ABSTRACT
INTRODUCTION: Mismatch repair (MMR) deficiency represents a biomarker and therapeutic target in various neoplasms, but its role in biliary tract cancers (BTCs) remains misunderstood. METHODS: MMR status was retrospectively assessed using immunohistochemistry in 163-BTCs patients. We identified MMR proficiency (pMMR)/deficiency (dMMR) according to the loss of MMR proteins (MLH1, PMS2, MSH2, MSH6). The primary objective of the study was to assess the incidence of dMMR in BTCs; the secondary purpose was to explore its association with prognosis and clinical features. RESULTS: dMMR was recorded in 9 patients, and it was strongly associated with mucinous histology (p < 0.01). Regarding the prognostic effect, in 122-radically resected patients, disease-free survival (DFS) resulted significantly shorter in dMMR patients compared to pMMR patients (10.7 vs. 31.3 months, p = 0.025) and so did nodal status (48.2 vs. 15.3 months in N0 vs. N+) (p < 0.01). Moreover, dMMR confirmed its prognostic role in terms of DFS at multivariate analysis (p = 0.03), together with nodal status (p = 0.01), and resection margin (p = 0.03). In 103 M+ patients (encompassing 41 metastatic de novo and 62 recurred after surgery patients) there were not differences between dMMR and pMMR regarding survival analyses. CONCLUSIONS: dMMR status is strongly correlated with mucinous histology and represents an independent prognostic factor in terms of disease relapse in patients with resected BTC. IMPLICATIONS FOR PRACTICE: MMR may play an independent role in promoting an aggressive behaviour in patients with radically resected BTC. These results could be useful in improving the selection of patients after resection and, above all, should justify the evaluation of MMR status as a therapeutic target in BTC, especially in patients with atypical histology.
Subject(s)
Biliary Tract Neoplasms , Brain Neoplasms , Colorectal Neoplasms , Neoplastic Syndromes, Hereditary , Humans , Prognosis , Retrospective Studies , Neoplasm Recurrence, Local , Colorectal Neoplasms/pathology , Biliary Tract Neoplasms/genetics , Biliary Tract Neoplasms/surgery , DNA Mismatch Repair/geneticsABSTRACT
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) harbouring germline BRCA1-2 pathogenic variants (gBRCA1-2pv) is a distinct nosological entity. Information on second-line therapy (2LT) outcome in this setting is lacking. METHODS: Data of gBRCA1-2pv metastatic PDAC patients treated with chemotherapy were collected. A primary analysis of 2LT RECIST response, median progression-free survival (mPFS2) and overall survival (mOS2), was performed. A secondary analysis addressed the impact of timing of platinum introduction on the outcome of patients receiving at least a first-line combination chemotherapy (1LT). RESULTS: Eighty-four gBRCA1-2pv metastatic PDAC patients were enrolled. The primary analysis, including 43 patients, highlighted a significant improvement of mPFS2 and a doubled response rate, in the platinum-based 2LT subgroup as compared to the platinum-free (8.8 versus 3.7 months, p = 0.013). Seventy-seven patients were included in the secondary analysis. Median PFS1 of 3- and 4-drug platinum-based 1LT significantly outperformed both platinum-free combinations and platinum-based doublets (11.4 versus 6.4 versus 7.9 months, p = 0.01). Albeit still immature, data on mOS paralleled those on mPFS. CONCLUSIONS: This study highlighted the beneficial role of platinum agents in gBRCA1-2pv PDAC patients also in second-line treatment setting. However, our data suggest that early use of 3- and 4-drug platinum-based chemotherapy combinations provides a survival outcome advantage.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Pancreatic Neoplasms/pathology , Carcinoma, Pancreatic Ductal/drug therapy , Germ-Line Mutation , Progression-Free Survival , BRCA1 Protein , Pancreatic NeoplasmsABSTRACT
INTRODUCTION: In locally advanced gastric cancer (GC), FLOT represents the standard perioperative regimen and combination with immunotherapy is under investigation. However, the role of immune tumor microenvironment (TME) is poorly recognized in this setting. We aimed to study TME characteristics and dynamics during FLOT. METHODS: Paired biopsy (PRE) and surgical (POST) samples of 25 patients treated with FLOT were prospectively analyzed. After collection of clinic-pathological data, NanoString analyses were performed. The primary objective of the study was to assess the changes induced by chemotherapy in POST compared to PRE samples. RESULTS: The unsupervised hierarchical method analysis clearly distinguished PRE and POST samples, even though some cases showed high immune gene expression at baseline. When POST samples were compared with PRE, a differential expression in hyper-expressed gene sets related to cytotoxicity, T-cell functions, complement system, tumor necrosis factor superfamily, cell cycle, and regulation was recognized. Downstaging of the primary tumor (T-regression, measured by pathologic compared to clinical T stage) was the covariate most frequently associated with these changes. Using the immune cell profiling, cases with T-regression reported a significant increase of T, CD8+ T and B cells and a decrease in mast cells, while nonresponders demonstrated an increase of T, B, cytotoxic, and mast cells. CONCLUSION: Our analysis shows that FLOT significantly influences immune TME of GC. While relevant modifications preferentially occur in tumors showing primary tumor regression, response to treatment seems to be associated with a specific immune profile.
Subject(s)
Stomach Neoplasms , Humans , Stomach Neoplasms/drug therapy , Stomach Neoplasms/surgery , Stomach Neoplasms/pathology , Docetaxel , Fluorouracil , Tumor Microenvironment , Leucovorin , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
Isocitrate dehydrogenase (IDH)1/2 mutations are the most frequent druggable alterations in intrahepatic cholangiocarcinoma (iCCA), reported in ~20% of cases. Preclinical evidence indicates that these mutations are associated with homologous recombination deficiency (HRD), which could be exploited as a target for platinum chemotherapy (ChT) and PARP inhibitors. However, the role of IDH1/2 mutations as surrogate biomarkers for platinum efficacy is unknown. We conducted a multicenter, propensity score-matched analysis to investigate the impact of IDH1/2 mutations on progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) in patients with iCCA treated with platinum-based ChT. An exploratory comparison of complex HRD estimates between IDH1/2 mutated and wild-type tumors from TCGA was also performed. A total of 120 cases were matched in a 1:1 ratio (60 IDH1/2 mutant and 60 wild-type). No differences were observed for platinum-based PFS (7.7 vs 7.3 months, P = .970), DCR (66.1% vs 74.1%, P = .361) and ORR (27.8% vs 25.0%, P = .741). IDH1/2 mutations showed mutual exclusivity with genomic alterations in ATM, BRCA2, MST1R, NF1, FGFR2 and CDKN2A/B losses, respectively, with no clear survival and response differences. Among TCGA tumors, IDH1/2 mutated CCA did not show higher HRD compared to wild-type cases. IDH1/2 mutations are not associated with increased sensitivity to platinum-based ChT in iCCA patients. Deeper genomic sequencing is needed to elucidate the HRD phenotype in IDH1/2 mutant iCCA and exploit its therapeutic vulnerabilities.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/pathology , Bile Ducts, Intrahepatic/pathology , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/genetics , Cholangiocarcinoma/pathology , Humans , Isocitrate Dehydrogenase/genetics , Mutation , Propensity ScoreABSTRACT
Modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine + nab-paclitaxel (GemNab) regimens represent a standard treatment in advanced pancreatic cancer (aPC). DPYD and UGT1A1 variants are relevant predictors of fluoropyrimidine and irinotecan-associated adverse events (AEs). Furthermore, data about the associations between polymorphisms in ABCB and CDA genes and GemNab-related toxicities are still controversial. The present study analyzes the association between DPYD, UGT, ABCB1, CDA variants, and AEs in aPC patients (pts) treated with mFOLFIRINOX or GemNab. Blood samples collected from 104 aPC pts treated with mFOLFIRINOX and 63 with GemNab were tested for DPYD c.1679T>G, IVS14+1G>A, c.2194G>A, c.2846A>T, UGT1A1*28, CDA c.79A>C, and ABCB1 c.1236C>T, c.2677G>T/A, c.3435C>T by real-time PCR and automatic sequencing. In mFOLFIRINOX cohort, DPYD IVS14+1GA genotype was associated with G4 hematological AEs, while the UGT1A1*28 significantly correlated with the risk of thrombocytopenia (p = 0.006). In the GemNab cohort, a significant association between CDA c.79CC and high-grade nausea was observed (p = 0.002). Moreover, the presence of at least a mutant allele in ABCB1 increased the risk of overall hematological AEs (p = 0.01), both further strengthened by the presence of CDA c.79CC (p = 0.0002). DPYD IVS14+1A allele is confirmed to be associated with fluoropyrimidine life-threatening toxicities, and UGT1A1*28 is related with a higher risk of hematologic AEs following irinotecan treatment. CDA c.79C and ABCB1 c.1236T, c.2677T/A, and c.3435T mutant alleles are predictive biomarkers of GemNab-related AEs. All these variants should be considered in aPC pts candidate to mFOLFIRINOX or GemNab treatments.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cytidine Deaminase/genetics , Glucuronosyltransferase/genetics , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Polymorphism, Genetic/genetics , ATP Binding Cassette Transporter, Subfamily B/genetics , Adult , Aged , Albumins/administration & dosage , Alleles , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Female , Fluorouracil/therapeutic use , Genotype , Humans , Leucovorin/therapeutic use , Male , Middle Aged , Organoplatinum Compounds/therapeutic use , Paclitaxel/administration & dosage , Pharmacogenomic Testing/methods , GemcitabineABSTRACT
OBJECTIVE: The aim of the study was to identify plasma microRNA (miRNA) biomarkers for stratifying and monitoring patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) treated with FOLFIRINOX, and to investigate their functional roles. SUMMARY BACKGROUND DATA: FOLFIRINOX has become a standard therapy for patients with advanced PDAC and can be used to potentially downstage disease. However, only a subset of patients respond, and biomarkers to guide decision-making are urgently needed. METHODS: We used microarray-based profiling to discover deregulated miRNAs in pre- and postchemotherapy plasma samples from patients based on their progression-free survival (PFS) after FOLFIRINOX. Nine candidate plasma miRNAs were validated in an independent cohort (n = 43). The most discriminative plasma miRNA was correlated with clinicopathological factors and survival, and also investigated in an additional cohort treated with gemcitabine plus nab-paclitaxel. Expression patterns were further evaluated in matched tumor tissues. In vitro studies explored its function, key downstream gene-targets, and interaction with 5-fluorouracil, irinotecan, and oxaliplatin. RESULTS: Plasma miR-181a-5p was significantly downregulated in non-progressive patients after FOLFIRINOX. In multivariate analysis, this decline correlated with improved PFS and overall survival, especially when combined with CA19-9 decline [hazard ratio (HR) = 0.153, 95% confidence interval (CI), 0.067-0.347 and HR = 0.201, 95% CI, 0.070-0.576, respectively]. This combination did not correlate with survival in patients treated with gemcitabine plus nab-paclitaxel. Tissue expression of miR-181a-5p reflected plasma levels. Inhibition of miR-181a-5p coupled with oxaliplatin exposure in pancreatic cell lines decreased cell viability. CONCLUSIONS: Plasma miR-181a-5p is a specific biomarker for monitoring FOLFIRINOX response. Decline in plasma miR-181a-5p and CA19-9 levels is associated with better prognosis after FOLFIRINOX and may be useful for guiding therapeutic choices and surgical exploration.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Pancreatic Ductal/blood , Down-Regulation , MicroRNAs/blood , Pancreatic Neoplasms/blood , Adult , Aged , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/blood , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/mortality , Female , Fluorouracil/therapeutic use , Humans , Immunohistochemistry , Irinotecan/therapeutic use , Leucovorin/therapeutic use , Male , MicroRNAs/genetics , Middle Aged , Netherlands/epidemiology , Oxaliplatin/therapeutic use , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/mortality , Survival Rate/trendsABSTRACT
BACKGROUND: HER2 overexpression has been investigated as a potential biomarker and therapeutic target in biliary tract cancer (BTC), but a prognostic role of such alteration has not been demonstrated yet. MATERIALS AND METHODS: We retrospectively evaluated HER2 protein expression by immunohistochemistry (IHC) in 100 patients with radically resected BTC. HER2 gene amplification was assessed by fluorescence in situ hybridization (FISH) in 2+ and 3+ cases at IHC. High HER2 protein expression was defined as either IHC 3+ or 2+ associated with FISH positivity. The primary objective of the study was to evaluate the prognostic role of HER2 overexpression in terms of disease-free survival (DFS) and overall survival (OS). Secondary endpoints were the prevalence of HER2 overexpression and the possible correlation with other clinicopathological features. RESULTS: HER2 overexpression was identified in 11 patients and was not related to other clinicopathological factors. DFS was significantly shorter in HER2-positive compared with HER2-negative patients (10.6 vs. 20.9 months, log-rank p = .017). HER2 confirmed its prognostic value for DFS at multivariate analysis (hazard ratio 2.512; 95% confidence interval, 1.232-5.125; p = .011) together with nodal stage (p < .001), resection margin (p = .027), and tumor site (p = .030). There was no difference in OS between HER2-positive and -negative patients (p = .068). CONCLUSION: HER2 overexpression represents an independent prognostic factor for disease recurrence in patients with BTC treated with potentially curative surgery. IMPLICATIONS FOR PRACTICE: HER2 overexpression may play an independent role in promoting an aggressive behavior in resectable biliary tract cancer. This evidence could be helpful in improving prognostic stratification after resection and, primarily, should endorse the rationale to investigate HER2 as a therapeutic target in biliary tract cancer.
Subject(s)
Biliary Tract Neoplasms , Neoplasm Recurrence, Local , Biliary Tract Neoplasms/genetics , Biliary Tract Neoplasms/surgery , Humans , In Situ Hybridization, Fluorescence , Neoplasm Recurrence, Local/genetics , Neoplasm Staging , Prognosis , Receptor, ErbB-2/genetics , Retrospective StudiesABSTRACT
Esophageal cancer remains a challenging disease due to limited treatment options and poor prognosis. In recent years, immune checkpoint inhibitors (ICI) have been proven to be safe and effective in the treatment of highly lethal malignancies, such as non-small cell lung cancer and melanoma. Recent clinical trials also showed promising activity in immune checkpoint inhibitors in pretreated advanced esophageal carcinoma and a potentially significant impact on the outcome of selected patients, independently of histology. Combination studies evaluating immunotherapy and chemotherapy and, in localized disease, radiotherapy are in progress and will hopefully confirm their promises in the near future. However, reliable predictive biomarkers are still lacking. Indeed, at present, the role of programmed cell death ligand 1 expression and other factors (such as microsatellite instability and tumor mutational burden) as predictive biomarkers of benefit to immune checkpoint inhibitors is still controversial. Our aim was to explore the rationale of ICIs in esophageal cancer, review the results already available in multiple settings, and investigate future perspectives with single-agent and combination strategies.
Subject(s)
Esophageal Neoplasms/immunology , Esophageal Neoplasms/therapy , Immunotherapy , Animals , Clinical Trials as Topic , DNA Damage , Esophageal Neoplasms/pathology , Gastrointestinal Microbiome , HumansABSTRACT
BACKGROUND: HER2 is the only validated predictive biomarker in gastro-oesophageal carcinoma (GOC). However, several factors, such as heterogeneity in protein expression, shortage of evaluable tumour tissue and need for quick target assessment, underline the usefulness of a pre-screening tool in order to anticipate HER2 status. METHODS: Data from 723 consecutive GOC analysed for HER2 at four Italian Institutions were collected. HER2 positivity was defined as 3+ by immunohistochemistry (IHC) or 2+ with gene amplification by in situ hybridisation (ISH). A multivariate logistic regression model was built using data from 413 cases, whereas 310 patients served as validation cohort. C-index, visual inspection of the calibration plot, Brier score and Spiegelhalter z-test were used to assess the performance of the nomogram. RESULTS: HER2 positive rate was 17.4%. Four variables were retained after adjustment in the final model: grading, Lauren's histotype, pathologic material analysed (surgical specimen/biopsy) and site of tissue collection (primary tumour/metastases). Visual inspection of the calibration plot revealed a very good overlap between predicted and observed probabilities, with a Brier score of 0.101 and a non-significant Spiegelhalter z-test (P = 0.319). C-index resulted in 0.827 (95%CI 0.741-0.913). CONCLUSION: A simple nomogram based on always-available pathologic information accurately predicts the probability of HER2 positivity in GOC.
Subject(s)
Carcinoma/metabolism , Esophagogastric Junction/metabolism , Receptor, ErbB-2/metabolism , Stomach Neoplasms/metabolism , Antineoplastic Agents, Immunological/therapeutic use , Carcinoma/drug therapy , Female , Gene Amplification , Humans , Immunohistochemistry , Logistic Models , Male , Multivariate Analysis , Nomograms , Reproducibility of Results , Stomach Neoplasms/drug therapy , Trastuzumab/therapeutic useABSTRACT
This corrects the article DOI: 10.1038/bjc.2017.85.
Subject(s)
Exosomes/genetics , Programmed Cell Death 1 Receptor/genetics , RNA, Messenger/biosynthesis , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/drug therapy , Exosomes/drug effects , Exosomes/immunology , Female , Humans , Lung Neoplasms/blood , Lung Neoplasms/drug therapy , Male , Melanoma/blood , Melanoma/drug therapy , Middle Aged , Nivolumab/administration & dosage , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/biosynthesis , Programmed Cell Death 1 Receptor/immunology , RNA, Messenger/blood , RNA, Messenger/geneticsABSTRACT
OBJECTIVES:: Never-smokers may be a distinct subgroup among patients with advanced non-small cell lung cancer, appearing to benefit less from immunotherapy than smokers. We report results from never-smokers enrolled in the Italian cohort of the nivolumab expanded access program in pre-treated patients with advanced squamous non-small cell lung cancer. MATERIALS AND METHODS:: Nivolumab (3 mg/kg every 2 weeks for ≤24 months) was available on physician request. Efficacy data included objective tumor response, date of progression, and survival information. Safety was monitored. RESULTS:: Overall, 371 patients received at least one dose of nivolumab, including 31 never-smokers (8%). Objective response rate, disease-control rate, and median overall survival were 23%, 45%, and 12.1 months (95% confidence interval: 3.7-20.4), respectively, in never-smokers, and 18%, 47%, and 7.9 months (95% confidence interval: 6.2-9.6), respectively, in the overall expanded access program population. Any-grade and grade 3-4 treatment-related adverse events were reported in 12 (39%) and 3 (10%) never-smokers, respectively, and in 109 (29%) and 21 (6%) patients, respectively, in the overall expanded access program population. Grade 3-4 treatment-related adverse events in non-smokers were increased transaminases (n = 2; 6%) and diarrhea (n = 1; 3%). Treatment-related adverse events led to treatment discontinuation in 4 non-smokers (17%) and in 26 patients (9%) overall. CONCLUSION:: Pre-treated never-smokers with advanced squamous non-small cell lung cancer in this Italian expanded access program demonstrated efficacy and safety that were consistent with those in the overall expanded access program population and clinical trials. These results suggest that a proportion of never-smoker patients with squamous non-small cell lung cancer may be responsive to immunotherapy. Other factors, such as the tumor mutational load and the status of programmed death-ligand 1, anaplastic lymphoma kinase, and epidermal growth factor receptor, might play a potential key role.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Squamous Cell/drug therapy , Health Services Accessibility , Lung Neoplasms/drug therapy , Nivolumab/therapeutic use , Non-Smokers/statistics & numerical data , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/pathology , Case-Control Studies , Cohort Studies , Disease Progression , Female , Follow-Up Studies , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Prognosis , Survival RateABSTRACT
AIM: To evaluate the impact on overall survival (OS) of gastrectomy in asymptomatic metastatic esophago-gastric cancer. PATIENTS & METHODS: Five hundred and thirteen patients were included. The role of surgery and other clinico-pathological factors was evaluated by univariate and Cox regression analyses. OS was the primary end point. RESULTS: Multivariate analysis confirmed that gastrectomy was a predictor of longer OS (p < 0.001), as well as preserved performance status and benefit from first-line chemotherapy. None of the investigated clinico-pathological variables identified preferable candidates for surgery (all p > 0.05). CONCLUSION: Palliative gastrectomy might play a role in asymptomatic metastatic esophago-gastric cancer patients with good performance status who received benefit from first-line chemotherapy. Future prospective trials integrating tumor biology among inclusion criteria may help defining the optimal candidates.
Subject(s)
Esophageal Neoplasms/pathology , Esophageal Neoplasms/surgery , Esophagogastric Junction/pathology , Gastrectomy , Patient Selection , Stomach Neoplasms/pathology , Stomach Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Combined Modality Therapy , Esophageal Neoplasms/diagnostic imaging , Esophageal Neoplasms/mortality , Female , Gastrectomy/methods , Humans , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Retrospective Studies , Stomach Neoplasms/diagnostic imaging , Stomach Neoplasms/mortality , Treatment OutcomeABSTRACT
FOLFIRINOX is a standard first-line treatment for advanced pancreatic cancer (aPC). The Gruppo Oncologico Nord Ovest (GONO) FOLFOXIRI regimen demonstrated efficacy in metastatic colorectal cancer. We aimed to evaluate activity and tolerability of FOLFOXIRI regimen in patients with aPC and to explore putative prognostic factors. One hundred thirty-seven consecutive aPC patients were treated with FOLFOXIRI in our institution between 2008 and 2014. Clinical, laboratory and pathological data were collected and their association with activity, progression free survival (PFS) and overall survival (OS) was investigated. After a median follow up of 30 months, median PFS and OS were 8.0 months (95% CI 6.19-9.81) and 12 months (95% CI 9.75-14.25), respectively. Response rate was 38.6%, while disease-control rate 72.2%. At multivariate analysis liver metastases (p = 0.019; Hazard Ratio, HR, 0.59, 95% Confidence Interval, CI, 0.380.96), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1 (p = 0.001; HR 2.26, 95%CI 1.42-3.59) and neutrophil-lymphocyte ratio (NLR)> 4 (p= 0.002; HR: 2.42; 95% CI 1.38-4.25) were associated with poorer OS. We categorized 119 pts with complete available data as good-risk (0 factors, 38 pts), intermediate-risk (1 factor, 49 pts) and poor-risk (≥2 factors, 32 pts). Median OS for these three groups were 17.6, 11.1 and 7.4 months, respectively (p < 0.001). FOLFOXIRI is active and feasible in aPC. Prognosis of aPC pts treated with FOLFOXIRI is influenced by easily available factors: our analysis revealed ECOG PS, liver metastases and NLR as the most important predictors of survival. These factors could be helpful for treatment decision and clinical trial design.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/analogs & derivatives , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Camptothecin/adverse effects , Camptothecin/therapeutic use , Cohort Studies , Female , Fluorouracil/adverse effects , Fluorouracil/therapeutic use , Humans , Leucovorin/adverse effects , Leucovorin/therapeutic use , Leukocyte Count , Lymphocytes , Male , Middle Aged , Neoplasm Grading , Neoplasm Metastasis , Neoplasm Staging , Neutrophils , Organoplatinum Compounds/adverse effects , Organoplatinum Compounds/therapeutic use , Pancreatic Neoplasms/mortality , Prognosis , Survival Analysis , Treatment OutcomeABSTRACT
PURPOSE: The aim of this study was to evaluate the activity of the combination of 5-fluorouracil/folinic acid and irinotecan (FOLFIRI) as third-line chemotherapy (CT) in metastatic gastric cancer (mGC) patients pretreated with platinum derivatives, fluoropyrimidines, and taxanes. METHODS: We prospectively collected data of mGC patients treated with third-line FOLFIRI at our institution from 2009 to 2014. Eligible patients should be treated with a fluoropyrimidine-platinum first-line CT and a subsequent taxane-based second-line CT. FOLFIRI consisted of irinotecan 180 mg/m2 and leucovorin 200 mg/m2, followed by 5-fluorouracil 2,800 mg/m2 (administered as 48-hour i.v. continuous infusion from day 1 to 3), with cycles repeated every 2 weeks. Response rate (RR) was evaluated according to RECIST version 1.0, while progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: A total of 33 patients were included. The majority (97%) had good performance status (0-1 according to ECOG), while median PFS after first-line and second-line CT was 5.2 and 4.4 months, respectively. Two patients experienced an objective response (RR: 6%), while 14 patients achieved disease stabilization (disease control rate: 42%). Median PFS and OS from the start of third-line CT were 3.3 and 7.5 months, respectively. Hematological and nonhematological grade 3-4 toxicities were uncommon and included neutropenia (6.1%), diarrhea (9.1%), vomiting (3%), and asthenia (3%). Febrile neutropenia was not reported. CONCLUSIONS: Third-line CT with FOLFIRI may be an option in heavily pretreated mGC patients with preserved performance status and organ function. This regimen has a favorable safety profile, and signs of activity have been observed after standard first- and second-line CT.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Stomach Neoplasms/drug therapy , Adenocarcinoma/secondary , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Asthenia/chemically induced , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Diarrhea/chemically induced , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Humans , Irinotecan , Leucovorin/administration & dosage , Male , Middle Aged , Neutropenia/chemically induced , Prospective Studies , Response Evaluation Criteria in Solid Tumors , Retreatment , Stomach Neoplasms/pathology , Survival Rate , Vomiting/chemically induced , White PeopleABSTRACT
BACKGROUND: FOLFIRINOX is a standard first-line treatment for advanced pancreatic cancer (aPC) and no accepted second-line regimen exists. MATERIAL & METHODS: We enrolled 71 aPC patients progressed to modified FOLFIRINOX (mFOLFIRINOX) treated with second-line chemotherapy. RESULTS: Five partial responses (7.1%) and 19 (27.1%) disease stabilizations were reported. After a median follow-up of 20.1 months, median progression-free survival was 2.5 months (95% CI: 2.1-2.9 months) and median overall survival was 6.2 months (95% CI: 5.3-7.1 months). At multivariate analysis, CA19.9 level ≥ 59 upper normal limit resulted associated with worse survival (hazard ratio: 2.32; 95% CI: 1.12-4.78; p = 0.023). CONCLUSION: Salvage chemotherapy could be useful for a subgroup of aPC patients. Prognostic factors might be helpful to identify patients with greater benefit.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Female , Humans , Male , Neoplasm Recurrence, Local , Neoplasm Staging , Pancreatic Neoplasms/mortality , Prognosis , Retreatment , Treatment OutcomeABSTRACT
Objective: This study aimed to compare robotic pancreatoduodenectomy with vein resection (PD-VR) based on the incidence of severe postoperative complications (SPC). Background: Robotic pancreatoduodenectomy has been gaining momentum in recent years. Vein resection is frequently required in this operation, but no study has compared robotic and open PD-VR using a matched analysis. Methods: This was an intention-to-treat study designed to demonstrate the noninferiority of robotic to open PD-VR (2011-2021) based on SPC. To achieve a power of 80% (noninferiority margin:10%; α error: 0.05; ß error: 0.20), a 1:1 propensity score-matched analysis required 35 pairs. Results: Of the 151 patients with PD-VR (open = 115, robotic = 36), 35 procedures per group were compared. Elective conversion to open surgery was required in 1 patient with robotic PD-VR (2.9%). One patient in both groups experienced partial vein thrombosis. SPC occurred in 7 (20.0%) and 6 patients (17.1%) in the robotic and open PD-VR groups, respectively (P = 0.759; OR: 1.21 [0.36-4.04]). Three patients died after robotic PD-VR (8.6%) and none died after open PD-VR (P = 0.239). Robotic PD-VR was associated with longer operative time (611.1 ± 13.9 minutes vs 529.0 ± 13.0 minutes; P < 0.0001), more type 2 vein resection (28.6% vs 5.7%; P = 0.0234) and less type 3 vein resection (31.4% vs 71.4%; P = 0.0008), longer vein occlusion time (30 [25.3-78.3] minutes vs 15 [8-19.5] minutes; P = 0.0098), less blood loss (450 [200-750] mL vs 733 [500-1070.3] mL; P = 0.0075), and fewer blood transfusions (intraoperative: 14.3% vs 48.6%; P = 0.0041) (perioperative: 14.3% vs 60.0%; P = 0.0001). Conclusions: In this study, robotic PD-VR was noninferior to open PD-VR for SPC. Robotic and open PD-VR need to be compared in randomized controlled trials.
ABSTRACT
BACKGROUND: Pancreatic cancer (PC) first-line therapy often consists of polychemotherapy regimens, but choosing a second-line therapy after disease progression, especially following first-line FOLFIRINOX, remains a clinical challenge. This study presents results from a large, multicenter, retrospective analysis of Italian patients with metastatic PC (mPC) treated with Nab-paclitaxel/Gemcitabine (AG) as second or later line of treatment. Main objective of the study is to identify prognostic factors that could inform treatment decisions. METHODS: The study included 160 mPC patients treated with AG in 17 Italian institutions. AG was administered according to labelling dose, until disease progression, unacceptable toxicity or patient refusal. Variations in schedules, dose modifications, supportive measures, and response evaluation were determined by individual clinicians' practice. RESULTS: AG was well-tolerated and exhibited promising clinical activity. The overall response rate (ORR) and the disease control rate (DCR) were 22.5% and 45.6%, respectively. Median progression-free survival (PFS) and overall survival (OS) were 3.9 and 6.8 months, respectively. Among the patients who received AG as a second-line therapy (n = 111, 66.9%), median PFS and OS were 4.2 and 7.4 months, respectively. Notably, in the 76 patients (68%) receiving AG after first-line FOLFIRINOX, an ORR of 19.7% and a DCR of 46.0% were observed, resulting in a median PFS of 3.5 and median OS of 5.7 months. The study identified specific clinical or laboratory parameters (LDH, NLR, fasting serum glucose, liver metastases, ECOG PS, and first-line PFS) as independent prognostic factors at multivariate level. These factors were used to create a prognostic nomogram that divided patients into three risk classes, helping to predict second-line OS and PFS. CONCLUSIONS: This study represents the largest real-world population of mPC patients treated with AG as a second or later line of therapy. It supports the feasibility of this regimen following first-line FOLFIRINOX, particularly in patients with specific clinical and laboratory characteristics who derived prolonged benefit from first-line therapy.