ABSTRACT
The aryl hydrocarbon receptor (AhR) is a sensor of products of tryptophan metabolism and a potent modulator of immunity. Here, we examined the impact of AhR in tumor-associated macrophage (TAM) function in pancreatic ductal adenocarcinoma (PDAC). TAMs exhibited high AhR activity and Ahr-deficient macrophages developed an inflammatory phenotype. Deletion of Ahr in myeloid cells or pharmacologic inhibition of AhR reduced PDAC growth, improved efficacy of immune checkpoint blockade, and increased intra-tumoral frequencies of IFNγ+CD8+ T cells. Macrophage tryptophan metabolism was not required for this effect. Rather, macrophage AhR activity was dependent on Lactobacillus metabolization of dietary tryptophan to indoles. Removal of dietary tryptophan reduced TAM AhR activity and promoted intra-tumoral accumulation of TNFα+IFNγ+CD8+ T cells; provision of dietary indoles blocked this effect. In patients with PDAC, high AHR expression associated with rapid disease progression and mortality, as well as with an immune-suppressive TAM phenotype, suggesting conservation of this regulatory axis in human disease.
Subject(s)
Immune Tolerance/immunology , Receptors, Aryl Hydrocarbon/immunology , Tryptophan/immunology , Tumor-Associated Macrophages/immunology , Animals , CD8-Positive T-Lymphocytes/immunology , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/mortality , Carcinoma, Pancreatic Ductal/pathology , Humans , Indoles/immunology , Indoles/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , Mice , Microbiota/immunology , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Prognosis , Receptors, Aryl Hydrocarbon/antagonists & inhibitors , Receptors, Aryl Hydrocarbon/genetics , Receptors, Aryl Hydrocarbon/metabolism , Tryptophan/metabolism , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Tumor-Associated Macrophages/metabolismABSTRACT
BACKGROUND AND AIMS: The incidence of biliary tract cancers (BTC) appears to be increasing worldwide. We analyzed the characteristics of BTC-related hospitalizations under medical services across 28 hospitals in Ontario, Canada. METHODS: This study uses data collected by GEMINI, a hospital research data network. BTC-related hospitalizations from 2015 to 2021 under the Department of Medicine or intensive care unit were captured using the International Classification of Diseases, 10th revision, codes for intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma, and gallbladder cancers. RESULTS: A total of 4596 BTC-related hospitalizations (2720 iCCA, 1269 extrahepatic cholangiocarcinoma, 607 gallbladder cancers) were analyzed. The number of unique patients with BTC-related hospitalizations increased over time. For iCCA-related hospitalizations, the total number of hospitalizations increased (from 385 in 2016 to 420 in 2021, p = .005), the hospital length of stay decreased over the study period (mean 10 days [SD, 12] in 2016 to 9 days [SD, 8] in 2021, p = .04), and the number of in-hospital deaths was stable (from 68 [18%] in 2016 to 55 [13%] in 2021, p = .62). Other outcomes such as 30-day readmissions, medical imaging tests, intensive care unit-specific hospitalizations, and length of stay were stable over time for all cohorts. The cost of hospitalization for the BTC cohort increased from median $8203 CAD (interquartile range, 5063-15,543) in 2017 to $8507 CAD (interquartile range, 5345-14,755) in 2021. CONCLUSIONS: This real-world data analysis showed a rising number of patients with BTC-related hospitalizations and rising number of iCCA-related hospitalizations across 28 hospitals in Ontario between 2015 and 2021.
Subject(s)
Biliary Tract Neoplasms , Hospitalization , Humans , Ontario/epidemiology , Female , Male , Aged , Hospitalization/statistics & numerical data , Biliary Tract Neoplasms/epidemiology , Middle Aged , Cholangiocarcinoma/epidemiology , Length of Stay/statistics & numerical data , Incidence , Hospitals/statistics & numerical data , Aged, 80 and over , Hospital Mortality , Cost of Illness , Gallbladder Neoplasms/epidemiology , Bile Duct Neoplasms/epidemiologyABSTRACT
Immune-oncology-based regimens have shown efficacy in advanced HCC and have been implemented as standard of care as first-line therapy. Their efficacy, including high response rates, and safety justify their evaluation in earlier disease stages. Following negative results for adjuvant sorafenib in the global STORM trial in 2015, 4 global phase 3 trials, featuring different immune checkpoint inhibitor combinations, entered in parallel the race in the adjuvant setting. The IMbrave050 trial, comparing adjuvant atezolizumab in combination with bevacizumab to active surveillance following curative-intent resection or ablation, was the first to report, fast-tracking the results of the first interim analysis and demonstrating an improvement in recurrence-free survival. The trial has provoked a discussion on the horizon of expectations from adjuvant treatment and the clinical relevance of efficacy endpoints. Moreover, major pathological responses reported from early phase 2 data in the neoadjuvant setting provide a strong rationale for the evaluation of these concepts in phase 3 trials. In this review, we summarize current evidence and outline future directions for systemic therapies in early-stage HCC.
ABSTRACT
The use of liquid biopsies for cancer detection and management is rapidly gaining prominence1. Current methods for the detection of circulating tumour DNA involve sequencing somatic mutations using cell-free DNA, but the sensitivity of these methods may be low among patients with early-stage cancer given the limited number of recurrent mutations2-5. By contrast, large-scale epigenetic alterations-which are tissue- and cancer-type specific-are not similarly constrained6 and therefore potentially have greater ability to detect and classify cancers in patients with early-stage disease. Here we develop a sensitive, immunoprecipitation-based protocol to analyse the methylome of small quantities of circulating cell-free DNA, and demonstrate the ability to detect large-scale DNA methylation changes that are enriched for tumour-specific patterns. We also demonstrate robust performance in cancer detection and classification across an extensive collection of plasma samples from several tumour types. This work sets the stage to establish biomarkers for the minimally invasive detection, interception and classification of early-stage cancers based on plasma cell-free DNA methylation patterns.
Subject(s)
Cell-Free Nucleic Acids/blood , Cell-Free Nucleic Acids/metabolism , DNA Methylation , DNA, Neoplasm/blood , DNA, Neoplasm/metabolism , Early Detection of Cancer/methods , Neoplasms/classification , Neoplasms/genetics , Adenocarcinoma/blood , Adenocarcinoma/genetics , Animals , Biomarkers, Tumor/genetics , Cell Line, Tumor , Colorectal Neoplasms/blood , Colorectal Neoplasms/genetics , DNA Mutational Analysis , Epigenesis, Genetic , Female , Heterografts , Humans , Liquid Biopsy , Male , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Transplantation , Neoplasms/blood , Organ Specificity , Pancreatic Neoplasms/blood , Pancreatic Neoplasms/geneticsABSTRACT
BACKGROUND: Systemic inflammatory scores may aid prognostication and patient selection for trials. We compared five scores in advanced pancreatic adenocarcinoma (PDAC). METHODS: Unresectable/metastatic PDAC patients enrolled in the Comprehensive Molecular Characterisation of Advanced Pancreatic Ductal Adenocarcinoma for Better Treatment Selection trial (NCT02750657) were included. Patients had pre-treatment biopsies for whole genome and RNA sequencing. CD8 immunohistochemistry was available in a subset. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, Prognostic Nutritional Index, Gustave Roussy Immune Score (GRIm-S), and Memorial Sloan Kettering Prognostic Score (MPS) were calculated. Overall survival (OS) was estimated using Kaplan-Meier methods. Associations between inflammatory scores, clinical/genomic characteristics, and OS were analysed. RESULTS: We analysed 263 patients. High-risk NLR, GRIm-S and MPS were poorly prognostic. The GRIm-S had the highest predictive ability: median OS 6.4 vs. 10 months for high risk vs. low-risk (P < 0.001); HR 2.26 (P < 0.001). ECOG ≥ 1, the basal-like subtype, and low-HRDetect were additional poor prognostic factors (P < 0.01). Inflammatory scores did not associate with RNA-based classifiers or homologous recombination repair deficiency genotypes. High-risk MPS (P = 0.04) and GRIm-S (P = 0.02) patients had lower median CD8 + tumour-infiltrating lymphocytes. CONCLUSIONS: Inflammatory scores incorporating NLR have prognostic value in advanced PDAC. Understanding immunophenotypes of poor-risk patients and using these scores in trials will advance the field.
Subject(s)
Adenocarcinoma , Pancreatic Neoplasms , Humans , Pancreatic Neoplasms/pathology , Prognosis , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Lymphocytes/pathology , Neutrophils/pathology , Retrospective StudiesABSTRACT
BACKGROUND: Prognostic scores that can identify patients at risk for early death are needed to aid treatment decision-making and patient selection for clinical trials. We compared the accuracy of four scores to predict early death (within 90 days) and overall survival (OS) in patients with metastatic gastric and esophageal (GE) cancer. METHODS: Advanced GE cancer patients receiving first-line systemic therapy were included. Prognostic risks were calculated using: Royal Marsden Hospital (RMH), MD Anderson Cancer Centre (MDACC), Gustave Roussy Immune (GRIm-Score), and MD Anderson Immune Checkpoint Inhibitor (MDA-ICI) scores. Overall survival (OS) was estimated using the Kaplan-Meier method. Cox proportional hazards models were used to analyze associations between prognostic scores and OS. The predictive discrimination was estimated using Harrell's c-index. Predictive ability for early death was measured using time-dependent AUCs. RESULTS: In total, 451 patients with metastatic GE cancer were included. High risk patients had shorter OS for all scores (RMH high- vs. low-risk median OS 7.9 vs. 12.2 months, P < .001; MDACC 6.8 vs. 11.9 months P < .001; GRIm-Score 5.3 vs. 13 months, P < .001; MDA-ICI 8.2 vs. 12.2 months, P < .001). On multivariable analysis, each prognostic score was significantly associated with OS. The GRIm-Score had the highest predictive discrimination and predictive ability for early death. CONCLUSIONS: The GRIm-Score had the highest accuracy in predicting early death and OS. Clinicians may use this score to identify patients at higher risk of early death to guide treatment decisions including clinical trial enrolment. This score could also be used as a stratification factor in future clinical trial designs.
Subject(s)
Esophageal Neoplasms , Stomach Neoplasms , Humans , Prognosis , Proportional Hazards Models , Retrospective Studies , Stomach Neoplasms/drug therapy , Treatment OutcomeABSTRACT
BACKGROUND AND AIMS: Following liver resection (LR) for HCC, the likelihood of survival is dynamic, in that multiple recurrences and/or metastases are possible, each having variable impacts on outcomes. We sought to evaluate the natural progression, pattern, and timing of various disease states after LR for HCC using multistate modeling and to create a practical calculator to provide prognostic information for patients and clinicians. APPROACH AND RESULTS: Adult patients undergoing LR for HCC between January 2000 and December 2018 were retrospectively identified at a single center. Multistate analysis modeled post-LR tumor progression by describing transitions between distinct disease states. In this model, the states included surgery, intrahepatic recurrence (first, second, third, fourth, fifth), distant metastasis with or without intrahepatic recurrence, and death. Of the 486 patients included, 169 (34.8%) remained recurrence-free, 205 (42.2%) developed intrahepatic recurrence, 80 (16.5%) developed distant metastasis, and 32 (7%) died. For an average patient having undergone LR, there was a 33.1% chance of remaining disease-free, a 31.0% chance of at least one intrahepatic recurrence, a 16.3% chance of distant metastasis, and a 19.8% chance of death within the first 60 months post-LR. The transition probability from surgery to first intrahepatic recurrence, without a subsequent state transition, increased from 3% (3 months) to 17.4% (30 months) and 17.2% (60 months). Factors that could modify these probabilities included tumor size, satellite lesions, and microvascular invasion. The online multistate model calculator can be found on https://multistatehcc.shinyapps.io/home/. CONCLUSIONS: In contrast to standard single time-to-event estimates, multistate modeling provides more realistic prognostication of outcomes after LR for HCC by taking into account many postoperative disease states and transitions between them. Our multistate modeling calculator can provide meaningful data to guide the management of patients undergoing postoperative surveillance and therapy.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Adult , Humans , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Retrospective Studies , Neoplasm Recurrence, Local/pathology , Hepatectomy , Prognosis , Risk FactorsABSTRACT
In this review, we present the current evidence and future perspectives on the use of circulating tumour DNA (ctDNA) in the diagnosis, management and understanding the prognosis of patients with intrahepatic cholangiocarcinoma (iCCA) undergoing surgery. Liquid biopsies or ctDNA maybe utilized to: (1) determine the molecular profile of the tumour and therefore guide the selection of molecular targeted therapy in the neoadjuvant setting, (2) form a surveillance tool for the detection of minimal residual disease or cancer recurrence after surgery, and (3) diagnose and screen for early iCCA detection in high-risk populations. The potential for ctDNA can be tumour-informed or -uninformed depending on the goals of its use. Future studies will require ctDNA extraction technique validations, with standardizations of both the platforms and the timing of ctDNA collections.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Circulating Tumor DNA , Humans , Circulating Tumor DNA/genetics , Neoplasm, Residual/diagnosis , Neoplasm, Residual/surgery , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/genetics , Cholangiocarcinoma/diagnosis , Cholangiocarcinoma/genetics , Cholangiocarcinoma/surgery , Bile Duct Neoplasms/diagnosis , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/surgery , Bile Ducts, Intrahepatic , Biomarkers, Tumor/geneticsABSTRACT
INTRODUCTION: Cisplatin and gemcitabine (CisGem) are standard chemotherapy for advanced biliary tract cancer (BTC). The MEK inhibitor selumetinib showed synergy with gemcitabine when administered sequentially in BTC. This randomised Phase 2 trial aimed to assess the efficacy of sequential or continuous selumetinib with CisGem. METHODS: Patients with advanced BTC received CisGem; arm A included selumetinib every day, arm B: selumetinib, days 1-5, 8-19 each cycle. Arm C received CisGem alone. Selumetinib was dosed at 75 mg BID but amended to 50 mg BID due to toxicity. RESULTS: In all, 51 participants were evaluable for response. No significant difference was seen in mean change in tumour size at 10 weeks between arms A and C (-7.8% vs -12.8%, P = 0.54) or arms B and C (-15% vs -12.8%, P = 0.78). There was no difference in median progression-free survival (6.0, 7.0, 6.3 months, P > 0.95) or overall survival (11.7, 11.7, 12.8 months, P = 0.70) for arms A, B and C, respectively. More participants experienced grade 3-4 toxicities in selumetinib-containing arms. More participants in arm A required chemotherapy dose reductions (P = 0.01) with lower chemotherapy dose intensity during the first 10 weeks. CONCLUSION: Adding sequential or continuous selumetinib to CisGem failed to improve efficacy and increased toxicity in patients with advanced BTC.
Subject(s)
Bile Duct Neoplasms , Biliary Tract Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzimidazoles , Bile Duct Neoplasms/drug therapy , Biliary Tract Neoplasms/pathology , Cisplatin , Deoxycytidine/analogs & derivatives , Humans , Mitogen-Activated Protein Kinase Kinases , GemcitabineABSTRACT
BACKGROUND AND AIMS: Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline (g) alterations in BRCA1, BRCA2, and PALB2. METHODS: We interrogated whole genome sequencing (WGS) data on 391 patients, including 49 carriers of pathogenic variants (PVs) in gBRCA and PALB2. HRD classifiers were applied to the dataset and included (1) the genomic instability score (GIS) used by Myriad's MyChoice HRD assay; (2) substitution base signature 3 (SBS3); (3) HRDetect; and (4) structural variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status. RESULTS: Biallelic tumor inactivation of gBRCA or PALB2 was evident in 43 of 49 germline carriers identifying HRD-PDAC. HRDetect (score ≥0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumor classifiers suggested that 7% to 10% of PDACs that do not harbor gBRCA/PALB2 have features of HRD. Of the somatic HRDetecthi cases, 69% were attributed to alterations in BRCA1/2, PALB2, RAD51C/D, and XRCC2, and a tandem duplicator phenotype. TP53 loss was more common in BRCA1- compared with BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC; however in advanced disease the GIS (P = .02), SBS3 (P = .03), and HRDetect score (P = .005) were predictive of platinum response and superior survival. PVs in gATM (n = 6) or gCHEK2 (n = 2) did not result in HRD-PDAC by any of the classifiers. In 4 patients, BRCA2 reversion mutations associated with platinum resistance. CONCLUSIONS: Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7% to 10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.
Subject(s)
Carcinoma, Pancreatic Ductal/genetics , Fanconi Anemia Complementation Group N Protein/genetics , Genes, BRCA1 , Genes, BRCA2 , Pancreatic Neoplasms/genetics , Recombinational DNA Repair , Aged , Alleles , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Pancreatic Ductal/therapy , Cisplatin/administration & dosage , DNA-Binding Proteins/genetics , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Drug Resistance, Neoplasm/genetics , Female , Fluorouracil/therapeutic use , Genomic Instability , Germ-Line Mutation , Homologous Recombination , Humans , Irinotecan/therapeutic use , Leucovorin/therapeutic use , Male , Middle Aged , Oxaliplatin/therapeutic use , Pancreatectomy , Pancreatic Neoplasms/therapy , Prognosis , Sensitivity and Specificity , Survival Rate , Tumor Suppressor Protein p53/genetics , Whole Genome Sequencing , GemcitabineABSTRACT
BACKGROUND: Individuals with a family history of pancreatic adenocarcinoma (PC) or with a germline mutation in a PC susceptibility gene are at increased risk of developing PC. These high-risk individuals (HRIs) may benefit from PC surveillance. METHODS: A PC surveillance program was developed to evaluate the detection of premalignant lesions and early-stage PCs using biannual imaging and to determine whether locally advanced or metastatic PCs develop despite biannual surveillance. From January 2013 to April 2020, asymptomatic HRIs were enrolled and followed with alternating MRI and endoscopic ultrasound every 6 months. RESULTS: Of 75 HRIs, 43 (57.3%) had a germline mutation in a PC susceptibility gene and 32 (42.7%) had a familial pancreatic cancer (FPC) pedigree. Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) were identified in 26 individuals (34.7%), but only 2 developed progressive lesions. One patient with Peutz-Jeghers syndrome (PJS) developed locally advanced PC arising from a BD-IPMN. Whole-genome sequencing of this patient's PC and of a second patient with PJS-associated PC from the same kindred revealed biallelic inactivation of STK11 in a KRAS-independent manner. A review of 3,853 patients from 2 PC registries identified an additional patient with PJS-associated PC. All 3 patients with PJS developed advanced PC consistent with the malignant transformation of an underlying BD-IPMN in <6 months. The other surveillance patient with a progressive lesion had FPC and underwent resection of a mixed-type IPMN that harbored polyclonal KRAS mutations. CONCLUSIONS: PC surveillance identifies a high prevalence of BD-IPMNs in HRIs. Patients with PJS with BD-IPMNs may be at risk for accelerated malignant transformation.
Subject(s)
Adenocarcinoma , Carcinoma, Pancreatic Ductal , Pancreatic Intraductal Neoplasms , Pancreatic Neoplasms , Carcinoma , Carcinoma, Pancreatic Ductal/pathology , Humans , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/epidemiology , Pancreatic Neoplasms/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Syndrome , Pancreatic NeoplasmsABSTRACT
OBJECTIVES: Transcriptional classifiers (Bailey, Moffitt and Collison) are key prognostic factors of pancreatic ductal adenocarcinoma (PDAC). Among these classifiers, the squamous, basal-like, and quasimesenchymal subtypes overlap and have inferior survival. Currently, only an invasive biopsy can determine these subtypes, possibly resulting in treatment delay. This study aimed to investigate the association between transcriptional subtypes and an externally validated preoperative CT-based radiomic prognostic score (Rad-score). METHODS: We retrospectively evaluated 122 patients who underwent resection for PDAC. All treatment decisions were determined at multidisciplinary tumor boards. Tumor Rad-score values from preoperative CT were dichotomized into high or llow categories. The primary endpoint was the correlation between the transcriptional subtypes and the Rad-score using multivariable linear regression, adjusting for clinical and histopathological variables (i.e., tumor size). Prediction of overall survival (OS) was secondary endpoint. RESULTS: The Bailey transcriptional classifier significantly associated with the Rad-score (coefficient = 0.31, 95% confidence interval [CI]: 0.13-0.44, p = 0.001). Squamous subtype was associated with high Rad-scores while non-squamous subtype was associated with low Rad-scores (adjusted p = 0.03). Squamous subtype and high Rad-score were both prognostic for OS at multivariable analysis with hazard ratios (HR) of 2.79 (95% CI: 1.12-6.92, p = 0.03) and 4.03 (95% CI: 1.42-11.39, p = 0.01), respectively. CONCLUSIONS: In patients with resectable PDAC, an externally validated prognostic radiomic model derived from preoperative CT is associated with the Bailey transcriptional classifier. Higher Rad-scores were correlated with the squamous subtype, while lower Rad-scores were associated with the less lethal subtypes (immunogenic, ADEX, pancreatic progenitor). KEY POINTS: ⢠The transcriptional subtypes of PDAC have been shown to have prognostic importance but they require invasive biopsy to be assessed. ⢠The Rad-score radiomic biomarker, which is obtained non-invasively from preoperative CT, correlates with the Bailey squamous transcriptional subtype and both are negative prognostic biomarkers. ⢠The Rad-score is a promising non-invasive imaging biomarker for personalizing neoadjuvant approaches in patients undergoing resection for PDAC, although additional validation studies are required.
Subject(s)
Adenocarcinoma , Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Carcinoma, Pancreatic Ductal/diagnostic imaging , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/surgery , Humans , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/surgery , Prognosis , Retrospective Studies , Tomography, X-Ray Computed/methods , Pancreatic NeoplasmsABSTRACT
OBJECTIVES: Skeletal muscle mass is a prognostic factor in pancreatic ductal adenocarcinoma (PDAC). However, it remains unclear whether changes in body composition provide an incremental prognostic value to established risk factors, especially the Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1). The aim of this study was to determine the prognostic value of CT-quantified body composition changes in patients with unresectable PDAC starting chemotherapy. METHODS: We retrospectively evaluated 105 patients with unresectable (locally advanced or metastatic) PDAC treated with FOLFIRINOX (n = 64) or gemcitabine-based (n = 41) first-line chemotherapy within a multicenter prospective trial. Changes (Δ) in skeletal muscle index (SMI), subcutaneous (SATI), and visceral adipose tissue index (VATI) between pre-chemotherapy and first follow-up CT were assessed. Cox regression models and covariate-adjusted survival curves were used to identify predictors of overall survival (OS). RESULTS: At multivariable analysis, adjusting for RECISTv1.1-response at first follow-up, ΔSMI was prognostic for OS with a hazard ratio (HR) of 1.2 (95% CI: 1.08-1.33, p = 0.001). No significant association with OS was observed for ΔSATI (HR: 1, 95% CI: 0.97-1.04, p = 0.88) and ΔVATI (HR: 1.01, 95% CI: 0.99-1.04, p = 0.33). At an optimal cutoff of 2.8 cm2/m2 per 30 days, the median survival of patients with high versus low ΔSMI was 143 versus 233 days (p < 0.001). CONCLUSIONS: Patients with a lower rate of skeletal muscle loss at first follow-up demonstrated improved survival for unresectable PDAC, regardless of their RECISTv1.1-category. Assessing ΔSMI at the first follow-up CT may be useful for prognostication, in addition to routine radiological assessment. KEY POINTS: ⢠In patients with unresectable pancreatic ductal adenocarcinoma, change of skeletal muscle index (ΔSMI) in the early phase of chemotherapy is prognostic for overall survival, even after adjusting for Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1) assessment at first follow-up. ⢠Changes in adipose tissue compartments at first follow-up demonstrated no significant association with overall survival. ⢠Integrating ΔSMI into routine radiological assessment may improve prognostic stratification and impact treatment decision-making at the first follow-up.
Subject(s)
Pancreatic Neoplasms , Sarcopenia , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Body Composition , Humans , Muscle, Skeletal/diagnostic imaging , Muscle, Skeletal/pathology , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Prognosis , Prospective Studies , Retrospective Studies , Sarcopenia/pathology , Tomography, X-Ray ComputedABSTRACT
PURPOSE: Small cell lung cancer (SCLC) is a highly fatal disease associated with significant morbidity, with a need for real-world symptom and health utility score (HUS) data. HUS can be measured using an EQ-5D-5L questionnaire, however most captured data is available in non-SCLC (NSCLC) only. As new treatment regimens become available in SCLC it becomes important to understand factors which influence health-related quality of life and health utility. METHODS: A prospective observational cohort study (2012-2017) of ambulatory histologically confirmed SCLC evaluated patient-reported EQ-5D-5L-derived HUS, toxicity and symptoms. A set of NSCLC patients was used to compare differential factors affecting HUS. Clinical and demographic factors were evaluated for differential interactions between lung cancer types. Comorbidity scores were documented for each patient. RESULTS: In 75 SCLC and 150 NSCLC patients, those with SCLC had lower mean HUS ((SCLC vs NSCLC: mean 0.69 vs 0.79); (p < 0.001)) when clinically stable and with progressive disease: ((SCLC mean HUS = 0.60 vs NSCLC mean HUS = 0.77), (p = 0.04)). SCLC patients also had higher comorbidity scores ((1.11 vs 0.73); (p < 0.015)). In multivariable analyses, increased symptom severity and comorbidity scores decreased HUS in both SCLC and NSCLC (p < 0.001); however, only comorbidity scores differentially affected HUS (p < 0.0001), with a greater reduction of HUS adjusted per unit of comorbidity in SCLC. CONCLUSION: Patients with advanced SCLC had significantly lower HUS than NSCLC. Both patient cohorts are impacted by symptoms and comorbidity, however, comorbidity had a greater negative effect in SCLC patients.
Subject(s)
Lung Neoplasms/psychology , Quality of Life/psychology , Small Cell Lung Carcinoma/psychology , Adult , Aged , Aged, 80 and over , Cohort Studies , Comorbidity , Data Analysis , Female , Humans , Male , Middle Aged , Prospective Studies , Young AdultABSTRACT
BACKGROUND: Radiomic features in pancreatic ductal adenocarcinoma (PDAC) often lack validation in independent test sets or are limited to early or late stage disease. Given the lethal nature of PDAC it is possible that there are similarities in radiomic features of both early and advanced disease reflective of aggressive biology. PURPOSE: To assess the performance of prognostic radiomic features previously published in patients with resectable PDAC in a test set of patients with unresectable PDAC undergoing chemotherapy. METHODS: The pre-treatment CT of 108 patients enrolled in a prospective chemotherapy trial were used as a test cohort for 2 previously published prognostic radiomic features in resectable PDAC (Sum Entropy and Cluster Tendency with square-root filter[Sqrt]). We assessed the performance of these 2 radiomic features for the prediction of overall survival (OS) and time to progression (TTP) using Cox proportional-hazard models. RESULTS: Sqrt Cluster Tendency was significantly associated with outcome with a hazard ratio (HR) of 1.27(for primary pancreatic tumor plus local nodes), (Confidence Interval(CI):1.01 -1.6, P-value = 0.039) for OS and a HR of 1.25(CI:1.00 -1.55, P-value = 0.047) for TTP. Sum entropy was not associated with outcomes. Sqrt Cluster Tendency remained significant in multivariate analysis. CONCLUSION: The CT radiomic feature Sqrt Cluster Tendency, previously demonstrated to be prognostic in resectable PDAC, remained a significant prognostic factor for OS and TTP in a test set of unresectable PDAC patients. This radiomic feature warrants further investigation to understand its biologic correlates and CT applicability in PDAC patients.
Subject(s)
Adenocarcinoma/diagnostic imaging , Adenocarcinoma/drug therapy , Carcinoma, Pancreatic Ductal/diagnostic imaging , Carcinoma, Pancreatic Ductal/drug therapy , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/drug therapy , Tomography, X-Ray Computed/methods , Aged , Cohort Studies , Female , Humans , Male , Middle Aged , Pancreas/diagnostic imaging , Prognosis , Reproducibility of Results , Retrospective StudiesABSTRACT
BACKGROUND: Pheochromocytoma (PCC) and paraganglioma (PGL) are uncommon neoplasms with high morbidity in advanced stages. Effective systemic treatments are limited. METHODS: A multisite phase 2 trial evaluated sunitinib in patients with progressive PCC/PGL. Patients received 50 mg orally for 4-6 weeks. RESULTS: Between May 2009 and May 2016, 25 patients were enroled. The median age was 50 years and 56% were male. Three patients (12%) received prior chemotherapy and 16 (64%) prior surgery. The DCR was 83% (95% CI: 61-95%) and median PFS 13.4 (95% CI: 5.3-24.6) months. Of 23 evaluable patients, 3 (13%) with germline mutations (SDHA, SDHB, RET) achieved a PR. The patient with mutated RET and MEN2A remains on treatment after 64 cycles. The median time on treatment was 12.4 (1-88.0) months. Grade 3 or 4 toxicities were as expected and manageable; fatigue (16%) and thrombocytopenia (16%) were most common. One patient with grade 3 hypertension and 2 with grade 3 cardiac events discontinued treatment. CONCLUSION: Although the primary endpoint of disease control was met, the overall response rate of sunitinib was low in unselected patients with progressive PCC/PGL. Patients with germline variants in RET or in the subunits of SDH may derive greatest benefit.
Subject(s)
Adrenal Gland Neoplasms/drug therapy , Paraganglioma/drug therapy , Pheochromocytoma/drug therapy , Sunitinib/therapeutic use , Adrenal Gland Neoplasms/pathology , Antineoplastic Agents/therapeutic use , Disease Progression , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Paraganglioma/pathology , Pheochromocytoma/pathology , Protein Kinase Inhibitors/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND: In lung cancer, brain metastases (BM) and their treatment are associated with high economic burden and inferior health-related quality of life. In the era of targeted therapy, real world evidence through health utility scores (HUS) is critical for economic analyses. MATERIALS AND METHODS: In a prospective observational cohort study (2014-2016), outpatients with stage IV lung cancer completed demographic and EQ-5D-3L surveys (to derive HUS). Health states and clinicopathologic variables were obtained from chart abstraction. Patients were categorized by the presence or absence of BM; regression analyses identified factors that were associated with HUS. A subset of patients prospectively completed neurocognitive function (NCF) tests and/or the FACT-brain (FACT-Br) questionnaire, which were then correlated with HUS (Spearman coefficients; regression analyses). RESULTS: Of 519 patients with 1,686 EQ-5D-3L-derived HUS, 94 (18%) completed NCF tests and 107 (21%) completed FACT-Br; 301 (58%) never developed BM, 24 (5%) developed first BM during study period, and 194 (37%) had BM at study entry. The sample was enriched (46%) for EGFR mutations (EGFRm) and ALK-rearrangements (ALKr). There were no HUS differences by BM status overall and in subsets by demographics. In multivariable analyses, superior HUS was associated with having EGFRm/ALKr (p < .0001), no prior radiation for extracranial disease (p < .001), and both intracranial (p = .002) and extracranial disease control (p < .01). HUS correlated with multiple elements of the FACT-Br and tests of NCF. CONCLUSION: Having BM in lung cancer is not associated with inferior HUS in a population enriched for EGFRm and ALKr. Patients exhibiting disease control and those with oncogene-addicted tumors have superior HUS. IMPLICATIONS FOR PRACTICE: In the setting of EGFR mutations or ALK rearrangement non-small cell lung cancer (NSCLC), a diagnosis of brain metastases no longer consigns the patient to an inferior health state suggesting that new economic analyses in NSCLC are needed in the era of targeted therapies. Additionally, the EQ-5D questionnaire is associated with measures of health-related quality of life and neurocognitive scores suggesting this tool should be further explored in prospective clinical studies.
Subject(s)
Brain Neoplasms/secondary , Carcinoma, Non-Small-Cell Lung/complications , Lung Neoplasms/complications , Neurocognitive Disorders/etiology , Quality of Life/psychology , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/pathology , ErbB Receptors/genetics , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Metastasis , Prospective StudiesABSTRACT
Purpose To assess the incidence of lung cancer in a cohort of patients with negative findings at previous lung cancer screening. Materials and Methods In this prospective cohort study, the authors first identified 4782 individuals who had negative screening results as part of the International Early Lung Cancer Action Program (1993-2005). Subjects were assigned a lung cancer risk score by using a validated risk model. Starting with those at highest risk, subjects were interviewed by phone and invited to undergo low-dose CT between March 2013 and October 2016. Subjects with a diagnosis of lung cancer and those who had died of lung cancer were determined. Descriptive statistics were used to summarize data. The independent samples t test and Fisher exact test were used to compare age, sex, and risk scores. Results A total of 327 study participants were contacted, and 200 subjects participated in this study. The average age was 74 years (range, 57-88 years), and the median time since previous CT was 7 years. The incidence rate of developing lung cancer during the next 6 years was estimated at 5.6%. The period prevalence of lung cancer was 20.8% (new and preexisting lung cancer, 68 of total cohort of 327). The detection rate of low-dose CT was 7% (14 of 200 subjects). Of the 14 screening-detected cancers, 12 were stage I or II. Conclusion High-risk individuals have a high incidence of lung cancer after previous negative lung cancer screening. Early-stage lung cancer can be successfully detected in older high-risk individuals. © RSNA, 2018 Online supplemental material is available for this article.