P < .01]). The rates of dose reduction or withdrawal were not significantly different between the arms (P = .08). The 3-year DFS rates were 85% and 83% in the GM1 and placebo arms, respectively (P = .19). There were no differences in toxicity between the arms. CONCLUSION: Patients receiving GM1 were less troubled by the symptoms of acute neuropathy. However, we do not support the use of GM1 to prevent cumulative neurotoxicity. (ClinicalTrials.gov number, NCT02251977).

Genome-wide RNAi Screening Identifies RFC4 as a Factor That Mediates Radioresistance in Colorectal Cancer by Facilitating Nonhomologous End Joining Repair.

PURPOSE: Neoadjuvant chemoradiotherapy (neoCRT) is a standard treatment for locally advanced rectal cancer (LARC); however, resistance to chemoradiotherapy is one of the main obstacles to improving treatment outcomes. The goal of this study was to identify factors involved in the radioresistance of colorectal cancer and to clarify the underlying mechanisms. EXPERIMENTAL DESIGN: A genome-wide RNAi screen was used to search for candidate radioresistance genes. After RFC4 knockdown or overexpression, colorectal cancer cells exposed to X-rays both in vitro and in a mouse model were assayed for DNA damage, cytotoxicity, and apoptosis. Moreover, the regulatory effects and mechanisms of RFC4 in DNA repair were investigated in vitro. Finally, the relationships between RFC4 expression and clinical parameters and outcomes were investigated in 145 patients with LARC receiving neoCRT. RESULTS: RFC4, NCAPH, SYNE3, LDLRAD2, NHP2, and FICD were identified as potential candidate radioresistance genes. RFC4 protected colorectal cancer cells from X-ray-induced DNA damage and apoptosis in vitro and in vivo. Mechanistically, RFC4 promoted nonhomologous end joining (NHEJ)-mediated DNA repair by interacting with Ku70/Ku80 but did not affect homologous recombination-mediated repair. Higher RFC4 expression in cancer tissue was associated with weaker tumor regression and poorer prognosis in patients with LARC treated with neoCRT, which likely resulted from the effect of RFC4 on radioresistance, not chemoresistance. CONCLUSIONS: RFC4 was identified as a radioresistance factor that promotes NHEJ-mediated DNA repair in colorectal cancer cells. In addition, the expression level of RFC4 predicted radiotherapy responsiveness and the outcome of neoadjuvant radiotherapy in patients with LARC.

Diagnostic value, safety, and histopathologic discrepancy risk factors for endoscopic forceps biopsy and transrectal ultrasound-guided core needle biopsy in rectum lesions.

BACKGROUND: Accurate preoperative pathologic diagnosis is very important for making appropriate therapeutic decisions for patients with rectal lesions. This study aimed (I) to determine diagnostic value and safety of endoscopic forceps biopsy (EFB) and transrectal ultrasound (TRUS)-guided core needle biopsy (CNB), and (II) to analyze the risk factors for their histopathologic discrepancies, with a particular focus in identifying the indicators for re-biopsy using TRUS-guided CNB after EFB. METHODS: We retrospectively reviewed the records of 102 patients who received EFB and TRUS-guided CNB before surgery. The histopathologic concordance and risk factors for underdiagnosis by EFB and TRUS-guided CNB were analyzed. RESULTS: Compared with postoperative pathology, the histopathologic discrepancy rate of EFB and TRUS-guided CNB was 51.0% (52/102 lesions) and 8.8% (9/102 lesions), respectively. The kappa value for consistency with postoperative pathology findings was 0.420 for EFB and 0.876 for TRUS-guided CNB. The multivariate analyses and receiver operating characteristic (ROC) curve indicated that lesions thickness ≥13.5 mm [OR 1.080 (95% CI: 1.021-1.142), P=0.007] and flat/depressed shape [OR 0.206 (95% CI: 0.076-0.564), P=0.002] were significantly associated with histopathologic discrepancies in EFB. CONCLUSIONS: EFB was of limited clinical value in identifying the preoperative diagnosis of rectal lesions. Lesions thickness and flat/depressed shape at EFB were independent risk factors for pathologic discrepancies. TRUS-guided CNB may serve as a safe and effective supplement to routine EFB.

Oxaliplatin-containing adjuvant chemotherapy improves the survival of locally advanced rectal cancer patients with pathological complete response after pre-operative chemoradiotherapy.

BACKGROUND: The necessity for adjuvant chemotherapy (ACT) in locally advanced rectal cancer (LARC) patients who achieve pathological complete response (pCR) after pre-operative chemoradiotherapy (CRT) is still not identified. We aimed to investigate the therapeutic value of ACT in these patients. METHODS: Clinical data were retrospectively collected from 105 consecutive LARC patients who achieved pCR after pre-operative CRT and underwent radical tumor resection between December 2008 and April 2014 in a comprehensive cancer center. Perioperative chemotherapy (CT) was administered by combining oxaliplatin with capecitabine (XELOX regimen). Disease-free survival (DFS) and overall survival (OS) rates of patients with or without ACT were compared. RESULTS: Eighty-three (79.0%) patients received ACT and 22 (21.0%) did not. With a median follow-up of 49 months, the ACT group had a significantly higher 3-year DFS rate (92.8 vs 86.4%, p = 0.029) and 3-year OS rate (95.1 vs 86.1%, p = 0.026) than the non-ACT group. In multivariable analyses, the presence of ACT was an independent prognostic factor for DFS (hazard ratio [HR]: 0.271; 95% confidence interval (CI): 0.080-0.916; p = 0.036) but not for OS. This benefit was more obvious in patients younger than 60 years via subgroup analysis (adjusted HR: 0.106; 95% CI: 0.019-0.606; p = 0.012). CONCLUSIONS: Oxaliplatin-containing ACT may confer survival benefits to patients with pCR, particularly younger patients. However, the routine use of ACT in patients with pCR needs further validation.

Neoadjuvant oxaliplatin and capecitabine combined with bevacizumab plus radiotherapy for locally advanced rectal cancer: results of a single-institute phase II study.

BACKGROUND: Neoadjuvant chemoradiotherapy followed by surgery is recommended as the standard of care for locally advanced rectal cancer, reducing local recurrence but not distant metastasis. Intensified systemic therapy is warranted to reduce the risk of distant metastasis. The present study aimed to evaluate the safety and efficacy of neoadjuvant oxaliplatin and capecitabine (XELOX) combined with bevacizumab plus radiotherapy for locally advanced rectal cancer. METHODS: Patients with stages II to III rectal cancer received one cycle of induction chemotherapy and concurrent chemoradiotherapy with XELOX plus bevacizumab. Surgery was performed 6-8 weeks after completion of radiotherapy, and postoperative chemotherapy with three cycles of XELOX and two cycles of capecitabine were given. The primary endpoints were pathologic complete response (pCR) rate and safety, and the secondary endpoints were 3-year overall survival and progression-free survival. RESULTS: Forty-five patients were enrolled between February 2013 and April 2015. All completed the neoadjuvant therapy. Seven patients (15.6%) refused subsequent surgical therapy for personal reasons, and the other 38 patients received radical resection, with a sphincter preservation rate of 84.2% and a pCR rate of 39.5%. Toxicity was acceptable, with grades 3-4 hematological toxicity and diarrhea observed in six and two patients, respectively. Incidence of anastomotic leak that required surgical intervention was 13.3%. After a median follow-up period of 37 months, five patients developed disease progression and two died of cancer. The 3-year overall survival rate and 3-year progression-free survival rate were 95.3% and 88.6%, respectively. CONCLUSIONS: The addition of bevacizumab to neoadjuvant chemoradiotherapy resulted in a satisfying pCR rate and 3-year survival, but also may increase the risk of anastomotic leak, thus this regimen is not suitable to be considered for regular recommendation for locally advanced rectal cancer. Trial registration Clinicaltrials.govidentifierNCT01818973.

Dihydroartemisinin inhibits colon cancer cell viability by inducing apoptosis through up-regulation of PPARγ expression.

The present study was aimed to investigate the effect of dihydroartemisinin on the colon cancer cell proliferation and apoptosis. The results from MTT assay revealed a concentration and time dependent relation between the inhibition of SW 948 cell viability and dihydroartemisinin addition. The viability of SW 948 cells was reduced to 45 and 24% on treatment with 30 and 50 µM, respectively concentrations of dihydroartemisinin after 48 h. Morphological examination of SW 948 cells showed attainment of rounded shape and cluster formation on treatment with dihydroartemisinin. Western blot analysis showed a significant increase in the activation of caspase-3 and expression of cleaved PARP by dihydroartemisinin treatment. The activation of PPARγ was increased significantly in SW 948 cells by treatment with dihydroartemisinin. Compared to control, the migration potential of SW 948 cells was reduced significantly (p < 0.005) and the expression levels of MMP-2 and -9 inhibited by dihydroartemisinin at 50 µM concentration. In the dihydroartemisinin treatment group colon tumor formation was significantly inhibited on treatment with 20 mg/kg doses of dihydroartemisinin after 30 days. Therefore, dihydroartemisinin inhibits colon cancer growth by inducing apoptosis and increasing the expression of PPARγ. Thus dihydroartemisinin can be used for the treatment of colon cancer.

The Immunoscore system predicts prognosis after liver metastasectomy in colorectal cancer liver metastases.

BACKGROUND: The Immunoscore was initially established to evaluate the prognosis of stage I/II/III colorectal cancer patients. However, the feasibility of the Immunoscore for the prognosis of colorectal cancer liver metastases (CRCLM) has not been reported. METHODS: Liver metastases in 249 CRCLM patients were retrospectively analyzed. The Immunoscore was assessed according to the counts and densities of CD3+ and CD8+ T cells in the central- and peritumoral areas by immunohistochemistry. The prognostic role of the Immunoscore for relapse-free survival (RFS) and overall survival (OS) was analyzed with Kaplan-Meier curves and Cox multivariate models, and confirmed via an internal validation. Receiver operating characteristic (ROC) curves were plotted to compare the prognostic values of the Immunoscore and the clinical risk score (CRS) system. RESULTS: CRCLM patients with high Immunoscores (> 2) had significantly longer RFS [median RFS (95% confidence interval; 95% CI) 21.4 (7.8-35.1) vs. 8.7 (6.8-10.5) months, P < 0.001] and OS [median OS (95% CI): not reached vs. 28.7 (23.2-34.2) months, P < 0.001] than those with low Immunoscores (≤ 2). After stratification by CRS, the Immunoscore retained a statistically significant prognostic value for OS. The areas under the ROC curves (AUROCs) of the Immunoscore and the CRS system for RFS were 0.711 [95% CI 0.642-0.781] and 0.675[95% CI 0.601-0.749] (P = 0.492), whereas the AUROC of the Immunoscore system for OS was larger than that of the CRS system [0.759 (95% CI 0.699-0.818) vs. 0.660 (95% CI 0.592-0.727); P = 0.029]. CONCLUSIONS: The Immunoscore of liver metastases can be applied to predict the prognosis of CRCLM patients following liver resection.

Lymphocyte-to-monocyte ratio before chemoradiotherapy represents a prognostic predictor for locally advanced rectal cancer.

Research indicates that cancer-triggered inflammation plays a pivotal role in carcinogenesis. Here, we aimed to evaluate the correlation of lymphocyte-to-monocyte ratio (LMR) before neoadjuvant chemoradiotherapy (CRT) with clinical outcomes in patients with locally advanced rectal cancer (LARC). We retrospectively enrolled 317 consecutive patients with LARC between 2004 and 2013. The optimal cutoff values of LMR were determined using receiver operating curve analysis. Overall survival (OS) and disease-free survival related to the LMR were analyzed using the log-rank test and multivariate Cox regression methods. We found that a low LMR (≤4.91) was prominently correlated with worse prognostic features and a shorter 3-year survival rate of LARC. Moreover, multivariate Cox analysis revealed that elevated LMR was an independent factor for better OS (hazard ratio 0.538, 95% confidence interval 0.292-0.991, P=0.047). In addition, univariate logistic regression analysis showed that the LMR was not associated with tumor pathologic regression. In conclusion, LMR is identified as a valuable prognostic marker for predicting the OS of LARC patients receiving CRT.

Pim-3 as a potential predictor of chemoradiotherapy resistance in locally advanced rectal cancer patients.

Approximately 30% of locally advanced rectal cancer patients might not benefit from chemoradiotherapy; however, the response to neoadjuvant chemoradiotherapy in these cases is difficult to predict. Pim-3 is a member of the provirus integration site for a moloney murine leukemia virus family of proteins that contributes to cell proliferation, survival, and chemotherapy resistance. Therefore, the relationship between Pim-3 expression and response to neoadjuvant chemoradiotherapy in rectal cancer patients is important to evaluate. 175 rectal cancer patients who underwent neoadjuvant treatment enrolled in this study. The relationship between Pim-3 expression on immunohistochemical analysis of rectal cancer tissue, which was obtained before treatment, the response to chemoradiotherapy and survival was investigated. The patients with no Pim-3 expression were more likely to achieve a pathologic complete response to chemoradiotherapy than patients with Pim-3 expression (P = 0.001). Cox multivariate analysis showed that the significant prognostic factors were Pim-3 expression (P = 0.003) and the number of neoadjuvant chemotherapy cycles (P = 0.005) for overall survival. Neoadjuvant chemotherapy cycles (P = 0.007), adjuvant chemotherapy cycles (P = 0.004) and pathology types (P = 0.049) were significant prognostic factors for disease-free survival. Pim-3 is a potential predictive biomarker for the response of rectal cancer to chemoradiotherapy.

Pathologic response after preoperative therapy predicts prognosis of Chinese colorectal cancer patients with liver metastases.

BACKGROUND: Pathologic response is evaluated according to the extent of tumor regression and is used to estimate the efficacy of preoperative treatment. Several studies have reported the association between the pathologic response and clinical outcomes of colorectal cancer patients with liver metastases who underwent hepatectomy. However, to date, no data from Chinese patients have been reported. In this study, we aimed to evaluate the association between the pathologic response to pre-hepatectomy chemotherapy and prognosis in a cohort of Chinese patients. PATIENTS AND METHODS: In this retrospective study, we analyzed the data of 380 liver metastases in 159 patients. The pathologic response was evaluated according to the tumor regression grade (TRG). The prognostic role of pathologic response in recurrence-free survival (RFS) and overall survival (OS) was assessed using Kaplan-Meier curves with the log-rank test and multivariate Cox models. Factors that had potential influence on pathologic response were also analyzed using multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests. RESULTS: Patients whose tumors achieved pathologic response after preoperative chemotherapy had significant longer RFS and OS than patients whose tumor had no pathologic response to chemotherapy (median RFS: 9.9 vs. 6.5 months, P = 0.009; median OS: 40.7 vs. 28.1 months, P = 0.040). Multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests showed that metastases with small diameter, metastases from the left-side primary tumors, and metastases from patients receiving long-duration chemotherapy had higher pathologic response rates than their control metastases (all P < 0.05). A decrease in the serum carcinoembryonic antigen (CEA) level after preoperative chemotherapy predicted an increased pathologic response rate (P < 0.05). Although the application of targeted therapy did not significantly influence TRG scores of all cases of metastases, the addition of cetuximab to chemotherapy resulted in a higher pathologic response rate when combined with irinotecan-based regimens rather than with oxaliplatin-based regimens. CONCLUSIONS: We found that the evaluation of pathologic response may predict the prognosis of Chinese colorectal cancer patients with liver metastases after preoperative chemotherapy. Small tumor diameter, long-duration chemotherapy, left primary tumor, and decreased serum CEA level after chemotherapy are associated with increased pathologic response rates.

Endocrine therapy inhibits proliferation and migration, promotes apoptosis and suppresses survivin protein expression in colorectal cancer cells.

The majority of colorectal cancers (CRCs) are hormone­dependent. Thus, endocrine therapy has become an attractive strategy to treat CRC. The aim of the present study was to investigate the inhibitory effect of combined tamoxifen (TAM) plus ß­estradiol (E2) treatment on human DLD­1 CRC cells. The human DLD­1 CRC cell line was treated with different concentrations of TAM, ß­estradiol, or a combination of these two agents. Cell viability was assessed using an MTT assay, while apoptosis was detected using flow cytometry analysis. Alterations in the RNA and protein levels of the apoptosis­associated factors cyclin D1 and survivin were measured in the treated DLD­1 cells using semi­quantitative polymerase chain reaction (sqPCR) and western blot analyses. Alterations in cellular migration ability were monitored using a Transwell migration assay. Treatment with TAM, ß­estradiol and TAM plus ß­estradiol inhibited DLD­1 cell viability. The flow cytometry results revealed that these drugs promoted cell apoptosis, and the Transwell migration assay results indicated that the reduction in cell migration was greater in the TAM+E2 treatment group when compared with each treatment alone. sqPCR and western blot analysis results demonstrated that TAM, E2 and a combination of the two affected survivin expression based on the drug concentration and the treatment duration; however, they demonstrated no significant effect on cyclin D1 expression. In conclusion, treatment of DLD­1 cells with TAM, ß­estradiol, or a combination of these two drugs, inhibited cell viability and migration, promoted cell apoptosis, and reduced the mRNA and protein expression levels of survivin in a dose­ and time­dependent manner. These results provide novel experimental basis for hormonal adjuvant therapy for the treatment of CRC.