ABSTRACT
BACKGROUND: Alterations in fibroblast growth factor receptor 2 (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors. METHODS: In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes. RESULTS: Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment. CONCLUSIONS: In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).
Subject(s)
Antineoplastic Agents , Bile Duct Neoplasms , Bile Ducts, Intrahepatic , Cholangiocarcinoma , Protein Kinase Inhibitors , Receptor, Fibroblast Growth Factor, Type 2 , Aged , Humans , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/metabolism , Bile Ducts, Intrahepatic/metabolism , Bile Ducts, Intrahepatic/pathology , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/genetics , Cholangiocarcinoma/metabolism , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Quality of Life , Receptor, Fibroblast Growth Factor, Type 2/genetics , Receptor, Fibroblast Growth Factor, Type 2/metabolism , Antineoplastic Agents/administration & dosageABSTRACT
The gastropod mollusk Aplysia is an important model for cellular and molecular neurobiological studies, particularly for investigations of molecular mechanisms of learning and memory. We developed an optimized assembly pipeline to generate an improved Aplysia nervous system transcriptome. This improved transcriptome enabled us to explore the evolution of cognitive capacity at the molecular level. Were there evolutionary expansions of neuronal genes between this relatively simple gastropod Aplysia (20,000 neurons) and Octopus (500 million neurons), the invertebrate with the most elaborate neuronal circuitry and greatest behavioral complexity? Are the tremendous advances in cognitive power in vertebrates explained by expansion of the synaptic proteome that resulted from multiple rounds of whole genome duplication in this clade? Overall, the complement of genes linked to neuronal function is similar between Octopus and Aplysia. As expected, a number of synaptic scaffold proteins have more isoforms in humans than in Aplysia or Octopus. However, several scaffold families present in mollusks and other protostomes are absent in vertebrates, including the Fifes, Lev10s, SOLs, and a NETO family. Thus, whereas vertebrates have more scaffold isoforms from select families, invertebrates have additional scaffold protein families not found in vertebrates. This analysis provides insights into the evolution of the synaptic proteome. Both synaptic proteins and synaptic plasticity evolved gradually, yet the last deuterostome-protostome common ancestor already possessed an elaborate suite of genes associated with synaptic function, and critical for synaptic plasticity.
Subject(s)
Aplysia , Biological Evolution , Cognition , Synapses , Animals , Aplysia/genetics , Aplysia/metabolism , Neuronal Plasticity/genetics , Neurons/metabolism , Protein Isoforms/genetics , Proteome , Synapses/metabolism , TranscriptomeABSTRACT
WHAT IS THIS SUMMARY ABOUT?: This summary describes the results from a phase 2 study called FOENIXCCA2. The study evaluated treatment with futibatinib in people with a rare form of advanced bile duct cancer called intrahepatic cholangiocarcinoma (or iCCA), where the tumors have changes in the structure of a gene called FGFR2. These changes include FGFR2 gene fusions. Bile duct cancer often returns after surgery or cannot be treated by surgery because the tumor has spread, so it requires treatment with chemotherapy. People live for a median of 1 year after their first chemotherapy treatment and 6 months after their second treatment. This study included people whose cancer had grown/spread after one or more chemotherapy treatments. The aims of the study were to see if futibatinib could shrink the size of tumors and stop the cancer from growing/spreading and to see how long people lived when treated with futibatinib. Clinicians also looked at side effects from taking futibatinib and at how it affected people's quality of life. WHAT WERE THE RESULTS?: Futibatinib treatment shrank tumors in over 80% of people who received treatment. Tumors shrank by at least 30% in 42% of people. Futibatinib stopped tumors from growing/spreading for a median of 9.7 months. People who took the medicine lived for a median of 21.7 months, and 72% of people were still alive after 1 year. Side effects from taking futibatinib were like those reported for similar medicines, and clinicians considered the side effects to be manageable by adjusting the dose of futibatinib or treating the side effects. Most people reported that their quality of life stayed the same or improved during the first 9 months of taking futibatinib. WHAT DO THE RESULTS MEAN?: The results support the use of futibatinib for treating people with advanced bile duct cancer. Based on the results of this study, futibatinib is now approved in the US, Europe, and Japan. Futibatinib is approved for treating adults with advanced bile duct cancer who have received previous treatment for their cancer, and whose tumors have a gene fusion or other change in the FGFR2 gene.Clinical Trial Registration: NCT02052778 (FOENIX-CCA2).
ABSTRACT
BACKGROUND: In preclinical pancreatic ductal adenocarcinoma (PDAC) models, inhibition of hepatocyte growth factor (HGF) signaling using ficlatuzumab, a recombinant humanized anti-HGF antibody, and gemcitabine reduced tumor burden. METHODS: Patients with previously untreated metastatic PDAC enrolled in a phase Ib dose escalation study with 3 + 3 design of 2 dose cohorts of ficlatuzumab 10 and 20 mg/kg administered intravenously every other week with gemcitabine 1000 mg/m2 and albumin-bound paclitaxel 125 mg/m2 given 3 weeks on and 1 week off. This was followed by an expansion phase at the maximally tolerated dose of the combination. RESULTS: Twenty-six patients (sex, 12 male:14 female; median age, 68 years [range, 49-83 years]) were enrolled, 22 patients were evaluable. No dose-limiting toxicities were identified (N = 7 pts) and ficlatuzumab at 20 mg/kg was chosen as the maximum tolerated dose. Among the 21 patients treated at the MTD, best response by RECISTv1.1: 6 (29%) partial response, 12 (57%) stable disease, 1 (5%) progressive disease, and 2 (9%) not evaluable. Median progression-free survival and overall survival times were 11.0 months (95% CI, 7.6-11.4 months) and 16.2 months (95% CI, 9.1 months to not reached), respectively. Toxicities attributed to ficlatuzumab included hypoalbuminemia (grade 3, 16%; any grade, 52%) and edema (grade 3, 8%; any grade, 48%). Immunohistochemistry for c-Met pathway activation demonstrated higher tumor cell p-Met levels in patients who experienced response to therapy. CONCLUSION: In this phase Ib trial, ficlatuzumab, gemcitabine, and albumin-bound paclitaxel were associated with durable treatment responses and increased rates of hypoalbuminemia and edema.
Subject(s)
Hypoalbuminemia , Pancreatic Neoplasms , Humans , Male , Female , Aged , Gemcitabine , Albumin-Bound Paclitaxel , Hypoalbuminemia/chemically induced , Paclitaxel/adverse effects , Pancreatic Neoplasms/pathology , Albumins/adverse effects , Edema/etiology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Pancreatic NeoplasmsABSTRACT
In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.
Subject(s)
Bile Duct Neoplasms , Biliary Tract Neoplasms , Cholangiocarcinoma , Gallbladder Neoplasms , Liver Neoplasms , Humans , Biliary Tract Neoplasms/diagnosis , Biliary Tract Neoplasms/therapy , Gallbladder Neoplasms/diagnosis , Gallbladder Neoplasms/therapy , Cholangiocarcinoma/diagnosis , Cholangiocarcinoma/therapy , Liver Neoplasms/diagnosis , Liver Neoplasms/therapy , Bile Ducts, IntrahepaticABSTRACT
BACKGROUND: Gallstones may result in inflammation, altered bile flow, and changes in metabolic hormone levels, thereby increasing cancer risk. However, previous studies for gallstones and cancers of the liver, biliary tract and pancreas in the U.S. were relatively limited. METHODS: We followed 115,036 women from the Nurses' Health Study (1982-2012) and 49,729 men from the Health Professionals Follow-up Study (1986-2012). History of gallstones, including with or without performed cholecystectomy, was reported at baseline and updated through biennial questionnaires. The Cox proportional hazard regression model was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS: During up to 30-year follow-up, we identified 204 incidents of liver cancer, 225 biliary tract cancer and 1147 pancreatic cancer cases. Compared to those without gallstones diagnosis, the multivariable HRs for individuals with gallstones (untreated or with cholecystectomy) were 1.60 for liver cancer (95% CI: 1.14-2.26), 4.79 for biliary tract cancer (95% CI: 3.02-7.58), and 1.13 for pancreatic cancer (95% CI: 0.96-1.32). The multivariable HRs for individuals with cholecystectomy were 1.33 for liver cancer (95% CI: 0.90-1.95) and 1.15 for pancreatic cancer (95% CI: 0.98-1.36). CONCLUSIONS: Gallstones were associated with a higher risk of cancers of the liver, biliary tract and possibly pancreas.
Subject(s)
Biliary Tract Neoplasms , Biliary Tract , Gallstones , Liver Neoplasms , Pancreatic Neoplasms , Biliary Tract Neoplasms/epidemiology , Female , Follow-Up Studies , Gallstones/complications , Gallstones/epidemiology , Humans , Male , Pancreas , Pancreatic Neoplasms/epidemiology , Prospective Studies , Risk Factors , Pancreatic NeoplasmsABSTRACT
Durvalumab, a PD-L1 inhibitor, is part of an immunotherapeutic drug class shown to have prolonged survival benefit in patients with advanced stage hepatocellular carcinoma (HCC). Tivozanib is a potent and selective VEGFR 1, 2 and 3 tyrosine kinase inhibitor. While these medications have both demonstrated single-agent activity in HCC and have been combined safely with other therapies, there is no data on their concurrent therapeutic effects. In the phase Ib DEDUCTIVE trial, the combination of tivozanib plus durvalumab is evaluated for safety and tolerability. Here, the design of and rationale for this trial in both treatment naive patients and those who progress on atezolizumab and bevacizumab for advanced or metastatic HCC are described. Clinical Trial Registration: NCT03970616.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/etiology , Liver Neoplasms/drug therapy , Liver Neoplasms/etiology , Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Multicenter Studies as Topic , Clinical Trials, Phase I as TopicABSTRACT
BACKGROUND: Preclinical studies have shown that modulation of the tumor microvasculature with anti-angiogenic agents decreases tumor perfusion and may increase the efficacy of radiofrequency ablation (RFA) in hepatocellular carcinoma (HCC). Retrospective studies suggest that sorafenib given prior to RFA promotes an increase in the ablation zone, but prospective randomized data are lacking. AIMS: We conducted a randomized, double-blind, placebo-controlled phase II trial to evaluate the efficacy of a short-course of sorafenib prior to RFA for HCC tumors sized 3.5-7 cm (NCT00813293). METHODS: Treatment consisted of sorafenib 400 mg twice daily for 10 days or matching placebo, followed by RFA on day 10. The primary objectives were to assess if priming with sorafenib increased the volume and diameter of the RFA coagulation zone and to evaluate its impact on RFA thermal parameters. Secondary objectives included feasibility, safety and to explore the relationship between tumor blood flow on MRI and RFA effectiveness. RESULTS: Twenty patients were randomized 1:1. Priming with sorafenib did not increase the size of ablation zone achieved with RFA and did not promote significant changes in thermal parameters, although it significantly decreased blood perfusion to the tumor by 27.9% (p = 0.01) as analyzed by DCE-MRI. No subject discontinued treatment owing to adverse events and no grade 4 toxicity was observed. CONCLUSION: Priming of sorafenib did not enhance the effect of RFA in intermediate sized HCC. Future studies should investigate whether longer duration of treatment or a different antiangiogenic strategy in the post-procedure setting would be more effective in impairing tumor perfusion and increasing RFA efficacy.
Subject(s)
Carcinoma, Hepatocellular , Catheter Ablation , Liver Neoplasms , Radiofrequency Ablation , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/surgery , Catheter Ablation/adverse effects , Catheter Ablation/methods , Humans , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/drug therapy , Liver Neoplasms/surgery , Niacinamide/adverse effects , Phenylurea Compounds/adverse effects , Prospective Studies , Radiofrequency Ablation/adverse effects , Radiofrequency Ablation/methods , Retrospective Studies , Sorafenib/therapeutic use , Treatment OutcomeABSTRACT
Subsets of esophagogastric (EG) cancers harbor genetic abnormalities, including amplification of HER2, MET, or FGFR2 or mutations in PIK3CA, EGFR, or BRAF. Ganetespib which is a novel triazolone heterocyclic inhibitor of HSP90, is a potentially biologically rational treatment strategy for advanced EG cancers with these gene amplification. This multicenter, single-arm phase 2 trial enrolled patients with histologically confirmed advanced EG cancer with progression on at least one line of systemic therapy. Patients received Ganetespib 200 mg/m2 IV on Days 1, 8, and 15 of a 28-day cycle. The primary endpoint was overall response rate (ORR). Secondary endpoints included: Progression Free Survival (PFS); to correlate the presence of HSP clients with ORR and PFS; evaluating the safety, tolerability and adverse events profile. In this study 26 eligible patients mainly: male 77%, median age 64 years were enrolled. The most common drug-related adverse events were diarrhea (77%), fatigue (65%), elevated ALKP (42%), and elevated AST (38%). The most common grade 3/4 AEs included: leucopenia (12%), fatigue (12%), diarrhea (8%), and elevated ALKP (8%). The ORR of 4% reflects the single patient of 26 who had a complete response and stayed on treatment for more than seventy (70) months. Median PFS and OS was 61 days (2.0 months), 94 days (3.1 months) respectively. Ganetespib showed manageable toxicity. While the study was terminated early due to insufficient evidence of single-agent activity, the durable CR and 2 minor responses suggest that there may be a subset of EG patients who could benefit from this drug.
Subject(s)
Antineoplastic Agents/therapeutic use , Esophageal Neoplasms/drug therapy , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Stomach Neoplasms/drug therapy , Triazoles/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Drug Resistance, Neoplasm , Esophageal Neoplasms/mortality , Female , Humans , Male , Middle Aged , Stomach Neoplasms/mortality , Treatment Outcome , Triazoles/adverse effectsABSTRACT
BACKGROUND: Antiangiogenic therapy is a proven therapeutic modality for refractory gastric and gastroesophageal junction adenocarcinoma. This trial assessed whether the addition of a high affinity angiogenesis inhibitor, ziv-aflibercept, could improve the efficacy of first-line mFOLFOX6 (oxaliplatin, leucovorin, and bolus plus infusional 5- fluorouracil) in metastatic esophagogastric adenocarcinoma. METHODS: Patients with treatment-naive metastatic esophagogastric adenocarcinoma were randomly assigned (in a 2:1 ratio) in a multicenter, placebo-controlled, double-blind trial to receive first-line mFOLFOX6 with or without ziv-aflibercept (4 mg/kg) every 2 weeks. The primary endpoint was 6-month progression-free survival (PFS). RESULTS: Sixty-four patients were randomized to receive mFOLFOX6 and ziv-aflibercept (43 patients) or mFOLFOX6 and a placebo (21 patients). There was no difference in the PFS, overall survival, or response rate. Patients treated with mFOLFOX6/ziv-aflibercept tended to be more likely to discontinue study treatment for reasons other than progressive disease (P = .06). The relative dose intensity of oxaliplatin and 5-fluorouracil was lower in the mFOLFOX6/ziv-aflibercept arm during the first 12 and 24 weeks of the trial. There were 2 treatment-related deaths due to cerebral hemorrhage and bowel perforation in the mFOLFOX6/ziv-aflibercept cohort. CONCLUSIONS: Ziv-aflibercept did not increase the anti-tumor activity of first-line mFOLFOX6 in metastatic esophagogastric cancer, potentially because of decreased dose intensity of FOLFOX. Further evaluation of ziv-aflibercept in unselected, chemotherapy-naive patients with metastatic esophagogastric adenocarcinoma is not warranted.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Esophageal Neoplasms/drug therapy , Esophagogastric Junction/drug effects , Stomach Neoplasms/drug therapy , Adenocarcinoma/secondary , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Double-Blind Method , Esophageal Neoplasms/pathology , Esophagogastric Junction/pathology , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Leucovorin/administration & dosage , Lymphatic Metastasis , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Prognosis , Stomach Neoplasms/pathology , Survival RateABSTRACT
The NCCN Guidelines for Hepatobiliary Cancers provide treatment recommendations for cancers of the liver, gallbladder, and bile ducts. The NCCN Hepatobiliary Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's discussion and updated recommendations regarding systemic therapy for first-line and subsequent-line treatment of patients with hepatocellular carcinoma.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , HumansABSTRACT
Importance: In observational studies, higher plasma 25-hydroxyvitamin D (25[OH]D) levels have been associated with improved survival in metastatic colorectal cancer (CRC). Objective: To determine if high-dose vitamin D3 added to standard chemotherapy improves outcomes in patients with metastatic CRC. Design, Setting, and Participants: Double-blind phase 2 randomized clinical trial of 139 patients with advanced or metastatic CRC conducted at 11 US academic and community cancer centers from March 2012 through November 2016 (database lock: September 2018). Interventions: mFOLFOX6 plus bevacizumab chemotherapy every 2 weeks and either high-dose vitamin D3 (n = 69) or standard-dose vitamin D3 (n = 70) daily until disease progression, intolerable toxicity, or withdrawal of consent. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) assessed by the log-rank test and a supportive Cox proportional hazards model. Testing was 1-sided. Secondary end points included tumor objective response rate (ORR), overall survival (OS), and change in plasma 25(OH)D level. Results: Among 139 patients (mean age, 56 years; 60 [43%] women) who completed or discontinued chemotherapy and vitamin D3 (median follow-up, 22.9 months), the median PFS for high-dose vitamin D3 was 13.0 months (95% CI, 10.1 to 14.7; 49 PFS events) vs 11.0 months (95% CI, 9.5 to 14.0; 62 PFS events) for standard-dose vitamin D3 (log-rank P = .07); multivariable hazard ratio for PFS or death was 0.64 (1-sided 95% CI, 0 to 0.90; P = .02). There were no significant differences between high-dose and standard-dose vitamin D3 for tumor ORR (58% vs 63%, respectively; difference, -5% [95% CI, -20% to 100%], P = .27) or OS (median, 24.3 months vs 24.3 months; log-rank P = .43). The median 25(OH)D level at baseline for high-dose vitamin D3 was 16.1 ng/mL vs 18.7 ng/mL for standard-dose vitamin D3 (difference, -2.6 ng/mL [95% CI, -6.6 to 1.4], P = .30); at first restaging, 32.0 ng/mL vs 18.7 ng/mL (difference, 12.8 ng/mL [95% CI, 9.0 to 16.6], P < .001); at second restaging, 35.2 ng/mL vs 18.5 ng/mL (difference, 16.7 ng/mL [95% CI, 10.9 to 22.5], P < .001); and at treatment discontinuation, 34.8 ng/mL vs 18.7 ng/mL (difference, 16.2 ng/mL [95% CI, 9.9 to 22.4], P < .001). The most common grade 3 and higher adverse events for chemotherapy plus high-dose vs standard-dose vitamin D3 were neutropenia (n = 24 [35%] vs n = 21 [31%], respectively) and hypertension (n = 9 [13%] vs n = 11 [16%]). Conclusions and Relevance: Among patients with metastatic CRC, addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy resulted in a difference in median PFS that was not statistically significant, but with a significantly improved supportive hazard ratio. These findings warrant further evaluation in a larger multicenter randomized clinical trial. Trial Registration: ClinicalTrials.gov Identifier: NCT01516216.
Subject(s)
Adenocarcinoma/drug therapy , Cholecalciferol/administration & dosage , Colorectal Neoplasms/drug therapy , Dietary Supplements , Progression-Free Survival , Vitamins/administration & dosage , Adenocarcinoma/mortality , Adenocarcinoma/secondary , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cholecalciferol/adverse effects , Colorectal Neoplasms/mortality , Colorectal Neoplasms/secondary , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Male , Middle Aged , Multivariate Analysis , Neoplasm Staging , Proportional Hazards Models , Vitamin D/analogs & derivatives , Vitamin D/blood , Vitamins/adverse effectsABSTRACT
Clinicians' positive demeanor and "strengths based" focus can include working to create a cheerful atmosphere in health care environments, cheering for improvements in assessment outcomes, and cheering up clients in situations of decline. Drawing from philosopher Karen Barad's theories of inclusions and exclusions, we investigated what comes to matter (and what is excluded from mattering) when there is cheerfulness, cheering, and so forth (cheer*) in the day-to-day practices of a neuromuscular clinic. We worked collaboratively with clinicians, young people with Duchenne muscular dystrophy, and their families to co-examine the clinic in three iterative exploratory method spaces: (a) group "dialogues" with clinicians; (b) consultative interviews with children, families, and clinicians; and (c) transdisciplinary research team analysis sessions. Cheer* made some things matter in the clinic ("normal" physical function, "positive" emotions, test scores, compliance); and excluded others (grief and loss, "non-normative" bodies and lives, alternative practices, embodied knowledge). We discuss implications across health care settings.
Subject(s)
Attitude of Health Personnel , Emotions , Muscular Dystrophy, Duchenne/psychology , Muscular Dystrophy, Duchenne/therapy , Canada , Humans , Interviews as Topic , Patient ComplianceABSTRACT
BACKGROUND: Patients with metastatic gastric cancer have a poor prognosis (5-year survival of less than 10%). This study was designed to describe the treatment patterns of patients with gastric cancer and to understand the factors associated with treatment choices to inform evidence-based care. METHODS: A retrospective observational study was conducted using two real-world databases to describe treatment trends and to quantify variability in treatment patterns of patients diagnosed with advanced/metastatic gastric cancer between 1/1/2007 and 9/30/2014 in the U.S. Heterogeneity was measured by the Herfindahl-Hirschman Index (HHI). Predictors (baseline clinical, treatment, and demographic variables) of treatment regimen choice were evaluated using logistic regression. RESULTS: A total of 5772 patients with advanced/metastatic gastric cancer were included in this study [5044 from claims data and 728 from electronic medical records (EMR)]. Of the 5044 from claims data, 2457 had evidence of metastatic disease at diagnosis. Only the fluorouracil + oxaliplatin regimen exceeded 10% utilization in the first-line setting [claims metastatic (12.1%), claims advanced (8.2%), and EMR metastatic (16.6%) cohorts]. The HHI demonstrated extreme heterogeneity (0.14 for first-line therapy and 0.13 for second-line therapy). Patient age and geographic region of residence were significantly associated with treatment choice across all three cohorts in the first-line setting (p < 0.05). CONCLUSION: Treatment of patients with gastric cancer was highly variable. Despite the availability of treatment guidelines, there is a lack of consistent treatment patterns. There is a need to improve evidence-based care for patients with gastric cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Aged , Databases, Factual , Electronic Health Records , Female , Fluorouracil/administration & dosage , Humans , Male , Middle Aged , Oxaliplatin/administration & dosage , Retrospective Studies , United StatesABSTRACT
For those with chronic, progressive conditions, high quality clinical care requires attention to the human dimensions of illness-emotional, social, and moral aspects-which co-exist with biophysical dimensions of disease. Reflexivity brings historical, institutional, and socio-cultural influences on clinical activities to the fore, enabling consideration of new possibilities. Continuing education methodologies that encourage reflexivity may improve clinical practice and trainee learning, but are rare. We piloted a dialogical methodology with a children's rehabilitation team to foster reflexivity (patient population: young people with Duchenne's or Becker's muscular dystrophy). The methodology involved three facilitated, interactive dialogues with the clinical team. Each dialogue involved clinicians learning to apply a social theory (Mol's The Logic of Care) to ethnographic fieldnotes of clinical appointments, to make routine practice less familiar and thus open to examination. Discourse analyses that preserve group dynamics were completed to evaluate the extent to which the dialogues spurred reflexive dialogue within the team. Overall, imagining impacts of clinical care on people's lives-emphasized in the social theory applied to fieldnotes-showed promise, shifting how clinicians interpreted routine practices and spurring many plans for change. However, this reflexive orientation was not sustained throughout, particularly when examining entrenched assumptions regarding 'best practices'. Clinicians defended institutional practices by co-constructing the metaphor of balancing logics in care delivery. When invoked, the balance metaphor deflected attention from emotional, social, and moral impacts of clinical care on patients and their families. Emergent findings highlight the value of analysing reflexivity-oriented dialogues using discourse analysis methods.
Subject(s)
Health Personnel/psychology , Muscular Dystrophy, Duchenne/rehabilitation , Patient Care Team/organization & administration , Quality of Life , Social Theory , Staff Development/organization & administration , Anthropology, Cultural , Child , Chronic Disease , Emotions , Humans , Learning , Male , Patient Safety , Quality of Health Care , TrustABSTRACT
BACKGROUND: Advanced cholangiocarcinoma carries a poor prognosis, and no standard treatment exists beyond first-line gemcitabine/platinum-based chemotherapy. A single-arm, phase 2 and biomarker study of cabozantinib, a multikinase inhibitor with potent activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET, was performed for patients with advanced refractory cholangiocarcinoma. METHODS: Previously treated patients with unresectable or metastatic cholangiocarcinoma received cabozantinib (60 mg orally and daily on a continuous schedule). The primary endpoint was progression-free survival (PFS). Tumor MET expression and plasma biomarkers were evaluated. RESULTS: The study enrolled 19 patients with cholangiocarcinoma (female, 68%; median age, 67 years; intrahepatic vs extrahepatic, 84% vs 16%). The median PFS was 1.8 months (95% confidence interval, 1.6-5.4 months), and the median overall survival (OS) was 5.2 months (95% confidence interval, 2.7-10.5 months). Grade 3/4 adverse events occurred in 89% of the patients and included neutropenia (5%), hyperbilirubinemia (5%), epistaxis (5%), bowel perforation (5%), enterocutaneous fistulas (5%), and hypertension (11%). One patient with 3 + MET expression in the tumor stayed on treatment for 278 days, but the MET expression did not correlate with the outcomes in the overall study population. Plasma vascular endothelial growth factor, placental growth factor, and stromal cell-derived factor 1α increased and soluble VEGFR2 and angiopoietin 2 decreased after treatment (all P values < .01). Plasma tissue inhibitor of matrix metalloproteinase 1 was inversely correlated with PFS, and soluble MET (sMET) and interleukin 6 were inversely correlated with OS. CONCLUSIONS: In unselected patients with cholangiocarcinoma, cabozantinib demonstrated limited activity and significant toxicity. In the first clinical trial to assess the role of MET inhibition in cholangiocarcinoma, 1 patient with a MET-high tumor had a prolonged benefit from treatment. Baseline plasma soluble MET was associated with OS. Any further development of this drug in cholangiocarcinoma should include a dose reduction and a biomarker-driven approach. Cancer 2017;123:1979-1988. © 2017 American Cancer Society.
Subject(s)
Anilides/therapeutic use , Bile Duct Neoplasms/drug therapy , Cholangiocarcinoma/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyridines/therapeutic use , Aged , Angiopoietin-2/metabolism , Bile Duct Neoplasms/metabolism , Bile Duct Neoplasms/pathology , Biomarkers, Tumor/metabolism , Chemokine CXCL12/metabolism , Cholangiocarcinoma/metabolism , Cholangiocarcinoma/pathology , Disease-Free Survival , Epistaxis/chemically induced , Female , Humans , Hyperbilirubinemia/chemically induced , Hypertension/chemically induced , Interleukin-6/metabolism , Intestinal Fistula/chemically induced , Intestinal Perforation/chemically induced , Male , Matrix Metalloproteinase 1/metabolism , Middle Aged , Neoplasm Metastasis , Neutropenia/chemically induced , Placenta Growth Factor/metabolism , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Proto-Oncogene Proteins c-met/metabolism , Survival Rate , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
PURPOSE: Few population studies have examined patterns of systemic therapy administration in metastatic pancreatic cancer (MPC) or the predictors associated with specific treatment choices. PATIENTS AND METHODS: We assessed 4,011 consecutive MPC patients who received chemotherapy between January 2005 and December 2015 at academic, private, and community-based oncology practices subscribing to a U.S.-wide chemotherapy order entry system capturing disease, patient, provider, and treatment data. Multivariate analyses of these prospectively recorded characteristics identified significant predictors of specific therapeutic choices. RESULTS: Overall, 100 different regimens were used in first-line treatment of MPC. First-line gemcitabine monotherapy usage fell steadily from 72% in 2006 to 16% in 2015. This steep decline mirrored increases in first-line usage of both 5 fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine + nab-paclitaxel. Younger male patients were more likely to receive FOLFIRINOX as first-line treatment, whereas patients treated at community practices and by oncologists with lower MPC patient volume were more likely to receive gemcitabine plus nab-paclitaxel (all p ≤ .05). Among all patients receiving first-line chemotherapy for MPC, 49% went on to receive second-line therapy and 19% received third-line therapy; administration of second- and third-line therapies increased steadily over the time course of follow-up. Younger patients and those treated by oncologists with higher MPC patient volume were more likely to receive second- and third-line therapies. CONCLUSION: This population-based study provides insight into treatment patterns of MPC in the U.S. Usage patterns varied greatly according to patient and provider characteristics. IMPLICATIONS FOR PRACTICE: This study examined real world metastatic pancreatic cancer treatment patterns in the United States with the goals of understanding changes in chemotherapy treatment frequencies over time and determining the individual predictors that underlie the chemotherapy choices oncologists make for their patients. Our data set is unique in that it captured not only patient-level data, but also oncologist-level data. It also captured data from private and community practices as well as academic centers. To our knowledge, this is the only data set that can give this degree of insight into oncologist decision making practices.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Camptothecin/analogs & derivatives , Pancreatic Neoplasms/drug therapy , Adenocarcinoma/epidemiology , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Albumins/administration & dosage , Albumins/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Camptothecin/administration & dosage , Camptothecin/adverse effects , Decision Making , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Leucovorin/administration & dosage , Leucovorin/adverse effects , Male , Middle Aged , Neoplasm Metastasis , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/adverse effects , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Pancreatic Neoplasms/epidemiology , Pancreatic Neoplasms/pathology , United States/epidemiology , GemcitabineABSTRACT
The NCCN Guidelines for Hepatobiliary Cancers provide treatment recommendations for cancers of the liver, gallbladder, and bile ducts. The NCCN Hepatobiliary Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding locoregional therapy for treatment of patients with hepatocellular carcinoma.
Subject(s)
Carcinoma, Hepatocellular/therapy , Liver Neoplasms/therapy , Humans , United StatesABSTRACT
BACKGROUND: Ganetespib (STA-9090) is an Hsp90 inhibitor that downregulates VEGFR, c-MET, HER2, IGF-IR, EGFR, and other Hsp90 client proteins involved in hepatocarcinogenesis, thereby making it an attractive therapy for HCC. This Phase I study was performed to establish the safety, tolerability, recommended Phase 2 dose (RP2D), and preliminary clinical activity of ganetespib in previously treated patients with advanced HCC. METHODS: Patients with advanced HCC, Child-Pugh A cirrhosis, progression on or intolerance to sorafenib, and ECOG PS ≤ 1 were enrolled in a standard 3x3 dose escalation study at doses of 100 mg/m(2), 150 mg/m(2), and 200 mg/m(2) IV given on days 1, 8, and 15 of each 28-day cycle. Objective response by RECIST version 1.1 criteria was evaluated by CT/MRI every 8 weeks. RESULTS: Fourteen patients were enrolled in this trial and received at least one dose of the study drug. Of the 14 patients: median age, 57 years old; male 71 %; Asian 36 %; HCC etiology (HBV 36 %, HCV 43 %, Hemachromatosis 7 %, unknown 21 %); Child Pugh Class (A 93 %, B 7 %); median number of prior treatments 2; median baseline AFP 70.1 ng/mL. The RP2D was determined to be 200 mg/m(2). The most commonly seen AEs were diarrhea (93 %), fatigue (71 %), AST elevation (64 %), and hyperglycemia (64 %). The most common Gr 3/4 AEs were hyperglycemia (21 %) and lipasemia (21 %). One (7 %) patient had a fatal AE, septic shock, within 30 days of receiving the study drug. One dose-limiting toxicity, grade 3 lipasemia, was observed at the 100 mg/m(2) dose. Pharmacokinetics studies showed a t1/2, CL, Tmax, and Vss of 6.45 h, 48.28 L/h (25.56 L/h/m(2)), 0.76 h, and 191 L (100.4 L/m(2)), respectively. No objective responses were seen; one patient (7 %) had stable disease at 16 weeks. Median time to progression was 1.8 months, and median overall survival was 7.2 months. CONCLUSION: Ganetespib had a manageable safety profile in patients with advanced HCC who had progressed on at least one line of systemic therapy. The pharmacokinetic profile showed that ganetespib exposure in patients with mild hepatic dysfunction is similar to that seen in patients with normal liver function. Ganetespib showed limited clinical benefit in patients with advanced HCC in this phase I trial.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Liver Neoplasms/drug therapy , Triazoles/therapeutic use , Adult , Aged , Aged, 80 and over , Carcinoma, Hepatocellular/metabolism , Female , Humans , Liver/metabolism , Liver Diseases/metabolism , Liver Neoplasms/metabolism , Male , Middle Aged , Treatment Outcome , Triazoles/adverse effects , Triazoles/blood , Triazoles/pharmacokineticsABSTRACT
PURPOSE: Resistance to cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), in colorectal cancer (CRC) may result from compensatory signaling through ErbB receptors, ErbB2/neu/HER2 (HER2) and ErbB3/HER3 (HER3). Pertuzumab is a monoclonal antibody that blocks HER2 hetero-dimerization; thus the combination of pertuzumab and cetuximab could possibly overcome cetuximab resistance. PATIENTS AND METHODS: This single-arm, open-label, multicenter phase I/II study was designed to assess the safety and efficacy of pertuzumab and cetuximab in patients with cetuximab-resistant KRAS wild type metastatic CRC. Thirteen patients were enrolled and received cetuximab in combination with pertuzumab at several dose levels in a 3 + 3 design. Patients were assessed for dose-limiting toxicity (DLT) during the first cycle. A phase II portion was planned, but not initiated due to toxicity. RESULTS: Six of the thirteen patients (46 %) experienced DLTs, therefore the study was terminated early. Grade 3 or higher DLTs included dermatitis with desquamation and/or acneiform rash (n = 6), mucositis or stomatitis (n = 5), and diarrhea (n = 2). There was one Grade 5 event (myocardial infarction) attributed to underlying disease. Among the 13 patients, seven (54 %) were evaluable for response. The objective response rate was 14 %: one patient had a partial response lasting 6 months. Two patients had stable disease (29 %), and four had progressive disease (57 %). Median progression free survival was 2.1 months (95 % CI, 1.5-4.9) and median overall survival was 3.7 months (95 % CI, 1.6-7.9). CONCLUSION: Combination pertuzumab and cetuximab in refractory CRC was associated with potential antitumor activity; however, the combination was not tolerable due to overlapping toxicities.