RÉSUMÉ
Pancreatic malignancy is the fourth cause of cancer-related death in Western countries and is predicted to become the second leading cause of cancer-related mortality by 2030. The standard therapies (FOLFIRINOX and gemcitabine with nab-paclitaxel) are not resolutive because this type of cancer is also characterized by a high chemoresistance, due in part to the activity of the ATP Binding Cassette (ABC) pumps accounting for the reduction in the intracellular concentration of the drugs. In this work, we analyze the occurrence of single-nucleotide polymorphisms (SNPs) in the MDR-1 gene, in different pancreatic cancer cell lines, and in tissues from pancreatic cancer patients by DNA sequencing, as well as the expression levels of MDR-1 mRNA and protein, by qRT-PCR and Western Blot analysis. We found that gemcitabine-resistant cells, in conjunction with homozygosis of analyzed SNPs, showed high MDR-1 basal levels with further increases after gemcitabine treatment. Nevertheless, we did not observe in the human PDAC samples a correlation between the level of MDR-1 mRNA and protein expression and SNPs. Preliminary, we conclude that in our small cohort, these SNPs cannot be used as molecular markers for predicting the levels of MDR-1 mRNA/protein levels and drug responses in patients with PDAC.
Sujet(s)
Sous-famille B de transporteurs à cassette liant l'ATP , Désoxycytidine , Résistance aux médicaments antinéoplasiques , , Tumeurs du pancréas , Polymorphisme de nucléotide simple , Humains , Tumeurs du pancréas/génétique , Tumeurs du pancréas/traitement médicamenteux , Tumeurs du pancréas/anatomopathologie , Tumeurs du pancréas/métabolisme , Résistance aux médicaments antinéoplasiques/génétique , Lignée cellulaire tumorale , Désoxycytidine/analogues et dérivés , Désoxycytidine/pharmacologie , Désoxycytidine/usage thérapeutique , Sous-famille B de transporteurs à cassette liant l'ATP/génétique , Sous-famille B de transporteurs à cassette liant l'ATP/métabolisme , Mâle , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Femelle , Adulte d'âge moyen , Sujet âgé , ARN messager/génétique , ARN messager/métabolismeRÉSUMÉ
BACKGROUND: Bazedoxifene is a third-generation selective estrogen receptor modulator that inhibits the IL6/IL6R/GP130 signaling pathway by inhibiting IL6-induced homodimerization of GP130. Considering that the IL6/IL6R/GP130 signaling pathway is important in tumorigenesis and metastasis, bazedoxifene is thought to have an antitumor effect, which has been proven preliminarily in breast cancer and pancreatic cancer but has not yet been studied in non-small cell lung cancer (NSCLC). This study is aimed at evaluating the antitumor effect of bazedoxifene in NSCLC. METHODS: A549 and H1299 NSCLC cell lines were employed and exposed to various concentrations of bazedoxifene, paclitaxel, gemcitabine, and their combinations for cell viability, colony formation, and wound healing assays to demonstrate the antitumor effect of bazedoxifene with or without paclitaxel or gemcitabine. RESULTS: MTT cell viability, colony formation, and wound healing assays showed that bazedoxifene was capable of inhibiting cell viability, colony formation, and cell migration in a dose-dependent manner. In addition, bazedoxifene was capable of working with paclitaxel or gemcitabine synergistically to inhibit cell viability, colony formation, and cell migration. CONCLUSION: This study demonstrated the potential antitumor effect of bazedoxifene and its ability to improve the treatment efficacy of paclitaxel and gemcitabine.
Sujet(s)
Carcinome pulmonaire non à petites cellules , Mouvement cellulaire , Survie cellulaire , Désoxycytidine , , Indoles , Tumeurs du poumon , Paclitaxel , Humains , Désoxycytidine/analogues et dérivés , Désoxycytidine/pharmacologie , Désoxycytidine/usage thérapeutique , Paclitaxel/pharmacologie , Mouvement cellulaire/effets des médicaments et des substances chimiques , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/anatomopathologie , Indoles/pharmacologie , Indoles/usage thérapeutique , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/anatomopathologie , Survie cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Modulateurs sélectifs des récepteurs des oestrogènes/pharmacologie , Modulateurs sélectifs des récepteurs des oestrogènes/usage thérapeutiqueRÉSUMÉ
OBJECTIVE: To evaluate the efficiency of pemetrexed cisplatin in comparison with gemcitabine cisplatin and to validate the EORTC (European Organisation for Research and Treatment of Cancer) prognostic score in combination chemotherapy treatment for malignant pleural mesothelioma. STUDY DESIGN: An observational study. Place and Duration of the Study: Department of Oncology, Dicle University Hospital, Diyarbakir, Turkiye, from October 2000 to November 2017. METHODOLOGY: Malignant pleural mesothelioma (MPM) patients with EORTC score 0- were recruited. Factors affecting the prognosis of the disease and the effectiveness of first-line treatment were retrospectively analysed. EORTC prognostic score was calculated with a cut-off and survival analyses were used by the Kaplan-Meier method. Log-rank and univariable Cox regression tests were used to search for prognostic factors' impact on survival. RESULTS: Patients who received gemcitabine cisplatin treatment had a median progression-free survival (PFS) of 9 months, while those who received pemetrexed cisplatin therapy had a median PFS of 7 months. Median overall survival (OS) was 17 months in the gemcitabine cisplatin group and 18 months in the pemetrexed cisplatin group (p = 0.051). When the low-risk group was compared with the high-risk group, the median OS was found to be statistically significant (p = 0.009). CONCLUSION: The EORTC prognostic score, which is used for prognostic prediction in the period when pemetrexed is not utilised in the treatment of MPM, accurately predicts prognosis subsequent to the administration of pemetrexed in treatment. In the context of first-line treatment, cisplatin in combination with gemcitabine and cisplatin in combination with pemetrexed demonstrated comparable efficacy with respect to both overall survival and progression-free survival. KEY WORDS: Chemotherapy, Mesothelioma, Prognosis, Gemcitabine, Progression-free survival.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique , Cisplatine , Désoxycytidine , , Mésothéliome malin , Pémétrexed , Tumeurs de la plèvre , Humains , Mâle , Femelle , Études rétrospectives , Pémétrexed/usage thérapeutique , Pémétrexed/administration et posologie , Cisplatine/usage thérapeutique , Cisplatine/administration et posologie , Adulte d'âge moyen , Mésothéliome malin/traitement médicamenteux , Pronostic , Sujet âgé , Tumeurs de la plèvre/traitement médicamenteux , Tumeurs de la plèvre/mortalité , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Désoxycytidine/analogues et dérivés , Désoxycytidine/usage thérapeutique , Désoxycytidine/administration et posologie , Adulte , Survie sans progressionRÉSUMÉ
BACKGROUND: With poor prognosis and high mortality, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Standard of care therapies for PDAC have included gemcitabine for the past three decades, although resistance often develops within weeks of chemotherapy initiation through an array of possible mechanisms. METHODS: We reanalyzed publicly available RNA-seq gene expression profiles of 28 PDAC patient-derived xenograft (PDX) models before and after a 21-day gemcitabine treatment using our validated analysis pipeline to identify molecular markers of intrinsic and acquired resistance. RESULTS: Using normalized RNA-seq quantification measurements, we first identified oxidative phosphorylation and interferon alpha pathways as the two most enriched cancer hallmark gene sets in the baseline gene expression profile associated with intrinsic gemcitabine resistance and sensitivity, respectively. Furthermore, we discovered strong correlations between drug-induced expression changes in glycolysis and oxidative phosphorylation genes and response to gemcitabine, which suggests that these pathways may be associated with acquired gemcitabine resistance mechanisms. Thus, we developed prediction models using baseline gene expression profiles in those pathways and validated them in another dataset of 12 PDAC models from Novartis. We also developed prediction models based on drug-induced expression changes in genes from the Molecular Signatures Database (MSigDB)'s curated 50 cancer hallmark gene sets. Finally, pathogenic TP53 mutations correlated with treatment resistance. CONCLUSION: Our results demonstrate that concurrent upregulation of both glycolysis and oxidative phosphorylation pathways occurs in vivo in PDAC PDXs following gemcitabine treatment and that pathogenic TP53 status had association with gemcitabine resistance in these models. Our findings may elucidate the molecular basis for gemcitabine resistance and provide insights for effective drug combination in PDAC chemotherapy.
Sujet(s)
Désoxycytidine , Résistance aux médicaments antinéoplasiques , , Tumeurs du pancréas , Protéine p53 suppresseur de tumeur , Tests d'activité antitumorale sur modèle de xénogreffe , Désoxycytidine/analogues et dérivés , Désoxycytidine/pharmacologie , Désoxycytidine/usage thérapeutique , Humains , Tumeurs du pancréas/traitement médicamenteux , Tumeurs du pancréas/anatomopathologie , Tumeurs du pancréas/génétique , Résistance aux médicaments antinéoplasiques/génétique , Protéine p53 suppresseur de tumeur/métabolisme , Protéine p53 suppresseur de tumeur/génétique , Animaux , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Carcinome du canal pancréatique/traitement médicamenteux , Carcinome du canal pancréatique/génétique , Carcinome du canal pancréatique/anatomopathologie , Carcinome du canal pancréatique/métabolisme , Souris ,RÉSUMÉ
Periampullary carcinoma is a malignant gastrointestinal tumor originating from the head of the pancreas, distal bile duct, duodenum, or the ampulla of Vater. Currently, surgery remains the primary treatment option, yet the postoperative recurrence rate remains high. Chemotherapy is the main approach for controlling postoperative recurrence. Histologically, periampullary carcinoma is categorized into two types: intestinal (IN) and pancreaticobiliary (PB) subtype. Each subtype requires different therapeutic approaches, with the PB type primarily treated with gemcitabine and the IN type with 5-FU. Despite these options, patient outcomes are still unsatisfactory. In recent years, the feasibility of immunotherapy in tumor treatment has been increasingly evidenced, although research on its efficacy in periampullary carcinoma treatment is still limited. In this report, we present a case of a periampullary carcinoma patient who experienced recurrence and metastasis after undergoing radical pancreatoduodenectomy and receiving gemcitabine-based chemotherapy post-surgery. Through next-generation sequencing (NGS), we identified high expression levels of programmed cell death-ligand 1 (PD-L1) with a combined positive score (CPS) of 35, high tumor mutation burden (TMB-H), and high microsatellite instability (MSI-H) in this patient. Therefore, we implemented a combination therapy using Tislelizumab and chemotherapy. According to the latest follow-up, the tumors are effectively controlled. Our utilization of immunotherapy combined with chemotherapy holds significant implication for the treatment of periampullary carcinoma.
Sujet(s)
Ampoule hépatopancréatique , Anticorps monoclonaux humanisés , Protocoles de polychimiothérapie antinéoplasique , Humains , Anticorps monoclonaux humanisés/usage thérapeutique , Anticorps monoclonaux humanisés/administration et posologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Ampoule hépatopancréatique/anatomopathologie , Mâle , Résultat thérapeutique , Adulte d'âge moyen , Désoxycytidine/analogues et dérivés , Désoxycytidine/administration et posologie , Désoxycytidine/usage thérapeutique , Tumeurs du cholédoque/traitement médicamenteux , Tumeurs du cholédoque/thérapie , , Duodénopancréatectomie , Femelle , Sujet âgéRÉSUMÉ
A woman in her 40s underwent evaluation for abdominal pain, jaundice and acholic stools and was diagnosed with metastatic pancreatic head adenocarcinoma. She was enrolled in a clinical trial investigating the benefits of ibrutinib with nab-paclitaxel and gemcitabine, and subsequently received modified FOLFIRINOX. Over the course of 6 years on chemotherapy, she experienced complete regression of the pancreatic and liver lesions, as well as normalisation of her tumour markers. She has been off chemotherapy for 6 months with no evidence of disease and normal tumour markers. Despite advances in chemotherapy and surgical options, metastatic pancreatic adenocarcinoma continues to carry a grim prognosis. This case report demonstrates a rare case of a long-term survivor of unresectable metastatic pancreatic adenocarcinoma treated with chemotherapy alone.
Sujet(s)
Adénocarcinome , Protocoles de polychimiothérapie antinéoplasique , Leucovorine , Oxaliplatine , Tumeurs du pancréas , Humains , Tumeurs du pancréas/traitement médicamenteux , Tumeurs du pancréas/anatomopathologie , Femelle , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Adénocarcinome/traitement médicamenteux , Adénocarcinome/secondaire , Leucovorine/usage thérapeutique , Oxaliplatine/usage thérapeutique , Oxaliplatine/administration et posologie , , Paclitaxel/usage thérapeutique , Paclitaxel/administration et posologie , Désoxycytidine/analogues et dérivés , Désoxycytidine/usage thérapeutique , Désoxycytidine/administration et posologie , Fluorouracil/usage thérapeutique , Irinotécan/usage thérapeutique , Adulte , Albumines/usage thérapeutique , Albumines/administration et posologie , Adulte d'âge moyen , Tumeurs du foie/secondaire , Tumeurs du foie/traitement médicamenteux , Résultat thérapeutiqueRÉSUMÉ
BACKGROUND: Monotherapy consisting of radiotherapy or chemotherapy has limited efficacy in pancreatic tumors. This study aims to investigate whether the combination of 125I brachytherapy and gemcitabine (GEM) chemotherapy has a synergistic effect on pancreatic cancer (PC). METHODS: In vitro, PANC-1 cells in the exponential phase were treated with 125I radioactive seeds (6 Gy) and GEM (30 nM). Cell proliferation, apoptosis, and mitochondrial membrane potential were measured using the Cell Counting Kit-8 (CCK-8) assay, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and flow cytometry, respectively. In vivo, we examined the inhibitory effect of three different treatment regimens on tumor growth in mice when combined with 125I brachytherapy and GEM. Next, we investigated the effects of the optimal scheme among the three on the tumor microenvironment, tumor tissue morphology, tumor cell apoptosis, systemic inflammatory response, and levels of apoptosis-related proteins in the tumor. Changes in the tumor microenvironment and levels of apoptosis-related proteins were measured by Western blot. The extent of damage to tumor tissue morphology was assessed by Hematoxylin and Eosin (HE) staining. Tumor cell apoptosis was measured by TUNEL staining. Changes in inflammation-related factors were determined by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: The results of in vitro cell experiments demonstrated that the combination of 125I radioactive seeds (6 Gy) and GEM (30 nM) had a stronger inhibitory effect on PANC-1 cells than either alone (p < 0.05). In vivo, data showed that the GEM (after 3 d) + 125I treatment group had the strongest tumor inhibition effect on PC (p < 0.05). Western blot analysis showed that the combined treatment of 125I brachytherapy and GEM caused changes in the expression of collagen and connexin in the tumor microenvironment, promoted tumor cell apoptosis, upregulated the expression of pro-apoptotic proteins, and helped to restore pancreatic function (p < 0.01). CONCLUSION: Our research results suggest that the strategy of 125I seed implantation surgery in mice after 3 days of GEM treatment has a more pronounced synergistic effect on the treatment of PC.
Sujet(s)
Apoptose , Curiethérapie , Désoxycytidine , , Radio-isotopes de l'iode , Tumeurs du pancréas , Tumeurs du pancréas/radiothérapie , Tumeurs du pancréas/anatomopathologie , Tumeurs du pancréas/traitement médicamenteux , Désoxycytidine/analogues et dérivés , Désoxycytidine/pharmacologie , Désoxycytidine/usage thérapeutique , Radio-isotopes de l'iode/usage thérapeutique , Curiethérapie/méthodes , Animaux , Souris , Apoptose/effets des médicaments et des substances chimiques , Apoptose/effets des radiations , Humains , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des radiations , Tests d'activité antitumorale sur modèle de xénogreffe , Microenvironnement tumoral/effets des médicaments et des substances chimiques , Microenvironnement tumoral/effets des radiations , Souris nudeRÉSUMÉ
PURPOSE: To describe the real-world treatment patterns of systemic therapies for biliary tract cancer (BTC) and to examine the frequency and management of biliary infection in Japan. METHODS: Patients diagnosed with BTC and prescribed systemic therapy between January 2011 and September 2020 were retrieved from the Japanese Medical Data Vision database. The look-back period was set to 5 years. Patient characteristics, treatment patterns, and biliary infection-induced treatment interruption were analyzed. RESULTS: The full analysis set comprised 22 742 patients with a mean age of 71.0 years and 61.6% were male. The most common BTC type was extrahepatic cholangiocarcinoma (44.6%). The three most common first-line regimens were S-1 monotherapy (33.0%), gemcitabine+cisplatin (32.5%), and gemcitabine monotherapy (18.7%) over the entire observation period (January 2011-September 2021). Patients who received monotherapies tended to be older. Biliary infection-induced treatment interruption occurred in 29.5% of patients, with a median time to onset of 64.0 (interquartile range 29.0-145.0) days. The median duration of intravenous antibiotics was 12.0 (interquartile range 4.0-92.0) days. CONCLUSIONS: These results demonstrated potential challenges of BTC in Japanese clinical practice particularly use of multiple regimens, commonly monotherapies, which are not recommended as first-line treatment, and the management of biliary infections during systemic therapy.
Sujet(s)
Tumeurs des voies biliaires , Bases de données factuelles , Humains , Mâle , Femelle , Sujet âgé , Japon , Tumeurs des voies biliaires/traitement médicamenteux , Adulte d'âge moyen , Désoxycytidine/analogues et dérivés , Désoxycytidine/usage thérapeutique , Désoxycytidine/administration et posologie , , Tégafur/administration et posologie , Tégafur/usage thérapeutique , Études rétrospectives , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Association médicamenteuse , Cisplatine/usage thérapeutique , Cisplatine/administration et posologie , Acide oxonique/administration et posologie , Acide oxonique/usage thérapeutique , Types de pratiques des médecins/statistiques et données numériquesRÉSUMÉ
Drug resistance remains a significant challenge in the treatment of pancreatic cancer. The development of drug-resistant cell lines is crucial to understanding the underlying mechanisms of resistance and developing novel drugs to improve clinical outcomes. Here, a novel pancreatic cancer cell line, PDAC-X1, derived from Chinese patients has been established. PDAC-X1 was characterized by the immune phenotype, biology, genetics, molecular characteristics, and tumorigenicity. In vitro analysis revealed that PDAC-X1 cells exhibited epithelial morphology and cell markers (CK7 and CK19), expressed cancer-associated markers (E-cadherin, Vimentin, Ki-67, CEA, CA19-9), and produced pancreatic cancer-like organs in suspension culture. In vivo analysis showed that PDAC-X1 cells maintained tumorigenicity with a 100% tumor formation rate. This cell line exhibited a complex karyotype, dominated by subtriploid karyotypes. In addition, PDAC-X1 cells exhibited intrinsic multidrug resistance to multiple drugs, including gemcitabine, paclitaxel, 5-fluorouracil, and oxaliplatin. In conclusion, the PDAC-X1 cell line has been established and characterized, representing a useful and valuable preclinical model to study the underlying mechanisms of drug resistance and develop novel drug therapeutics to improve patient outcomes.
Sujet(s)
Carcinome du canal pancréatique , Multirésistance aux médicaments , Résistance aux médicaments antinéoplasiques , Tumeurs du pancréas , Humains , Lignée cellulaire tumorale , Carcinome du canal pancréatique/anatomopathologie , Carcinome du canal pancréatique/traitement médicamenteux , Carcinome du canal pancréatique/génétique , Carcinome du canal pancréatique/métabolisme , Tumeurs du pancréas/anatomopathologie , Tumeurs du pancréas/traitement médicamenteux , Tumeurs du pancréas/génétique , Tumeurs du pancréas/métabolisme , Animaux , Souris , Multirésistance aux médicaments/génétique , Tests d'activité antitumorale sur modèle de xénogreffe , Mâle , Femelle , Antinéoplasiques/pharmacologie , Antinéoplasiques/usage thérapeutique , Marqueurs biologiques tumoraux/génétique , Marqueurs biologiques tumoraux/métabolisme , , Désoxycytidine/analogues et dérivés , Désoxycytidine/pharmacologie , Désoxycytidine/usage thérapeutiqueSujet(s)
Antifongiques , Ciclopirox , Désoxycytidine , , Tumeurs du pancréas , Pyridones , Ciclopirox/usage thérapeutique , Ciclopirox/pharmacologie , Tumeurs du pancréas/traitement médicamenteux , Tumeurs du pancréas/anatomopathologie , Humains , Désoxycytidine/analogues et dérivés , Désoxycytidine/usage thérapeutique , Désoxycytidine/pharmacologie , Pyridones/usage thérapeutique , Antifongiques/usage thérapeutique , Animaux , SourisRÉSUMÉ
Pancreatic cancer (PC) has the poorest prognosis among digestive cancers; only 15-20% of cases are resectable at diagnosis. This review explores multidisciplinary treatments for advanced PC, emphasizing resectability classification and treatment strategies. For locally advanced unresectable PC, systemic chemotherapy using modified FOLFIRINOX and gemcitabine with albumin-bound paclitaxel is standard, while the role of chemoradiation is debated. Induction chemotherapy followed by chemoradiation may be a promising therapy. Conversion surgery after initial chemotherapy or chemoradiotherapy offers favorable survival, however criteria for conversion need further refinements. For metastatic PC, clinical trials using immune checkpoint inhibitors and molecular targeted therapies are ongoing. Multidisciplinary approaches and further research are crucial for optimizing treatment and improving outcomes for advanced PC.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique , Tumeurs du pancréas , Humains , Tumeurs du pancréas/thérapie , Tumeurs du pancréas/anatomopathologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Chimioradiothérapie/méthodes , Chimioradiothérapie/tendances , , Désoxycytidine/analogues et dérivés , Désoxycytidine/usage thérapeutique , Irinotécan/usage thérapeutique , Inhibiteurs de points de contrôle immunitaires/usage thérapeutique , Fluorouracil/usage thérapeutique , Oxaliplatine/usage thérapeutique , Oxaliplatine/administration et posologie , Thérapie moléculaire ciblée/méthodes , Thérapie moléculaire ciblée/tendances , Leucovorine/usage thérapeutiqueRÉSUMÉ
BACKGROUND: Empirical chemotherapy remains the standard of care in patients with unfavourable cancer of unknown primary (CUP). Gene-expression profiling assays have been developed to identify the tissue of origin in patients with CUP; however, their clinical benefit has not yet been demonstrated. We aimed to evaluate the efficacy and safety of site-specific therapy directed by a 90-gene expression assay compared with empirical chemotherapy in patients with CUP. METHODS: This randomised controlled trial was conducted at Fudan University Shanghai Cancer Center (Shanghai, China). We enrolled patients aged 18-75 years, with previously untreated CUP (histologically confirmed metastatic adenocarcinoma, squamous cell carcinoma, poorly differentiated carcinoma, or poorly differentiated neoplasms) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, who were not amenable to local radical treatment. Patients were randomly assigned (1:1) by the Pocock and Simon minimisation method to receive either site-specific therapy or empirical chemotherapy (taxane [175 mg/m2 by intravenous infusion on day 1] plus platinum [cisplatin 75 mg/m2 or carboplatin area under the curve 5 by intravenous infusion on day 1], or gemcitabine [1000 mg/m2 by intravenous infusion on days 1 and 8] plus platinum [same as above]). The minimisation factors were ECOG performance status and the extent of the disease. Clinicians and patients were not masked to interventions. The tumour origin in the site-specific therapy group was predicted by the 90-gene expression assay and treatments were administered accordingly. The primary endpoint was progression-free survival in the intention-to-treat population. The trial has been completed and the analysis is final. This study is registered with ClinicalTrials.gov (NCT03278600). FINDINGS: Between Sept 18, 2017, and March 18, 2021, 182 patients (105 [58%] male, 77 [42%] female) were randomly assigned to receive site-specific therapy (n=91) or empirical chemotherapy (n=91). The five most commonly predicted tissues of origin in the site-specific therapy group were gastro-oesophagus (14 [15%]), lung (12 [13%]), ovary (11 [12%]), cervix (11 [12%]), and breast (nine [10%]). At the data cutoff date (April 30, 2023), median follow-up was 33·3 months (IQR 30·4-51·0) for the site-specific therapy group and 30·9 months (27·6-35·5) for the empirical chemotherapy group. Median progression-free survival was significantly longer with site-specific therapy than with empirical chemotherapy (9·6 months [95% CI 8·4-11·9] vs 6·6 months [5·5-7·9]; unadjusted hazard ratio 0·68 [95% CI 0·49-0·93]; p=0·017). Among the 167 patients who started planned treatment, 46 (56%) of 82 patients in the site-specific therapy group and 52 (61%) of 85 patients in the empirical chemotherapy group had grade 3 or worse treatment-related adverse events; the most frequent of these in the site-specific therapy and empirical chemotherapy groups were decreased neutrophil count (36 [44%] vs 42 [49%]), decreased white blood cell count (17 [21%] vs 26 [31%]), and anaemia (ten [12%] vs nine [11%]). Treatment-related serious adverse events were reported in five (6%) patients in the site-specific therapy group and two (2%) in the empirical chemotherapy group. No treatment-related deaths were observed. INTERPRETATION: This single-centre randomised trial showed that site-specific therapy guided by the 90-gene expression assay could improve progression-free survival compared with empirical chemotherapy among patients with previously untreated CUP. Site-specific prediction by the 90-gene expression assay might provide more disease information and expand the therapeutic armamentarium in these patients. FUNDING: Clinical Research Plan of Shanghai Hospital Development Center, Program for Shanghai Outstanding Academic Leader, and Shanghai Anticancer Association SOAR PROJECT. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique , Métastases d'origine inconnue , Humains , Adulte d'âge moyen , Mâle , Femelle , Métastases d'origine inconnue/traitement médicamenteux , Métastases d'origine inconnue/génétique , Métastases d'origine inconnue/anatomopathologie , Métastases d'origine inconnue/mortalité , Sujet âgé , Adulte , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , , Analyse de profil d'expression de gènes , Désoxycytidine/analogues et dérivés , Désoxycytidine/administration et posologie , Désoxycytidine/usage thérapeutique , Cisplatine/administration et posologie , Cisplatine/usage thérapeutique , Carboplatine/administration et posologie , Chine , Taxoïdes/administration et posologie , Taxoïdes/usage thérapeutique , Jeune adulte , AdolescentRÉSUMÉ
This study aimed to compare second-line treatment outcomes for patients with unresectable pancreatic cancer previously treated with gemcitabine plus nab-paclitaxel (GnP) therapy. We conducted an integrated analysis of two retrospective studies included 318 patients receiving nanoliposomal irinotecan + 5-fluorouracil/folinic acid (NFF) (n = 102), S-1 (n = 57), or FOLFIRINOX (n = 14) as second-line treatment. Median overall survival (OS) in the NFF group was 9.08 months, significantly better than S-1 (4.90 months, P = 0.002). FOLFIRINOX had a median OS of 4.77 months, not statistically different from NFF. Subgroup analyses of OS indicated NFF was generally superior, however, a statistical interaction was observed between the treatment regimen in serum Alb < 3.5 g/dL (P = 0.042) and serum CRP ≥ 0.3 mg/dL (P = 0.006). Median progression-free survival (PFS) was 2.93 months for NFF, significantly better than S-1 (2.53 months, P = 0.024), while FOLFIRINOX had a comparable PFS (3.04 months, P = 0.948). Multivariate analysis identified the serum CRP, serum CA19-9, duration of first-line GnP therapy, and use (yes/no) of S-1 for second-line treatment as independent predictors for OS. This study concludes that second-line NFF therapy demonstrated a more favorable OS compared to S-1 therapy, however, it is still important to consider the patient background characteristics while selecting the most appropriate treatment.
Sujet(s)
Albumines , Protocoles de polychimiothérapie antinéoplasique , Désoxycytidine , Association médicamenteuse , Fluorouracil , , Irinotécan , Leucovorine , Oxaliplatine , Paclitaxel , Tumeurs du pancréas , Humains , Tumeurs du pancréas/traitement médicamenteux , Tumeurs du pancréas/anatomopathologie , Tumeurs du pancréas/mortalité , Mâle , Femelle , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Leucovorine/usage thérapeutique , Leucovorine/administration et posologie , Irinotécan/administration et posologie , Irinotécan/usage thérapeutique , Adulte d'âge moyen , Paclitaxel/administration et posologie , Paclitaxel/usage thérapeutique , Sujet âgé , Fluorouracil/administration et posologie , Fluorouracil/usage thérapeutique , Albumines/administration et posologie , Désoxycytidine/analogues et dérivés , Désoxycytidine/administration et posologie , Désoxycytidine/usage thérapeutique , Oxaliplatine/administration et posologie , Oxaliplatine/usage thérapeutique , Études rétrospectives , Acide oxonique/administration et posologie , Acide oxonique/usage thérapeutique , Tégafur/administration et posologie , Tégafur/usage thérapeutique , Adulte , Liposomes , Résultat thérapeutique , Sujet âgé de 80 ans ou plusRÉSUMÉ
Gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX are widely used as first-line regimens for unresectable pancreatic cancer (PC). When GnP therapy is selected, considering patient age or condition, second-line FOLFIRINOX is sometimes difficult to administer owing to its toxicity. This study aimed to determine the recommended dose (RD) of S-IROX (S-1, oxaliplatin, and irinotecan combination) regimens in patients with unresectable PC after first-line GnP failure. This phase-I study used the "3 + 3" dose-escalation design with two dose levels. Patients who failed first-line GnP therapy for unresectable PC were enrolled. Oxaliplatin and irinotecan were administered on day 1, and S-1 was administered orally twice daily on days 1-7, followed by 7 days of rest. The primary endpoints were dose-limiting toxicities (DLTs) and determination of RD. The secondary endpoint was the evaluation of potential antitumor activity. Nine patients received the second-line S-IROX regimen. In level-0 (S-1, 80 mg/m2; oxaliplatin, 85 mg/m2; and irinotecan, 120 mg/m2), no patient experienced DLT; however, one patient experienced grade 3 neutropenia. At level-1 (irinotecan increased to 150 mg/m2), one of six patients experienced DLTs, including G3 diarrhea. The RD was confirmed at the level-1 dose. The response rate, disease control rate, median progression-free survival, and median overall survival were 33.3%, 77.8%, 172 (range:77-422) days, and 414 (101-685) days, respectively. One patient underwent surgery after the second-line S-IROX therapy. Second-line S-IROX treatment was deemed acceptable. The RD was set at level-1 dose (S-1, 80 mg/m2; oxaliplatin, 85 mg/m2; and irinotecan, 150 mg/m2).
Sujet(s)
Albumines , Protocoles de polychimiothérapie antinéoplasique , Désoxycytidine , Association médicamenteuse , , Irinotécan , Oxaliplatine , Acide oxonique , Paclitaxel , Tumeurs du pancréas , Tégafur , Humains , Tumeurs du pancréas/traitement médicamenteux , Tumeurs du pancréas/anatomopathologie , Mâle , Adulte d'âge moyen , Femelle , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Sujet âgé , Albumines/administration et posologie , Albumines/usage thérapeutique , Albumines/effets indésirables , Oxaliplatine/administration et posologie , Oxaliplatine/usage thérapeutique , Oxaliplatine/effets indésirables , Désoxycytidine/analogues et dérivés , Désoxycytidine/administration et posologie , Désoxycytidine/effets indésirables , Désoxycytidine/usage thérapeutique , Paclitaxel/administration et posologie , Paclitaxel/effets indésirables , Paclitaxel/usage thérapeutique , Irinotécan/administration et posologie , Irinotécan/usage thérapeutique , Tégafur/administration et posologie , Tégafur/effets indésirables , Tégafur/usage thérapeutique , Acide oxonique/administration et posologie , Acide oxonique/effets indésirables , Acide oxonique/usage thérapeutique , AdulteRÉSUMÉ
BACKGROUND: Although adjuvant gemcitabine (GEM) monotherapy improves the overall survival (OS) of patients with resected pancreatic cancer, its efficacy requires further improvement. This multicenter, phase II study investigated the efficacy of adjuvant portal vein infusion (PVI) chemotherapy followed by GEM therapy in patients with resected pancreatic cancer. METHODS: 5-fluorouracil (250 mg/day) and heparin (2000 IU/day) PVI chemotherapy were combined with systemic administration of mitomycin C (4 mg; days 6, 13, 20, and 27) and cisplatin (10 mg; days 7, 14, 21, and 28) for 4 weeks (PI4W), followed by GEM (1000 mg/m2; days 1, 8, and 15 every 4 weeks for 6 months). The primary endpoint was relapse-free survival (RFS) and the secondary endpoints were OS and treatment completion. RESULTS: Between November 2010 and August 2013, 53 patients who underwent complete resection were enrolled, including 30, 20, and 3 patients who underwent pancreaticoduodenectomies and distal and total pancreatectomies, respectively. In total, 51 (96.2%) patients underwent R0 resection, of whom 3, 2, 12, 35, 0, and 1 had stages IA, IB, IIA, IIB, III, and IV cancer, respectively, and 47 (88.7%) patients completed PI4W. The median RFS was 22.0 months (1-, 3-, 5, and 10 years RFS: 64.9%, 38.1%, 38.1%, and 38.1%, respectively), whereas the median OS was 32.0 months (1-, 3-, 5, and 10 years OS:86.6%, 47.2%, 44.4%, and 44.4%, respectively). CONCLUSION: Treatment with PI4W followed by GEM for 6 months after surgery may be beneficial in patients undergoing curative resection of pancreatic cancer.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique , Désoxycytidine , Fluorouracil , , Tumeurs du pancréas , Veine porte , Humains , Tumeurs du pancréas/traitement médicamenteux , Tumeurs du pancréas/mortalité , Tumeurs du pancréas/chirurgie , Tumeurs du pancréas/anatomopathologie , Mâle , Fluorouracil/administration et posologie , Fluorouracil/usage thérapeutique , Femelle , Adulte d'âge moyen , Désoxycytidine/analogues et dérivés , Désoxycytidine/administration et posologie , Désoxycytidine/usage thérapeutique , Sujet âgé , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Traitement médicamenteux adjuvant/méthodes , Adulte , Résultat thérapeutique , Perfusions veineuses , Cisplatine/administration et posologie , Cisplatine/usage thérapeutique , Stadification tumoraleRÉSUMÉ
BACKGROUND: In the treatment of advanced pancreatic cancer, chemotherapy plays a pivotal role. Despite its effectiveness, this regimen is often marred by side effects such as anemia, neuropathy, fatigue, nausea, and malnutrition, which significantly affect patients' tolerance to the treatment. Some studies have shown that vitamin C could potentially augment chemotherapy's tolerability, notably by boosting iron absorption, ameliorating anemia, and relieving pain and numbness in hands and feet. Nevertheless, the integration of vitamin C with chemotherapy to mitigate toxic side effects and enhance the quality of life for advanced pancreatic cancer patients has not been examined in any randomized controlled trials to date. METHODS: A prospective, single-center, open-label, randomized controlled trial will be conducted at Fudan University Shanghai Cancer Center from September 2023 to September 2026. A total of at least 100 patients with advanced pancreatic adenocarcinoma exhibiting distant metastases will be recruited and randomly assigned to the chemotherapy group or the chemotherapy plus vitamin C group. The primary endpoint is the rate of anemia. Secondary endpoints include the rate of grade 3 neuropathy, change of numeric rating scale, quality of life, and overall survival. DISCUSSION: This study aims to assess the impact of low-dose vitamin C on enhancing the quality of life for patients with metastatic pancreatic cancer undergoing gemcitabine and nab-paclitaxel chemotherapy. TRIAL REGISTRATION: The trial was registered with the ClinicalTrials.gov (NCT06018883) on August 31, 2023.
Sujet(s)
Anémie , Protocoles de polychimiothérapie antinéoplasique , Acide ascorbique , Tumeurs du pancréas , Qualité de vie , Essais contrôlés randomisés comme sujet , Humains , Tumeurs du pancréas/traitement médicamenteux , Tumeurs du pancréas/mortalité , Acide ascorbique/usage thérapeutique , Acide ascorbique/effets indésirables , Acide ascorbique/administration et posologie , Anémie/traitement médicamenteux , Études prospectives , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , , Désoxycytidine/analogues et dérivés , Désoxycytidine/effets indésirables , Désoxycytidine/usage thérapeutique , Désoxycytidine/administration et posologie , Paclitaxel/effets indésirables , Paclitaxel/administration et posologie , Résultat thérapeutique , Chine , Adulte d'âge moyen , Albumines/effets indésirables , Albumines/administration et posologie , Albumines/usage thérapeutique , Mâle , Femelle , AdulteRÉSUMÉ
Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer, a disease with dismal overall survival. Advances in treatment are hindered by a lack of preclinical models. Here, we show how a personalized organotypic "avatar" created from resected tissue allows spatial and temporal reporting on a complete in situ tumor microenvironment and mirrors clinical responses. Our perfusion culture method extends tumor slice viability, maintaining stable tumor content, metabolism, stromal composition, and immune cell populations for 12 days. Using multiplexed immunofluorescence and spatial transcriptomics, we identify immune neighborhoods and potential for immunotherapy. We used avatars to assess the impact of a preclinically validated metabolic therapy and show recovery of stromal and immune phenotypes and tumor redifferentiation. To determine clinical relevance, we monitored avatar response to gemcitabine treatment and identify a patient avatar-predictable response from clinical follow-up. Thus, avatars provide valuable information for syngeneic testing of therapeutics and a truly personalized therapeutic assessment platform for patients.
Sujet(s)
Carcinome du canal pancréatique , Tumeurs du pancréas , Médecine de précision , Microenvironnement tumoral , Animaux , Humains , Carcinome du canal pancréatique/immunologie , Carcinome du canal pancréatique/thérapie , Carcinome du canal pancréatique/anatomopathologie , Lignée cellulaire tumorale , Désoxycytidine/analogues et dérivés , Désoxycytidine/usage thérapeutique , Désoxycytidine/pharmacologie , , Immunothérapie/méthodes , Tumeurs du pancréas/immunologie , Tumeurs du pancréas/anatomopathologie , Tumeurs du pancréas/traitement médicamenteux , Tumeurs du pancréas/thérapie , Médecine de précision/méthodes , Microenvironnement tumoral/immunologieRÉSUMÉ
BACKGROUND: Locally advanced pancreatic cancer (LAPC) comprises 40% of pancreatic cancer diagnoses and has a relatively poor prognosis. Trans-arterial micro perfusion (TAMP)-mediated chemotherapy delivery to the primary tumor is a novel approach worthy of investigation. The RR1 (dose escalation) and RR2 (observational) studies examined the safety and preliminary efficacy of TAMP-delivered gemcitabine for LAPC. PATIENTS AND METHODS: RR1 and RR2 data were pooled. Both studies enrolled patients with LAPC with histologically confirmed adenocarcinoma. Participant data, including age, sex, race, stage, previous treatments, toxicity, disease progression, and death, were collected. Median number of cycles and average treatment dosage were calculated. Overall survival (OS) was determined for the whole group and separately for patients who received and did not receive previous treatments. Aims of the analysis were to assess procedure safety, OS, and evaluate factors associated with OS. RESULTS: The median age of the 43 patients enrolled in RR1 and RR2 was 72 years (range, 51-88 years). Median OS for the 35 eligible patients with stage III disease was 12.6 months (95% CI, 2.1-54.2 months). Previous chemoradiation was associated with significantly longer OS [27.1 months (95% CI, 8.4-40.6 months)] compared to previous systemic chemotherapy [14.6 months (95% CI, 6.4-54.2 months)] or no prior treatment [7.0 months (95% CI, 2.1-35.4 months)] (Pâ <â .001). The most common adverse events were GI related (abdominal pain, emesis, and vomiting); the most common grade 3 toxicity was sepsis. CONCLUSION: Study results indicate that TAMP-mediated gemcitabine delivery in patients with LAPC is potentially safe, feasible, and provides potential clinical benefits. CLINICAL TRIAL REGISTRATION: NCT02237157 (RR1) and NCT02591082 (RR2).
Sujet(s)
Désoxycytidine , , Tumeurs du pancréas , Humains , Désoxycytidine/analogues et dérivés , Désoxycytidine/administration et posologie , Désoxycytidine/usage thérapeutique , Désoxycytidine/effets indésirables , Tumeurs du pancréas/traitement médicamenteux , Tumeurs du pancréas/anatomopathologie , Adulte d'âge moyen , Sujet âgé , Femelle , Mâle , Sujet âgé de 80 ans ou plus , Antimétabolites antinéoplasiques/usage thérapeutique , Antimétabolites antinéoplasiques/administration et posologie , Antimétabolites antinéoplasiques/effets indésirables , Adénocarcinome/traitement médicamenteux , Adénocarcinome/anatomopathologieRÉSUMÉ
Chemotherapy treatment against pancreatic ductal adenocarcinoma (PDAC) is thwarted by tumoral activation of multiple therapy resistance pathways. The growth hormone (GH)-GH receptor (GHR) pair is a covert driver of multimodal therapy resistance in cancer and is overexpressed in PDAC tumors, yet the therapeutic potential of targeting the same has not been explored. Here, we report that GHR expression is a negative prognostic factor in patients with PDAC. Combinations of gemcitabine with different GHR antagonists (GHRAs) markedly improve therapeutic outcomes in nude mice xenografts. Employing cultured cells, mouse xenografts, and analyses of the human PDAC transcriptome, we identified that attenuation of the multidrug transporter and epithelial-to-mesenchymal transition programs in the tumors underlie the observed augmentation of chemotherapy efficacy by GHRAs. Moreover, in human PDAC patients, GHR expression strongly correlates with a gene signature of tumor promotion and immune evasion, which corroborate with that in syngeneic tumors in wild-type vs. GH transgenic mice. Overall, we found that GH action in PDAC promoted a therapy-refractory gene signature in vivo, which can be effectively attenuated by GHR antagonism. Our results collectively present a proof of concept toward considering GHR antagonists to improve chemotherapeutic outcomes in the highly chemoresistant PDAC.
Sujet(s)
Carcinome du canal pancréatique , Désoxycytidine , , Tumeurs du pancréas , Récepteur STH , Tests d'activité antitumorale sur modèle de xénogreffe , Animaux , Humains , Désoxycytidine/analogues et dérivés , Désoxycytidine/pharmacologie , Désoxycytidine/usage thérapeutique , Tumeurs du pancréas/traitement médicamenteux , Tumeurs du pancréas/métabolisme , Tumeurs du pancréas/anatomopathologie , Tumeurs du pancréas/génétique , Souris , Récepteur STH/métabolisme , Récepteur STH/antagonistes et inhibiteurs , Récepteur STH/génétique , Carcinome du canal pancréatique/traitement médicamenteux , Carcinome du canal pancréatique/métabolisme , Carcinome du canal pancréatique/anatomopathologie , Carcinome du canal pancréatique/génétique , Lignée cellulaire tumorale , Souris nude , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , FemelleRÉSUMÉ
BACKGROUND: The TOPAZ-1 phase III trial showed a survival benefit with durvalumab plus gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). To understand this combination's real-world efficacy and tolerability, we conducted a global multicenter retrospective analysis of its first-line treatment outcomes. METHODS: We included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab, gemcitabine, and cisplatin at 39 sites in 11 countries (Europe, the United States, and Asia). The primary endpoint was overall survival (OS). RESULTS: 666 patients were enrolled. Median OS was 15.1 months and median PFS was 8.2 months. The investigator-assessed overall response rate was 32.7 %, with stable disease in 45.2 % of patients. High baseline CEA levels, ECOG PS > 0, metastatic disease, and NLR > 3 were associated with poor survival. Any grade adverse events (AEs) occurred in 92.9 % of patients (grade >2: 46.6 %). Immune-related AEs (irAEs) occurred in 20.0 % (grade >2: 2.5 %). Three deaths (0.5 %) were deemed treatment-related, none linked to immunotherapy. Common irAEs were rash (8.2 % all grades; 0.3 % grade >2), itching (10.3 % all grades; 0.2 % grade >2), and hypothyroidism (5.1 % all grades; 0.3 % grade >2). Durvalumab discontinuation rate due to AEs was 1.5 %. ESMO-recommended genes were analyzed and no outcome differences were found. A comparative analysis with a historical cohort of patients treated with chemotherapy alone confirmed the positive survival impact of durvalumab in combination with cisplatin/gemcitabine. CONCLUSION: This first global real-world analysis largely confirmed the TOPAZ-1 findings, supporting gemcitabine, cisplatin, and durvalumab as a first-line standard of care for patients with advanced BTC.