Treatment Of Advanced Colorectal Cancer Research Articles

Updates, Controversies, and Emerging Approaches in Colorectal Screening.

Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related deaths. Despite the threatening statistics, the US burden for CRC has been decreasing, which is likely multifactorial and has partial contribution from widespread timely screening, more advanced CRC treatment, and daily aspirin use in some patients. While overall death rate from CRC decreased by approximately a half between 1975 and 2012, epidemiologic studies demonstrate that CRC incidence is increasing in the younger population. This pattern has prompted the American Cancer Society (ACS) to revise their guidelines. In this review, we plan to discuss the most recent changes in guidelines, data to support them, controversies concerning CRC screening methods, age to start and to stop screening, and post-colonoscopy/polypectomy surveillance guidelines.

422P The efficacy and safety of irinotecan plus raltitrexed as second-line treatment in advanced colorectal cancer (ACC) patients: A summary analysis of a multicenter, phase II trial

Colorectal cancer (CRC) is the third most common cancer. There are limited therapeutic options for the treatment of advanced CRC which fail first-line chemotherapy. Pre-clinical and phase I/II studies have shown that the combined application of the irinotecan and raltitrexed has significant synergistic effect and acceptable toxicity. The aim of this multicenter study was to assess the efficacy and toxicity of second-line raltitrexed plus irinotecan in Chinese patients with advanced colorectal cancer.

428P Retrospective cohort study of low-dose apatinib plus S-1 versus regorafenib and fruquintinib for refractory metastatic colorectal cancer

Colorectal cancer (CRC) is the fifth most common cancer and one of the leading causes of cancer-related death in China. Although apatinib and S-1, respectively, are used in the treatment of advanced colorectal cancer, the efficacy and safety of the combination of the two drugs are unclear. The aim of this study was to investigate the efficacy and safety of low-dose apatinib plus S-1 compared with regorafenib and fruquintinib in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies.

509TiP REPROGRAM-01, a phase II study of regorafenib in combination with a multimodal metronomic chemotherapy in patients with metastatic colorectal cancer

Angiogenesis is associated with tumor progression, and antiangiogenic molecules have become a cornerstone in the treatment of advanced colorectal cancer (CRC). Regorafenib is a multi-kinase inhibitor targeting VEGFR1, 2, 3, TIE2, KIT, RET, RAF-1, BRAF, BRAFV600E, PDGFR, FGFR, and is an effective option in 20-25% of heavily pre-treated patients. Other therapies target the tumoral micro-environment, as metronomic chemotherapy (CT), with continuous low dose administration of a cytotoxic agent. This allows an anti-tumor effect, an anti-angiogenic activity, a stimulation of the immune system, and a better tolerance.

The efficacy and safety of bevacizumab combined with FOLFOX regimen in the treatment of advanced colorectal cancer: A systematic review and meta-analysis.

Background:It is necessary to systematically evaluate the clinical efficacy and safety of bevacizumab (BEV) combined with 5-fluorouracil + leucovorin + oxaliplatin (FOLFOX) regimen in the treatment of advanced colorectal cancer.Methods:We searched the PubMed et al databases for randomized controlled trials (RCTs) on the BEV combined with the FOLFOX regimen in the treatment of advanced colorectal cancer up to January 20, 2021. The Cochrane Collaborations’ risk of bias tool was used for the quality assessment of included RCTs. Revman5.3 software was used for meta-analysis.Results:Eleven RCTs with a total of 3178 patients with advanced colorectal cancer were included, meta-analysis results showed that the objective response rate (odds ratio [OR] = 3.15, 95% confidence intervals [CI]: 2.25–4.40, P < .001) and cancer control rate (OR = 2.73, 95% CI: 1.91–3.90, P < .001) of BEV + FOLFOX were higher than that of FOLFOX group. And the incidence of gastrointestinal adverse reactions (OR = 1.29, 95% CI: 1.07–1.55, P = .008) in the BEV + FOLFOX group was higher than that of the FOLFOX group, there were no significant differences in the incidence of leukopenia (OR = 1.04, 95% CI: 0.72–1.50, P = .83), hypertension (OR = 3.92, 95% CI: 0.81–18.88, P = .09) and neurotoxicity (OR = 1.00, 95% CI: 0.8–1.27, P = .98) between the 2 groups.Conclusion:BEV combined with the FOLFOX regimen is more effective than the FOLFOX regimen alone in the treatment of advanced colorectal cancer, but it may also increase the risk of gastrointestinal adverse reactions.

18F-FDG PET/CT Imaging Features of Cardiac Arrhythmia in a Patient Treated with Panitumumab

Panitumumab is a new humanized antiepidermal growth factor receptor monoclonal antibody (mAb) approved for the treatment of advanced colorectal cancer. There is an increase in the use of this drug due to a good response rate and possible secondary resection in advanced colorectal cancer. Here, we present 18F-FDG PET/CT imaging findings of cardiac arrhythmia in a patient receiving panitumumab for the treatment of metastatic infiltrating rectal adenocarcinoma. Cardiotoxicity is a known adverse effect associated with panitumumab. So far, to our knowledge, no documented imaging findings for the same are available in the literature.

Evaluation of Micro Satellite Instability and Mismatch Repair Status in Different Solid Tumors: A Multicenter Analysis in a Real World Setting.

Immune-checkpoint inhibitors (ICIs) play a key role in the treatment of advanced stage colorectal cancer (CRC) patients featuring a deficient DNA mismatch repair (dMMR) system or a high microsatellite instability (MSI-H) profile. However, beyond the established role in CRC patients, ICIs have highly proven efficacy in other solid tumors featuring MSI-H/dMMR status represented by endometrial, gastric, ovarian, prostatic, and pancreatic carcinomas (EC, GC, OC, PrC, and PaC). Our aim was to compare the concordance rates among the Idylla™ MSI test, TapeStation 4200, and immunohistochemical (IHC) analysis in assessing MSI-H/dMMR status in EC, GC, OC, PrC, and PaC patients. The Sanger sequencing-based Titano MSI test was used in discordant cases. One hundred and eighty-five cases (n = 40 PrC, n = 39 GC, n = 38 OC, n = 35 PaC, and n = 33 EC) were retrospectively selected. MMR protein expression was evaluated by IHC. After DNA quality and quantity evaluations, the IdyllaTM and TapeStation 4200 platforms were adopted for the evaluation of MSI status. Remarkably, compared to IHC, the Idylla™ platform achieved a global concordance rate of 94.5% (154/163) for the microsatellite stable (MSS)/proficient MMR (pMMR) cases and 77.3% (17/22) for the MSI-H/dMMR cases. Similarly, a global concordance rate of 91.4% (149/163) and 68.2% (15/22) for MSS/pMMR and MSI-H/dMMR cases was also identified between IHC and the TapeStation 4200 microfluidic system. In addition, a global concordance of 93.1% (148/159) and 69.2% (18/26) for MSS/pMMR and MSI-H/dMMR cases was observed between the Idylla™ and TapeStation 4200 platforms. Discordant cases were analyzed using the Titano MSI kit. Overall, our data pinpointed a central role for molecular techniques in the diagnostic evaluation of dMMR/MSI-H status not only in CRC patients but also in other types of solid tumors.

P-240 The diagnosis and treatment of advanced colorectal cancer in China: A national multi-center cross-sectional study

Colorectal cancer is the third most common malignant tumors globally, affecting public health seriously. In decades, the disease burden of colorectal cancer in China has been increasing significantly. However, the profile for colorectal cancer patients, especially advanced stage groups, is still not clear currently. Therefore, the current study was designed to determine the situation related to the diagnosis and treatment for advanced colorectal cancer patients.

Retrospective pilot study of regorafenib combined with ICIs in the third-line treatment of advanced colorectal cancer.

e15582 Background: An increasing number of patients with advanced colorectal cancer tend to receive third-line treatment. Although there are several treatment options, concerns about efficacy and adverse events still remained. Regorafenib seems to enhance the effect of immune checkpoint inhibitors (ICIs) by modulate tumor microenvironment. In the absence of stage III clinical trial data, the real-world study might show certain clinical value. Methods: From Aug 2019 to June 2020, 23 advanced MSS colorectal cancer patients underwent third-line treatment of regorafenib combined with ICI. All patients received regorafenib 80 mg QD for 21 days, as a 28-day cycle, combined with ICIs until disease progression or intolerable adverse events. We retrospectively collected the overall response data, survival data and adverse events data from these patients. Results: The characteristics of all 23 patients is shown in the table. All patients had received at least 2 lines of prior systemic chemotherapy, the median time from diagnosis to third-line treatment was 31 months. The overall response rate was 26% (6/23), including one complete response. Almost all the responders were male (5/6) and with pulmonary metastasis (5/6). The disease control rate was 60% (14/23). The progression free survival ranges from 0.69 month to 19.3 months (median 4.8 months), with 6 patients continued response and constantly treatment. Duration of response range from 6.4 months to 19.4 months. Serious adverse events were hepatitis occurred in two patients and lead to the termination of subsequent anticancer therapy, which was considered to be related to immunotherapy. Conclusions: Regorafenib combined with ICIs might favor a certain group of advanced colorectal cancer patients, with a acceptable response rate and comparatively long duration of response. Interestingly, this retrospective pilot study was in consistence with that of REGONIVO trials to some extent for that the male patients with pulmonary metastasis appeared to response better. Key words: colorectal cancer; regorafenib; immune check point inhibitors Clinical characteristics of 23 patients.[Table: see text]

A retrospective study of local hepatic artery infusion chemotherapy combined with regorafenib in the treatment of advanced colorectal cancer with predominant liver metastases.

e15563 Background: The hepatic arterial infusion chemotherapy (HAIC) as a second/third-line therapy has resulted in promising clinical outcomes for unresectable liver metastatic colorectal cancer (CRC). HAIC combined with regorafenib has not been reported for advanced CRC patients with predominant liver metastases. This retrospective study explored the benefits and tolerability in advanced hepatic metastatic CRC patients who received HAIC combined with regorafenib after failure of standard systemic chemotherapy. Methods: This retrospective study collected and analyzed 47 patients treated with HAIC in combination with regorafenib after standard systemic oxaliplatin and/or irinotecan in combination with Bevacizumab or Cetuximab between Jan 2017 and Jun 2020 at the Beijing cancer hospitals in China. Regorafenib was taken for 3 weeks every 4-week cycles and mostly taken 5-7 days before or after the first HAIC. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were observed. Results: Among these 47 patients, 32(68%) were males. The median age was 61 (range: 29-75) . The median follow-up was 22.2 months (range:3.7-50.7 months). Before receiving HAIC in combination with regorafenib, 34 (72.3%) patients had previously received ≥ 2 prior lines of systemic therapy and 37 (78.7%) patients had previously received targeted biological treatment (anti-VEGF or anti-EGFR, or both).These patients underwent HAIC for a median of 4 sessions (range2--8,). The starting doses of regorafenib were 40 mg/d (n = 1, 2.13%), 80 mg/d (n = 11, 23.43%), 120 mg/d (n = 2, 4.26%), and 160 mg/d (n = 23, 48.94%). The median OS was 22.2 months. The median PFS was 10.8 (95% CI: 9.0-13.7) months. The ORR was 51.3% and DCR was 100% among 39 patients whose tumor responses were evaluated in the liver. The ORR was 13.8% and DCR was 48.3% among 29 patients whose tumor responses were evaluated outside the liver. Toxicity profile of regorafenib was as expected, with common AE were hand-foot skin reaction (12.77%), fatigue (6.38%), vomiting (6.38%), and decreased appetite (6.38%). The most common grade 3 and 4 adverse events were hand-foot skin reaction (4.26%), hypertension (2.13%), diarrhea (2.13%), and stomachache (2.13%). Only 2 patients stopped regorafenib due to AEs. Conclusions: This real-world study demonstrated that regorafenib combined with HAIC was beneficial and tolerable in advanced CRC patients with liver metastases whose disease had progressed after standard systemic therapy. It also indicated a new promising treatment strategy for late stage CRC. Additional prospective and large-scale studies are required for further confirmation. Key words: hepatic artery infusion chemotherapy; regorafenib; colorectal cancer

Use of circulating tumor DNA in colorectal cancer patients to assess tumor burden and response to therapy: An observational study.

3528 Background: Residual disease after treatment for colorectal cancer (CRC) poses a risk for recurrence but imaging and CEA are limited in their capacity to detect residual disease. A simple test is needed for assessing treatment response. This study determined whether levels of methylated BCAT1/IKZF1 DNA in blood correlate with tumor burden and whether post-treatment levels inform efficacy of different treatments for CRC. Methods: Patients with primary CRC had blood collected prior to treatment (n = 282, 59.9% males, median age 68.5y). Cell free DNA (cfDNA) was extracted from plasma and assayed for methylation in BCAT1 and IKZF1. Detection of methylation in either gene deemed a sample positive; levels were expressed as %methylation (average methylation/average cfDNA). Positive patients had additional samples collected post-treatment for early stage CRC (surgery, n = 31), advanced/metastatic CRC (surgery + adjuvant chemotherapy, n = 15), and rectal cancer (neoadjuvant therapy, surgery +/- chemotherapy, n = 6), or following mid-therapy suspension of treatment in advanced CRC (n = 24). Tumor size was expressed as the maximum diameter of the primary (assessed surgically or by MRI). Results: Pretreatment results increased with CRC stage. Positivity by stage was: I, 23.7% (14/59); II, 62.1% (54/87); III, 68.6% (70/102); IV, 85.3% (29/34). Level by stage: I, 0.0%; II, 0.06%; III, 0.07%; IV, 4.07%, p &lt; 0.001). Pretreatment levels correlated significantly with tumor size (r = 0.372, p &lt; 0.001). Post-treatment blood was collected a median 2.4mo (IQR 1.7-3.9) after therapy completion. Positivity decreased after completing treatment (Table), with 88.4% of cases (46/52) becoming ctDNA negative. All cases with complete treatment had a reduction in biomarker levels, whereas in those with incomplete therapy, 54.5% (12/22) remained positive and the pre- and post-treatment levels were not significantly different. Of those positive after treatment, 13 had a further blood sample: 8 had become ctDNA negative and all but one remained disease free. Five remained positive and all had further suspected or confirmed disease. Conclusions: Levels of methylated BCAT1 and IKZF1 DNA in blood correlated with tumor burden; levels became undetectable in the majority of patients following completion of planned curative intent treatment. The methylated ctDNA blood test aids monitoring of responses to therapy and identification of those cases with residual cancer who might benefit from ongoing therapy.[Table: see text]

Safety and pharmacokinetic analysis of UGT1A1 genotype-guided dosing of irinotecan.

3574 Background: Irinotecan is commonly used in the treatment of advanced colorectal and pancreatic cancer. The polymorphisms UGT1A1*28 (7 TA repeats) and UGT1A1*93 (SNP -3156G &gt; A) are significantly associated with increased systemic exposure of irinotecan’s active metabolite SN-38 and subsequently severe irinotecan-associated adverse-events (AEs) including (febrile) neutropenia and diarrhea. Severe AEs may lead to hospitalization, loss of quality of life, treatment delay and/or treatment discontinuation. Nonetheless, prospective genetic screening is not yet routinely performed. The aim of this study was to determine the safety and pharmacokinetics of UGT1A1 genotype-guided dosing of irinotecan in UGT1A1 poor metabolizers (PMs), i.e. UGT1A1 *28/*28 and/or UGT1A1*93/*93 individuals, in order to reduce the incidence of severe irinotecan-associated AEs. Methods: A prospective, multi-center, non-randomized study was conducted in patients intended to be treated with irinotecan at a dose of ≥ 180 mg/m2 or 450-600 mg flat dose. All patients were pre-therapeutically genotyped for UGT1A1*28 and UGT1A1*93. In UGT1A1 PMs, an initial 30% dose reduction in the first cycle was applied followed by further individual dose titration based on neutrophil count and clinical tolerability. The primary endpoint was the incidence of febrile neutropenia in the first 2 cycles of irinotecan treatment. UGT1A1 PMs were compared to 1] historical control patients, i.e. homozygous polymorphic patients treated with full dose therapy identified from systematic literature review and to 2] UGT1A1 non-PMs treated with standard dose therapy. In addition, systemic SN-38 exposure (AUC0-500h) of reduced dosing in the UGT1A1 PM cohort was compared to a standard dosed irinotecan patient cohort [doi: 10.1200/JCO.2000.18.1.195] by an independent T-test. Results: A total of 349 patients were pre-therapeutically genotyped and included for analysis. Thirty-one (8.9%) patients were UGT1A1 PM, in whom an initial median 30% dose reduction was applied. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical controls (n = 50) (p = 0.042) and comparable with the incidence (4.1%; p = 0.632) in UGT1A1 non-PMs treated with full dose therapy. The systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs (n = 17) was comparable to the systemic exposure of the standard dosed irinotecan patient cohort (n = 46) with a relative difference of +24% (p = 0.054) with a geometric mean (CV) of SN-38 AUC0-500h of 391 (43.7%) versus 298 (75.3%) ng*h/mL, respectively. Conclusions: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan. In addition, systemic drug exposure remained adequate, despite the 30% dose reduction. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve the individual patient safety. Clinical trial information: Trial NL6270 (NTR6612).

MiR-454-3p Promotes Oxaliplatin Resistance by Targeting PTEN in Colorectal Cancer.

Colorectal cancer is one of the most common malignancies worldwide. Oxaliplatin is the first-line chemotherapeutic agent for the treatment of advanced colorectal cancer. However, acquired resistance to oxaliplatin limits its therapeutic efficacy, and the underlying mechanism remains largely unclear. In this study, we compared the expression of a panel of microRNAs (miRNAs) between oxaliplatin-sensitive and -resistant HCT-116 colorectal cancer cells. We found that miR-454-3p was significantly up-regulated in oxaliplatin-resistant cells and was the most differently expressed miRNA. Interestingly, we observed that inhibition of miR-454-3p resensitized resistant cells to oxaliplatin and enhanced oxaliplatin-induced cellular apoptosis. Moreover, we determined that miR-454-3p promoted oxaliplatin resistance through targeting PTEN and activating the AKT signaling pathway. In vivo study revealed that overexpression of miR-454-3p decreased the sensitivity of HCT-116 xenograft tumors to oxaliplatin treatment in a mouse model. Clinically, overexpression of miR-454-3p was associated with decreased responsiveness to oxaliplatin-based chemotherapy, as well as a short progression-free survival. Taken together, our study indicated that the expression of miR-454-3p could be used to predict oxaliplatin sensitivity, and targeting miR-454-3p could overcome oxaliplatin resistance in colorectal cancer.

Treatment of Locally Advanced/Metastatic Colorectal Cancer

Few treatment advances have been observed in recent years for the treatment of advanced colorectal cancer (CRC). The goal remains to find approaches beyond FOLFOX and bevacizumab that will prolong remission. Immunotherapy for patients with microsatellite instability–high tumors represents progress, but this is a very small subset and approximately 30% of patients will not experience response. In locally advanced CRC, good long-term outcomes and manageable toxicity are being achieved with contemporary treatment strategies. Total neoadjuvant therapy, which incorporates induction or consolidation chemotherapy, has improved the treatment of patients with rectal cancer and is now a standard of care, although optimal sequencing is still being debated. Nonoperative management is an emerging option for sphincter preservation, and ongoing studies are evaluating the omission of radiation in select patients.

The Correlation Between UGT1A1 Gene Phenotypes and the Clinical Prognosis of Advanced Colorectal Cancer After FOLFIRI Therapy

Objective: This study investigated the correlations between the different phenotypes of the uridine diphosphate glucuronyl transferase (UGT) 1A1 gene and the treatment of advanced colorectal cancer after the FOLFIRI regimen. Materials and Methods: A total of 240 advanced colorectal cancer patients with stage IV colon cancer or recurrence after radical surgery between January 2014 and December 2018 were included in a retrospective study. All participants were treated with the FOLFIRI regimen until the disease progressed or an intolerable level of toxicity occurred. Results: In this study, three phenotypes of the UGT1A1 gene promoter were found: the homozygous wild type (TA6/6 type, 78.3%), the heterozygous mutant type (TA6/7 type, 19.6%), and the homozygous mutant type (TA7/7 type, 2.1%). Compared with TA6/7 and TA6/6, the risk of nonresponse to FOLFIRI chemotherapy increased by 16%, but the difference was not significant. The risk of death increased by 24%, and there was no significant difference. There was a risk of hematologic and nonhematologic adverse reactions occurring in TA6/7 and TA6/6, and the total risk of adverse reactions increased by 9.3773 times among patients with more than two metastatic organs. Compared with patients with TA6/6, the risk of toxic side-effects increased by 42.8066 times (p = 0.0259) for patients with TA6/7. Among patients who received FOLFIRI chemotherapy for more than four cycles, the proportion with TA6/7 was greater than that with TA6/6. Compared with those with TA6/6, patients with TA6/7 showed a higher risk of hematologic toxicity (22.3246 times, p = 0.0035). Conclusion: The TA6/7 in patients with advanced colorectal cancer had more than two metastatic organs, and received FOLFIRI chemotherapy for more than four cycles compared with TA6/6 patients. Furthermore, the risk of hematologic and nonhematologic adverse reactions significantly increased, and the risk of digestive-tract and hematologic toxicity was more significant.

TOX Acts as a Tumor Suppressor by Inhibiting mTOR Signaling in Colorectal Cancer.

The treatment and prognosis of advanced colorectal cancer (CRC) remain a challenging clinical research focus. Here, we describe a new CRC tumor suppressor and potential therapeutic target: thymocyte selection associated high mobility group box (TOX) protein. The expression of TOX was lower in CRC than para-CRC. With the increase of tumor stage, TOX expression decreased, indicating the presence of TOX relates to better overall survival (OS). TOX suppressed the mechanistic target of rapamycin kinase (mTOR) signaling to inhibit cell proliferation, migration, invasion, and change the epithelial-mesenchymal transition (EMT) process. In addition, TOX promoted apoptosis. As tumor mutation burden and tumor microenvironment play vital roles in the occurrence and development of tumors, we analyzed the TOX expression in the immune microenvironment of CRC. The high TOX expression was negatively correlated with TumorPurity. Moreover, it was positively related to ImmuneScore, StromalScore, microsatellite instability (MSI) status, and Consensus Molecular Subtypes (CMS) 3 typing. Based on gene set enrichment analysis (GSEA), the reduced expression of TOX activated mTOR. We found rapamycin, a mTOR inhibitor, partly inhibited cell proliferation, invasion, and migration in shTOX HCT116 cells. Lastly, TOX suppressed tumorigenesis and lung metastasis of CRC in vivo. Rapamycin alone or combined with PD1 inhibitor is more effective than PD1 inhibitor alone in a tumor model. Taken together, these findings highlight the tumor-suppressive role of TOX in CRC, especially in MSI CRC, and provide valuable information that rapamycin alone or combined with PD1 inhibitor has therapeutic potential in CRC.

Inhibition of Human Uracil DNA Glycosylase Sensitizes a Large Fraction of Colorectal Cancer Cells to 5-Fluorodeoxyuridine and Raltitrexed but Not Fluorouracil.

Previous short-hairpin RNA knockdown studies have established that depletion of human uracil DNA glycosylase (hUNG) sensitizes some cell lines to 5-fluorodeoxyuridine (FdU). Here, we selectively inhibit the catalytic activity of hUNG by lentiviral transduction of uracil DNA glycosylase inhibitor protein into a large panel of cancer cell lines under control of a doxycycline-inducible promoter. This induced inhibition strategy better assesses the therapeutic potential of small-molecule targeting of hUNG. In total, 6 of 11 colorectal lines showed 6- to 70-fold increases in FdU potency upon hUNG inhibition ("responsive"). This hUNG-dependent response was not observed with fluorouracil (FU), indicating that FU does not operate through the same DNA repair mechanism as FdU in vitro. Potency of the thymidylate synthase inhibitor raltitrexed (RTX), which elevates deoxyuridine triphosphate levels, was only incrementally enhanced upon hUNG inhibition (<40%), suggesting that responsiveness is associated with incorporation and persistence of FdU in DNA rather than deoxyuridine. The importance of FU/A and FU/G lesions in the toxicity of FdU is supported by the observation that dT supplementation completely rescued the toxic effects of U/A lesions resulting from RTX, but dT only increased the IC50 for FdU, which forms both FU/A and FU/G mismatches. Contrary to previous reports, cellular responsiveness to hUNG inhibition did not correlate with p53 status or thymine DNA glycosylase expression. A model is suggested in which the persistence of FU/A and FU/G base pairs in the absence of hUNG activity elicits an apoptotic DNA damage response in both responsive and nonresponsive colorectal lines. SIGNIFICANCE STATEMENT: The pyrimidine base 5-fluorouracil is a mainstay chemotherapeutic for treatment of advanced colorectal cancer. Here, this study shows that its deoxynucleoside form, 5-fluorodeoxyuridine (FdU), operates by a distinct DNA incorporation mechanism that is strongly potentiated by inhibition of the DNA repair enzyme human uracil DNA glycosylase. The hUNG-dependent mechanism was present in over 50% of colorectal cell lines tested, suggesting that a significant fraction of human cancers may be sensitized to FdU in the presence of a small-molecule hUNG inhibitor.

Characteristics and Absolute Survival of Metastatic Colorectal Cancer Patients Treated With Biologics: A Real-World Data Analysis From Three European Countries.

Introduction: Biologics were approved for the treatment of advanced colorectal cancer (CRC) based on favorable benefit-risk-assessments from randomized controlled trials (RCTs), but evidence on their use in the real-world setting is scarce. Based on descriptive analyses we therefore aimed to assess characteristics and survival of CRC patients treated with biologics using large healthcare databases from three European countries (Netherlands, Italy, Germany).Methods: We included CRC patients treated with a biologic in 2010 or 2014 and characterized them regarding age, sex, comorbidities, and absolute survival.Results: Among 4,758 patients, the mean age ranged from 64.8 to 66.8 years, the majority was male, and comorbidities used as exclusion criteria in RCTs were coded in up to 30% of these patients. The proportion of bevacizumab users decreased between 2010 (72–93%) and 2014 (63–85%). In 2014, the absolute 12-month survival in new users was 64% (95% CI 51–77%), 56% (30–80%), and 61% (58–63%) in the Dutch, Italian, and German database, respectively, varying by age and comorbidity.Conclusions: Our study suggests that in the real-world setting, CRC patients treated with biologics are older and less selected regarding comorbidities compared to patients in RCTs, potentially explaining the relatively low 12-month survival we found. Treatment decisions in the real-world setting may require careful evaluation given that the risk-benefit ratio may vary depending on age and co-existing conditions.

Treatment sequences of patients with advanced colorectal cancer and use of second-line FOLFIRI with antiangiogenic drugs in Japan: A retrospective observational study using an administrative database.

The objectives were to describe treatment sequences for advanced colorectal cancer (CRC), use of second-line FOLFIRI (leucovorin, 5-fluorouracil, irinotecan) plus antiangiogenic drug (bevacizumab, ramucirumab, aflibercept beta) therapy, and the factors associated with the duration of antitumor drug treatment from second-line antiangiogenic therapy in Japan. This retrospective observational study was conducted using a Japanese hospital-based administrative database. Patients were enrolled if they started adjuvant therapy (and presumably experienced early recurrence) or first-line treatment for advanced CRC between May 2016 and July 2019, and were analysed until September 2019. Factors associated with overall treatment duration from second-line treatment with FOLFIRI plus antiangiogenic drugs were explored with multivariate Cox regression analysis. The most common first-line treatments were FOLFOX (leucovorin, 5-fluorouracil, oxaliplatin) or CAPOX (capecitabine, oxaliplatin) with bevacizumab (presumed RAS-mutant CRC) and FOLFOX with panitumumab (presumed RAS-wild type CRC). The most common second-line treatments were FOLFIRI-based. Many patients did not transition to subsequent lines of therapy. For second-line treatment, antiangiogenic drugs were prescribed more often for patients with presumed RAS-mutant CRC, right-sided CRC, and independent activities of daily living (ADL). The median duration of second-line FOLFIRI plus antiangiogenic drug treatment was 4.5 months; 66.2% of patients transitioned to third-line therapy. Low body mass index and not fully independent ADL were significantly associated with shorter overall duration of antitumor drug treatment from second-line therapy. Left-sided CRC, presumed RAS-wild type CRC, previous use of oral fluoropyrimidines and use of proteinuria qualitative tests, antihypertensives, or anticholinergics during second-line therapy were significantly associated with longer treatment. Treatment of advanced CRC in Japan is consistent with both international and Japanese guidelines, but transition rates to subsequent therapies need improvement. In addition to antitumor drug treatment, better ADL, higher body mass index, management of hypertension, and proteinuria tests were associated with continuation of sequential therapy that included antiangiogenic drugs.

Efficacy and safety of traditional Chinese medicine decoction combined with chemotherapy in the treatment of advanced colorectal cancer: A protocol of a systematic review and meta-analysis.

Colorectal cancer has become a major chronic and difficult disease endangering human health. After thousands of years of precipitation, traditional Chinese medicine in China is now also being applied in clinical treatment, with its unique advantages in the treatment of cancer. However, the efficacy of traditional Chinese medicine in the treatment of advanced colorectal cancer still cannot reach consensus in the world. Therefore, the aim of this study was to provide a scheme to evaluate the efficacy and safety of traditional Chinese medicine decoction in the treatment of advanced colorectal cancer, thus providing clinical decision-making. The systematic review and meta-analysis will be conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. The following 8databases will be searched: China National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), Wan Fang Data, the Chinese Science and Technology Periodical Database (VIP), PubMed, Cochrane Library, Embase, and Web of Science. Relevant data will be performed by Revman 5.3 software provided (Cochrane Collaboration) and Stata 14.0 statistical software. The results of this systematic review and meta-analysis will be published in a peer-reviewed journal. INPLASY202080102.