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BMC Geriatrics May 2024The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older...
Preoperative chemoradiotherapy in older patients with rectal cancer guided by comprehensive geriatric assessment within a multidisciplinary team-a multicenter phase II trial.
BACKGROUND
The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as "fit" by comprehensive geriatric assessment (CGA).
METHODS
A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of "fit" (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22).
RESULTS
One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47).
CONCLUSION
This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA.
TRIAL REGISTRATION
The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).
Topics: Humans; Aged; Male; Female; Rectal Neoplasms; Aged, 80 and over; Geriatric Assessment; Chemoradiotherapy; Disease-Free Survival; Preoperative Care; Thiophenes; Patient Care Team; Quinazolines
PubMed: 38773457
DOI: 10.1186/s12877-024-05046-6 -
Journal of Gastrointestinal Oncology Apr 2024After the failure of standard first- and second-line treatments, including oxaliplatin, irinotecan, and 5-fluorouracil (5-FU) combined with targeted drugs, the currently...
BACKGROUND
After the failure of standard first- and second-line treatments, including oxaliplatin, irinotecan, and 5-fluorouracil (5-FU) combined with targeted drugs, the currently recommended third-line regimens for metastatic colorectal cancer (mCRC) include TAS-102, regorafenib, and fruquintinib. However, these regimens have the drawbacks of mediocre efficacy, substantive side effects, and high cost. Therefore, more effective, economical regimens with fewer side effects are needed in clinical practice. In this study, we assessed the efficacy and safety of gemcitabine plus raltitrexed or S-1 as a third- or later-line treatment in comparison to those of standard third-line therapies for patients with mCRC.
METHODS
Patients with previous failures of at least two lines of standard therapy with oxaliplatin, 5-FU, irinotecan, or capecitabine combined with targeted drugs were included. The participants received standard third-line therapies (including TAS-102, regorafenib, and fruquintinib) or gemcitabine plus raltitrexed or S-1 until disease progression, death, or intolerable toxicity arose. Imaging follow-up was performed every 3 months during their treatment. Progression-free survival (PFS) and overall survival (OS) were recorded. Cox regression analysis was used to investigate the potential predictors of survival.
RESULTS
From April 2018 to October 2022, 60 patients with mCRC were enrolled in our study. The numbers of patients in the chemotherapy, fruquintinib, regorafenib, and TAS-102 groups were 13, 15, 17, and 15, respectively; the median OS of the four groups was 7.4, 6.1, 8.3, and 6.7 months (P=0.384), respectively; the median PFS was 4.1, 3.4, 4.4, and 2.3 months (P=0.656), respectively; the overall response rate was 7.69%, 6.67%, 0.00%, and 13.33%, respectively; and the disease control rate was 61.54%, 60.00%, 70.59%, and 60.00%, respectively. Additionally, multivariate analysis revealed that primary lesion located in the rectum was adverse independent prognostic factors for OS. A typical case is presented in this article.
CONCLUSIONS
The gemcitabine plus raltitrexed or S-1 regimen is a potential regimen with tolerable adverse reactions and low cost for patients with mCRC.
PubMed: 38756629
DOI: 10.21037/jgo-24-76 -
Cureus Apr 2024Colorectal cancer (CRC) ranks as the second leading cause of cancer-related mortality among women and the third leading cause of cancer-associated mortality among men....
INTRODUCTION
Colorectal cancer (CRC) ranks as the second leading cause of cancer-related mortality among women and the third leading cause of cancer-associated mortality among men. Treatment of colon cancer is very crucial for a patient's survival. In this study, we assessed the reliability, efficacy, and safety of raltitrexed in intraoperative intraperitoneal chemotherapy for colon cancer.
METHODOLOGY
A total of 57 patients with clinical stages II and III of colon cancer were included in the study. R0 resection surgery + hyperthermic intraperitoneal chemotherapy (HIPEC) procedure was done with raltitrexed. It was given in a dose of 3 mg/m in a 0.9% NS injection in a volume of 500 milliliters. Postoperative complications were observed.
RESULT
The most common postoperative complication was nausea/vomiting, which was seen in 21 out of 57 patients (37%). The second most common complication was fever (18/57). None of the patients died or developed renal toxicity, hepatic toxicity, and intestinal obstruction.
CONCLUSION
Raltitrexed is a reliable, efficient, and safe drug and can be used in intraoperative intraperitoneal chemotherapy of colon cancer.
PubMed: 38644947
DOI: 10.7759/cureus.58481 -
Science Advances Mar 2024There is a compelling need to find drugs active against (). 4'-Phosphopantetheinyl transferase (PptT) is an essential enzyme in that has attracted interest as a...
There is a compelling need to find drugs active against (). 4'-Phosphopantetheinyl transferase (PptT) is an essential enzyme in that has attracted interest as a potential drug target. We optimized a PptT assay, used it to screen 422,740 compounds, and identified raltitrexed, an antineoplastic antimetabolite, as the most potent PptT inhibitor yet reported. While trying unsuccessfully to improve raltitrexed's ability to kill and remove its ability to kill human cells, we learned three lessons that may help others developing antibiotics. First, binding of raltitrexed substantially changed the configuration of the PptT active site, complicating molecular modeling of analogs based on the unliganded crystal structure or the structure of cocrystals with inhibitors of another class. Second, minor changes in the raltitrexed molecule changed its target in from PptT to dihydrofolate reductase (DHFR). Third, the structure-activity relationship for over 800 raltitrexed analogs only became interpretable when we quantified and characterized the compounds' intrabacterial accumulation and transformation.
Topics: Humans; Mycobacterium tuberculosis; Thymidylate Synthase; Bacterial Proteins; Neoplasms; Quinazolines; Thiophenes; Transferases (Other Substituted Phosphate Groups)
PubMed: 38489355
DOI: 10.1126/sciadv.adj6406 -
BMC Cancer Mar 2024There are various recommendations for third-line treatment in mCRC, however, there is no consensus on who is more suitable for particular strategy. Chemotherapy re-use...
BACKGROUND
There are various recommendations for third-line treatment in mCRC, however, there is no consensus on who is more suitable for particular strategy. Chemotherapy re-use in third-line setting is a common option in clinical practice. This study aimed to investigate the efficacy of third-line chemotherapy re-use by the comparison with that of anti-angiogenic monotherapy, and further find the population more suitable for third-line chemotherapy.
METHODS
Using electronic medical records of patients with mCRC, a retrospective cohort study was conducted. A total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting as control group were retrospectively collected. Baseline characteristics were analyzed using the χ² test or the Fisher's exact test. ROC curve and surv_cutpoint function of 'survminer' package in R software were used to calculate the cut-off value. Survival curves were plotted with the Kaplan-Meier method and were compared using the log-rank test. The Cox proportional hazard regression model was used to analyze the potential risk factors.
RESULTS
A total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting were retrospectively collected. Chemotherapy rechallenge was recorded in 93 patients (93/143, 65.0%), and the remaining patients chose new chemotherapeutic drugs that had not been previously used, including irinotecan-based (22/50), oxaliplatin-based (9/50), raltitrexed (9/50), gemcitabine (5/50) and other agents (5/50). The ORR and DCR of third-line chemotherapy reached 8.8%, 61.3%, respectively (anti-angiogenic monotherapy group: ORR 2.6%, DCR 47.4%). The mPFS and mOS of patients receiving chemotherapy were 4.9 and 12.0 m, respectively (anti-angiogenic monotherapy group: mPFS 2.7 m, mOS 5.2 m). Subgroup analyses found that patients with RAS/RAF mutation, longer PFS (greater than 10.6 m) in front-line treatment or larger tumor burden had better prognosis with third-line chemotherapy rather than anti-angiogenic monotherapy.
CONCLUSIONS
Third-line chemotherapy re-use was effective in mCRC. Those with more aggressive characteristics (RAS/RAF mutant, larger tumor burden) or better efficacy of previous chemotherapy (longer PFS) were more appropriate for third-line chemotherapy, rather than anti-angiogenic monotherapy.
Topics: Humans; Retrospective Studies; Cohort Studies; Immunotherapy; Colonic Neoplasms; Rectal Neoplasms
PubMed: 38443891
DOI: 10.1186/s12885-024-12072-5 -
Alternative Therapies in Health and... Feb 2024Intraperitoneal chemotherapy is an effective way to kill free tumor cells in the abdominal cavity. The safety and efficacy of raltitrexed perfusion during radical...
BACKGROUND
Intraperitoneal chemotherapy is an effective way to kill free tumor cells in the abdominal cavity. The safety and efficacy of raltitrexed perfusion during radical surgery for elderly patients with colorectal cancer are still unclear.
METHODS
In accordance with computer-generated random allocation sequences, 116 elderly patients with colorectal cancer who received radical surgery were randomly grouped into the raltitrexed intraperitoneal perfusion group or the saline intraperitoneal perfusion group from January 2020 to December 2021 in the First Affiliated Hospital of Bengbu Medical University. t tests and χ2 tests were used to analyze the difference between the two groups of the clinical characteristics, pathological features, perioperative parameters, and carcinoembryonic antigen mRNA in the peritoneal lavage fluid.
RESULTS
No statistically significant differences in postoperative complications after radical surgery were observed between the two groups. No statistically significant differences in peripheral blood indexes were observed between the two groups before surgery or on the first and third days after surgery. One day after radical surgery, the alanine transaminase (54.33 ± 4.93 vs 51.01 ± 5.56) and aspartate transaminase (49.28 ± 4.30 vs 50.99 ± 3.88) in the peripheral blood were higher in the raltitrexed intraperitoneal perfusion group than in the saline intraperitoneal perfusion group. At the same time, no significant difference was found on the third day after surgery. No significant differences in side effects of chemotherapy were observed between the two groups. The positive rate of carcinoembryonic antigen mRNA in the raltitrexed intraperitoneal perfusion group (8.47%) was significantly lower than that in the saline intraperitoneal perfusion group (22.81%) after surgery.
CONCLUSION
Raltitrexed perfusion during radical surgery is safe and feasible for elderly patients with CRC and can reduce the positive rate of carcinoembryonic antigen mRNA in peritoneal lavage fluid, so it can be explored as a treatment option.
PubMed: 38401095
DOI: No ID Found -
Therapeutic Advances in Medical Oncology 2024The most common loadable chemotherapeutic drugs in drug-eluting bead transarterial chemoembolization (DEB-TACE) include doxorubicin, epirubicin, etc. CalliSpheres beads...
Efficacy and safety of raltitrexed-eluting CalliSpheres bead transarterial chemoembolization in patients with intermediate-stage hepatocellular carcinoma: a single-arm, prospective study.
BACKGROUND
The most common loadable chemotherapeutic drugs in drug-eluting bead transarterial chemoembolization (DEB-TACE) include doxorubicin, epirubicin, etc. CalliSpheres beads have exhibited efficient loadability and eluting characteristics for raltitrexed as well as and animal experiments. However, the efficacy and safety of raltitrexed-loaded DEB-TACE in patients with intermediate-stage hepatocellular carcinoma (HCC) remain unclear.
OBJECTIVES
To assess the efficacy and safety of raltitrexed-loaded DEB-TACE in patients with intermediate-stage HCC.
DESIGN
The study was conducted as a single-arm prospective study.
METHODS
This study was a prospective, single-arm trial conducted between June 2019 and June 2022. CalliSpheres beads loaded with raltitrexed were used in the DEB-TACE procedure. The follow-up lasted for at least 1 year or until death. The primary endpoint was overall survival (OS), and the secondary endpoints were time to progression (TTP), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs).
RESULTS
The 6-month ORR and disease control rates were 90.1% and 93.8%, respectively. The median OS was 33.0 months. The 1-, 2-, and 3-year survival rates were 95.1%, 82.1%, and 43.6%, respectively. Child-Pugh class and bilobar disease occurrence were identified as independent OS predictors. The median TTP and PFS were 22.7 and 19.8 months, respectively. Eleven (11.5%) patients experienced at least one grade 3 AE, and serious AEs were reported in five participants (5.2%). No patient experienced grade 4 or 5 AEs.
CONCLUSION
Raltitrexed-loaded DEB-TACE is feasible, safe, and effective in patients with intermediate-stage HCC.
TRIAL REGISTRATION
This trial was registered at www.chictr.org.cn under the identifier: 1900024097 on 25 June 2019.
PubMed: 38362379
DOI: 10.1177/17588359241229661 -
Journal of Gastrointestinal Oncology Dec 2023There are limited treatment options available for patients with metastatic colorectal cancer (mCRC). About 95% of CRC patients have mismatch repair...
Significant response from fruquintinib plus anti-PD-1 immunotherapy for microsatellite stable metastatic colorectal cancer with liver and lung metastasis in the third line: case report.
BACKGROUND
There are limited treatment options available for patients with metastatic colorectal cancer (mCRC). About 95% of CRC patients have mismatch repair proficient/microsatellite stable (pMMR/MSS) tumors are virtually unresponsive to programmed cell death protein 1 (PD-1) antibody treatment. This report shows that a patient with pMMR/MSS mCRC achieved significant response and the longest progression-free survival (PFS) of 28 months currently reported from tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor receptor (VEGFR) family (VEGFR-1,2,3) (fruquintinib) plus anti-PD-1 immunotherapy in the third line, providing a new and promising treatment option for some MSS mCRC patients.
CASE DESCRIPTION
This case details a 65-year-old male with CRC who was diagnosed with pT4aN2bM0, IIIC, and pMMR/MSS after curative surgery in August 2018. Subsequently, he received adjuvant chemotherapy [FOLFOX (folinic acid, fluorouracil, and oxaliplatin) for 5 cycles], first-line treatment (pelvic radiation plus capecitabine), and second-line treatment [TOMIRI (raltitrexed and irinotecan) plus cetuximab for 2 cycles]. Lung, liver, and pelvic cavity metastases worsened in October 2019. He began receiving the fruquintinib plus PD-1 inhibitor (FP) regimen as third-line treatment and after 3 cycles, the size of the lung lesions was significantly reduced and evaluated as partial response (PR), whereas the liver and pelvic cavity lesions remained stable. As of December 2021, he had received a total of 33 courses of FP regimen. In February 2022, liver metastases progressed. In brief, he achieved a long PFS of 28 months and an overall survival (OS) of 40 months from the third-line treatment. Additionally, the patient only experienced mild proteinuria after the combined treatment and tolerated well.
CONCLUSIONS
Fruquintinib combined with immunotherapy could exert good therapeutic effects with safety in MSS mCRC patients. And patients with lung metastasis may be the principal beneficiaries.
PubMed: 38196522
DOI: 10.21037/jgo-23-862 -
ACS Omega Oct 2023Stearoyl chitosan (SC), derived from the acylation of chitosan, contributes to the efficiency of drug delivery systems because of its structure, which accommodates the...
Stearoyl chitosan (SC), derived from the acylation of chitosan, contributes to the efficiency of drug delivery systems because of its structure, which accommodates the drug in a particle. Nonetheless, its role in chemotherapy has been largely unexplored. The present study involves the synthesis of stearoyl chitosan through the reaction of depolymerized chitosan with stearoyl chloride under mild reaction conditions. The resulting compound was subjected to structural analysis utilizing Fourier-transform infrared (FTIR) spectroscopy, H NMR, and X-ray diffraction (XRD) spectroscopy. The dispersion of SC molecules in phosphate-buffered saline (PBS) forms SC nanoparticles. The best dispersion of SC in the solution was achieved at a 1:60 chitosan-to-stearoyl chloride weight ratio. Three antimetabolite drugs, methotrexate, pemetrexed, and raltitrexed, were selected to examine the loading efficacy of SC. Pemetrexed had the highest drug-loading value of 36.8% among the three antimetabolites incorporated into SC, along with an encapsulation efficiency of 85.1%. The size of SC loaded with antimetabolites ranged from 225 to 369 nm, and their spherical form was verified via a transmission electron microscope. The in vitro release study showed that SC demonstrated controlled drug release, suggesting that SC nanoparticles have significant promise as a delivery strategy for chemotherapy.
PubMed: 37929136
DOI: 10.1021/acsomega.3c05108 -
Bioinformation 2023Myeloid leukemia 1 (MCL-1), a BCL-2 protein family member, acts as an anti-apoptotic protein by interacting with pro-apoptotic BCL-2 proteins. Its overexpression is...
Myeloid leukemia 1 (MCL-1), a BCL-2 protein family member, acts as an anti-apoptotic protein by interacting with pro-apoptotic BCL-2 proteins. Its overexpression is frequently observed in numerous cancer types including breast cancer, and is closely linked to the initiation and progression of tumors as well as poor prognosis and resistance to therapeutic interventions. Here, a database of 3402 chemicals with established therapeutic activity against various diseases was chosen and systematically screened against the MCL-1 protein. Visual inspection and binding energy analysis revealed that the compounds OSU-03012, Raltitrexed, Ostarine (MK-2866), Dovitinib (TKI-258), and Varespladib (LY315920) had strong binding affinity for the MCL-1 protein. Notably, their binding affinity was higher than that of the control compounds. These compounds exhibited strong interactions with critical amino acid residues of the MCL-1 protein. Furthermore, these compounds shared several common amino acid residue interactions with the control compounds. These findings suggest that these compounds may be useful as MCL-1 inhibitors in the treatment of breast cancer. However, additional experimental validation is required to confirm these findings.
PubMed: 37885779
DOI: 10.6026/97320630019707