Treatment Of Advanced Colorectal Cancer Research Articles

An open-label, single-center, phase II study of exploration on optimizing the administration time of fruquintinib combined with camrelizumab in the third-line treatment of MSS advanced colorectal cancer.

TPS225 Background: Immune checkpoint inhibitors monotherapy has limited clinical benefits in patients with MSS or pMMR metastatic colorectal cancer (CRC), which may be attributed to low level of tumor-infiltrating lymphocytes in MSS advanced CRC. Combination immunotherapy is changing the landscape of cancer treatment, especially combination of immunotherapy with small molecule angiogenesis inhibitors. Preclinical studies have shown that there is a time window from anti-angiogenesis to vascular normalization and this has been initially demonstrated in the clinical study of breast cancer. However, the time window is rarely considered in clinical practice. It is necessary to explore the optimal administration timing of angiogenesis inhibitors when combined with immunotherapy. Here, we conduct an open-label, single-center, phase II study to explore the issue. Methods: Patients eligible for the trial are included: 1) pathologically confirmed advanced colon or rectal adenocarcinoma, MSS or pMMR; 2) previously received only 2 standard regimens after recurrence or metastasis; 3) aged 18-70 years (boundary value included); 4) ECOG performance status of 0 or 1; 5) at least 3 months of survival expectations; 6) patient must present with measurable lesions according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST version 1.1; 7) patients with asymptomatic central nervous system metastases or asymptomatic brain metastases after treatment, with stable disease for at least 3 months, and need not be treated with steroids for at least 4 weeks; 8) had adequate organ function before the enrollment; 9) patients of reproductive age should agree to use effective contraceptive measures from the time of signing the informed form until 3 months after the last dose; 10) sign an informed consent form voluntarily, and be willing to and be able to follow and complete all experimental procedures. The patients enrolled were given oral fruquintinib (3 mg, qd, for 2 consecutive weeks, and then discontinued for 1 week, in 3 weeks [21 days] cycle); on the day 5, administered with intravenous camrelizumab (200mg, once every 3 weeks). The treatment was administered continuously until disease progression, unacceptable toxicity, or required withdrawal from patients. The primary endpoint is progression free survival (PFS), and the secondary endpoints are overall survival (OS), objective response rate (ORR), disease control rate (DCR) and drug safety. As of September 23, 2021, a total of 21 patients have been enrolled. Clinical trial information: ChiCTR2100048528.

Efficacy of apatinib combined with FOLFIRI in the first-line treatment of patients with metastatic colorectal cancer

SummaryObjective. To evaluate the efficacy and safety of apatinib combined with FOLFIRI in the first-line treatment of advanced metastatic colorectal cancer (mCRC) and explore potential factors of efficacy. Methods. Twenty mCRC patients treated at Affiliated Cancer Hospital of Shanxi Medical University from March 2017 to March 2019 were included according to the enrolment criteria. They provided informed consent and were treated with apatinib combined with FOLFIRI according to the scheduled regimen until disease progression or unacceptable toxicity occurred. The primary endpoint was OS. The secondary endpoints included PFS, ORR, DCRand safety. OS and PFS were calculated using Kaplan–Meier curves. Univariate and multivariate Cox regression analyses were used to evaluate independent prognostic factors of OS and PFS. R was used to determine cut-off values for biochemical indicators. Forest maps were drawn for Cox univariate results and the relationships between NLR and ECOG, which were significant in univariate analysis, and OS were represented by Kaplan–Meier curves. Results. The median OS and PFS were 16.135 months (95% CI: 9.211–22.929) and 6 months (95% CI: 5.425–6.525). Multivariate Cox analysis showed that NLR and CEA were independent prognostic factors. The most common grade 3–4 adverse events were hypertension, diarrhoea, increased alkaline phosphatase, decreased leukocytes and decreased neutrophils. Conclusion. Apatinib combined with FOLFIRI for the first-line treatment of advanced unresectable mCRC showed good efficacy and safety. The baseline NLR was predictive of efficacy, and a low baseline NLR (HR: 0.2895, P = 0.0084) was associated with improved OS.Clinical Research Registration Number: ChiCTR1800015308.

POSC167 A Meta-Analysis and Cost-Minimization Analysis of Oxaliplatin-Based Chemotherapy Versus Irinotecan-Based Chemotherapy with Targeted Molecular Agents in the First-Line Treatment of Metastatic Advanced Colorectal Cancer in China

To evaluate the efficacy, safety and long-term cost-effectiveness of Oxaliplatin-based chemotherapy plus targeted molecular agents (Ox-based regimens) versus Irinotecan-based chemotherapy plus targeted molecular agents (Iri-based regimens) as the first-line treatment of metastatic advanced colorectal cancer (mCRC) from Chinese healthcare system perspective.

POSA168 Meta-Analysis and Cost-Effectiveness Analysis of Oxaliplatin-Based Chemotherapy Versus Irinotecan-Based Chemotherapy for the First-Line Treatment of Metastatic Advanced Colorectal Cancer in China

To evaluate efficacy, safety and the long-term cost-effectiveness of oxaliplatin-based chemotherapy versus irinotecan-based chemotherapy for the first-line treatment of metastatic advanced colorectal cancer (mCRC) in China.

Outcomes of Patients Undergoing Liver Resection for Colorectal Liver Metastases within the OBELICS Randomized Phase 3 Trial

Background: OBELICS was a randomized phase 3 trial evaluating the optimization of bevacizumab schedule in the treatment of advanced colorectal cancer, not suitable for curative surgery. The sequential schedule of bevacizumab, given 3 days before chemotherapy, did not improve response rate nor progression-free survival (PFS), while prolonged median overall survival (OS) of about 6 months

Efficacy and Safety of Regorafenib Combined with Toripalimab in the Third-Line and beyond Treatment of Advanced Colorectal Cancer.

Background The most effective treatment of immune checkpoint inhibitors (ICIs) is restricted in microsatellite instability (MSI-H) subsets of advanced colorectal cancer, but MSI-H only accounts for 4-5% among them. ICIs are completely ineffective in advanced colorectal cancer patients with microsatellite stable (MSS), according to literatures published. Regorafenib is a novel tyrosine kinase inhibitor (TKIs) that could normalize tumor blood vessels by inhibiting vascular endothelial growth factor receptor and its downstream, thus improving cytotoxic T cell infiltration in tumor microenvironment, which has a synergistic effect with ICIs. Toripalimab is a type of anti-PD-1 monoclonal antibody produced by Junshi Biosciences in China. Herein, we aimed to explore the efficacy and safety of regorafenib combined with toripalimab in the third-line and beyond treatment of advanced colorectal cancer. Methods We evaluated the outcomes of MSS patients with advanced colorectal cancer who received regorafenib combined with toripalimab in the Second Affiliated Hospital of Nanchang University from June 2019 to January 2021. These patients had previously received at least second-line treatment; the regimens were oxaliplatin and irinotecan-based chemotherapy and/or accompanied with bevacizumab or cetuximab. Thirty-three patients were treated orally with regorafenib 80 mg or 120 mg once daily for 21 days, 28 days as a cycle, combined with intravenous toripalimab until disease progression or intolerant to adverse reactions. We used the Kaplan–Meier method to estimate the rate of progression-free survival (PFS) and log-rank method to do a statistical test of the survival curve. The Cox regression model was used to analyze the influence of multiple factors on PFS. The primary endpoints were objective remission rate (ORR) and disease control rate (DCR). The secondary endpoints were the incidence of adverse reactions and median progression-free survival (mPFS). Results The evaluation of treatment effects was assessed according to RECIST 1.1. Four patients (12.12%) got partial response, twelve patients (36.36%) experienced stable disease, and seventeen patients (51.52%) suffered progressive disease. ORR was 12.12% and DCR was 48.48%. mPFS was 113 days (95% CI: 0–272.1). In univariate analysis, patients who had previously received second-line treatment were significantly better than those who had received third-line or more treatment (p=0.005). Lung metastasis was a negative factor in combined therapy (p=0.032). Five patients without previous treatment of bevacizumab were effective. Previous treatment without bevacizumab showed a trend of effective when combination therapy (p=0.034). It was also a positive factor that the Eastern Cooperative Oncology Group performance status (ECOG) score was 0 (p=0.034). Multivariable Cox regression analysis showed the number of previous chemotherapy lines and excision of primary lesions were independent prognostic factors. The most common treatment-related adverse reactions were hand-foot syndrome (33.33%), liver dysfunction (27.27), hypothyroidism (24.24%), fever (24.24%), fatigue (21.21%), leukopenia (15.15%), hypertension (12.12%), platelet count decreased (6.06%), diarrhea (3.03%), and myocarditis (3.03%); one patient stopped treatment as myocarditis. The incidence of grade 3/4 adverse reactions was 9.09%. Conclusions Regorafenib combined with toripalimab has a promising effect in the third-line and beyond treatment of advanced colorectal cancer. In the early use of combination therapy, excision of primary lesions can have a positive impact in regorafenib and toripalimab combination. This treatment-related adverse reactions are tolerant in combined therapy.

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.