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PURPOSE: Metastatic pancreatic adenocarcinoma (mPC) remains a difficult-to-treat disease. Fluorouarcil, oxaliplatin, irinotecan, and leucovorin (FFX) is a standard first-line therapy for mPC for patients with a favorable performance status and good organ function. In a phase I study, devimistat (CPI-613) in combination with modified FFX (mFFX) was deemed safe and exhibited promising efficacy in mPC. METHODS: The AVENGER 500 trial (ClinicalTrials.gov identifier: NCT03504423) is a global, randomized phase III trial conducted at 74 sites across six countries to investigate the efficacy and safety of devimistat in combination with mFFX (experimental arm) compared with standard-dose FFX (control arm) in treatment-naïve patients with mPC. Treatment, administered in once-every-2-weeks cycles until disease progression or intolerable toxicity, included intravenous devimistat at 500 mg/m2 total per day on days 1 and 3 in the experimental arm. The primary end point of the study was overall survival (OS). RESULTS: Five hundred and twenty-eight patients were randomly assigned (266 in the experimental arm and 262 in the control arm). The median OS was 11.10 months for devimistat plus mFFX versus 11.73 months for FFX (hazard ratio [HR], 0.95 [95% CI, 0.77 to 1.18]; P = .655) and median progression-free survival was 7.8 months versus 8.0 months, respectively (HR, 0.99 [95% CI, 0.76 to 1.29]; P = .94). Grade ≥3 treatment-emergent adverse events with >10% frequency in the devimistat plus mFFX arm versus the FFX arm were neutropenia (29.0% v 34.5%), diarrhea (11.2% v 19.6%), hypokalemia (13.1% v 14.9%), anemia (13.9% v 13.6%), thrombocytopenia (11.6% v 13.6%), and fatigue (10.8% v 11.5%), respectively. CONCLUSION: Devimistat in combination with mFFX did not improve long- and short-term mPC patient outcomes compared with standard FFX. There were no new toxicity signals with the addition of devimistat.
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Background: Bacterial peritonitis (BP) in patients with gastrointestinal (GI) cancer has been poorly described, and its prevalence is unknown. Objectives: This study aimed to evaluate in patients with both GI cancer and ascites the prevalence of BP, associated features, mechanisms, prognosis, and the diagnostic performance of neutrophil count in ascites. Design: A retrospective, multicenter, observational study. Methods: All patients with GI cancer and ascites who underwent at least one paracentesis sample analyzed for bacteriology over a 1-year period were included. BP was defined by a positive ascites culture combined with clinical and/or biological signs compatible with infection. Secondary BP was defined as BP related to a direct intra-abdominal infectious source. Results: Five hundred fifty-seven ascites from 208 patients included were analyzed. Twenty-eight patients had at least one episode of BP and the annual prevalence rate of BP was 14%. Among the 28 patients with BP, 19 (65%) patients had proven secondary BP and 17 (59%) patients had multi-microbial BP, mainly due to Enterobacterales. A neutrophil count greater than 110/mm3 in ascites had negative and positive predictive values of 96% and 39%, respectively, for the diagnosis of BP. The median survival of patients with BP was 10 days (interquartile range 6-40) after the diagnosis. Conclusion: BP is not rare in patients with GI cancer and is associated with a poor short-term prognosis. When a patient with GI cancer is diagnosed with BP, a secondary cause should be sought. Further studies are needed to better define the best management of these patients.
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BACKGROUND: Von Hippel-Lindau disease (VHL) is a rare autosomal dominant hereditary cancer-predisposition syndrome caused by germline pathogenic variants (PV) in VHL gene. It is associated with a high penetrance of benign and malignant vascular tumors in multiples organs, including pancreatic neuroendocrine tumors (PanNETs), whose long-term natural history is ill-known. METHODS: Patients with both documented germline PV in VHL gene and PanNETs included in the French PREDIR database between 1995 and 2022 were included. Primary endpoint was the proportion of patients with PanNET-related metastases and secondary endpoint was overall survival (OS). Genotype/phenotype correlations were studied. RESULTS: We included 121 patients with 259 PanNETs. Median age at diagnosis was 38 years. Median follow-up was 89.5 months. PanNET surgical resection was performed in 51 patients. Overall, 29 patients (24%) had metastases (5 synchronous, 10 metachronous), with a higher risk in case of larger PanNET size (p=0.0089; best threshold 28 mm) and grade 2 PanNET (p=0.048), and a pejorative prognostic impact (p=0.043). Patients with PV in VHL exon 1 had larger PanNETs (p=0.018), more often metastatic disease (48% vs 11.5%; p < 0.001) and a trend toward shorter OS (p=0.16). CONCLUSION: The risk of metastases associated to VHL-related PanNETs remains low (24%) but increases with tumor size >28 mm, higher grade and in case of PV located VHL exon 1. These data might help improving the management of these patients, who should be referred to an expert center.
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Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death referred to as ferroptosis1-3. Identifying where this chemistry takes place in the cell can inform the design of drugs capable of inducing or inhibiting ferroptosis in various disease-relevant settings. Whereas genetic approaches have revealed underlying mechanisms of lipid peroxide detoxification1,4,5, small molecules can provide unparalleled spatiotemporal control of the chemistry at work6. Here, we show that the ferroptosis inhibitor liproxstatin-1 (Lip-1) exerts a protective activity by inactivating iron in lysosomes. Based on this, we designed the bifunctional compound fentomycin that targets phospholipids at the plasma membrane and activates iron in lysosomes upon endocytosis, promoting oxidative degradation of phospholipids and ferroptosis. Fentomycin effectively kills primary sarcoma and pancreatic ductal adenocarcinoma cells. It acts as a lipolysis-targeting chimera (LIPTAC), preferentially targeting iron-rich CD44high cell-subpopulations7,8 associated with the metastatic disease and drug resistance9,10. Furthermore, we demonstrate that fentomycin also depletes CD44high cells in vivo and reduces intranodal tumour growth in an immunocompetent murine model of breast cancer metastasis. These data demonstrate that lysosomal iron triggers ferroptosis and that lysosomal iron redox chemistry can be exploited for therapeutic benefits.
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PURPOSE: GemPred, a transcriptomic signature predictive of the efficacy of adjuvant gemcitabine (GEM), was developed from cell lines and organoids and validated retrospectively. The phase III PRODIGE-24/CCTG PA6 trial has demonstrated the superiority of modified folinic acid, fluorouracil, irinotecan, and oxaliplatin (mFOLFIRINOX) over GEM as adjuvant therapy in patients with resected pancreatic ductal adenocarcinoma at the expense of higher toxicity. We evaluated the potential predictive value of GemPred in this population. PATIENTS AND METHODS: Routine formalin-fixed paraffin-embedded surgical specimens of 350 patients were retrieved for RNA sequencing and GemPred prediction (167 in the GEM arm and 183 in the mFOLFIRINOX [mFFX] arm). Survival analyses were stratified by resection margins, lymph node status, and cancer antigen 19-9 level. RESULTS: Eighty-nine patients' tumors (25.5%) were GemPred+ and were thus predicted to be gemcitabine-sensitive. In the GEM arm, GemPred+ patients (n = 50, 30%) had a significantly longer disease-free survival (DFS) than GemPred- patients (n = 117, 70%; median 27.3 v 10.2 months, hazard ratio [HR], 0.43 [95% CI, 0.29 to 0.65]; P < .001) and cancer-specific survival (CSS; median 68.4 v 28.6 months, HR, 0.42 [95% CI, 0.27 to 0.66]; P < .001). GemPred had no prognostic value in the mFFX arm. DFS and CSS were similar in GemPred+ patients who received adjuvant GEM and mFFX (median 27.3 v 24.0 months, and 68.4 v 51.4 months, respectively). The statistical interaction between GEM and GemPred+ status was significant for DFS (P = .008) and CSS (P = .004). GemPred+ patients had significantly more adverse events of grade ≥3 in the mFFX arm (76%) compared with those in the GEM arm (40%; P = .001). CONCLUSION: This ancillary study of a phase III randomized trial demonstrates that among the quarter of patients with a GemPred-positive transcriptomic signature, survival was comparable with that of mFOLFIRINOX, whereas those receiving adjuvant gemcitabine had fewer adverse events.
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Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Gemcitabina , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirugía , Desoxicitidina/efectos adversos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/cirugía , Estudios Retrospectivos , Fluorouracilo/efectos adversos , Adyuvantes Inmunológicos/uso terapéutico , ARN/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: The impact of adapted physical activity (APA) on health-related quality of life (HRQoL) in patients with advanced pancreatic ductal adenocarcinoma (aPDAC) is unknown. This study evaluated whether APA in addition to standard care improved HRQoL in patients who have aPDAC who are receiving first-line chemotherapy. PATIENTS AND METHODS: Patients with locally advanced/metastatic PDAC and an ECOG performance status of 0 to 2 were randomized (1:1) to receive standard care (standard arm) or standard care plus a home-based 16-week APA program (APA arm). The primary objective was the effect of the APA program on 3 dimensions of the EORTC QLQ-C30: global health status, physical function, and fatigue at week 16 (W16), with a one-sided type I error of 0.017 for each dimension. The primary HRQoL analysis was performed in patients with available baseline and W16 scores for the dimensions (ie, the modified intention-to-treat population 1 [mITT1]), and secondary longitudinal HRQoL analyses using the mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD) methods were performed in the mITT1 population and in patients with baseline and at least one follow-up questionnaire (mITT2 population). A difference of ≥5 points was considered to be clinically relevant. RESULTS: Of 326 included patients, 313 were randomized to the standard (n=157) or APA (n=156) arms. In the mITT1 population (n=172), the mean differences in global health status, physical function, and fatigue at W16 adjusted from baseline were -0.98 (SD, 23.9; P=.39), -2.08 (SD, 21.3; P=.26), and 4.16 (SD, 29.2; P=.17), respectively, showing a non-statistically significant benefit with APA. In the mITT2 population (n=259), APA was associated with statistically significant and clinically relevant improvement in 5 and 8 dimensions of the HRQoL in the longitudinal MMRM and TUDD analyses, respectively. CONCLUSIONS: APA improved several dimensions of HRQoL in patients with aPDAC receiving first-line chemotherapy and standard care.
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Ejercicio Físico , Neoplasias Pancreáticas , Calidad de Vida , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Fatiga/etiología , Estado de Salud , Neoplasias Pancreáticas/tratamiento farmacológico , Proyectos de InvestigaciónRESUMEN
Pancreatic ductal adenocarcinoma is associated with a poor prognosis and there are few treatment options. The development of immunotherapy in pancreatic ductal adenocarcinoma has been difficult, and immune checkpoint inhibitors are only effective in a very small subset of patients. Most obstacles for treatment have been related to intertumoural and intratumoural heterogeneity, the composition of tumour stroma, and crosstalk with cancer cells. Improved molecular characterisation of pancreatic ductal adenocarcinoma and a better understanding of its microenvironment have paved the way for novel immunotherapy strategies, including the identification of predictive biomarkers, the development of rational combinations to optimise effectiveness, and the targeting of new mechanisms. Future immunotherapy strategies should consider individual characteristics to move beyond the traditional immune targets and circumvent the resistance to therapies that have been developed so far.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/patología , Inmunoterapia , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
Prognosis is generally poor for patients with pancreatic ductal adenocarcinoma. However, patients with germline BRCA1 or BRCA2 mutations (gBRCAm) may benefit from first-line platinum-based chemotherapy and maintenance therapy with the poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib following at least 16 weeks of first-line platinum-based chemotherapy without disease progression. Germline breast cancer gene (BRCA) testing is therefore important to ensure that patients receive the most effective treatment. In addition, testing for other DNA damage response gene mutations beyond gBRCAm may also guide treatment decisions. However, clinical pathways for genetic testing are often suboptimal, leading to delays in treatment initiation or missed opportunities for personalized therapy. Barriers to testing include low rates of referral and uptake, delays to referral and slow result turnaround times, cost, and biopsy and assay limitations if somatic testing is performed, leading to the requirement for subsequent dedicated germline testing. Low rates of referral may result from lack of awareness among physicians of the clinical value of testing, coupled with low confidence in interpreting test results and poor availability of genetic counseling services. Among patients, barriers to uptake may include similar lack of awareness of the clinical value of testing, anxiety regarding the implications of test results, lack of insurance coverage, fear of negative insurance implications, and socioeconomic factors. Potential solutions include innovative approaches to testing pathways, including 'mainstreaming' of testing in which BRCA tests are routinely arranged by the treating oncologist, with the involvement of genetic counselors if a patient is found to have a gBRCAm. More recently, the utility of multigene panel analyses has also been explored. Access to genetic counseling may also be improved through initiatives such as having a genetic counseling appointment for all new patient visits and telemedicine approaches, including the use of telephone consultations or DVD-assisted counseling. Educational programs will also be beneficial, and cost effectiveness is likely to improve as the number of targeted treatments increases and when the earlier detection of tumors in family members following cascade testing is considered.
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IMPORTANCE: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) can affect patient health-related quality of life (HRQoL). Appropriate information may improve their adherence to treatment and quality of life. OBJECTIVE: To evaluate the change in patient's perceptions of the level of information at lanreotide (LAN) treatment initiation for GEP-NETs vs after 6 months. DESIGN: OPERA (NCT03562091) was a prospective, longitudinal, noninterventional study. SETTING: Thirty-one centers in France specialized in the management of patients with NETs. INTERVENTION: Planned clinical visits at enrollment and end-of-study visits at month 6, with completion of the European Organisation for Research and Treatment of Cancer 25-item Quality of Life Questionnaire-Information Module (QLQ-INFO25) and 30-item Quality of Life Questionnaire-Core. MAIN OUTCOME: Absolute change in the patient's perception of the information between baseline and month 6, using the relevant domains of the QLQ-INFO25. Endpoints measured at baseline and month 6 for at least 1 of the 3 targeted QLQ-INFO25 dimensions of the primary endpoint. RESULTS: Ninety-three of the 115 patients enrolled completed ≥1 primary endpoint information dimension. Mean (SD) scores for the primary endpoint information dimensions were high at baseline (disease, 63.41 [20.71]; treatment, 58.85 [19.00]; supportive care, 26.53 [24.69]; maximum 100). There were no significant changes between baseline (98.34% CI) and 6 months (disease, -2.84 [-8.69, 3.01; P = .24]; treatment, -4.37 [-11.26, 2.52; P = .13]; supportive care, 0.46 [-6.78, 7.70; P = .88]), and in HRQoL between baseline and 6 months. CONCLUSIONS AND RELEVANCE: The lack of change in patient's perceptions of the disease, treatment, and supportive care information provided over the first 6 months of LAN treatment may suggest that physicians provided adequate information at the treatment initiation.
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Antineoplásicos , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Tumores Neuroendocrinos/terapia , Calidad de Vida , Estudios Prospectivos , Antineoplásicos/uso terapéutico , Péptidos Cíclicos/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , PercepciónRESUMEN
BACKGROUND: Several cancer immunotherapies that target the PD-L1/PD-1 pathway show promising clinical activity in patients with hepatocellular carcinoma (HCC). However, the standard of care in first-line treatment with atezolizumab (anti-PD-L1 therapy) in combination with bevacizumab is associated with a limited objective response rate. Telomerase reverse transcriptase (TERT) activation meets the criteria of oncogenic addiction in HCC and could be actionable therapeutic target and a relevant tumor antigen. Therefore we hypothesized that combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine might be an attractive therapy in HCC. UCPVax is a therapeutic cancer vaccine composed of two separate peptides derived from telomerase (human TERT). UCPVax has been evaluated in a multicenter phase I/II study in non-small cell lung cancers and has demonstrated to be safe and immunogenic, and is under evaluation in combination with atezolizumab in a phase II clinical trial in tumors where telomerase reactivation contributes to an oncogene addiction (HPV+ cancers). The aim of the TERTIO study is to determine the clinical interest and immunological efficacy of a treatment combining the CD4 helper T-inducer cancer anti-telomerase vaccine (UCPVax) with atezolizumab and bevacizumab in unresectable HCC in a multicenter randomized phase II study. METHODS: Patients with locally advanced, metastatic or unresectable HCC who have not previously received systemic anti-cancer treatment are eligible. The primary end point is the objective response rate at 6 months. Patients will be allocated to a treatment arm with a randomization 2:1. In both arms, patients will receive atezolizumab at fixed dose of 1200 mg IV infusion and bevacizumab at fixed dose of 15 mg/kg IV infusion, every 3 weeks, according to the standard of care. In the experimental arm, these treatments will be combined with the UCPVax vaccine at 0.5 mg subcutaneously. DISCUSSION: Combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine gains serious consideration in HCC, in order to extend the clinical efficacy of anti-PD-1/PD-L1. Indeed, anti-cancer vaccines can induce tumor-specific T cell expansion and activation and therefore restore the cancer-immunity cycle in patients lacking pre-existing anti-tumor responses. Thus, there is a strong rational to combine immune checkpoint blockade therapy and anticancer vaccine (UCPVax) in order to activate antitumor T cell immunity and bypass the immunosuppression in the tumor microenvironment in HCC. This pivotal proof of concept study will evaluate the efficacy and safety of the combination of a CD4 Th1-inducer cancer vaccine derived from telomerase (UCPVax) and atezolizumab plus bevacizumab in unresectable HCC, as well as confirming their synergic mechanism, and settling the basis for a new combination for future clinical trials. TRIAL REGISTRATION: NCT05528952.
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Vacunas contra el Cáncer , Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias Pulmonares , Telomerasa , Humanos , Bevacizumab , Vacunas contra el Cáncer/efectos adversos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Microambiente TumoralRESUMEN
Two tumor (Classical/Basal) and stroma (Inactive/active) subtypes of Pancreatic adenocarcinoma (PDAC) with prognostic and theragnostic implications have been described. These molecular subtypes were defined by RNAseq, a costly technique sensitive to sample quality and cellularity, not used in routine practice. To allow rapid PDAC molecular subtyping and study PDAC heterogeneity, we develop PACpAInt, a multi-step deep learning model. PACpAInt is trained on a multicentric cohort (n = 202) and validated on 4 independent cohorts including biopsies (surgical cohorts n = 148; 97; 126 / biopsy cohort n = 25), all with transcriptomic data (n = 598) to predict tumor tissue, tumor cells from stroma, and their transcriptomic molecular subtypes, either at the whole slide or tile level (112 µm squares). PACpAInt correctly predicts tumor subtypes at the whole slide level on surgical and biopsies specimens and independently predicts survival. PACpAInt highlights the presence of a minor aggressive Basal contingent that negatively impacts survival in 39% of RNA-defined classical cases. Tile-level analysis ( > 6 millions) redefines PDAC microheterogeneity showing codependencies in the distribution of tumor and stroma subtypes, and demonstrates that, in addition to the Classical and Basal tumors, there are Hybrid tumors that combine the latter subtypes, and Intermediate tumors that may represent a transition state during PDAC evolution.
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Adenocarcinoma , Aprendizaje Profundo , Neoplasias Pancreáticas , Humanos , Adenocarcinoma/genética , Neoplasias Pancreáticas/genética , Agresión , Neoplasias PancreáticasRESUMEN
INTRODUCTION: Circadian clocks regulate cellular proliferation and drug effects. Tolerability and/or efficacy of anticancer therapies have been improved by their administration according to circadian rhythms, while being predicted by circadian robustness. The combination of leucovorin, fluorouracil, irinotecan and oxaliplatin (mFOLFIRINOX) is a standard treatment for pancreatic ductal adenocarcinoma (PDAC), that generates grades 3-4 adverse events in the majority of patients and an estimated 15%-30% emergency admission rate. The MultiDom study evaluates whether mFOLFIRINOX safety can be improved using a novel circadian-based telemonitoring-telecare platform in patients at home. The detection of early warning signals of clinical toxicities could guide their early management, possibly preventing emergency hospital admissions. METHODS AND ANALYSIS: This multicentre, interventional, prospective, longitudinal, single-arm study hypothesises that the mFOLFIRINOX-related emergency admission rate will be 5% (95% CI 1.7% to 13.7%), among 67 patients with advanced PDAC. Study participation is 7 weeks for each patient, including a reference week before chemotherapy onset and 6 weeks afterwards. Accelerometry and body temperature are measured q1-min using a continuously worn telecommunicating chest surface sensor, daily body weight is self-measured with a telecommunicating balance and 23 electronic patient-reported outcomes (e-PROs) are self-rated using a tablet. Hidden Markov model, spectral analyses and other algorithms automatically compute physical activity, sleep, temperature, body weight change, e-PRO severity and 12 circadian sleep/activity parameters, including the dichotomy index IAsunto(s)
Neoplasias Pancreáticas
, Humanos
, Estudios Prospectivos
, Neoplasias Pancreáticas/tratamiento farmacológico
, Ritmo Circadiano
, Medición de Resultados Informados por el Paciente
, Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
, Estudios Multicéntricos como Asunto
, Neoplasias Pancreáticas
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Background: Chemotherapy options in patients with advanced pancreatic ductal adenocarcinoma (PDAC) after failure of standard chemotherapies are limited. Objectives: We aimed to report the efficacy and safety of the leucovorin and 5-fluorouracil (LV5FU2) and carboplatin combination in this setting. Design: We performed a retrospective study including consecutive patients with advanced PDAC who received LV5FU2-carboplatin between 2009 and 2021 in an expert center. Methods: We measured overall survival (OS) and progression-free survival (PFS), and explored associated factors using Cox proportional hazard models. Results: In all, 91 patients were included (55% male, median age 62), with a performance status of 0/1 in 74% of cases. LV5FU2-carboplatin was mainly used in third (59.3%) or fourth line (23.1%), with three (interquartile range: 2.0-6.0) cycles administered on average. The clinical benefit rate was 25.2%. Median PFS was 2.7 months (95% CI: 2.4-3.0). At multivariable analysis, no extrahepatic metastases (p = 0.083), no ascites or opioid-requiring pain (p = 0.023), <2 prior treatment lines (p < 0.001), full dose of carboplatin (p = 0.004), and treatment initiation >18 months after initial diagnosis (p < 0.001) were associated with longer PFS. Median OS was 4.2 months (95% CI: 3.48-4.92) and was influenced by the presence of extrahepatic metastases (p = 0.058), opioid-requiring pain or ascites (p = 0.039), and number of prior treatment lines (0.065). Prior tumor response under oxaliplatin did not impact either PFS or OS. Worsening of preexisting residual neurotoxicity was infrequent (13.2%). The most common grade 3-4 adverse events were neutropenia (24.7%) and thrombocytopenia (11.8%). Conclusion: Although the efficacy of LV5FU2-carboplatin appears limited in patients with pretreated advanced PDAC, it may be beneficial in selected patients.
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By 2030, pancreatic cancer will become the second leading cause of cancer-related deaths in the United States and in Europe. The management of patients with advanced pancreatic cancer relies on chemotherapy and poly (ADP-ribose) polymerase inhibitors for patients who carry BRCA1/2 inactivating alterations. Some variants, such as large insertion/deletions (Indels), inactivating BRCA1/2 and therefore of clinical relevance can be hard to detect by next-generation sequencing techniques. Here we report a 47-year-old patient presenting with pancreatic cancer whose tumour harbours a large somatic intra-exonic deletion of BRCA2 of 141 bp. This BRCA2 deletion, located in the C-terminal domain, can be considered as pathogenic and consequently affect tumorigenesis because it is involved in the interaction between the DSS1 protein and DNA. Thanks to the optimized bioinformatics algorithm, this intermediate size deletion in BRCA2 was identified, enabling personalized patient management via the inclusion of the patients in a clinical trial.
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Pancreatic adenosquamous carcinoma (PASC) account for <5% of pancreatic malignancies. The efficacy of modern chemotherapy regimens in patients with advanced PASC is unknown. Patients with advanced PASC from 2008 to 2021 were consecutively included in this retrospective multicenter study. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method. Ninety-four PASC from 16 French centers were included (median age, 67.3 years; males, 56.4%; metastatic disease, 85.1%). The first-line treatment was chemotherapy for 79 patients (84.0%) (37 FOLFIRINOX (FX), 7 Gemcitabine-nab paclitaxel (GN) and 35 for all other regimen) or best supportive care (BSC) alone for 15 patients (16.0%). No significant difference was observed between FX and GN in terms of PFS (P = .67) or OS (P = .5). Modern regimens pooled together (FX and GN) as compared to all others chemotherapy regimens showed an improvement of overall response rate (39.5% and 9.7%, P = .002), PFS (median, 7.8 vs 4.7 months, P = .02) and OS (median, 12.7 vs 9.2 months, P = .35). This large study evaluating first-line treatment regimens in advanced PASC suggests that modern regimens as FX or GN may be preferable to all other chemotherapy regimens. These results deserve confirmation in prospective studies.
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Carcinoma Adenoescamoso , Neoplasias Pancreáticas , Masculino , Humanos , Anciano , Neoplasias Pancreáticas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Gemcitabina , Desoxicitidina , Carcinoma Adenoescamoso/tratamiento farmacológico , Carcinoma Adenoescamoso/inducido químicamente , Estudios Prospectivos , Paclitaxel/uso terapéutico , Fluorouracilo/uso terapéutico , Estudios Retrospectivos , Leucovorina/uso terapéutico , Neoplasias PancreáticasRESUMEN
Importance: Early results at 3 years from the PRODIGE 24/Canadian Cancer Trials Group PA6 randomized clinical trial showed survival benefits with adjuvant treatment with modified FOLFIRINOX vs gemcitabine in patients with resected pancreatic ductal adenocarcinoma; mature data are now available. Objective: To report 5-year outcomes and explore prognostic factors for overall survival. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial was conducted at 77 hospitals in France and Canada and included patients aged 18 to 79 years with histologically confirmed pancreatic ductal adenocarcinoma who had undergone complete macroscopic (R0/R1) resection within 3 to 12 weeks before randomization. Patients were included from April 16, 2012, through October 3, 2016. The cutoff date for this analysis was June 28, 2021. Interventions: A total of 493 patients were randomized (1:1) to receive treatment with modified FOLFIRINOX (oxaliplatin, 85 mg/m2 of body surface area; irinotecan, 150-180 mg/m2; leucovorin, 400 mg/m2; and fluorouracil, 2400 mg/m2, every 2 weeks) or gemcitabine (1000 mg/m2, days 1, 8, and 15, every 4 weeks) as adjuvant therapy for 24 weeks. Main Outcomes and Measures: Primary end point was disease-free survival. Secondary end points included overall survival, metastasis-free survival, and cancer-specific survival. Prognostic factors for overall survival were determined. Results: Of the 493 patients, 216 (43.8%) were women, and the mean (SD) age was 62.0 (8.9) years. At a median of 69.7 months' follow-up, 367 disease-free survival events were observed. In patients receiving chemotherapy with modified FOLFIRINOX vs gemcitabine, median disease-free survival was 21.4 months (95% CI, 17.5-26.7) vs 12.8 months (95% CI, 11.6-15.2) (hazard ratio [HR], 0.66; 95% CI, 0.54-0.82; P < .001) and 5-year disease-free survival was 26.1% vs 19.0%; median overall survival was 53.5 months (95% CI, 43.5-58.4) vs 35.5 months (95% CI, 30.1-40.3) (HR, 0.68; 95% CI, 0.54-0.85; P = .001), and 5-year overall survival was 43.2% vs 31.4%; median metastasis-free survival was 29.4 months (95% CI, 21.4-40.1) vs 17.7 months (95% CI, 14.0-21.2) (HR, 0.64; 95% CI, 0.52-0.80; P < .001); and median cancer-specific survival was 54.7 months (95% CI, 45.8-68.4) vs 36.3 months (95% CI, 30.5-43.9) (HR, 0.65; 95% CI, 0.51-0.82; P < .001). Multivariable analysis identified modified FOLFIRINOX, age, tumor grade, tumor staging, and larger-volume center as significant favorable prognostic factors for overall survival. Shorter relapse delay was an adverse prognostic factor. Conclusions and Relevance: The final 5-year results from the PRODIGE 24/Canadian Cancer Trials Group PA6 randomized clinical trial indicate that adjuvant treatment with modified FOLFIRINOX yields significantly longer survival than gemcitabine in patients with resected pancreatic ductal adenocarcinoma. Trial Registration: EudraCT: 2011-002026-52; ClinicalTrials.gov Identifier: NCT01526135.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Femenino , Masculino , Leucovorina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Irinotecán/uso terapéutico , Oxaliplatino/uso terapéutico , Neoplasias Pancreáticas/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Canadá , Fluorouracilo , Carcinoma Ductal Pancreático/tratamiento farmacológico , Quimioterapia Adyuvante , Gemcitabina , Neoplasias PancreáticasRESUMEN
Background: Excessive waiting time intervals for the diagnosis and treatment of patients with pancreatic cancer can influence their prognosis but they remain unclear. The objective was to describe time intervals from the medical visit to diagnostic imaging and to treatment and their prognostic impact in pancreatic cancer in one French region. Methods: This retrospective observational multicentre study included all patients with pancreatic cancer seen for the first time in 2017 in multidisciplinary team meetings (MTMs), where clinical data were collected. A probabilistic matching with the medico-administrative data from the French national healthcare database (Système National des Données de Santé) was performed to define the care pathway from clinical presentation to the beginning of treatment. Median key time intervals were estimated for both resected and unresected tumours. Factors associated with 1-year survival were studied using Cox model. Results: A total of 324 patients (88% of total patients with MTM presentation) were matched and included: male 54%, mean age 72 years ±9.2, Eastern Cooperative Oncology Group (ECOG) PS > 1 19.5%, metastatic disease at diagnosis 47.4%, tumour resection 16%. At 1 year, 57% had died (65% in the unresected group and 17% in the resected group). The median time interval from the medical visit to diagnostic imaging was 15 days [Q1-Q3: 8-44]. After imaging, median time intervals to definite diagnosis and to first treatment were 11 and 20 days, respectively. Significant prognostic factors associated with the risk of death at 1 year were ECOG PS > 1 (hazard ratio (HR) 2.1 [1.4-3.0]), metastasis (HR 2.7 [1.9-3.9]), no tumour resection (HR 2.7 [1.3-5.6]) and time interval between the medical visit and diagnostic imaging ⩾25 days (HR 1.7 [1.2-2.3]). Conclusion: Delay in access to diagnostic imaging impacted survival in patients with pancreatic cancer, regardless of whether tumour resection had been performed.
RESUMEN
Mortality from pancreatic ductal adenocarcinoma (PDAC) is increasing worldwide and effective new treatments are urgently needed. The current treatment of metastatic PDAC in fit patients is based on two chemotherapy combinations (FOLFIRINOX and gemcitabine plus nab-paclitaxel) which were validated more than 8 years ago. Although almost all treatments targeting specific molecular alterations have failed so far when administered to unselected patients, encouraging results were observed in the small subpopulations of patients with germline BRCA 1/2 mutations, and somatic gene fusions (neurotrophic tyrosine receptor kinase, Neuregulin 1, which are enriched in KRAS wild-type PDAC), KRAS G12C mutations, or microsatellite instability. While targeted tumor metabolism therapies and immunotherapy have been disappointing, they are still under investigation in combination with other drugs. Optimizing pharmacokinetics and adapting available chemotherapies based on molecular signatures are other promising avenues of research. This review evaluates the current expectations and limits of available treatments and analyses the existing trials. A permanent search for actionable vulnerabilities in PDAC tumor cells and microenvironments will probably result in a more personalized therapeutic approach, keeping in mind that supportive care must also play a major role if real clinical efficacy is to be achieved in these patients.
RESUMEN
After failure of first line FOLFOX-bevacizumab for metastatic colorectal cancer (mCRC), adding either bevacizumab or aflibercept to second-line FOLFIRI increases survival compared to FOLFIRI alone. In this French retrospective multicentre cohort, we included patients with a mCRC treated with either FOLFIRI-aflibercept or FOLFIRI-bevacizumab. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS), disease control rate (DCR: CR + PR + SD) and safety. We included 681 patients from 36 centers, 326 and 355 in the aflibercept and bevacizumab groups, respectively. Median age was 64.2 years and 45.2% of patients were men. Most patients had RAS-mutated tumors (80.8%) and synchronous metastases (85.7%). After a median follow up of 31.2 months, median OS was 13.0 months (95% CI: 11.3-14.7) and 10.4 months (95% CI: 8.8-11.4) in the bevacizumab and aflibercept groups, respectively (P < .0001). Median PFS was 6.0 months (95% CI: 5.4-6.5) and 5.1 months (95% CI: 4.3-5.6) (P < .0001). After adjustment on age, PS, PFS of first line, primary tumor resection, metastasis location and RAS/BRAF status, bevacizumab was still associated with better OS (HR: 0.71, 95% CI: 0.59-0.86, P = .0003). FOLFIRI-bevacizumab combination was associated with longer OS and PFS, and a better tolerability, as compared to FOLFIRI-aflibercept after progression on FOLFOX-bevacizumab.