Extensive Profiling of Polyphenols from two Trollius Species Using a Combination of Untargeted and Targeted Approaches.

Various species of globeflowers, belonging to the genus Trollius, have been extensively used in traditional Chinese medicine due to their anti-inflammatory, antimicrobial, and antiviral properties, which are mainly attributed to their high polyphenol content. Differences in polyphenol composition, and abundances, will lead to varying treatment efficacies of globeflowers. Herein, we employ a combination of targeted and untargeted mass spectrometry (MS) approaches to characterize and quantify a comprehensive array of polyphenols, mainly including flavonoids and phenolic acids in two globeflower species commonly used in Chinese medicine, Trollius chinensis Bunge and Trollius ledebouri Reichb. In addition, free radical scavenging activity was investigated to evaluate the association between polyphenol composition and antioxidation capacity. Liquid chromatography (LC)-based separation and multiple-reaction-monitoring (MRM) transitions were optimized using a library of 78 polyphenol reference compounds to achieve absolute quantification on triple quadrupoles MS (QqQ). The analytical method was further expanded via high-resolution MS to provide relative quantitation of an additional 104 endogenous polyphenols in globeflowers not included in our reference library. Our results revealed stark differences in polyphenol content between T. chinensis and T. ledebouri, emphasizing the need for systematic characterization of polyphenol composition to ensure treatment efficacy and consistency in standardizing the use of globeflowers in Chinese medicine.

Neoadjuvant Modified FOLFOX6 With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Final Results of the Chinese FOWARC Trial.

PURPOSE: In the multicenter, open-label, phase III FOWARC trial, modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus radiotherapy resulted in a higher pathologic complete response rate than fluorouracil plus radiotherapy in Chinese patients with locally advanced rectal cancer. Here, we report the final results. METHODS: Adults ages 18 to 75 years with stage II/III rectal cancer were randomly assigned (1:1:1) to five cycles of infusional fluorouracil (leucovorin 400 mg/m2, fluorouracil 400 mg/m2, and fluorouracil 2.4 g/m2 over 48 hours) plus radiotherapy (46.0 to 50.4 Gy delivered in 23 to 25 fractions during cycles 2 to 4) followed by surgery and seven cycles of infusional fluorouracil, the same treatment plus intravenous oxaliplatin 85 mg/m2 on day 1 of each cycle (mFOLFOX6), or four to six cycles of mFOLFOX6 followed by surgery and six to eight cycles of mFOLFOX6. The primary end point was 3-year disease-free survival (DFS). RESULTS: In total, 495 patients were randomly assigned to treatment. After a median follow-up of 45.2 months, DFS events were reported in 46, 39, and 46 patients in the fluorouracil plus radiotherapy, mFOLFOX6 plus radiotherapy, and mFOLFOX6 arms. In each arm, the probability of 3-year DFS was 72.9%, 77.2%, and 73.5% (P = .709 by the log-rank test), the 3-year probability of local recurrence after R0/1 resection was 8.0%, 7.0%, and 8.3% (P = .873 by the log-rank test), and the 3-year overall survival rate was 91.3%, 89.1%, and 90.7% (P = .971 by log-rank test), respectively. CONCLUSION: mFOLFOX6, with or without radiation, did not significantly improve 3-year DFS versus fluorouracil with radiation in patients with locally advanced rectal cancer. No significant difference in outcomes was found between mFOLFOX6 without radiotherapy and fluorouracil with radiotherapy, which requires additional investigation of the role of radiotherapy in these regimens.

Neoadjuvant Chemotherapy With mFOLFOXIRI Without Routine Use of Radiotherapy for Locally Advanced Rectal Cancer.

INTRODUCTION: Although neoadjuvant chemo-radiotherapy (CRT) achieves low local recurrence rates in locally advanced rectal cancer (LARC), it raises a lot of concerns about long-term anal and sexual functions. We explored the efficacy of preoperative chemotherapy with mFOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) in patients with LARC. PATIENTS AND METHODS: Patients with LARC evaluated by pelvic magnetic resonance imaging (MRI) were enrolled in this trial. All received 4 to 6 cycles of mFOLFOXIRI. MRI was performed to assess clinical response after chemotherapy. Patients with mesorectal fascia-positive or ycT4a/b after re-evaluation would receive radiation before surgery, whereas responders would have immediate total mesorectal excision (TME). Adjuvant chemotherapy with mFOLFOX6 (folinic acid, 5-fluorouracil, and oxaliplatin) was recommended. The primary endpoint was the proportion of tumor downstaging to ypT0-2N0M0. The secondary endpoints were pathologic complete response rate (pCR), 3-year disease-free survival rate, and safety. RESULTS: Overall, 106 patients were enrolled and received neoadjuvant mFOLFOXIRI chemotherapy. A total of 103 participants underwent TME surgery. Among 103 patients who completed at least 4 cycles of preoperative chemotherapy, 2 received short-term radiation before TME, and 12 underwent long-term CRT after MRI evaluation. The pCR rate was 20.4%, and the tumor downstaging rate was 42.7%. Among patients without preoperative long-term radiotherapy, the pCR rate and tumor downstaging rate were 17.4% and 41.3%, respectively. Among the per-protocol population, the tumor downstaging rate was 48.1%, and the pCR rate was 20.3%. The chemotherapy-related toxicity was well-tolerated. CONCLUSION: Neoadjuvant chemotherapy with mFOLFOXIRI and selective radiation does not seem to compromise outcomes in LARC. It could be a reasonable alternative to CRT in previously untreated patients with LARC.

Impact of Preoperative Radiotherapy on Anastomotic Leakage and Stenosis After Rectal Cancer Resection: Post Hoc Analysis of a Randomized Controlled Trial.

BACKGROUND: Evidence regarding the effect of preoperative radiotherapy on anastomotic integrity remains conflicting in rectal cancer surgery. Prospective comparisons with appropriate controls are needed. OBJECTIVE: This study aimed to assess the impact of preoperative radiotherapy on anastomotic leakage and stenosis after rectal cancer resection. DESIGN: This was a post hoc analysis of a randomized controlled trial (NCT01211210). SETTINGS: Data were retrieved from the leading center of the trial, which is a tertiary hospital. PATIENTS: The full analysis population of 318 patients was included. INTERVENTIONS: Patients were randomly assigned to receive preoperative radiation (50 Gy per 25 fractions) and 5-fluorouracil infusion, alone (arm A) or combined with oxaliplatin (arm B), or preoperative chemotherapy with 5-fluorouracil and oxaliplatin without radiation (arm C). MAIN OUTCOME MEASURES: The rates of anastomotic leakage and stenosis were calculated for each treatment arm. Multivariate analysis was used to verify the effect of preoperative radiotherapy. RESULTS: The treatment arms were comparable in terms of most baseline characteristics, but more diversions were used in the chemoradiotherapy arms. Anastomotic leakage occurred in 20.2% of patients in arm A, 23.6% of patients in arm B, and 8.5% of patients in arm C (p = 0.007). The corresponding rates of stenosis were 17.0%, 18.9%, and 6.8% (p = 0.02). Multivariate analysis confirmed the correlation between preoperative radiotherapy and clinical leakage (p = 0.02), which was associated with delayed stenosis (p < 0.001). For patients undergoing chemoradiotherapy, radiation proctitis was identified as an independent risk factor for clinical leakage (p = 0.01) and stenosis (p < 0.001). LIMITATIONS: The main limitations were discrepancies in stoma creation and chemotherapy regimen among the treatment arms. CONCLUSIONS: Preoperative radiotherapy increases the risk of anastomotic leakage and stenosis after rectal cancer resection. Clinical leakage independently contributes to the development of stenosis.

Modified FOLFOX6 With or Without Radiation Versus Fluorouracil and Leucovorin With Radiation in Neoadjuvant Treatment of Locally Advanced Rectal Cancer: Initial Results of the Chinese FOWARC Multicenter, Open-Label, Randomized Three-Arm Phase III Trial.

PURPOSE: Total mesorectal excision with fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy is a standard treatment of locally advanced rectal cancer. This study investigated the addition of oxaliplatin with and without preoperative radiotherapy. METHODS: In this multicenter, open-label, phase III trial, we randomly assigned (1:1:1) Chinese adults (age 18 to 75 years) with locally advanced stage II/III rectal cancer to three treatments: five 2-week cycles of infusional fluorouracil (leucovorin 400 mg/m(2), fluorouracil 400 mg/m(2), and fluorouracil 2.4 g/m(2) over 48 h) plus radiotherapy (46.0 to 50.4 Gy delivered in 23 to 25 fractions during cycles 2 through 4) followed by surgery and seven cycles of infusional fluorouracil, the same treatment plus intravenous oxaliplatin 85 mg/m(2) on day 1 of each cycle (modified FOLFOX6 [mFOLFOX6]), or four to six cycles of mFOLFOX6 followed by surgery and six to eight cycles of mFOLFOX6. Random assignment was performed by using computer-generated block randomization codes. The primary end point was 3-year disease-free survival. Secondary end points of histopathologic response and toxicity are reported. RESULTS: A total of 495 patients were enrolled from June 2010 to February 2015; 475 were evaluable (fluorouracil-radiotherapy, n = 155; mFOLFOX6-radiotherapy, n = 157; mFOLFOX6, n = 163). In the fluorouracil-radiotherapy, mFOLFOX6-radiotherapy, and mFOLFOX6 groups, the rate of pathologic complete response (pCR) was 14.0%, 27.5%, and 6.6%, and downstaging (ypStage 0 to 1) was achieved by 37.1%, 56.4%, and 35.5% of patients, respectively. Higher toxicity and more postoperative complications were observed in patients who received radiotherapy. CONCLUSION: mFOLFOX6-based preoperative chemoradiotherapy results in a higher pCR rate than fluorouracil-based treatment. Perioperative mFOLFOX6 alone had inferior results and a lower pCR rate than chemoradiotherapy but led to a similar downstaging rate as fluorouracil-radiotherapy, with less toxicity and fewer postoperative complications.