Chinese Metastatic Colorectal Cancer Research Articles

Does physical activity associate with gut microbiome and survival outcomes of Chinese metastatic colorectal cancer patients? A secondary analysis of a randomized controlled trial

BackgroundThis study aimed to evaluate associations between physical activities, gut microbiome and survival outcomes among Chinese metastatic colorectal cancer (mCRC) patients. MethodsWe conducted a secondary analysis nested in a randomized controlled clinical trial (RCT) of a traditional Chinese herbal medicine for mCRC patients (ChiCTR2000029599). After one-month intervention, we followed up patients every six months for survival outcomes and the last follow-up was in August 2022 (median follow-up time 28.6 months). We assessed patients’ physical activity (PA) through short form of the International Physical Activity Questionnaire (IPAQ-SF) and collected patients’ stool samples at baseline. Kaplan–Meier survival analyses and Cox regression models were used to evaluate the association between PA level and overall survival outcomes. 16S rRNA sequencing approaches were utilized for the gut microbiome analysis. ResultsAmong 40 mCRC patients enrolled in the original RCT, 15 patients were still alive at the time of the last follow-up. The mean IPAQ score was 2569.5 MET-min/week for all patients, indicating a moderate PA level. Specifically, there were 7 patients in high PA level group, 2 patients in low PA level group and the rest were in middle PA group. Gut microbiome community difference analysis showed that patients with high PA levels had a significantly higher alpha diversity than that of the middle PA group (131.53 vs. 98.12, p = 0.04), an increased abundance of Phascolarctobacterium and Ruminococcaceae and a decreased abundance of Megasphaera at the genus level. Cox regression model showed that after controlling for the original tumor site and TCM treatment, high PA level was independently associated with a lower risk of death (relative risk 0.13, p = 0.014). ConclusionsHigh PA level could be associated with survival benefits among Chinese mCRC patient through its potential role on modulating gut microbiome. Our results could be referred to patients’ education and future clinical study design.

A multiple centers real-world study of regorafenib treatment modalities in Chinese metastatic colorectal cancer patients.

e15543 Background: To evaluate the efficacy and safety of different treatment modalities of regorafenib in patients with previously treated metastatic colorectal cancer (mCRC) in the real-world setting. Methods: Individual patient data were retrieved from three leading oncology centers in China from January 2016 to March 2021. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS) and safety. Results: The characteristics of patients who received treatment are shown in the table. Twenty-one patients received regorafenib combined with capecitabine as the second-line treatment for those who cannot visit hospital for their chemotherapies because of the COVID-19 pandemic. The median PFS and median OS were 8 (95% CI 4.36 - 11.00) months and 26.9 (95%CI 20.54 -NR) months. 101 patients received regorafenib and 69 patients received regorafenib plus immune checkpoint inhibitor (ICIs) as third or higher line treatment, the overall response was 4.1%(7/170), including one complete response. Patients combined with ICIs have longer PFS than those with regorafenib monotherapy (median PFS = 3.3 versus 2.1 months; p = 0.01). Starting dose was 80、120 and 160 mg in 64、40 and 39 patients, respectively. Dose reduction was observed in 43.3% (39/79) of patients receiving 120 and 160 mg as the initial dose. Conclusions: Different treatment modalities of regorafenib all showed promising efficacy and safety in the treatment of mCRC. Regorafenib combination is better than regorafenib monotherapy. Regorafenib combined with capecitabine provided a new treatment strategy during the epidemic but requires further investigation. Key words:Colorectal cancer; Regorafenib; Immune check point inhibitors; Real world[Table: see text]

Efficacy, treatment modalities, and safety of regorafenib in Chinese metastatic colorectal cancer patients: A multiple centers real-world study.

e15569 Background: For patients with refractory metastatic colorectal cancer (mCRC) treatment with regorafenib improved the overall survival (OS) in two phase 3 trials. Regorafenib has been recognized as a standard third line treatment in mCRC. However, the efficacy and safety of regorafenib in real world for Chinese patients is lacking. Methods: Patients of mCRC treated with at least one cycle of regorafenib (40, 80, 120 or 160mg OD for 21 days, as a 28-day cycle) from August 2017 to June 2020 in three Chinese medical centers were enrolled. Data of demographic, treatment, dosimetry, safety and survival was collected retrospectively. The primary endpoint was OS. Secondary endpoints were progression free survival (PFS), objective response rate (ORR), disease control rate (DCR) and the incidence of adverse events (AEs). Results: 372 patients were enrolled, of whom 266 (71.5%) accepted regorafenib alone and 106 (28.5%) received combination therapy with regorafenib. In these patients, 75 (20.16%) and 275 (73.9%) patients received regorafenib as third or higher line treatment. Starting dose was 160mg in 93 (25.0%) patients, 120mg in 74 (19.9%) patients, 80mg in 142 (38.2%) patients and 40mg in 7 (1.9%) patients. The maintenance dose was confirmed in 236 patients. Among them, 111 (46.6%) and 75 (31.8%) accepted 80 and 120mg as the last daily dose. Only 50 (21.2%) patients could receive 160mg as a long-term therapy. Median follow-up time was 15.2 months. ORR and DCR were 3.8% and 55.3%. The mPFS was 3.1 months (95%CI: 2.50-3.53) and mOS was 10.2 months (95% CI: 9.27-11.93) . The mOS of 80, 120 and 160mg last daily dose were 10.5, 14.1 and 14.3 months, respectively. Patients received regorafenib in combination with other drugs including chemotherapy or PD-1 inhibitor had longer survival compared with regorafenib alone with mOS of 15.5 (95% CI: 10.1-19.0) and 9.7 months (95% CI: 7.8-11.0) (p = 0.004). The mOS of patients developed lung metastasis and the counterpart with liver metastasis was13.3 versus 9.7 months. The common AEs were anemia (26.1%), hyperbilirubinemia (25.3%), liver injury (24.7%), thrombocytopenia (18.0%) and recorded hand-foot skin reaction (HFSR) (19.6%). The most common grade 3-4 AEs included hyperbilirubinemia (3.5%), recorded HFSR (3.5%), anemia (2.2%) and thrombocytopenia (1.1%). Due to most patients was reviewed in clinic, some data of AEs was missing or incomplete. Conclusions: In the real world, regorafenib showed promising efficacy and manageable toxicities in Chinese patients with refractory mCRC. The dose of 120mg of regorafenib seemed to have a similar survival benefit compared with 160mg. In addition to a better tolerance, 120mg may be a more suitable dose for Chinese mCRC patients. Clinical trial information: NCT04735991. [Key words] Colorectal cancer; Regorafenib; Real world

Role of circulating free DNA in evaluating clinical tumor burden and predicting survival in Chinese metastatic colorectal cancer patients

BackgroundThe aim of this study was to explore the utility of circulating free DNA (cfDNA) in the evaluation of clinical tumor burden and survival in Chinese patients with metastatic colorectal cancer (mCRC) and to preliminarily summarize some metastatic characteristics associated with mutational status.MethodsA panel covering a total of 197 hotspot mutations of KRAS, NRAS, BRAF and PIK3CA was used to evaluate the mutational status in plasma by next-generation sequencing (NGS) technology in 126 patients with mCRC. An amplification-refractory mutation system (ARMS) was used to analyze genomic DNA from matched tissue samples. Clinical markers including carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), carbohydrate antigen 125 (CA125), neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) in serum and the sum of all tumor diameters on CT or PET/CT were collected to indicate clinical tumor burden. The correlations between cfDNA and clinical tumor burden were analyzed using Pearson correlation and linear regression models. The median progression-free survival (PFS) and 1-year overall survival (OS) rates were calculated by Kaplan-Meier (K-M) survival analysis.ResultsOf the 126 enrolled patients, patients who were tested positive for mutations in plasma accounted for 45.2% (57/126). Mutations in KRAS, NRAS, BRAF and PIK3CA were detected in 37.3% (47/126), 1.6% (2/126), 3.2% (4/126) and 13.5% (17/126) of patients, respectively. The overall concordance rate of mutational status between plasma and matched tissues was 78.6% (99/126). Sixteen patients had mutations in plasma that were not detected in tissue, including some rare hotspot mutations. The cfDNA concentration was significantly correlated with the levels of clinical markers, especially CEA (P < 0.0001, Pearson r = 0.81), LDH (P < 0.0001, Pearson r = 0.84) and the sum of tumor diameters (P < 0.0001, Pearson r = 0.80). Patients with a high cfDNA concentration (> 17.91 ng/ml) had shorter median progression-free survival (6.6 versus 11.7 months, P < 0.0001) and lower 1-year overall survival rate (56% versus 94%, P < 0.0001) than those with a low cfDNA concentration (≤17.91 ng/ml). The most common metastatic site was the liver (77.8%), followed by the lymph nodes (62.7%), lung (40.5%), peritoneum (14.3%) and bone (10.3%), in all patients. There was no significant difference in metastasis between different mutational statuses.ConclusionAnalyzing mutations in plasma could provide a more comprehensive overview of the mutational landscape than analyzing mutations in tissue. The cfDNA concentration could be a quantitative biomarker of tumor burden and could predict survival in Chinese patients with mCRC.

Association between hand-foot skin reaction (HFSR) and survival benefit of fruquintinib in FRESCO trial.

e15012 Background: In phase 3 FRESCO trial, fruquintinib demonstrated a statistically significant and clinically meaningful overall survival benefit in Chinese metastatic colorectal cancer (mCRC) patients. As a known adverse effect of vascular endothelial growth factor receptor (VEGFR) inhibitors, hand-foot skin reaction (HFSR) was commonly reported as a drug-related adverse event (AE) in fruquintinib group. This retrospective analysis explored whether HFSR in fruquintinib group is associated with survival benefit in FRESCO. Methods: This analysis used a subpopulation of intent-to-treat population who at least completed one cycle and entered cycle two of fruquintinib treatment. Patients randomized to receive fruquintinib 5 mg/day during the first 3 weeks of each 4-week cycle were divided into subgroups based on whether they reported HFSR. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method. Hazard ratio (HR) was estimated through Cox proportional hazards model. P-value was generated from log-rank test. Results: Among a total of 255 fruquintinib-treated patients who at least completed one cycle and entered cycle two, 52% (n = 133) reported HFSR of any grade. The median time-to-onset of HFSR (any grade) was 21 days and approximate 75% patients reported HFSR after cycle two treatment completion. The baseline characteristics were well balanced between HFSR reported and non-reported subgroups. Patients who reported HFSR showed both OS and PFS benefit with statistical significant difference comparing with HFSR non-reported patients in fruquintinib group. Fruquintinib significantly decreased 43% death risk in HFSR reported patients and prolonged the median OS to 11.14 months in comparison with HFSR non-reported patients (median: 11.24 vs 7.54 months; HR = 0.57, 95% CI: 0.42-0.78; p &lt; 0.001). Similarly, Patients reported HFSR had a significantly longer PFS than those who did not reported HFSR in the fruquintinib group (median: 5.49 vs 3.48 months; HR = 0.70, 95% CI: 0.54-0.91; p = 0.008). Conclusions: This post-hoc analysis indicates that patients who had HFSR had a greater survival benefit from fruquintinib in Chinese mCRC patients. Clinical trial information: NCT02314819 .

PCN145 COST EFFECTIVENESS OF FRUQUINTINIB VERSUS REGORAFENIB AS THE THIRD-LINE THERAPY FOR PATIENTS WITH METASTATIC COLORECTAL CANCER IN CHINA

This study aimed to assess the cost-effectiveness of Fruquintinib versus Regorafenib as the third-line therapyfor patients with metastatic colorectal cancer in China. A Three-state Markov model with monthly cycle was developed to estimate lifetime incremental cost-effectiveness ratio (ICER) of Fruquintinib versus Regorafenib as the third-line therapy for patients with metastatic colorectal cancer from Chinese health-care system perspective. Survival analysis was conducted to calculate transition probabilities using the data from two clinical trials (FRESCO and CONCUR) from which we also extracted the incidence of adverse events. Mortality rate and drug costs were derived from government published data. Costs for medical services were obtained from published literatures and a real world study about economic burden of Chinese metastatic colorectal cancer patients. Utilities applied to calculate the quality adjusted life years (QALYs) were obtained through literature review. Costs and QALYs were discounted at a 5% annual rate. One way sensitivity analysis and probabilistic sensitivity analysis were conducted to demonstrate the robustness of the results. Fruquintinib provided 0.74 QALYs at a cost of CNY 177863.75, whereas Regorafenib provided 0.79 QALYs at a cost of CNY 248277.29. Compared to Fruquintinib, the ICER of Regorafenib was CNY 1416749.10/QALY, which was above three times GDP per capita of China in 2017 (CNY 59660) as the threshold to define the cost-effectiveness. One-way sensitivity analysis showed the results were generally robust. Cost-effectiveness acceptability curves derived from the probabilistic sensitivity analysis demonstrated that Fruquintinib was 100% more cost-effective, when the threshold was three times GDP per capita of China. Compared to Regorafenib, Fruquintinib can be regarded as a cost-effective choice as the third-line therapy for patients with metastatic colorectal cancer in China.

PCN67 - Treatment Patterns and Economic Burden of Chinese Metastatic Colorectal Cancer Patients: a Retrospective Study of Electronic Medical Records from Urban China

PCN67 - Treatment Patterns and Economic Burden of Chinese Metastatic Colorectal Cancer Patients: a Retrospective Study of Electronic Medical Records from Urban China

SMAD4 and NF1 mutations as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese metastatic colorectal cancer patients

BackgroundCetuximab, an anti-EGFR monoclonal antibody, is used in combination with chemotherapy in clinic to enhance the outcome in metastatic colorectal cancer (mCRC) patients with only ~ 20% response rate. To date only activating mutations in KRAS and NRAS have been identified as poor prognosis biomarkers in cetuximab-based treatment, which makes an urgent need for identification of novel prognosis biomarkers to precisely predict patients’ response in order to maximize the benefit.MethodsIn this study, we analysed the mutation profiles of 33 Chinese mCRC patients using comprehensive next-generation sequencing (NGS) targeting 416 cancer-relevant genes before cetuximab treatment. Upon receiving cetuximab-based therapy, patients were evaluated for drug response, and the progression-free survival (PFS) was monitored. The association of specific genetic alterations and cetuximab efficacy was analyzed.ResultsPatients carrying SMAD4 mutations (SMAD4mut, n = 8) or NF1 mutations (NF1mut, n = 4) had significantly shorter PFS comparing to those carrying wildtype SMAD4 (SMAD4wt, n = 25) (P = 0.0081) or wildtype NF1 (NF1wt, n = 29) (P = 0.0028), respectively. None of the SMAD4mut or NF1mut patients showed response to cetuximab when assessed at 12-week post-treatment. Interestingly, two patients carrying both SMAD4mut and NF1mut showed the shortest PFS among all the patients.ConclusionsOur results demonstrated that SMAD4 and NF1 mutations can serve as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese mCRC patients.

A prospective, multicenter, observational study of bevacizumab in combined with chemotherapy as first-line or second-line treatment in Chinese metastatic colorectal cancer.

e15012Background: Bevacizumab (BV) was approved in February 2010 in China with indication of combined with 5-FU for metastatic colorectal cancer (mCRC). Post-marketing surveillance of patients (Pts...

Potentially functional SNPs (pfSNPs) as novel genomic predictors of 5-FU response in metastatic colorectal cancer patients.

5-Fluorouracil (5-FU) and its pro-drug Capecitabine have been widely used in treating colorectal cancer. However, not all patients will respond to the drug, hence there is a need to develop reliable early predictive biomarkers for 5-FU response. Here, we report a novel potentially functional Single Nucleotide Polymorphism (pfSNP) approach to identify SNPs that may serve as predictive biomarkers of response to 5-FU in Chinese metastatic colorectal cancer (CRC) patients. 1547 pfSNPs and one variable number tandem repeat (VNTR) in 139 genes in 5-FU drug (both PK and PD pathway) and colorectal cancer disease pathways were examined in 2 groups of CRC patients. Shrinkage of liver metastasis measured by RECIST criteria was used as the clinical end point. Four non-responder-specific pfSNPs were found to account for 37.5% of all non-responders (P<0.0003). Five additional pfSNPs were identified from a multivariate model (AUC under ROC = 0.875) that was applied for all other pfSNPs, excluding the non-responder-specific pfSNPs. These pfSNPs, which can differentiate the other non-responders from responders, mainly reside in tumor suppressor genes or genes implicated in colorectal cancer risk. Hence, a total of 9 novel SNPs with potential functional significance may be able to distinguish non-responders from responders to 5-FU. These pfSNPs may be useful biomarkers for predicting response to 5-FU.

Impact ofKRASmutation and PTEN expression on cetuximab-treated colorectal cancer

To investigate the prognostic value of KRAS mutation, and phosphatase and tensin (PTEN) expression in Chinese metastatic colorectal cancer metastatic colorectal cancer (mCRC) patients treated with cetuximab. Ninety Chinese mCRC patients treated with cetuximab were evaluated for KRAS mutation and PTEN protein expression by DNA sequencing of codons 12 and 13 and immunohistochemistry, respectively. We then selected 61 patients treated with cetuximab, either in combination with chemotherapy, or alone as a second-line or third-line regimen to assess whether KRAS mutation or PTEN protein expression is associated with the response and the survival time of mCRC patients treated with cetuximab. KRAS mutation was found in 30 (33.3%) tumor samples from the 90 patients, and positive PTEN expression was detected in 58 (64.4%) of the 90 patients. Among the 61 patients who were treated with cetuximab as a second-line or third-line regimen, the resistance to cetuximab was found in 22 patients with KRAS mutation and in 39 patients without KRAS mutation, with a response rate of 4.5% and 46.1% respectively (P = 0.001), a shorter median progression-free survival (PFS) time of 14 ± 1.3 wk and 32 ± 2.5 wk respectively (P < 0.001), a median overall survival (OS) time of 11 ± 1.2 mo and 19 ± 1.8 mo respectively (P < 0.001), as well as in 24 patients with negative PTEN expression and in 37 patients with positive PTEN expression respectively (P < 0.001), with a responsive rate of 4.2% and 48.6% respectively, a shorter median PFS survival time of 17 ± 2.0 wk and 28 ± 1.9 wk respectively (P = 0.07), and a median OS time of 11 ± 1.3 mo and 18 ± 1.9 mo respectively (P = 0.004). Combined KRAS mutation and PTEN expression analysis showed that the PFS and OS time of patients with two favorable prognostic factors were longer than those of patients with one favorable prognostic factor or no favorable prognostic factor (P < 0.001). KRAS mutation and PTEN protein expression are significantly correlated with the response rate and survival time of Chinese mCRC patients treated with cetuximab.

Clinical significance of a transient increase in carcinoembryonic antigen and carbohydrate antigen 19-9 in patients with metastatic colorectal cancer receiving chemotherapy

An increase in carcinoembryonic antigen (CEA) and/or carbohydrate antigen 19-9 (CA19-9) levels is generally considered as tumor progression in patients with metastatic colorectal cancer (MCRC). However, a transient CEA surge has been observed in patients with MCRC responding to chemotherapy. This study was to investigate the clinical significance of transient CEA/CA19-9 surges in Chinese MCRC patients. One hundred and twenty-one MCRC patients with histologically proven adenocarcinoma and baseline ECOG performance status of < or =2 were treated with oxaplatin and (or) irinotecan-based chemotherapy regimens. Serum CEA and CA 19-9 levels were measured before and after chemotherapy. Of the 121 patients, 14 (11.6%) had transient CEA surges with median baseline CEA level of 45 microg/L (9.67-2208 microg/L) and median surge peak level of 80.1 microg/L (13.38-4044 microg/L). The transient CEA surge occurred at a median of 4 weeks (2-6 weeks), and lasted for a medium of 6.5 weeks (4-14 weeks). Of the 14 patients, 11 received oxaplatin-based chemotherapy; three received irinotecan-based chemotherapy. All the 14 patients showed clinical benefit from chemotherapy, among which seven achieved partial response and seven had stable disease. In the meantime, five patients (3.8%) had transient CA19-9 surges. However, no significant correlation was found between an increase in the CA19-9 level and clinical benefits. Transient CEA surges can be observed in Chinese MCRC patients receiving oxaplatin or irinotecan-based chemotherapy, which does not indicate tumor progression, but good therapeutic efficacy. A transient elevation of CA19-9 is not correlated to short-term clinical benefits.

XELOX causes less disabling peripheral neuropathy than FOLFOX 4 for Chinese colorectal cancer patients

14592 Background: Infusional 5-FU plus leucovorin and oxaliplatin (FOLFOX4) is an efficacious treatment for colorectal cancer patients in both the adjuvant and metastatic settings. However, around 10% of FOLFOX4 patients will develop with disabling grade 3–4 neuropathy. Recent phase II studies have demonstrated that oral capecitabine in combination with oxaliplatin (XELOX) is as least as effective as FOLFOX4 for colorectal cancer. In this study, we assessed the toxicities of XELOX in Chinese colorectal cancer patients. Methods: Patients who received XELOX at Queen Mary Hospital, Hong Kong between November 2004 and November, 2006 were analyzed. Toxicities were graded by the National Cancer Institute common toxicity system. Results: Thirty-five patients received XELOX on an outpatient basis during the study period: Twenty-four as adjuvant therapy and 11 as treatment for metastatic disease. The most common side effect was grade 1–2 peripheral neuropathy which occurred in 77% of patients. No grade 3–4 neuropathy was reported. Grade 1–2 diarrhea and palmar-plantar erythrodysesthesia (PPE) also occurred in 40 % and 37 % of patients, respectively. The commonest grade 3 toxicities was diarrhea which occurred in 17% of the patients followed by 9% of patients experienced grade 3 PPE. No grade 4 toxicities were reported in our patient’s cohort. Overall, only one (3%) patient had neutropenic sepsis and 36% of patients required 20% reduction in drug dosage. No treatment related death was reported. Conclusions: Our study suggests that XELOX is a well-tolerated and convenient treatment regime. Although mild neuropathy is common in patients receiving XELOX, it causes far less disabling neuropathy than FOLFOX4 in Chinese metastatic colorectal cancer patients. No significant financial relationships to disclose.