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3.
Cancer Med ; 12(12): 13100-13110, 2023 06.
Article in English | MEDLINE | ID: mdl-37148554

ABSTRACT

BACKGROUND: Sunitinib is a multi-target tyrosine kinase inhibitor (TKI) that inhibits VEGF receptor 1, 2, 3 (VEGFRs), platelet-derived growth factor receptor (PDGFR), colony-stimulating factor receptor (CSFR), and the stem cell factor receptor c-KIT. Temsirolimus inhibits mammalian target of rapamycin (mTOR) through binding to intracellular protein FKBP-12. Both agents are approved for the treatment of metastatic renal cell carcinoma (mRCC), have different anticancer mechanisms, and non-overlapping toxicities. These attributes form the scientific rationale for sequential combination of these agents. The primary objective of the study was to investigate the efficacy of alternating sunitinib and temsirolimus therapy on progression-free survival (PFS) in mRCC. METHODS: We undertook a phase II, multi-center, single cohort, open-label study in patients with mRCC. Patients were treated with alternating dosing of 4 weeks of sunitinib 50 mg PO daily, followed by 2 weeks rest, then 4 weeks of temsirolimus 25 mg IV weekly, followed by 2 weeks rest (12 weeks total per cycle). The primary endpoint was PFS. Secondary endpoints included clinical response rate and characterization of the toxicity profile of this combination therapy. RESULTS: Nineteen patients were enrolled into the study. The median observed PFS (n = 13 evaluable for PFS) was 8.8 months (95% CI 6.8-25.2 months). Best responses achieved were five partial response, nine stable disease, and three disease progression according to RECIST 1.1 guidelines (two non-evaluable). The most commonly observed toxicities were fatigue, platelet count decrease, creatinine increased, diarrhea, oral mucositis, edema, anemia, rash, hypophosphatemia, dysgeusia, and palmar-plantar erythrodysesthesia syndrome. CONCLUSION: Alternating sunitinib and temsirolimus did not improve the PFS in patients with mRCC.


Subject(s)
Antineoplastic Agents , Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/pathology , Disease-Free Survival , Kidney Neoplasms/pathology , Pyrroles/therapeutic use , Sirolimus/therapeutic use , Sunitinib/therapeutic use
4.
J Gastrointest Oncol ; 14(2): 480-493, 2023 Apr 29.
Article in English | MEDLINE | ID: mdl-37201058

ABSTRACT

Background: A standard of care for nonmetastatic esophageal cancer is trimodality therapy consisting of neoadjuvant chemoradiation and esophagectomy, with evidence for improved overall survival versus surgery alone in the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial. Patients who receive treatment with curative intent but are poor candidates for or decline surgery receive definitive bimodality therapy. Literature characterizing patients who receive bimodality therapy compared to trimodality therapy, and their relative outcomes, is sparse, especially among patients who are too old or too frail to qualify for clinical trials. In this study, we assess a single-institution real-world dataset of patients receiving bimodality and trimodality management. Methods: Patients treated for clinically resectable, nonmetastatic esophageal cancer between 2009 and 2019 who received bimodality or trimodality therapy were reviewed, generating a dataset of 95 patients. Clinical variables and patient characteristics were assessed for association with modality on multivariable logistic regression. Overall, relapse-free, and disease-free survival were assessed with Kaplan-Meier analyses and Cox proportional modeling. For patients nonadherent to planned esophagectomy, reasons for nonadherence were recorded. Results: Bimodality therapy was associated with greater age-adjusted comorbidity index, worse performance status, higher N-stage, presenting symptom other than dysphagia, and held chemotherapy cycles on multivariable analysis. Compared to bimodality therapy, trimodality therapy was associated with higher overall (3-year: 62% vs. 18%, P<0.001), relapse-free (3-year: 71% vs. 18%, P<0.001), and disease-free (3-year: 58% vs. 12%, P<0.001) survival. Similar results were observed among patients who did not meet CROSS trial qualifying criteria. Only treatment modality was associated with overall survival after adjusting for covariates (HR 0.37, P<0.001, reference group: bimodality). Patient choice accounted for 40% of surgery nonadherence in our population. Conclusions: Patients receiving trimodality therapy were observed to have superior overall survival compared to bimodality therapy. Patient preference for organ-preserving therapies appears to impact resection rate; further characterization of patient decision-making may be helpful. Our results suggest patients who wish to prioritize overall survival should be encouraged to pursue trimodality therapy and obtain early consultation with surgery. Development of evidence-based interventions to physiologically prepare patients before and during neoadjuvant therapy as well as efforts to optimize the tolerability of the chemoradiation plan are warranted.

6.
J Pain Symptom Manage ; 63(6): e621-e632, 2022 06.
Article in English | MEDLINE | ID: mdl-35595375

ABSTRACT

CONTEXT: Outcomes after cardiopulmonary resuscitation (CPR) remain poor. We have spent 10 years investigating an "informed assent" (IA) approach to discussing CPR with chronically ill patients/families. IA is a discussion framework whereby patients extremely unlikely to benefit from CPR are informed that unless they disagree, CPR will not be performed because it will not help achieve their goals, thus removing the burden of decision-making from the patient/family, while they retain an opportunity to disagree. OBJECTIVES: Determine the acceptability and efficacy of IA discussions about CPR with older chronically ill patients/families. METHODS: This multi-site research occurred in three stages. Stage I determined acceptability of the intervention through focus groups of patients with advanced COPD or malignancy, family members, and physicians. Stage II was an ambulatory pilot randomized controlled trial (RCT) of the IA discussion. Stage III is an ongoing phase 2 RCT of IA versus attention control in in patients with advanced chronic illness. RESULTS: Our qualitative work found the IA approach was acceptable to most patients, families, and physicians. The pilot RCT demonstrated feasibility and showed an increase in participants in the intervention group changing from "full code" to "do not resuscitate" within two weeks after the intervention. However, Stages I and II found that IA is best suited to inpatients. Our phase 2 RCT in older hospitalized seriously ill patients is ongoing; results are pending. CONCLUSIONS: IA is a feasible and reasonable approach to CPR discussions in selected patient populations.


Subject(s)
Cardiopulmonary Resuscitation , Decision Making , Aged , Critical Illness , Hospitalization , Humans , Inpatients , Resuscitation Orders
7.
Cancer Med ; 11(8): 1817-1826, 2022 04.
Article in English | MEDLINE | ID: mdl-35129311

ABSTRACT

BACKGROUND: The relationship between metastatic colorectal cancer (mCRC) and venous thromboembolism (VTE) is poorly defined in the modern era. Our objective was to examine impact of putative risk factors including newer treatments and anti-angiogenic therapy on VTE incidence and survival in a modern older mCRC cohort. METHODS: This is a SEER-Medicare cohort analysis of mCRC patients diagnosed in 2004-2009. Risk factor analysis was conducted using Cox models adjusted for sex, diagnosis age, race, primary tumor location, comorbidity, and prior VTE history, with cancer treatments as time-varying covariates. Main outcomes were VTE incidence and overall survival. RESULTS: Ten thousand nine hundred and seventy six mCRC cases with mean age 77.9 years (range 65-107), 49.7% women, 83.5% white. There were 1306 VTE cases corresponding to 13.7% incidence at 1 year and 20.3% at 3 years. Independent VTE predictors included female sex (HR 1.27; 95% CI 1.14-1.42), African American race (HR 1.49; 1.27-1.73), prior VTE history (HR 16.3; 12.1-22.1), and right sided cancers (HR 1.16; 1.04-1.29). After adjustment, any therapy and bevacizumab (HR 0.68, 0.58-0.78) in particular were protective. Overall survival was 40.1% (39.4-41.3) at 1 year but improved significantly with any treatment. VTE following diagnosis of mCRC was associated with inferior OS (HR 1.09; 1.02-1.15). CONCLUSIONS: In this large contemporary mCRC cohort, effective systemic therapy including anti-angiogenic treatment was associated with lower VTE risk. Overall survival was poor, and modestly worse if a patient had a VTE at any time during treatment.


Subject(s)
Colonic Neoplasms , Rectal Neoplasms , Venous Thromboembolism , Aged , Aged, 80 and over , Female , Humans , Incidence , Male , Medicare , Risk Factors , United States/epidemiology , Venous Thromboembolism/epidemiology , Venous Thromboembolism/etiology
8.
Clin Colorectal Cancer ; 21(1): 19-35, 2022 03.
Article in English | MEDLINE | ID: mdl-35031237

ABSTRACT

With increased therapeutic options in rectal cancer, a central question has become how to tailor therapy to patient preferences to avoid both over and under treatment. Total Neoadjuvant Therapy (TNT), defined as delivering all planned chemotherapy and radiation therapy (RT) before surgery, was developed with the primary goal of improving overall survival through early elimination of micrometastatic disease. In this narrative review assessing patients with operable adenocarcinoma of the rectum, we sought to evaluate TNT versus alternative options with regard to both quality of life (QoL) and oncologic outcomes. Survey data of patient preferences reveal that an increased focus on QoL when discussing options is essential. While evidence favors TNT improving distant metastases-free survival, this has not yet translated to a clear OS benefit. The improved pathologic complete response rate with TNT compared to short course RT or chemoradiation alone suggests proceeding to surgery might result in overtreatment, lending support to a watch-and-wait option for patients with a goal for nonoperative management if a clinical complete response is achieved. Similarly, for select low-risk patients, surgery may be the only local therapy required allowing for safe omission of RT. In the treatment of rectal cancer, the future appears to be moving toward one local therapy. As an alternative to TNT, there is growing support for the concept we define herein as total definitive therapy instead: chemoradiation followed by consolidation chemotherapy, saving surgery only for incomplete responders rather than as part of the initial treatment plan. Also, selective use of RT should be considered for low-risk patients. By thoroughly assessing how these treatment de-escalation options compare to more traditional treatment algorithms, this narrative review provides guidance on how to honor patient preferences for QoL by avoiding treatments that might offer negligible benefits in oncologic outcomes.


Subject(s)
Neoadjuvant Therapy , Rectal Neoplasms , Chemoradiotherapy , Humans , Neoplasm Recurrence, Local/drug therapy , Overtreatment , Quality of Life , Rectal Neoplasms/pathology
9.
JCO Oncol Pract ; 18(1): 23-34, 2022 01.
Article in English | MEDLINE | ID: mdl-34339260

ABSTRACT

PURPOSE: Cyberattacks targeting health care organizations are becoming more frequent and affect all aspects of care delivery. Cancer care is particularly susceptible to major disruptions because of the potential of immediate and long-term consequences for patients who often rely on timely diagnostic testing and regular administration of systemic therapy in addition to other local treatment modalities to cure or control their diseases. On October 28, 2020, a cyberattack was launched on the University of Vermont Health Network with wide-ranging consequences for oncology, including loss of access to all network intranet servers, e-mail communications, and the electronic medical record (EMR). METHODS: This review details the immediate challenges faced by hematology and oncology during the cyberattack. The impact and response on inpatient, outpatient, and special patient populations are described. Steps that other academic- and community-based oncology practices can take to lessen the brunt of such an assault are suggested. RESULTS: The two areas of immediate impact after the cyberattack were communications and lack of EMR access. The oncology-specific impact included loss of the individualized EMR chemotherapy plan templates and electronic safeguards built into multistep treatment preparation and delivery. With loss of access to schedules, basic patient information, encrypted communications platforms and radiology, and laboratory and pharmacy services, clinical outpatient care delivery was reduced by 40%. The infusion visit volume dropped by 52% in the first week and new patients could not access necessary services for timely diagnostic evaluation, requiring the creation of command centers to oversee ethical and transparent triage and allocation of systemic therapies and address new patient referrals. This included appropriate transfer of patients to alternate sites to minimize delays. Inpatient care including transitions of care was particularly challenging and addressing patient populations whose survival might be affected by delays in care. CONCLUSION: Oncology health care leaders and providers should be aware of the potential impact of a cyberattack on cancer care delivery and preventively develop processes to mitigate the impact.


Subject(s)
Hematology , Neoplasms , Ambulatory Care , Humans , Medical Oncology , Neoplasms/therapy , Referral and Consultation
10.
J Thorac Oncol ; 16(6): 1017-1029, 2021 06.
Article in English | MEDLINE | ID: mdl-33676017

ABSTRACT

INTRODUCTION: MET amplification is a rare, potentially actionable, primary oncogenic driver in patients with NSCLC. METHODS: The influence of MET amplification on the clinical activity of the ALK, ROS1, and MET inhibitor, crizotinib (250 mg twice daily), was examined in patients with NSCLC (NCT00585195) who were enrolled into high (≥4 MET-to-CEP7 ratio), medium (>2.2 to <4 MET-to-CEP7 ratio), or low (≥1.8 to ≤2.2 MET-to-CEP7 ratio) amplification categories. Retrospective next-generation sequencing profiling was performed on archival tumor tissue. End points included objective response rate (ORR), duration of response, and progression-free survival. RESULTS: A total of 38 patients with a MET-to-CEP7 ratio greater than or equal to 1.8 by local fluorescence in situ hybridization testing received crizotinib. All patients were response-assessable, among whom 21, 14, and 3 had high, medium, and low MET amplification, respectively. ORRs of 8 of 21 (38.1%), 2 of 14 (14.3%), and 1 of 3 (33.3%), median duration of response of 5.2, 3.8, and 12.2 months, and median progression-free survival values of 6.7, 1.9, and 1.8 months were observed for those with high, medium, and low MET amplification, respectively. MET amplification gene copy number greater than or equal to 6 was detected by next-generation sequencing in 15 of 19 (78.9%) analyzable patients. Of these 15 patients, objective responses were observed in six (40%), two of whom had concurrent MET exon 14 alterations. No responses were observed among five patients with concurrent KRAS, BRAF, or EGFR mutations. CONCLUSIONS: Patients with high-level, MET-amplified NSCLC responded to crizotinib with the highest ORR. Use of combined diagnostics for MET and other oncogenes may potentially identify patients most likely to respond to crizotinib.


Subject(s)
Lung Neoplasms , Protein-Tyrosine Kinases , Crizotinib/pharmacology , Crizotinib/therapeutic use , Humans , In Situ Hybridization, Fluorescence , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins/genetics , Retrospective Studies
11.
JAMA Netw Open ; 4(1): e2033787, 2021 01 04.
Article in English | MEDLINE | ID: mdl-33439266

ABSTRACT

Importance: Prostate radiation therapy (PRT) is a treatment option in men with low-volume metastatic prostate cancer based on the results of the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy Arm H (STAMPEDE-H) trial. However, the cost-effectiveness of this treatment remains unaddressed. Objective: To assess the cost-effectiveness of PRT when added to androgen deprivation therapy (ADT) for men with low-volume metastatic hormone-sensitive prostate cancer (mHSPC). Design, Setting, and Participants: This economic evaluation used microsimulation modeling to evaluate the cost-effectiveness of adding PRT to ADT. A simulated cohort of 10 000 individuals with low-volume mHSPC was created. Data from men with low-volume mHSPC were extracted and analyzed from January 18, 2019, through July 4, 2020. Transition probabilities were extracted from the STAMPEDE-H study. Health states included stable disease, progression, second progression, and death. Individual grade 2 or higher genitourinary and gastrointestinal toxic events associated with PRT were tracked. Univariable deterministic and probabilistic sensitivity analyses explored uncertainty with regard to the model assumptions. Health state utility estimates were based on the published literature. Exposures: The combination of PRT and ADT using regimens of 20 fractions and 6 weekly fractions. Main Outcomes and Measures: Outcomes included net quality-adjusted life-years (QALYs), costs in US dollars, and incremental cost-effectiveness ratios. A strategy was classified as dominant if it was associated with higher QALYs at lower costs than the alternative and dominated if it was associated with fewer QALYs at higher costs than the alternative. Results: For the base case scenario of men 68 years of age with low-volume mHSPC, the modeled outcomes were similar to the target clinical data for overall survival, failure-free survival, and rates of PRT-related toxic effects. The addition of PRT was a dominant strategy compared with ADT alone, with a gain of 0.16 QALYs (95% CI, 0.15-0.17 QALYs) and a reduction in net costs by $19 472 (95% CI, $23 096-$37 362) at 37 months of follow-up and a gain of 0.81 QALYs (95% CI, 0.73-0.89 QALYs) and savings of $30 229 (95% CI, $23 096-$37 362) with lifetime follow-up. Conclusions and Relevance: In the economic evaluation, PRT was a dominant treatment strategy compared with ADT alone. These findings suggest that addition of PRT to ADT is a cost-effective treatment for men with low-volume mHSPC.


Subject(s)
Cost-Benefit Analysis , Prostatic Neoplasms/radiotherapy , Radiotherapy/economics , Aged , Androgen Antagonists/therapeutic use , Humans , Male , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Quality-Adjusted Life Years , Tumor Burden
12.
Oncologist ; 25(12): 1009-1012, 2020 12.
Article in English | MEDLINE | ID: mdl-33017484

ABSTRACT

Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening microangiopathic hemolytic anemia characterized by thrombocytopenia, hemolytic anemia, and ischemic organ damage. It is mainly caused by an autoreactive antibody directed at ADAMTS13. Immunotherapy is frequently associated with autoimmune complications in patients with cancer, but only three cases of TTP have been reported, none implicating single treatment with the anti-programmed cell death receptor 1 ligand antibody nivolumab. We present the first identified and reported case of nivolumab-associated TTP in a 51-year-old woman with stage IIIc anal carcinoma who achieved complete response following chemoradiation and received adjuvant nivolumab as part of a randomized clinical trial. Twelve weeks into treatment, she presented with dark urine, progressive fatigue, and headache. TTP diagnosis was based on laboratory evidence of hemolytic anemia, thrombocytopenia, and ADAMTS13 activity of 9% associated with an inhibitor. She was treated with daily plasma exchange and oral prednisone and responded well to treatment, with platelet counts over 100 K/cmm within 4 days. We reviewed and summarized data from all reported cases of TTP associated with cancer immunotherapy. We provide guidance on identification and management of this devastating hematologic complication, focusing on the importance of early recognition, as most patients achieve complete recovery with appropriate treatment. KEY POINTS: Thrombotic thrombocytopenic purpura (TTP) was originally excluded from previous reviews of hematologic immune-related adverse events; however, several cases have been reported in the past 2 years in patients treated with either single agent or combination of cytotoxic T-lymphocyte-associated antigen 4 and the programmed cell death receptor 1 (PD-1) or the PD-1 ligand inhibitors. Although rare, TTP is a life-threatening condition that could be challenging to diagnose, and early recognition is key as delayed treatment is associated with significant increase in mortality. The pathophysiology of immunotherapy-induced TTP is likely related to autoimmune inhibition of ADAMTS13; the addition of prednisone and rituximab to urgent plasmapheresis appears to be effective and should be part of the up-front management for these patients.


Subject(s)
Carcinoma, Squamous Cell , Purpura, Thrombotic Thrombocytopenic , Female , Humans , Immunotherapy/adverse effects , Middle Aged , Nivolumab/adverse effects , Plasma Exchange , Purpura, Thrombotic Thrombocytopenic/chemically induced , Purpura, Thrombotic Thrombocytopenic/therapy
13.
JCO Oncol Pract ; 16(9): e868-e874, 2020 09.
Article in English | MEDLINE | ID: mdl-32267798

ABSTRACT

PURPOSE: Guidelines recommend venous thromboembolism (VTE) risk assessment in outpatients with cancer and pharmacologic thromboprophylaxis in selected patients at high risk for VTE. Although validated risk stratification tools are available, < 10% of oncologists use a risk assessment tool, and rates of VTE prophylaxis in high-risk patients are low in practice. We hypothesized that implementation of a systems-based program that uses the electronic health record (EHR) and offers personalized VTE prophylaxis recommendations would increase VTE risk assessment rates in patients initiating outpatient chemotherapy. PATIENTS AND METHODS: Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic (VTEPACC) was a multidisciplinary program implemented by nurses, oncologists, pharmacists, hematologists, advanced practice providers, and quality partners. We prospectively identified high-risk patients using the Khorana and Protecht scores (≥ 3 points) via an EHR-based risk assessment tool. Patients with a predicted high risk of VTE during treatment were offered a hematology consultation to consider VTE prophylaxis. Results of the consultation were communicated to the treating oncologist, and clinical outcomes were tracked. RESULTS: A total of 918 outpatients with cancer initiating cancer-directed therapy were evaluated. VTE monthly education rates increased from < 5% before VTEPACC to 81.6% (standard deviation [SD], 11.9; range, 63.6%-97.7%) during the implementation phase and 94.7% (SD, 4.9; range, 82.1%-100%) for the full 2-year postimplementation phase. In the postimplementation phase, 213 patients (23.2%) were identified as being at high risk for developing a VTE. Referrals to hematology were offered to 151 patients (71%), with 141 patients (93%) being assessed and 93.8% receiving VTE prophylaxis. CONCLUSION: VTEPACC is a successful model for guideline implementation to provide VTE risk assessment and prophylaxis to prevent cancer-associated thrombosis in outpatients. Methods applied can readily translate into practice and overcome the current implementation gaps between guidelines and clinical practice.


Subject(s)
Neoplasms , Thrombosis , Venous Thromboembolism , Anticoagulants , Humans , Neoplasms/complications , Risk Factors , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & control
14.
J Oncol Pharm Pract ; 26(7): 1637-1642, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32046579

ABSTRACT

INTRODUCTION: Drug options for VTE prophylaxis are increasing for ambulatory cancer patients and data regarding anticoagulant-drug interactions and their relationship to VTE and bleeding are needed to improve care. METHODS: Over one year, 108 cancer patients with high VTE risk were prospectively identified. Potential anticoagulant-drug interactions were ascertained by chart review and graded on need for intervention. Providers selected anticoagulant prophylaxis based on potential drug interactions and patient-provider discussion. A cross-sectional analysis was performed thereafter to evaluate VTE and bleeding endpoints within one year of anticoagulant initiation. RESULTS: The average number of potential drug interactions per patient was higher for warfarin than others (3.04 vs. 1.28 (apixaban), 1.02 (rivaroxaban), and 0.98 (LMWH)). The severity of the interactions based on grade was, for apixaban: 1.6% grade X, 50.8% grade D, and 47.5% grade C; for rivaroxaban: 2.1% grade X, 64.9% grade D, 33.0% grade C; for LMWH, 0% grade X, 66.7% grade D, 33.3% grade C; and for warfarin, 0% grade X, 29.4% grade D, 70.6% grade C. At the end of the investigational period, 11 bleeds and 7 VTEs were reported. Drug combinations significantly associated with an increased bleeding risk were crizotinib with apixaban or rivaroxaban and PPIs with warfarin. The use of sulfamethoxazole-trimethoprim with warfarin was associated with an increased VTE risk. CONCLUSIONS: DOACs had fewer DDIs than warfarin, although interaction severity differed between anticoagulants. Some anticoagulant-drug interactions were associated with bleeding or VTE. Although not powered for analysis, DDI severity did not affect bleeding rates and inversely correlated with VTE risk.


Subject(s)
Anticoagulants/therapeutic use , Hemorrhage/chemically induced , Neoplasms/drug therapy , Venous Thromboembolism/prevention & control , Adult , Aged , Aged, 80 and over , Anticoagulants/adverse effects , Cross-Sectional Studies , Drug Interactions , Female , Humans , Male , Middle Aged , Prospective Studies
15.
J Thromb Haemost ; 17(12): 2152-2159, 2019 12.
Article in English | MEDLINE | ID: mdl-31423717

ABSTRACT

BACKGROUND: The Khorana Score is a validated risk score for predicting 6-month incidence of cancer-associated venous thromboembolism (CAT) among patients starting chemotherapy. Venous thromboembolism (VTE) risk factors important in the general population, including age, sex, prior VTE, and hospitalization, are not included in this score, their association with VTE in cancer patients is unknown. OBJECTIVE: To examine risk factors for CAT and the impact of incorporating longitudinal hospitalization into risk assessment. METHODS: Risk factors were recorded among patients starting chemotherapy at a single institution from 2012-14. Hospitalization and time-periods after hospitalization were assessed as time-varying covariates. Logistic regression was used to determine factors related to 6-month CAT risk (the Khorana Score endpoint). Proportional hazard models were used for risk factor identification throughout the 3-year observation period. RESULTS: Among 1,583 patients starting chemotherapy (mean age 60, 48% male), 187 developed CAT (11.8%) with 129 (69%) cases occurring within 6 months of starting chemotherapy. In the 6-month analysis, no additional risk factors were associated with CAT. In the 3-year analysis, male sex (HR 1.57, 95%CI 1.21, 2.07), prior VTE (HR 2.12, 95%CI 1.41, 3.18), and hospitalization (HR 2.69, 95%CI 1.92, 3.75) were associated with increased hazard of CAT, adjusting for risk factors in the Khorana score. CONCLUSIONS: When time-to-event data were incorporated into CAT risk assessment, male sex, prior VTE, and hospitalization were important risk factors. These data highlight the need to consider dynamic methods for assessing VTE risk in cancer patients, with particular attention to the period around hospitalizations.


Subject(s)
Decision Support Techniques , Neoplasms/epidemiology , Venous Thromboembolism/epidemiology , Aged , Female , Hospitalization , Humans , Incidence , Male , Middle Aged , Neoplasms/blood , Neoplasms/diagnosis , Neoplasms/therapy , Predictive Value of Tests , Recurrence , Retrospective Studies , Risk Assessment , Risk Factors , Sex Factors , Time Factors , Venous Thromboembolism/blood , Venous Thromboembolism/diagnosis , Venous Thromboembolism/prevention & control , Vermont/epidemiology
16.
Biomark Res ; 6: 15, 2018.
Article in English | MEDLINE | ID: mdl-29713473

ABSTRACT

BACKGROUND: Well-differentiated neuroendocrine tumors (NET) most frequently arise from the gastrointestinal tract (GI), pancreas, and lung. Patients often present as metastasis with an unknown primary, and the clinical management and outcome depend on multiple factors, including the accurate diagnosis with the tumor primary site. Determining the site of the NET with unknown primary remains challenging. Many biomarkers have been investigated in primary NETs and metastatic NETs, with heterogeneous sensitivity and specificity observed. METHODS: We used high-throughput tissue microarray (TMA) and immunohistochemistry (IHC) with antibodies against a panel of transcriptional factors including NKX2.2, PDX-1, PTF1A, and CDX-2 on archived formalin-fixed paraffin-embedded NETs, and investigated the protein expression pattern of these transcription factors in 109 primary GI (N = 81), pancreatic (N = 17), and lung (N = 11) NETs. RESULTS: Differential expression pattern of these markers was observed. In the GI and pancreatic NETs (N = 98), NKX2.2, PDX-1, and CDX-2 were immunoreactive in 82 (84%), 14 (14%), and 52 (52%) cases, respectively. PDX-1 was expressed mainly in the small intestinal and appendiceal NETs, occasionally in the pancreatic NETs, and not in the colorectal NETs. All three biomarkers including NKX2.2, PDX-1, and CDX-2 were completely negative in lung NETs. PTF1A was expressed in all normal and neuroendocrine tumor cells. CONCLUSIONS: Our findings suggest that NKX2.2 was a sensitive and specific biomarker for the GI and pancreatic neuroendocrine tumors. We proposed that a panel of immunostains including NKX2.2, PDX-1, and CDX-2 may show diagnostic utility for the most common NETs.

17.
J Cell Physiol ; 233(9): 6408-6417, 2018 09.
Article in English | MEDLINE | ID: mdl-29663383

ABSTRACT

Prostate cancer is screened by testing circulating levels of the prostate-specific antigen (PSA) biomarker, monitoring changes over time, or a digital rectal exam. Abnormal results often lead to prostate biopsy. Prostate cancer positive patients are stratified into very low-risk, low-risk, intermediate-risk, and high-risk, based on clinical classification parameters, to assess therapy options. However, there remains a gap in our knowledge and a compelling need for improved risk stratification to inform clinical decisions and reduce both over-diagnosis and over-treatment. Further, current strategies for clinical intervention do not distinguish clinically aggressive prostate cancer from indolent disease. This mini-review takes advantage of a large number of functionally characterized microRNAs (miRNA), epigenetic regulators of prostate cancer, that define prostate cancer cell activity, tumor stage, and circulate as biomarkers to monitor disease progression. Nanoparticles provide an effective platform for targeted delivery of miRNA inhibitors or mimics specifically to prostate tumor cells to inhibit cancer progression. Several prostate-specific transmembrane proteins expressed at elevated levels in prostate tumors are under investigation for targeting therapeutic agents to prostate cancer cells. Given that prostate cancer progresses slowly, circulating miRNAs can be monitored to identify tumor progression in indolent disease, allowing identification of miRNAs for nanoparticle intervention before the crucial point of transition to aggressive disease. Here, we describe clinically significant and non-invasive intervention nanoparticle strategies being used in clinical trials for drug and nucleic acid delivery. The advantages of mesoporous silica-based nanoparticles and a number of candidate miRNAs for inhibition of prostate cancer are discussed.


Subject(s)
Nanoparticles/administration & dosage , Prostatic Neoplasms/drug therapy , Animals , Disease Progression , Epigenomics/methods , Humans , Male , MicroRNAs/genetics , Prostate-Specific Antigen/genetics , Prostatic Neoplasms/genetics
18.
Int J Clin Oncol ; 22(2): 397-404, 2017 Apr.
Article in English | MEDLINE | ID: mdl-27628064

ABSTRACT

BACKGROUND: Methylnaltrexone is a peripherally acting mu-opioid receptor antagonist that has been shown to relieve severe opioid-induced constipation (OIC) in patients with advanced disease receiving palliative care. Its efficacy remains unknown in cancer patients who are not terminally ill. The primary aim of this study was to evaluate the efficacy of methylnaltrexone over 48 h in cancer patients who were not terminally ill. METHODS: In this single-dose phase II trial, cancer patients with a prognosis of ≥3 months and OIC with <3 laxations during the preceding week were eligible. The primary endpoint was a rescue-free laxation ≤4 h after a single dose of methylnaltrexone. Friedman's two-way analysis of variance was conducted for the number of laxations, pain and withdrawal scales, and laxation- and constipation-related symptoms. Univariate/bivariate Cox proportional hazard models for laxation times were employed. RESULTS: Twelve patients received methylnaltrexone. Eleven patients had an ECOG performance status of 1 or 2. Four (33.3 %) and 5 (41.7 %) patients had rescue-free laxation within 4 and 24 h, respectively, and 10 (83.3 %) had laxation within 48 h (p = 0.006). Difficulty passing a stool improved significantly over 48 h (p = 0.029). The bivariate Cox models revealed that a shorter time to laxation was associated with a higher baseline morphine equivalent daily dose (hazard ratio, 1.02 per 1 mg; p = 0.018) and a smaller number of laxations in the preceding week (hazard ratio, 0.13 per one laxation; p = 0.035). Patients tolerated methylnaltrexone well without opioid withdrawal. CONCLUSIONS: Methylnaltrexone may relieve severe OIC in cancer patients who are not terminally ill. A larger prospective study is justified in this population. (NCT01004393, https://clinicaltrials.gov/show/NCT01004393 ).


Subject(s)
Analgesics, Opioid/adverse effects , Constipation/drug therapy , Naltrexone/analogs & derivatives , Narcotic Antagonists/therapeutic use , Neoplasms/complications , Adult , Aged , Aged, 80 and over , Constipation/chemically induced , Female , Humans , Injections, Subcutaneous , Male , Middle Aged , Naltrexone/therapeutic use , Neoplasm Staging , Neoplasms/drug therapy , Prognosis , Quaternary Ammonium Compounds/therapeutic use
19.
Support Care Cancer ; 25(5): 1503-1510, 2017 05.
Article in English | MEDLINE | ID: mdl-28032216

ABSTRACT

PURPOSE: Despite a lower risk of nausea and vomiting in patients receiving radiotherapy to the upper abdomen (UA-RINV) with prophylactic 5-HT3 antagonist therapy, patients can still experience UA-RINV. The aim of this multicenter phase II study was to assess effectiveness, safety, and tolerability of protracted dual NK1-receptor and 5-HT3 antagonist prophylaxis against UA-RINV. METHODS: Patients receiving fractionated radiotherapy with radiosensitizing chemotherapy received oral ondansetron 8 mg po q12 h and aprepitant 125/80/80 mg on a Monday, Wednesday, Friday schedules throughout radiotherapy. The primary outcome was complete response (CR) defined as no vomiting or rescue therapy during the entire observation period of radiotherapy (OP). Nausea, vomiting, and use of rescue medication were recorded in a modified version of the MASCC antiemesis tool completed twice weekly. RESULTS: Fifty-five patients were enrolled at 5 sites, 52 of whom were evaluable. 57.7% of patients (30/52, 95% CI 43.2-71.3%) achieved CR on study, with 73.1% (38/52, 95% CI 59.0-84.4%) who did not vomit, and 71.2% (37/52, 95% CI 56.9-82.9%) who did not use rescue medication during the OP. Overall, participants vomited or experienced significant nausea (SN) for an average of 6.8% (95% CI 11.4-21.0) and 8.4% (95% CI 4.2-12.7%) of time on study, respectively. Nausea was common with 32 (61.5%) reporting SN at any time during the OP. CONCLUSIONS: UA-RINV remains an important morbidity despite the advent of modern radiotherapy. Aprepitant and ondansetron as dosed in this trial was not superior to standard ondansetron monotherapy.


Subject(s)
Abdomen/radiation effects , Antiemetics/therapeutic use , Morpholines/therapeutic use , Nausea/prevention & control , Ondansetron/therapeutic use , Radiotherapy/adverse effects , Vomiting/prevention & control , Aged , Antiemetics/administration & dosage , Antiemetics/pharmacology , Aprepitant , Dose Fractionation, Radiation , Female , Humans , Male , Middle Aged , Morpholines/administration & dosage , Morpholines/pharmacology , Nausea/chemically induced , Nausea/drug therapy , Ondansetron/administration & dosage , Ondansetron/pharmacology , Vomiting/chemically induced , Vomiting/drug therapy
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