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The New England Journal of Medicine Jul 2023Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain.
METHODS
We conducted a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by <20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Noninferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects.
RESULTS
From June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P = 0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy.
CONCLUSIONS
In patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.).
Topics: Adult; Humans; Anal Canal; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Chemotherapy, Adjuvant; Disease-Free Survival; Fluorouracil; Leucovorin; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Organ Sparing Treatments; Oxaliplatin; Rectal Neoplasms; Preoperative Care; Preoperative Period
PubMed: 37272534
DOI: 10.1056/NEJMoa2303269 -
Nature Medicine Aug 2023There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or... (Randomized Controlled Trial)
Randomized Controlled Trial
There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Claudin-18 isoform 2 (CLDN18.2) is expressed in normal gastric cells and maintained in malignant G/GEJ adenocarcinoma cells. GLOW (closed enrollment), a global, double-blind, phase 3 study, examined zolbetuximab, a monoclonal antibody that targets CLDN18.2, plus capecitabine and oxaliplatin (CAPOX) as first-line treatment for CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. Patients (n = 507) were randomized 1:1 (block sizes of two) to zolbetuximab plus CAPOX or placebo plus CAPOX. GLOW met the primary endpoint of progression-free survival (median, 8.21 months versus 6.80 months with zolbetuximab versus placebo; hazard ratio (HR) = 0.687; 95% confidence interval (CI), 0.544-0.866; P = 0.0007) and key secondary endpoint of overall survival (median, 14.39 months versus 12.16 months; HR = 0.771; 95% CI, 0.615-0.965; P = 0.0118). Grade ≥3 treatment-emergent adverse events were similar with zolbetuximab (72.8%) and placebo (69.9%). Zolbetuximab plus CAPOX represents a potential new first-line therapy for patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. ClinicalTrials.gov identifier: NCT03653507 .
Topics: Humans; Adenocarcinoma; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Claudins; Esophagogastric Junction; Oxaliplatin; Stomach Neoplasms
PubMed: 37524953
DOI: 10.1038/s41591-023-02465-7 -
European Heart Journal Nov 2023Mavacamten is a first-in-class, targeted, cardiac-specific myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic... (Review)
Review
Mavacamten is a first-in-class, targeted, cardiac-specific myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic New York Heart Association Classes II and III obstructive hypertrophic cardiomyopathy (oHCM). Mavacamten was developed to target the hyper-contractile phenotype, which plays a critical role in the pathophysiology of the disease. In Phase 2 and 3 clinical trials, mavacamten was well tolerated, reduced left ventricular outflow tract gradients, improved exercise capacity and symptoms, and was associated with improvements in other clinically relevant parameters, such as patient-reported outcomes and circulating biomarkers. In addition, treatment with mavacamten was associated with evidence of favourable cardiac remodelling in multi-modality imaging studies. Mavacamten substantially reduced guideline eligibility for septal reduction therapy candidates with oHCM and drug-refractory symptoms. In this article, the available efficacy and safety data from completed and ongoing clinical studies of mavacamten in patients with symptomatic oHCM are reviewed. Longer term extension studies may help address questions related to the positioning of mavacamten in current oHCM management algorithms, interactions with background therapy, as well as the potential for disease modification beyond symptomatic relief of left ventricular outflow tract obstruction.
Topics: Adult; Humans; Benzylamines; Cardiomyopathy, Hypertrophic; Heart; United States; Uracil
PubMed: 37804245
DOI: 10.1093/eurheartj/ehad637 -
Cell Reports. Medicine Oct 2023The GLOW randomized double-blind phase 3 trial shows that Claudin-18.2 targeting antibody zolbetuximab combined with capecitabine and oxaliplatin improves outcome... (Randomized Controlled Trial)
Randomized Controlled Trial
The GLOW randomized double-blind phase 3 trial shows that Claudin-18.2 targeting antibody zolbetuximab combined with capecitabine and oxaliplatin improves outcome compared to placebo and chemotherapy as first-line treatment in Claudin-18.2-positive, HER2-negative gastric or gastroesophageal junction adenocarcinomas.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Claudins; Esophageal Neoplasms; Receptor, ErbB-2; Stomach Neoplasms
PubMed: 37852180
DOI: 10.1016/j.xcrm.2023.101233 -
Nature Communications Aug 2023Colorectal cancer (CRC) therapy efficiency can be influenced by the microbiota in the gastrointestinal tract. Compared with traditional intervention, prebiotics delivery...
Colorectal cancer (CRC) therapy efficiency can be influenced by the microbiota in the gastrointestinal tract. Compared with traditional intervention, prebiotics delivery into the gut is a more controllable method for gut microbiota modulatory therapy. Capecitabine (Cap), the first-line chemotherapeutic agent for CRC, lacks a carrier that can prolong its half-life. Here, we construct a Cap-loaded nanoparticle using the prebiotic xylan-stearic acid conjugate (SCXN). The oral administration of SCXN delays the drug clearance in the blood and increases the intra-tumoral Cap concentration in the CRC mouse model. SCXN also facilitates the probiotic proliferation and short chain fatty acid production. Compared with free Cap, SCXN enhances the anti-tumor immunity and increases the tumor inhibition rate from 5.29 to 71.78%. SCXN exhibits good biocompatibility and prolongs the median survival time of CRC mice from 14 to 33.5 d. This prebiotics-based nanoparticle provides a promising CRC treatment by combining gut microbiota modulation and chemotherapy.
Topics: Mice; Animals; Prebiotics; Gastrointestinal Microbiome; Capecitabine; Colorectal Neoplasms; Nanoparticles
PubMed: 37550297
DOI: 10.1038/s41467-023-40439-y -
Annals of Surgical Oncology Jul 2023Pancreatic cancer often presents as locally advanced (LAPC) or borderline resectable (BRPC). Neoadjuvant systemic therapy is recommended as initial treatment. It is... (Meta-Analysis)
Meta-Analysis Review
FOLFIRINOX or Gemcitabine-based Chemotherapy for Borderline Resectable and Locally Advanced Pancreatic Cancer: A Multi-institutional, Patient-Level, Meta-analysis and Systematic Review.
BACKGROUND
Pancreatic cancer often presents as locally advanced (LAPC) or borderline resectable (BRPC). Neoadjuvant systemic therapy is recommended as initial treatment. It is currently unclear what chemotherapy should be preferred for patients with BRPC or LAPC.
METHODS
We performed a systematic review and multi-institutional meta-analysis of patient-level data regarding the use of initial systemic therapy for BRPC and LAPC. Outcomes were reported separately for tumor entity and by chemotherapy regimen including FOLFIRINOX (FIO) or gemcitabine-based.
RESULTS
A total of 23 studies comprising 2930 patients were analyzed for overall survival (OS) calculated from the beginning of systemic treatment. OS for patients with BRPC was 22.0 months with FIO, 16.9 months with gemcitabine/nab-paclitaxel (Gem/nab), 21.6 months with gemcitabine/cisplatin or oxaliplatin or docetaxel or capecitabine (GemX), and 10 months with gemcitabine monotherapy (Gem-mono) (p < 0.0001). In patients with LAPC, OS also was higher with FIO (17.1 months) compared with Gem/nab (12.5 months), GemX (12.3 months), and Gem-mono (9.4 months; p < 0.0001). This difference was driven by the patients who did not undergo surgery, where FIO was superior to other regimens. The resection rates for patients with BRPC were 0.55 for gemcitabine-based chemotherapy and 0.53 with FIO. In patients with LAPC, resection rates were 0.19 with Gemcitabine and 0.28 with FIO. In resected patients, OS for patients with BRPC was 32.9 months with FIO and not different compared to Gem/nab, (28.6 months, p = 0.285), GemX (38.8 months, p = 0.1), or Gem-mono (23.1 months, p = 0.083). A similar trend was observed in resected patients converted from LAPC.
CONCLUSIONS
In patients with BRPC or LAPC, primary treatment with FOLFIRINOX compared with Gemcitabine-based chemotherapy appears to provide a survival benefit for patients that are ultimately unresectable. For patients that undergo surgical resection, outcomes are similar between GEM+ and FOLFIRINOX when delivered in the neoadjuvant setting.
Topics: Humans; Gemcitabine; Antineoplastic Combined Chemotherapy Protocols; Oxaliplatin; Pancreatic Neoplasms; Fluorouracil; Leucovorin; Neoadjuvant Therapy; Paclitaxel; Multicenter Studies as Topic
PubMed: 37020094
DOI: 10.1245/s10434-023-13353-2 -
Nature Communications Jan 2024How cells coordinate cell cycling with cell survival and death remains incompletely understood. Here, we show that cell cycle arrest has a potent suppressive effect on...
How cells coordinate cell cycling with cell survival and death remains incompletely understood. Here, we show that cell cycle arrest has a potent suppressive effect on ferroptosis, a form of regulated cell death induced by overwhelming lipid peroxidation at cellular membranes. Mechanistically, cell cycle arrest induces diacylglycerol acyltransferase (DGAT)-dependent lipid droplet formation to sequester excessive polyunsaturated fatty acids (PUFAs) that accumulate in arrested cells in triacylglycerols (TAGs), resulting in ferroptosis suppression. Consequently, DGAT inhibition orchestrates a reshuffling of PUFAs from TAGs to phospholipids and re-sensitizes arrested cells to ferroptosis. We show that some slow-cycling antimitotic drug-resistant cancer cells, such as 5-fluorouracil-resistant cells, have accumulation of lipid droplets and that combined treatment with ferroptosis inducers and DGAT inhibitors effectively suppresses the growth of 5-fluorouracil-resistant tumors by inducing ferroptosis. Together, these results reveal a role for cell cycle arrest in driving ferroptosis resistance and suggest a ferroptosis-inducing therapeutic strategy to target slow-cycling therapy-resistant cancers.
Topics: Humans; Lipid Droplets; Ferroptosis; Fatty Acids, Unsaturated; Lipid Peroxidation; Triglycerides; Cell Cycle Checkpoints; Neoplasms; Diacylglycerol O-Acyltransferase; Fluorouracil
PubMed: 38167301
DOI: 10.1038/s41467-023-44412-7 -
International Journal of Molecular... Jun 2023Hepatocellular carcinoma (HCC) is the most common primary liver tumor and is often diagnosed at an unresectable advanced stage. Systemic chemotherapy as well as... (Review)
Review
Hepatocellular carcinoma (HCC) is the most common primary liver tumor and is often diagnosed at an unresectable advanced stage. Systemic chemotherapy as well as transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) are used to treat advanced HCC. TACE and HAIC have long been the standard of care for patients with unresectable HCC but are limited to the treatment of intrahepatic lesions. Systemic chemotherapy with doxorubicin or chemohormonal therapy with tamoxifen have also been considered, but neither has demonstrated survival benefits. In the treatment of unresectable advanced HCC, cisplatin is administered transhepatic arterially for local treatment. Subsequently, for cisplatin-refractory cases due to drug resistance, a shift to systemic therapy with a different mechanism of action is expected to produce new antitumor effects. Cisplatin is also used for the treatment of liver tumors other than HCC. This review summarizes the action and resistance mechanism of cisplatin and describes the treatment of the major hepatobiliary cancers for which cisplatin is used as an anticancer agent, with a focus on HCC.
Topics: Humans; Liver Neoplasms; Carcinoma, Hepatocellular; Cisplatin; Fluorouracil; Chemoembolization, Therapeutic; Treatment Outcome
PubMed: 37446035
DOI: 10.3390/ijms241310858 -
Journal of Cancer Research and... Oct 2023The incidence of 5-Fluorouracil (5FU)- induced leukoencephalopathy is <5% among the patients treated with this agent. It may present with disorientation, confusion,...
The incidence of 5-Fluorouracil (5FU)- induced leukoencephalopathy is <5% among the patients treated with this agent. It may present with disorientation, confusion, agitation, seizure, and coma. It should be suspected when patients present with any of these symptoms during or immediately after 5FU chemotherapy. Early detection of drug-induced leukoencephalopathy is important as the clinical symptoms can be reversed by early discontinuation of the drug. Therefore, clinicians should be aware of the possibility of this adverse neurologic effect of 5FU. We describe the case of a 35-year-old female with carcinoma esophagus with 5FU-induced leukoencephalopathy.
Topics: Female; Humans; Adult; Awareness; Carcinoma; Drug-Related Side Effects and Adverse Reactions; Fluorouracil; Leukoencephalopathies
PubMed: 38376324
DOI: 10.4103/jcrt.jcrt_2165_21 -
Signal Transduction and Targeted Therapy Sep 2023The majority of hepatocellular carcinoma (HCC) cases are diagnosed at an advanced stage. Currently, there are only a few therapeutic methods available for patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
Combined FOLFOX4 with all-trans retinoic acid versus FOLFOX4 with placebo in treatment of advanced hepatocellular carcinoma with extrahepatic metastasis: a randomized, double-blind comparative study.
The majority of hepatocellular carcinoma (HCC) cases are diagnosed at an advanced stage. Currently, there are only a few therapeutic methods available for patients with advanced HCC and extrahepatic metastasis (EHM). Systemic chemotherapy, such as FOLFOX4 (infusions of fluorouracil, leucovorin, and oxaliplatin), has been reported for treating advanced HCC with EHM, but its effectiveness is very poor. In this randomized, double-blind, placebo-controlled study, we aimed to assess the efficacy and safety of FOLFOX4 with all-trans-retinoic acid (ATRA) as a palliative treatment for HCC patients with EHM, compared to FOLFOX4 with a placebo. The primary endpoint was overall survival (OS), and subsequently, an exploratory model was developed based on bioinformatics to predict the efficacy of FOLFOX4-ATRA treatment. A total of 108 patients were randomly assigned in a 1:1 ratio to receive either FOLFOX4-ATRA or FOLFOX4-placebo. The intention-to-treat (ITT) population showed a median OS of 16.2 months for the FOLFOX4-ATRA group, compared with 10.7 months for the FOLFOX4-placebo group (HR 0.56, 95% CI 0.33-0.93; p = 0.025). The median progression-free survival (PFS) was 7.1 months for the FOLFOX4-ATRA group and 4.2 months for the FOLFOX4-placebo group (HR 0.62, 95% CI 0.41-0.94; p = 0.024). A panel of proteins with unique upregulation during complete response (CR) (SOD3, TTR, SSC5D, GP5, IGKV1D-33) and partial response (PR) (TGFB1, GSS, IGHV5-10-1) effectively predicted CR and PR in patients treated with FOLFOX4-ATRA, as compared to FOLFOX4-placebo. The results suggest that FOLFOX4-ATRA is a safe and effective treatment for patients with advanced HCC and EHM in eastern China.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Fluorouracil; Treatment Outcome; Tretinoin
PubMed: 37752117
DOI: 10.1038/s41392-023-01604-3