Clinical and cost-effectiveness analysis of mFOLOFX6 with or without a targeted drug among patients with metastatic colorectal cancer: inverse probability of treatment weighting.

This study investigated the cost-effectiveness and quality of life (QoL) within 1 year of receiving mFOLOFX6 with or without a targeted drug (bevacizumab or ramucirumab) as second-line treatment among patients with metastatic colorectal cancer (mCRC) following the failure of FOLFIRI + bevacizumab as first-line treatment. This prospective cohort study included patients who received a diagnosis of mCRC between March 2015 and May 2020. QoL was evaluated before treatment and at 6 months and 1 year posttreatment. All related variables were controlled using the inverse probability of treatment weighting method. Generalized estimating equations with the difference-in-difference method was used to explore changes in QoL. The incremental cost-utility ratio (ICUR) of the two groups was simulated using the annual-cycle Markov decision tree model. Finally, 39 and 76 patients were included in the targeted and nontargeted agent groups, respectively. At 6 months after treatment, QoL of the two groups improved significantly, but the targeted agent group had significantly better QoL than did the nontargeted agent group at 1 year posttreatment (P < 0.05). When the time frame was set to 20 years, the ICUR of the targeted agent group compared with the nontargeted agent group was US$32,052 per quality-adjusted life years. Addition of a targeted drug to the second-line mFOLOFX6 regimen not only improved the patients' QoL but was also more cost effective when the willingness-to-pay threshold was set at US$33,004 (the per capita gross domestic product of Taiwan). These patients should be reimbursed for these targeted agents by the National Health Insurance scheme in Taiwan.

Efficacy of concurrent radiotherapy in patients with locally advanced rectal cancer and synchronous metastasis receiving systemic therapy.

Background: Neoadjuvant chemoradiotherapy followed by total mesorectal excision is the standard treatment for patients with nonmetastatic locally advanced rectal cancer (LARC). However, for patients with LARC and synchronous metastasis, the optimal treatment strategy and sequence remain inconclusive. In the present study, we evaluated the efficacy and safety of concurrent radiotherapy in patients with de novo metastatic rectal cancer who received chemotherapy and targeted therapy. Methods: We retrospectively reviewed the data of 63 patients with LARC and synchronous metastasis who received intensive therapy at the study hospital between April 2015 and November 2018. The included patients were divided into two groups: RT-CT, those who received systemic chemotherapy with targeted therapy and concurrent radiotherapy (for primary rectal cancer), and CT, those who received only systemic chemotherapy with targeted therapy. Results: Treatment response was better in the RT-CT group than in the CT group. The rate of primary tumor resection (PTR) was higher in the RT-CT group than in the CT group (71.4% and 42.9%, respectively; P = .0286). The RT-CT group exhibited considerably longer local recurrence-free survival (P = .0453) and progression-free survival (PFS; from 13.3 to 22.5 months) than did the CT group (P = .0091); however, the groups did not differ in terms of overall survival (OS; P = .49). Adverse events were almost similar between the groups, except frequent diarrhea, the prevalence of which was higher in the RT-CT group than in the CT group (59.5% and 23.8%, respectively; P = .0075). Conclusions: In the era of biologics, radiotherapy may increase the resectability of primary rectal tumors, reducing the risk of locoregional failure and prolonging PFS. Concurrent pelvic radiotherapy may not substantially improve OS, which is indicated by metastasis. Hence, the resection of the distant metastases may be essential for improving long-term OS. To further determine the efficacy of concurrent radiotherapy, additional prospective, randomized studies must combine preoperative pelvic radiotherapy with PTR and metastectomy to treat patients with stage IV LARC.

Clinicopathological Features and Oncological Outcomes of Early and Late Recurrence in Stage III Colorectal Cancer Patients after Adjuvant Oxaliplatin-Based Therapy.

Aims: An adjuvant oxaliplatin-based regimen is the standard of care for patients with stage III colorectal cancer (CRC). Few reports have compared the clinicopathological features and oncological outcomes of such treatment between patients with early (≤1 year) and late recurrence (>1 year). Methods: Between January 2012 and December 2019, CRC recurred in 128 (24.1%) of 531 patients with consecutive stage III CRC after they received curative resection and an adjuvant oxaliplatin-based regimen. The clinicopathological features and oncological outcomes of the 128 patients were analyzed retrospectively. Results: The median follow-up period after the first chemotherapy cycle was 35.0 months (range, 7-100.9), and the median recurrence time was 16.1 months. Forty-seven patients (36.7%) had an early recurrence and eighty-one patients (63.3%) had a late recurrence. Compared with patients with late recurrence, those with early recurrence were mostly younger (median: 58 vs. 64 years, p=0.009), had less oxaliplatin-based therapy cycles (median: 8 vs. 12 cycles, p < 0.001), and had a shorter overall survival time (median: 23.3 vs. 39.7 months, p < 0.001). The area under the curve of patient age and chemotherapy cycles for predicting early recurrence was 0.629 and 0.705 (p=0.015 and p < 0.001), respectively. The receiver operating characteristic curve analysis demonstrated that the cutoff level for patient age was 57 years and the number of chemotherapy cycles was 8. A multivariate analysis revealed that patient age ≤57 years and oxaliplatin-based therapy ≤8 cycles were independent risk factors for early recurrence (odds ratio (OR) = 3.049, p=0.022; OR = 4.995, p=0.002). These factors were associated with an approximately 77.8% risk of recurrence within 1 year, compared with the 21.5% risk associated with patient age >57 years and oxaliplatin-based therapy >8 cycles (p = 0.003). Conclusion: Patients with early recurrence had poorer survival than those with late recurrence. If >8 cycles of oxaliplatin-based therapy can be administered without disease progression, then patients with stage III CRC would have a lower risk of early recurrence.

MicroRNA-148a induces apoptosis and prevents angiogenesis with bevacizumab in colon cancer through direct inhibition of ROCK1/c-Met via HIF-1α under hypoxia.

Angiogenesis and antiapoptosis effects are the major factors influencing malignancy progression. Hypoxia induces multiple mechanisms involving microRNA (miRNA) activity. Vascular endothelial growth factor (VEGF) is correlated with angiogenesis. An antiapoptotic factor, myeloid leukemia 1 (Mcl-1) is the main regulator of cell death. This study examined the role of miR-148a in inhibiting VEGF and Mcl-1 secretion by directly targeting ROCK1/c-Met by downregulating HIF-1α under hypoxia. The protein expression of ROCK1 or Met/HIF-1α/Mcl-1 in HCT116 and HT29 cells (all P < 0.05) was significantly reduced by miR-148a. The tube-formation assay revealed that miR-148a significantly suppressed angiogenesis and synergistically enhanced the effects of bevacizumab (both P < 0.05). The MTT assay revealed the inhibitory ability of miR-148a in HCT116 and HT29 cells (both P < 0.05). miR-148a and bevacizumab exerted synergistic antitumorigenic effects (P < 0.05) in an animal model. Serum miR-148a expression of metastatic colorectal cancer (mCRC) patients with a partial response was higher than that of mCRC patients with disease progression (P = 0.026). This result revealed that miR-148a downregulated HIF-1α/VEGF and Mcl-1 by directly targeting ROCK1/c-Met to decrease angiogenesis and increase the apoptosis of colon cancer cells. Furthermore, serum miR-148a levels have prognostic/predictive value in patients with mCRC receiving bevacizumab.

Irinotecan dose reduction in metastatic colorectal cancer patients with homozygous UGT1A1*28 polymorphism: a single-center case series.

OBJECTIVE: The UGT1A1*28 polymorphism reduces UGT1A1 enzymatic activity, which may increase the risk of severe toxicity in patients who receive standard-dose irinotecan, such as severe neutropenia and diarrhea. This real-world study assessed the optimal irinotecan dose in terms of efficacy and toxicity in metastatic colorectal cancer (mCRC) patients homozygous for the UGT1A1*28 polymorphism and receiving FOLFIRI plus bevacizumab or cetuximab as first-line therapy. METHODS: We analyzed toxicity and treatment outcomes in seven mCRC patients who were homozygous for UGT1A1*28 and received FOLFIRI plus bevacizumab or cetuximab, with an initial irinotecan dose of 120 mg/m2. RESULTS: Six of the seven patients tolerated 120 mg/m2 irinotecan without requiring dose reductions in subsequent cycles. The overall response and disease control rates were 43.0% (3/7) and 71.4% (5/7), respectively. The median progression-free survival and overall survival were 11.0 and 33.0 months, respectively. Only one severe adverse event, grade III neutropenia (2.5%), was observed. CONCLUSIONS: mCRC patients homozygous for the UGT1A1*28 allele can tolerate irinotecan at an initial dose of 120 mg/m2 with favorable oncological outcomes and toxicity profiles. Further prospective studies are warranted to optimize irinotecan-based chemotherapy in these patients.

Comparison of Next-Generation Sequencing and Polymerase Chain Reaction for Personalized Treatment-Related Genomic Status in Patients with Metastatic Colorectal Cancer.

Personalized treatments based on the genetic profiles of tumors can simultaneously optimize efficacy and minimize toxicity, which is beneficial for improving patient outcomes. This study aimed to integrate gene alterations associated with predictive and prognostic outcomes in patients with metastatic colorectal cancer (mCRC) with polymerase chain reaction (PCR) and in-house next-generation sequencing (NGS) to detect KRAS, NRAS, and BRAF mutations. In the present study, 41 patients with mCRC were assessed between August 2017 and June 2019 at a single institution. The overall concordance between NGS and PCR results for detecting KRAS, NRAS, and BRAF mutations was considerably high (87.8-92.7%), with only 15 discrepant results between PCR and NGS. Our companion diagnostic test analyzes KRAS, NRAS, and BRAF as a panel of CRC molecular targets; therefore, it has the advantages of requiring fewer specimens and being more time and cost efficient than conventional testing for separate analyses, allowing for the simultaneous analysis of multiple genes.

Clinical Outcomes of Patients with Peritoneal Metastasis-Only Colorectal Cancer Treated with First-Line Bevacizumab and FOLFIRI Through Irinotecan Dose Escalation According to UGT1A1 Polymorphism: Compared to Liver Metastasis-Only, and Lung Metastasis-Only.

Background: The prognosis of metastatic colorectal cancer (mCRC) depends on the metastatic site and systemic therapy regimen. Peritoneal metastases are associated with a relatively unfavorable prognosis among patients with mCRC. In this article, we present the treatment outcomes of patients with peritoneal carcinomatosis (PC)-only, liver metastasis (LiM)-only, and lung metastasis (LuM)-only CRC. Methods: Overall, 206 mCRC patients with single-site metastasis and who had received treatment from January 2014 to December 2018 were recruited. Among 206 patients with mCRC, 15 had PC-only mCRC, 145 had LiM-only mCRC, and 46 had LuM-only mCRC. They attended regular follow-ups until November 2020, and the median follow-up period was 24.7 months (5.1-41.3 months). Patients' characteristics, including clinical data, gene mutation profiles, and clinical outcomes, were evaluated. All patients with PC-only CRC were treated with first-line bevacizumab and FOLFIRI, and the irinotecan dose escalation depended on UGT1A1 polymorphism. Results: Of the 206 patients, no statistical difference was observed between the PC-only, LiM-only, and LuM-only groups in terms of age, primary tumor location, RAS mutation status, BRAF mutation status, and epidermal growth factor receptor overexpression (all P > 0.05). Patients with PC-only CRC had a median progression-free survival (mPFS) of 18.0 months and a median overall survival (mOS) of 24.6 months. Patients with LiM-only or LuM-only CRC had mPFS of 18.2 and 26.6 months and mOS of 25.0 and 44.5 months, respectively. No significant differences regarding PFS and OS (both P > 0.05) between the three groups of patients with mCRC were observed. Conclusion: Our study revealed that in patients with PC-only mCRC treatment of first-line bevacizumab and FOLFIRI through irinotecan dose escalation according to UGT1A1 polymorphism could confer such patients with comparable outcomes to that of patients with LiM-only and LuM-only mCRC.

Effectiveness and Cost-Utility Analysis of Different Doses of Irinotecan Plus Bevacizumab in Patients With Metastatic Colorectal Cancer: A Long-Term and Prospective Cohort Study.

Objective: Patients with metastatic colorectal cancer (mCRC) had oncological benefits with irinotecan dose escalation of FOLFIRI regimen combined with bevacizumab according to UGT1A1 genotypes in our previous study. In the current study, we performed a quality of life (QOL) outcome evaluation and cost-utility analysis of different irinotecan dose regimens in patients with mCRC. Materials and Methods: With inverse probability-of-treatment weighting (IPTW) matching on all covariates, 75 patients with dose escalation of irinotecan (study group) and 121 patients with the recommended dose of irinotecan (control group) were recruited between October 2015 and December 2019. The QOL outcome measures were Functional Assessment of Cancer Therapy-Colorectal, Beck Anxiety Inventory, Beck Depression Inventory, and SF-36; cost-utility outcome measures were medical direct costs, quality-adjusted life-years (QALYs), and incremental cost-utility ratios (ICURs). Results: All mCRC patients exhibited a significant decrease in both emotional wellbeing and depression from pretherapeutic period to posttherapeutic 6th month (P < 0.05); however, from the posttherapeutic 1st year to the 2nd year, improvement in most QOL measures was significantly better in the study group than in the control group (P < 0.05). Over a 2-year time period, the study group had higher total medical direct costs than the control group (US$ 54,742 ± 14,013 vs. US$ 54,608 ± 9,673) and higher average QALYs gained (1.88 vs. 1.65), with an ICUR of US$ 583 per QALY gained. Conclusion: For patients with mCRC, irinotecan dose escalation appeared cost-effective with considerable QOL improvements during the study period. Further randomized, multi-institutional controlled trials are warranted to corroborate these results.

Surgical Efficacy and Safety of Patients with Locally Advanced Gastric Cancer following Neoadjuvant Concurrent Chemoradiotherapy and Chemotherapy.

Background: The safety and efficacy of gastrectomy for locally advanced gastric cancer (LAGC) following neoadjuvant therapy have gained increasing attention. In this article, we present our preliminary treatment results and compare the surgical safety and outcomes of neoadjuvant concurrent chemoradiotherapy (CCRT) with those of chemotherapy in patients with LAGC. Patients and Methods. Sixty-three patients with a diagnosis of LAGC (clinical staging cT3N2+, cT4aN+, or cT4b) who had received neoadjuvant therapy at any period from January 2014 to December 2020 were enrolled. Among 63 patients who received neoadjuvant therapy, 38 were treated with CCRT and 25 were treated with chemotherapy. They regularly received follow-up until July 2021. The patients' characteristics, including their clinical data, perioperative results, and pathologic outcomes, were analyzed. Results: The CCRT and chemotherapy groups did not significantly differ with respect to age, sex, or clinical stage (all p > 0.05). Finally, radical gastrectomy was performed in 15 (39.5%) patients with neoadjuvant CCRT and 10 (40.0%) patients with neoadjuvant chemotherapy. Both groups did not significantly differ with respect to operation time, blood loss, operative morbidities, or postoperative length of stay (both p > 0.05). The patients in the CCRT group exhibited favorable pathologic responses after treatment: three patients exhibited a pathologic complete response (pCR) and four, seven, and one patients exhibited a response at pathologic stages I, II, and III, respectively. By contrast, among the patients in the chemotherapy group after treatment, one patient exhibited a pCR and one, four, and four patients exhibited a response at pathologic stages I, II, and III, respectively. Conclusions: Radical resection in patients with LAGC is challenging. This study reports that neoadjuvant CCRT is associated with better pathologic response with no increase in serious postoperative complications. However, further prospective randomized trials involving patients with LAGC receiving neoadjuvant CCRT should be conducted to verify the findings of this retrospective study.

Comparison of UGT1A1 Polymorphism as Guidance of Irinotecan Dose Escalation in RAS Wild-Type Metastatic Colorectal Cancer Patients Treated With Cetuximab or Bevacizumab Plus FOLFIRI as the First-Line Therapy.

Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism plays a crucial role in the increased susceptibility and toxicity of patients to irinotecan. This retrospective, observational study compared the clinical outcomes and adverse events (AEs) in RAS wild-type metastatic colorectal cancer (mCRC) patients treated with cetuximab or bevacizumab plus FOLFIRI with UGT1A1 genotyping and irinotecan dose escalation as the first-line therapy. In total, 173 patients with mCRC with RAS wild-type were enrolled. Among them, 98 patients were treated with cetuximab, whereas 75 patients were treated with bevacizumab. All patients received irinotecan dose escalation based on UGT1A1 genotyping. We compared the progression-free survival (PFS), overall survival (OS), objective response rates (ORRs), disease control rates (DCRs), metastatectomy, and severe adverse events (SAEs) between the two groups. The clinical effects of primary tumor sidedness and target therapy crossover were further analyzed. Over a median follow-up of 23.0 months [interquartile range (IQR), 15.032.5 months], no significant differences were observed between the cetuximab and bevacizumab groups in PFS [18.0 months vs. 14.0 months; 95% confidence interval (CI), 0.5171.027; hazard ratio (HR), 0.729; p=0.071], OS (40.0 months vs. 30.0 months; 95% CI, 0.4101.008; HR, 0.643; p=0.054), ORR (65.3% vs. 62.7%; p=0.720), DCR (92.8% vs. 86.7%; p=0.175), metastatectomy (36.7% vs. 29.3%; p=0.307), and SAEs (p=0.685). Regardless of primary tumor sidedness and target therapy crossover, no significant differences were noted in efficacy and safety between the two groups (all p>0.05). Our results revealed that patients with wild-type RAS mCRC, regardless of biologics, with UGT1A1 genotyping can tolerate escalated doses of irinotecan and potentially achieve a more favorable clinical outcome without significantly increased toxicity.

Low Ligation Plus High Dissection Versus High Ligation of the Inferior Mesenteric Artery in Sigmoid Colon and Rectal Cancer Surgery: A Meta-Analysis.

BACKGROUND: Whether high or low ligation of the inferior mesenteric artery (IMA) is superior in surgery for rectal and sigmoid colon cancers remains controversial. Although several meta-analyses have been conducted, the level of lymph node clearance was poorly defined. We performed a meta-analysis comparing high and low ligation of the IMA for sigmoid colon and rectal cancers, with emphasis on high dissection of the lymph node at the IMA root in all the included studies. METHODS: PubMed, MEDLINE, and EMBASE databases were searched to identify relevant articles published until 2020. The patient's perioperative and oncologic outcomes were analyzed. Statistical analysis was performed using the statistical software RevMan version 5.4. RESULTS: A total of 17 studies, including four randomized controlled trials, published between 2011 and 2020 were selected. In total, 1,846 patients received low ligation of the IMA plus high dissection of lymph nodes (LL+HD), and 2,648 patients received high ligation of the IMA (HL). LL+HD was associated with low incidence of anastomotic leakage (p < 0.001), borderline long operative time (p = 0.06), and less yields of total lymph nodes (p = 0.03) but equivalent IMA root lymph nodes (p = 0.07); moreover, LL+HD exhibited non-inferior long-term oncological outcomes. CONCLUSION: In comparison with HL, LL+HD was an effective and safe oncological procedure for sigmoid colon and rectal cancers. Therefore, to ligate the IMA below the level of the left colic artery with D3 high dissection for sigmoid colon and rectal cancers might be suggested once the surgeons are familiar with this technique. SYSTEMATIC REVIEW REGISTRATION: INPLASY.com, identifier 202190029.

Critical reappraisal of neoadjuvant concurrent chemoradiotherapy for treatment of locally advanced colon cancer.

BACKGROUND: Locally advanced colon cancer (LACC) is associated with surgical challenges during R0 resection, increased postoperative complications, and unfavorable treatment outcomes. Neoadjuvant concurrent chemoradiotherapy followed by surgical resection is an effective treatment strategy that can increase the complete surgical resection rate and improve the patient survival rate. This study investigated the efficacy and toxicity of concurrent chemoradiotherapy in patients with LACC as well as the prognosis and long-term clinical outcomes of these patients. MATERIALS: From January 2012 to July 2020, we retrospectively reviewed the real-world data of 75 patients with LACC who received neoadjuvant concurrent chemoradiotherapy. The chemotherapy regimen consisted of folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX). The following data were obtained from medical records: patients' characteristics, pathologic results, toxicity, and long-term oncologic outcome. RESULTS: Of the 75 patients, 13 (17.3%) had pathologic complete responses. Hematologic adverse effects were the most common (grade 1 anemia: 80.0% and leukopenia: 82.7%). Conversely, grade 2 or 3 adverse effects were relatively uncommon (<10%). Pathologic N downstaging, ypT0, and pathologic complete responses were significant prognostic factors for patient survival. Multivariate analysis revealed that pathologic N downstaging was an independent predictor of patients' overall survival (P = 0.019). The estimated 5-year overall and disease-free survival rates were 68.6% and 50.6%, and the medians of overall and disease-free survival periods were 72.3 and 58.7 months, respectively. Moreover, patients with pathologic complete responses had improved overall survival (P = 0.039) and an improved local recurrence control rate (P = 0.042) but an unfavorable distant metastasis control rate (P = 0.666) in the long-term follow-up. CONCLUSION: The long-term oncologic outcome of patients with LACC following concurrent chemoradiotherapy is acceptable, and the adverse effects seem to be tolerable. Pathologic N downstaging was an independent prognostic factor for patients' overall survival. However, a large prospective, randomized control study is required to confirm the current results.

Low-Molecular-Weight Fucoidan as Complementary Therapy of Fluoropyrimidine-Based Chemotherapy in Colorectal Cancer.

This study investigated the roles of low-molecular-weight fucoidan (LMWF) in enhancing the anti-cancer effects of fluoropyrimidine-based chemotherapy. HCT116 and Caco-2 cells were treated with LMWF and 5-FU. Cell viability, cell cycle, apoptosis, and migration were analyzed in both cell types. Potential mechanisms underlying how LMWF enhances the anti-cancer effects of fluoropyrimidine-based chemotherapy were also explored. The cell viability of HCT116 and Caco-2 cells was significantly reduced after treatment with a LMWF--5FU combination. In HCT116 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through the (1) induction of cell cycle arrest in the S phase and (2) late apoptosis mediated by the Jun-N-terminal kinase (JNK) signaling pathway. In Caco-2 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through both the c-mesenchymal-epithelial transition (MET)/Kirsten rat sarcoma virus (KRAS)/extracellular signal-regulated kinase (ERK) and the c-MET/phosphatidyl-inositol 3-kinases (PI3K)/protein kinase B (AKT) signaling pathways. Moreover, LMWF enhanced the suppressive effects of 5-FU on tumor cell migration through the c-MET/matrix metalloproteinase (MMP)-2 signaling pathway in both HCT116 and Caco-2 cells. Our results demonstrated that LMWF is a potential complementary therapy for enhancing the efficacies of fluoropyrimidine-based chemotherapy in colorectal cancers (CRCs) with the wild-type or mutated KRAS gene through different mechanisms. However, in vivo studies and in clinical trials are required in order to validate the results of the present study.

Correlations between Urinary Monoethylhexyl Phthalate Concentration in Healthy Individuals, Individuals with Colorectal Adenomas, and Individuals with Colorectal Cancer.

Colorectal cancer (CRC) is the third leading cause of cancer death in Taiwan. A recent study suggested a link between exposure to endocrine-disrupting chemicals (EDCs) and increased susceptibility to pathology. Exposure to di-(2-ethylhexyl) phthalate (DEHP), an EDC and plasticizer widely used in consumer products, has been reported to be significantly positively correlated with increased risks of various cancers. We explored this connection of DEHP exposure with the development of CRC through the detection of urinary monoethylhexyl phthalate (MEHP), a potent metabolite of DEHP. Participants comprised 221 individuals recruited between October 2016 and November 2019 from a single institution. Overall, urinary MEHP concentrations were significantly higher in patients with CRC than in the patients with adenoma or healthy participants (both P < 0.001). Higher exposure to DEHP may contribute to the occurrence of CRC. Urinary MEHP detection may serve as a beneficial noninvasive indicator of increased CRC risk.

A Pilot Study of Silymarin as Supplementation to Reduce Toxicities in Metastatic Colorectal Cancer Patients Treated With First-Line FOLFIRI Plus Bevacizumab.

Irinotecan, a topoisomerase inhibitor, is a common cytotoxic agent prescribed for metastatic colorectal cancer (mCRC) patients. Diarrhea is the most common adverse event (AE). The underlying mechanism of irinotecan-induced diarrhea is intestinal mucosal damage caused by SN-38 (active metabolite of irinotecan) hydrolyzed from SN-38G (inactive metabolite) by bacterial -glucuronidase (G). According to an animal study, silymarin reduces the activity of bacterial G without impairing antitumor efficacy. We conducted a prospective open-label pilot study to evaluate the effect of silymarin as supplementation in reducing toxicities of mCRC patients undergoing irinotecan-based chemotherapy. We enrolled and randomized 70 mCRC patients receiving first-line FOLFIRI (5-fluorouracil/leucovorin/irinotecan) plus bevacizumab. In each treatment cycle, the study group was administered silymarin capsules (150 mg) three times daily for 7 days. The study group experienced less AEs in diarrhea (5.7% vs. 14.6%, p=0.002) and nausea (27.0% vs. 40.2%, p=0.005) in comparison with the control group, but no significant differences in hepatic toxicities were observed. In conclusion, simultaneous administration of silymarin is a potential effective supplementation for reducing toxicities in mCRC patients undergoing first-line FOLFIRI plus bevacizumab, especially in diarrhea and nausea.

UGT1A1 Polymorphism for Irinotecan Dose Escalation in Patients with BRAF-Mutated Metastatic Colorectal Cancer Treated with First-Line Bevacizumab and FOLFIRI.

BACKGROUND: Patients with metastatic colorectal cancer (mCRC) and BRAF V600E mutation have a poor prognosis, with a median progression-free survival (PFS) of only 5-7 months after initial therapy. The current standard first-line chemotherapy for these patients includes FOLFOX or FOLFIRI plus bevacizumab. In this study, we explored the effects and oncological outcomes of UGT1A1 polymorphism for irinotecan escalation in patients with BRAF-mutated mCRC. Patients and Methods. This retrospective study included 17 patients with BRAF-mutated mCRC between April 2016 and December 2019. UGT1A1 genotyping was performed on all patients prior to initiating bevacizumab plus FOLFIRI chemotherapy. The primary endpoint was PFS, and the secondary endpoints were toxicity, response rate, disease control rate, and overall survival (OS). RESULTS: Fifteen and two patients had UGT1A1 1∗/1∗ and 1∗/28∗, respectively. Eight underwent irinotecan dose escalation with tolerable adverse effects (AEs), and nine maintained an irinotecan dose of 180 mg/m2 or required deescalation to 150 mg/m2 due to intolerable AEs. After a median follow-up period of 15.7 (range, 3-54) months, the median PFS and OS were 9.4 and 15.7 months, respectively. Grade 3/4 AEs were observed in three (6%) patients. The disease control and partial response rates were 64.7% and 11.8%, respectively, indicating that most patients (14, 82.3%) could maintain this as a first-line line therapy with stable disease or proceed to second-line therapy if disease progression occurred, thereby maintaining acceptable performance status. CONCLUSIONS: The oncological outcomes of patients with BRAF-mutated mCRC treated using FOLFIRI plus bevacizumab with irinotecan dose escalation as a first-line therapy are acceptable with tolerable AEs; this may be a feasible treatment option in such patients. Pretherapeutic UGT1A1 genotyping-guided dose adjustment can achieve favorable outcomes.

Oncological outcomes of robotic-assisted total mesorectal excision after neoadjuvant concurrent chemoradiotherapy in patients with rectal cancer.

AIMS: This study analyzed the oncological outcomes of robotic-assisted total mesorectal excision (TME) in patients with rectal cancer after neoadjuvant concurrent chemoradiotherapy (CCRT). METHODS: We enrolled 109 consecutive patients with stage II-III rectal cancer who underwent robotic-assisted TME after neoadjuvant CCRT at one hospital between July 2013 and June 2018. RESULTS: All 109 patients underwent preoperative CCRT. Of them, 37 (33.9%) achieved a pathologic complete response, and 29 (26.6%) experienced relapse, with local recurrence in 9 (8.3%) and distant metastasis in 20 (18.3%). R0 resection was performed in 104 (95.7%) patients; however, 7 (6.7%) of them developed local recurrence and 17 (16.3%) developed distant metastasis. Over a median follow-up of 42 months, the 3-year disease-free survival and overall survival rates were 73.4% and 87.2%, respectively. CONCLUSIONS: Robotic-assisted TME after neoadjuvant CCRT is safe and effective for treating patients with stage II-III rectal cancer in one institution with acceptable short-term oncological outcomes. It may be a therapeutic alternative to salvage surgery for T4 tumors invading adjacent organs, such as the bladder, prostate, and uterus.

Oncological Outcomes of Robotic-Assisted Surgery With High Dissection and Selective Ligation Technique for Sigmoid Colon and Rectal Cancer.

Background: Curative resection of sigmoid colon and rectal cancer includes "high tie" of the inferior mesenteric artery (IMA). However, IMA ligation compromises blood flow to the anastomosis, which may increase the complication rate. We present preliminary experiences of operative and oncologic outcomes of patients with rectal or sigmoid colon cancer who underwent robotic surgery employing the high dissection and selective ligation technique. Methods: Over May 2013 to April 2017, 113 stage I-III rectal or sigmoid colon cancer patients underwent robotic surgery with the single-docking technique at one institution. We performed D3 lymph node dissection and low-tie ligation of the IMA (i.e., high dissection and selective ligation technique). Clinicopathological features, perioperative parameters, and postoperative outcomes were retrospectively analyzed. Overall survival (OS) and disease-free survival (DFS) were calculated using the Kaplan-Meier method. Results: Sphincter preservation rate was 96.3% in rectal cancer patients. Median number of harvested lymph nodes was 12. Apical nodes were pathologically harvested in 84 (82.4%) patients. R0 resection was performed in 108 (95.6%) patients. Overall complication rate was 17.7%; but most complications were mild and the patients recovered uneventfully. Estimated 5-year OS was 86.1% and 3-year DFS was 79.6% after median follow-up periods of 49.1 months (range, 5.3-85.3). Conclusions: High dissection of the IMA and selective ligation of the major feeding vessel to the sigmoid colon or rectum can be safely performed using da Vinci Surgical System,yielding favorable clinical, and oncologic outcomes in rectal or sigmoid colon cancer treatment.

Impact of previous abdominal surgery on robotic-assisted rectal surgery in patients with locally advanced rectal adenocarcinoma: a propensity score matching study.

BACKGROUND: The application of minimally invasive surgery in patients with colorectal cancer (CRC) and a history of previous abdominal surgery (PAS) remains controversial. This retrospective study with propensity score matching (PSM) investigated the impact of PAS on robotic-assisted rectal surgery outcomes in patients with locally advanced rectal adenocarcinoma undergoing preoperative concurrent chemoradiotherapy (CCRT). METHODS: In total, 203 patients with locally advanced rectal adenocarcinoma who underwent preoperative CCRT and robotic-assisted rectal surgery between May 2013 and December 2019 were enrolled. Patients were categorized into PAS and non-PAS groups based on the PAS history. The PSM caliper matching method with 1-to-3 matches was used to match PAS patients with non-PAS. RESULTS: Of the 203 enrolled patients, 35 were PAS patients and 168 were non-PAS patients. After PSM, 32 PAS patients and 96 non-PAS patients were included for analysis. No significant between-group differences were noted in the perioperative outcomes, including median console time (165 min (PAS) vs. 175 min (non-PAS), P = 0.4542) and median operation time (275 min (PAS) vs. 290 min (non-PAS), P = 0.5943) after PSM. Postoperative recovery and overall complication rates were also similar (all P > 0.05). Moreover, the between-group differences in pathological or short-term oncological outcomes were also nonsignificant (all P > 0.05). No 30-day postoperative deaths were observed in either group. CONCLUSION: The current results indicate that robotic-assisted surgery is safe and feasible for PAS patients with locally advanced rectal adenocarcinoma undergoing preoperative CCRT. However, future prospective randomized clinical trials are required to verify these findings.

Time interval between the completion of radiotherapy and robotic-assisted surgery among patients with stage I-III rectal cancer undergoing preoperative chemoradiotherapy.

BACKGROUND: This aim of this study was to evaluate the effects of time interval between the completion of radiotherapy and robotic-assisted surgery on the outcomes among patients with rectal cancer undergoing preoperative concurrent chemoradiotherapy (CCRT). METHODS: In total, 116 patients with stage I-III rectal cancer who underwent preoperative CCRT and robotic-assisted surgery between September 2013 and February 2019 were enrolled. Patients were categorized into two groups based on the time interval: group A (10-12 weeks) and group B (≥ 12 weeks). RESULTS: Among the 116 enrolled patients, 98 (84.5%) had middle and lower rectal cancers. Two (1.7%) patients underwent abdominoperineal resection with a sphincter preservation rate of 98.3%. Thirty-seven (31.9%) patients had a pathologic complete response (pCR). The circumferential resection margin and distal resection margin were positive in 2 (1.7%) and 1 (0.9%) patients, respectively. Therefore, the R0 resection rate was 97.4%. A total of 24 (22.4%) patients experienced postoperative relapse and 12 (10.3%) patients died; these were slightly more common in group B than in group A (28.8% vs 15.8% and 15.3% vs 5.3%, respectively; both P > 0.05); however, this difference was nonsignificant. Three-year disease-free survival (DFS) and overall survival (OS) were 75% and 89%, respectively, among all patients. Non-significant trend of favorable 3-year DFS, 3-year OS, 3-year locoregional control rate and 3-year distant metastasis control rate were observed in group A compared with group B (all P > 0.05). CONCLUSION: Robotic-assisted surgery after a longer interval is safe and feasible for patients with rectal cancer undergoing preoperative CCRT. The present study's results suggested that the time interval of 10-12 weeks can be considered because comparable clinical and perioperative outcomes and preferable oncological outcomes were observed for interval of this length. However, future prospective randomized clinical trials are required to verify the present finding.