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LESSONS LEARNED: Palbociclib monotherapy demonstrated minimal clinical activity in patients with previously treated gastroesophageal cancers. Further clinical evaluation of palbociclib monotherapy is not warranted in gastroesophageal cancers, but improved understanding of resistance mechanisms may permit rational combination approaches. BACKGROUND: Dysregulation of the cell cycle is a hallmark of cancer. Progression through the G1/S transition requires phosphorylation of retinoblastoma (RB) by cyclin-dependent kinases (CDKs) 4 and 6, which are regulated by cyclins D and E. Amplifications of cyclin D loci and activating mutations in CDKs are frequent molecular aberrations in gastroesophageal malignancies. We conducted a phase II trial of the CDK4/6 inhibitor palbociclib as an initial test of efficacy. METHODS: Patients with previously treated metastatic gastroesophageal cancers with intact RB nuclear expression by immunohistochemistry were treated with 125 mg daily of palbociclib for days 1-21 of 28-day cycles. The primary endpoint was overall response rate. RESULTS: We screened 29 patients and enrolled 21 patients: 5 with gastric adenocarcinoma, 3 with gastroesophageal junction adenocarcinoma, 8 with esophageal adenocarcinoma, and 5 with esophageal squamous cell carcinoma. All 29 tumors screened had intact nuclear RB expression, and four treated patients tested positive for CCND1 overexpression. No objective responses were seen. Median progression-free survival was 1.8 months, and median overall survival was 3.0 months. All recurrent grade 3 or 4 toxicities were hematologic, with neutropenia in eight patients (38%), anemia in four patients (19%), and thrombocytopenia in two patients (10%). CONCLUSION: Palbociclib has limited single-agent activity in gastroesophageal tumors.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Neoplasias Gástricas , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Esofágicas/tratamento farmacológico , Humanos , Piperazinas/efeitos adversos , Piridinas , Neoplasias Gástricas/tratamento farmacológicoRESUMO
BACKGROUND: The addition of cisplatin or cetuximab to radiation therapy (RT) improves outcomes in comparison with RT alone in the nonoperative management of head and neck squamous cell carcinoma (HNSCC), but limited data exist for comparing these approaches. Using Veterans Health Affairs data, this study compared the outcomes of patients treated with RT plus cisplatin or cetuximab. METHODS: Patients with stage III to IVb HNSCC who had been treated nonsurgically with RT and cisplatin or cetuximab from 2000 to 2016 within the Veterans Health Affairs system were identified. Patients were analyzed by the drug used in the first treatment cycle (intent to treat). Overall survival (OS) was compared by treatment group with Cox regression models, and propensity score (PS) methods were used to account for a treatment allocation bias. The risk of toxicities was determined, with logistic regression models fit into propensity-matched cohorts. RESULTS: A total of 4520 patients were included in the analysis with a median follow-up of 3 years: 83% received cisplatin. Cisplatin patients were younger (P < .001) and had fewer comorbidities (P < .001). In an unmatched analysis, cetuximab was associated with inferior OS (P < .001). After PS matching, cetuximab treatment remained statistically significantly associated with inferior OS (1.7 vs 4.1 years; hazard ratio, 1.61; 95% confidence interval, 1.44-1.79; P < .001). These differences remained significant across all primary HNSCC subsites and in comparison with low- and high-dose cisplatin. CONCLUSIONS: Cetuximab with RT yields inferior OS in comparison with cisplatin for the nonoperative management of stage III to IVb HNSCC. According to this study, cisplatin may be the most appropriate partner for RT in this setting.
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Cetuximab/uso terapêutico , Quimiorradioterapia , Cisplatino/uso terapêutico , Neoplasias de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Idoso , Bases de Dados Factuais , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Análise de Sobrevida , Resultado do Tratamento , Veteranos/estatística & dados numéricos , Saúde dos VeteranosRESUMO
BACKGROUND: Next-generation sequencing has identified actionable genetic aberrations in intrahepatic cholangiocarcinomas (iCCA), including the fibroblast growth factor receptor 2 (FGFR2) fusions. Derazantinib (ARQ 087), an orally bioavailable, multi-kinase inhibitor with potent pan-FGFR activity, has shown preliminary therapeutic activity against FGFR2 fusion-positive iCCA. METHODS: This multicentre, phase 1/2, open-label study enrolled adult patients with unresectable iCCA with FGFR2 fusion, who progressed, were intolerant or not eligible to first-line chemotherapy (NCT01752920). Subjects received derazantinib in continuous daily doses. Tumour response was assessed according to RECIST 1.1 every 8 weeks. RESULTS: Twenty-nine patients (18 women/11 men; median age, 58.7 years), 2 treatment-naive and 27 who progressed after at least one prior systemic therapy, were enrolled. Overall response rate was 20.7%, disease control rate was 82.8%. Estimated median progression-free survival was 5.7 months (95% CI: 4.04-9.2 months). Treatment-related adverse events (AE) were observed in 27 patients (93.1%, all grades), including asthenia/fatigue (69.0%), eye toxicity (41.4%), and hyperphosphatemia (75.9%). Grade ≥ 3 AEs occurred in 8 patients (27.6%). CONCLUSION: Derazantinib demonstrated encouraging anti-tumour activity and a manageable safety profile in patients with advanced, unresectable iCCA with FGFR2 fusion who progressed after chemotherapy. A pivotal trial of derazantinib in iCCA is ongoing (NCT03230318).
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Alcaloides/administração & dosagem , Colangiocarcinoma/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alcaloides/efeitos adversos , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
BACKGROUND: Tivantinib (ARQ 197), a selective, oral MET inhibitor, improved overall survival and progression-free survival compared with placebo in a randomised phase 2 study in patients with high MET expression (MET-high) hepatocellular carcinoma previously treated with sorafenib. The aim of this phase 3 study was to confirm the results of the phase 2 trial. METHODS: We did a phase 3, randomised, double-blind, placebo-controlled study in 90 centres in Australia, the Americas, Europe, and New Zealand. Eligible patients were 18 years or older and had unresectable, histologically confirmed, hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0-1, high MET expression (MET-high; staining intensity score ≥2 in ≥50% of tumour cells), Child-Pugh A cirrhosis, and radiographically-confirmed disease progression after receiving sorafenib-containing systemic therapy. We randomly assigned patients (2:1) in block sizes of three using a computer-generated randomisation sequence to receive oral tivantinib (120 mg twice daily) or placebo (twice daily); patients were stratified by vascular invasion, extrahepatic spread, and α-fetoprotein concentrations (≤200 ng/mL or >200 ng/mL). The primary endpoint was overall survival in the intention-to-treat population. Efficacy analyses were by intention to treat and safety analyses were done in all patients who received any amount of study drug. This study is registered with ClinicalTrials.gov, number NCT01755767. FINDINGS: Between Dec 27, 2012, and Dec 10, 2015, 340 patients were randomly assigned to receive tivantinib (n=226) or placebo (n=114). At a median follow-up of 18·1 months (IQR 14·1-23·1), median overall survival was 8·4 months (95% CI 6·8-10·0) in the tivantinib group and 9·1 months (7·3-10·4) in the placebo group (hazard ratio 0·97; 95% CI 0·75-1·25; p=0·81). Grade 3 or worse treatment-emergent adverse events occurred in 125 (56%) of 225 patients in the tivantinib group and in 63 (55%) of 114 patients in the placebo group, with the most common being ascites (16 [7%] patients]), anaemia (11 [5%] patients), abdominal pain (nine [4%] patients), and neutropenia (nine [4%] patients) in the tivantinib group. 50 (22%) of 226 patients in the tivantinib group and 18 (16%) of 114 patients in the placebo group died within 30 days of the last dose of study medication, and general deterioration (eight [4%] patients) and hepatic failure (four [2%] patients) were the most common causes of death in the tivantinib group. Three (1%) of 225 patients in the tivantinib group died from a treatment-related adverse event (one sepsis, one anaemia and acute renal failure, and one acute coronary syndrome). INTERPRETATION: Tivantinib did not improve overall survival compared with placebo in patients with MET-high advanced hepatocellular carcinoma previously treated with sorafenib. Although this METIV-HCC trial was negative, the study shows the feasibility of doing integral tissue biomarker studies in patients with advanced hepatocellular carcinoma. Additional randomised studies are needed to establish whether MET inhibition could be a potential therapy for some subsets of patients with advanced hepatocellular carcinoma. FUNDING: ArQule Inc and Daiichi Sankyo (Daiichi Sankyo Group).
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Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirrolidinonas/administração & dosagem , Quinolinas/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , América , Antineoplásicos/efeitos adversos , Austrália , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Método Duplo-Cego , Esquema de Medicação , Europa (Continente) , Feminino , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirrolidinonas/efeitos adversos , Quinolinas/efeitos adversos , Fatores de Tempo , Adulto JovemRESUMO
OBJECTIVE: To examine the dose-response effects of aerobic exercise on health-related quality of life (HRQoL) among colon cancer survivors. METHODS: Thirty-nine stage I to III colon cancer survivors were randomized to 1 of 3 groups: usual-care control, 150 min·wk-1 of aerobic exercise (low-dose) and 300 min·wk-1 of aerobic exercise (high-dose) for 6 months. HRQoL outcomes included the Short Form (SF)-36 physical and mental component summary, Functional Assessment of Cancer Therapy-Colorectal, Pittsburgh Sleep Quality Index, Fear of Cancer Recurrence Inventory, Fatigue Symptom Inventory, and North Central Cancer Treatment Group bowel function questionnaire, assessed at baseline and post intervention. The primary hypothesis was that exercise would improve HRQoL outcomes in a dose-response fashion, such that high-dose aerobic exercise would yield the largest improvements in HRQoL outcomes. RESULTS: Over 6 months, the low-dose group completed 141 ± 10 min·wk-1 of aerobic exercise, and the high-dose group completed 247 ± 11 min·wk-1 of aerobic exercise. Over 6 months, exercise improved the physical component summary score of the SF-36 (Ptrend = 0.002), the Functional Assessment of Cancer Therapy-Colorectal (Ptrend = 0.025), the Pittsburgh Sleep Quality Index (Ptrend = 0.049), and the Fatigue Symptom Inventory (Ptrend = 0.045) in a dose-response fashion. Between-group standardized mean difference effects sizes for the above-described findings were small to moderate in magnitude (0.35-0.75). No dose-response effects were observed for the mental component summary score of the SF-36, the Fear of Cancer Recurrence Inventory, or bowel function. CONCLUSION: Higher doses of aerobic exercise, up to 300 min·wk-1 , improve multiple HRQoL outcomes among stage I to III colon cancer survivors. These findings provide evidence that aerobic exercise may provide multiple health benefits for colon cancer survivors.
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Sobreviventes de Câncer/psicologia , Neoplasias do Colo/psicologia , Terapia por Exercício/métodos , Exercício Físico/psicologia , Qualidade de Vida , Neoplasias do Colo/fisiopatologia , Neoplasias do Colo/reabilitação , Exercício Físico/fisiologia , Fadiga/fisiopatologia , Fadiga/psicologia , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo PacienteRESUMO
BACKGROUND: Physical activity is associated with a lower risk of disease recurrence among colon cancer survivors. Excess visceral adipose tissue is associated with a higher risk of disease recurrence among colon cancer survivors. The pathways through which physical activity may alter disease outcomes are unknown, but may be mediated by changes in visceral adipose tissue. METHODS: Thirty-nine stage I-III colon cancer survivors were randomised to one of three groups: usual-care control, 150 min wk-1 of aerobic exercise (low dose) and 300 min wk-1 of aerobic exercise (high dose) for 6 months. The prespecified key body composition outcome was visceral adipose tissue quantified using dual energy X-ray absorptiometry. RESULTS: Exercise reduced visceral adipose tissue in dose-response fashion (Ptrend=0.008). Compared with the control group, the low- and high-dose exercise groups lost 9.5 cm2 (95% CI: -22.4, 3.5) and 13.6 cm2 (95% CI: -27.0, -0.1) in visceral adipose tissue, respectively. Each 60 min wk-1 increase in exercise predicted a 2.7 cm2 (95% CI: -5.4, -0.1) reduction in visceral adipose tissue. CONCLUSIONS: Aerobic exercise reduces visceral adipose tissue in dose-response fashion among patients with stage I-III colon cancer. Visceral adipose tissue may be a mechanism through which exercise reduces the risk of disease recurrence among colon cancer survivors.
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Composição Corporal , Sobreviventes de Câncer , Neoplasias do Colo/metabolismo , Neoplasias do Colo/mortalidade , Exercício Físico , Adulto , Idoso , Feminino , Humanos , Gordura Intra-Abdominal/metabolismo , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controleRESUMO
BACKGROUND: National guidelines advocate use of multimodality therapy (MMT) for treatment of T4 gastric cancer (T4GC). Prior studies demonstrate poor compliance with these guidelines. We sought to assess treatment trends and association between different treatment approaches and overall survival (OS) in a large cohort of U.S. METHODS: Patients diagnosed with clinical T4 gastric adenocarcinoma were selected from the National Cancer Data Base (1998-2011). Temporal trends, risk factors associated with failure to receive treatment, and effect of treatments on OS were assessed. RESULTS: Of 4369 patients with T4GC, only 15 % (n = 652) received MMT. Treatment with MMT increased over time, and was utilized in 25 % of patients after 2006. Older age, African American race, nonprivate insurance, proximal tumor location, and clinical node-negative disease were associated with failure to receive surgery; older age, female sex, poorly differentiated tumor grade, clinical node-negative disease, and prolonged postoperative length of stay were associated with failure to complete MMT in patients who underwent surgical resection. Median OS was longest in patients receiving MMT (19.2 months), and was similarly poor in patients undergoing surgical resection (9.0 months) or nonsurgical therapy (8.3 months; p < 0.001). Median OS was longer in patients receiving neoadjuvant therapy compared to patients receiving adjuvant therapy (27.8 vs. 16.6 months; p = 0.004). CONCLUSIONS: Treatment with neoadjuvant MMT is increasing and is associated with prolonged survival. Surgery alone and chemotherapy with or without radiotherapy without resection are associated with similarly poor outcomes. Appropriate treatment sequencing may facilitate delivery of MMT and improve outcomes in patients with T4GC.
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Adenocarcinoma/mortalidade , Terapia Combinada/mortalidade , Terapia Combinada/estatística & dados numéricos , Neoplasias Gástricas/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Idoso , Quimioterapia Adjuvante , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Prognóstico , Radioterapia Adjuvante , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Taxa de Sobrevida , Estados UnidosRESUMO
PURPOSE: Capecitabine-Temozolomide (CapTem) is an oral chemotherapy regimen for NETs. Both drugs are radiosensitizers. Integrating CapTem and Y90 transarterial radioembolization (TARE) in patients with grade 2 neuroendocrine tumor (NET) liver metastases achieved an encouraging objective response rate (ORR) and progression-free survival (PFS) in a feasibility study. This study expands that report to a larger cohort with longer follow-up. METHODS: Therapy consisted of monthly cycles of capecitabine 600 mg/m2 twice daily for 14 days and temozolomide 150-200 mg/m2 on day 10-14. Simulation angiography was performed during the initial cycle. The dominant lobe was treated with 90Y-resin microspheres using BSA dosimetry on day 7 of the second cycle of CapTem. Patients with bilobar disease had the other lobe treated on day 7 of the third or fourth cycle. CapTem was continued until progression or intolerance. Clinical and laboratory assessment was done monthly and imaging every 3 months. RESULTS: 35/37 patients completed the prescribed regimen. Primary sites of disease were pancreas (16), lung (10), gut (7) and unknown (4). Mean duration of CapTem was 12 months (range, 4-32 months). ORR in the liver was 72% with a disease control rate of 100%. Median PFS was 36 months (95% CI, 25-45 months). Median overall survival was 41 months (95% CI, 24-87 months) from initiation of CapTemY90 therapy and 130 months (95% CI, 56-172 months) from initial diagnosis. CONCLUSION: Chemoradiation with CapTem and TARE provided durable control of G2 NET liver metastases for substantially longer than expectations for embolotherapy or chemotherapy alone.
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Neoplasias Hepáticas , Tumores Neuroendócrinos , Humanos , Capecitabina/uso terapêutico , Temozolomida/uso terapêutico , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Tumores Neuroendócrinos/patologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/tratamento farmacológicoRESUMO
PURPOSE: Telegenetics services can expand access to guideline-recommended cancer genetic testing. However, access is often not distributed equitably to all races and ethnicities. We evaluated the impact of an on-site nurse-led cancer genetics service in a diverse Veterans Affairs Medical Center (VAMC) oncology clinic on likelihood of germline testing (GT) completion. METHODS: We conducted an observational retrospective cohort study of patients who were referred for cancer genetics services at the Philadelphia VAMC between October 1, 2020, and February 28, 2022. We evaluated the association between genetics service (on-site v telegenetics) and likelihood of GT completion in a subcohort of new consults, excluding patients with prior consults and those referred for known history of germline mutations. RESULTS: A total of 238 Veterans, including 108 (45%) seen on site, were identified for cancer genetics services during the study period, with the majority referred for a personal (65%) or family (26%) history of cancer. In the subcohort of new consults, 121 Veterans (54% self-identified race/ethnicity [SIRE]-Black), including 60 (50%) seen on site, were included in the analysis of germline genetic testing completion. In a univariate analysis, patients who were seen by the on-site genetics service had 3.2-fold higher likelihood of completing GT (relative risk, 3.22; 95% CI, 1.89 to 5.48) compared with the telegenetics service. In multivariable regression analysis, the on-site genetics service was associated with higher likelihood of GT completion, but this association was only statistically significant in SIRE-Black compared with SIRE-White Veterans (adjusted RR, 4.78; 95% CI, 1.53 to 14.96; P < .001; P-interaction of race × genetics service = .016). CONCLUSION: An on-site nurse-led cancer genetics service embedded in a VAMC Oncology practice was associated with higher likelihood of germline genetic testing completion than a telegenetics service among self-identified Black Veterans.
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Neoplasias , Veteranos , Humanos , Estudos Retrospectivos , Papel do Profissional de Enfermagem , Testes Genéticos , Neoplasias/genéticaRESUMO
Background: Fluoropyrimidines (fluorouracil [5-FU], capecitabine) and irinotecan are commonly prescribed chemotherapy agents for gastrointestinal (GI) malignancies. Pharmacogenetic (PGx) testing for germline DPYD and UGT1A1 variants associated with reduced enzyme activity holds the potential to identify patients at high risk for severe chemotherapy-induced toxicity. Slow adoption of PGx testing in routine clinical care is due to implementation barriers, including long test turnaround times, lack of integration in the electronic health record (EHR), and ambiguity in test cost coverage. We sought to establish PGx testing in our health system following the Exploration, Preparation, Implementation, Sustainment (EPIS) framework as a guide. Our implementation study aims to address barriers to PGx testing. Methods: The Implementing Pharmacogenetic Testing in Gastrointestinal Cancers (IMPACT-GI) study is a non-randomized, pragmatic, open-label implementation study at three sites within a major academic health system. Eligible patients with a GI malignancy indicated for treatment with 5-FU, capecitabine, or irinotecan will undergo PGx testing prior to chemotherapy initiation. Specimens will be sent to an academic clinical laboratory followed by return of results in the EHR with appropriate clinical decision support for the care team. We hypothesize that the availability of a rapid turnaround PGx test with specific dosing recommendations will increase PGx test utilization to guide pharmacotherapy decisions and improve patient safety outcomes. Primary implementation endpoints are feasibility, fidelity, and penetrance. Exploratory analyses for clinical effectiveness of genotyping will include assessing grade ≥3 treatment-related toxicity using available clinical data, patient-reported outcomes, and quality of life measures. Conclusion: We describe the formative work conducted to prepare our health system for DPYD and UGT1A1 testing. Our prospective implementation study will evaluate the clinical implementation of this testing program and create the infrastructure necessary to ensure sustainability of PGx testing in our health system. The results of this study may help other institutions interested in implementing PGx testing in oncology care. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04736472, identifier [NCT04736472].
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TGFß is a pleiotropic cytokine with immunosuppressive activity. In preclinical models, blockade of TGFß enhances the activity of radiation and invokes T-cell antitumor immunity. Here, we combined galunisertib, an oral TGFß inhibitor, with stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC) and assessed safety, efficacy, and immunologic correlatives. Patients (n = 15) with advanced HCC who progressed on, were intolerant of, or refused sorafenib were treated with galunisertib (150 mg orally twice a day) on days 1 to 14 of each 28-day cycle. A single dose of SBRT (18-Gy) was delivered between days 15 to 28 of cycle 1. Site of index lesions treated with SBRT included liver (9 patients), lymph node (4 patients), and lung (2 patients). Blood for high-dimensional single cell profiling was collected. The most common treatment-related adverse events were fatigue (53%), abdominal pain (46.6%), nausea (40%), and increased alkaline phosphatase (40%). There were two instances of grade 2 alkaline phosphatase increase and two instances of grade 2 bilirubin increase. One patient developed grade 3 achalasia, possibly related to treatment. Two patients achieved a partial response. Treatment with galunisertib was associated with a decrease in the frequency of activated T regulatory cells in the blood. Distinct peripheral blood leukocyte populations detected at baseline distinguished progressors from nonprogressors. Nonprogressors also had increased CD8+PD-1+TIGIT+ T cells in the blood after treatment. We found galunisertib combined with SBRT to be well tolerated and associated with antitumor activity in patients with HCC. Pre- and posttreatment immune profiling of the blood was able to distinguish patients with progression versus nonprogression.
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Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Pirazóis/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Pirazóis/farmacologia , Quinolinas/farmacologia , RadiocirurgiaRESUMO
BACKGROUND: Cancer prevention clinical trials seek to enroll individuals at increased risk for cancer. Little is known about attitudes among physicians and at-risk individuals towards cancer prevention clinical trials. We sought to characterize barriers to prevention trial participation among medical oncologists and first-degree relatives of their patients. METHODS: Physician participants were practicing oncologists in Pennsylvania. Eligible first-degree participants were adult relatives of a cancer patient being treated by one of the study physicians. The influence of perceived psychosocial and practical barriers on level of willingness to participate in cancer prevention clinical trials was investigated. RESULTS: Response rate was low among physicians, 137/478 (29%), and modest among eligible first-degree relatives, 82/129 (64%). Lack of access to an eligible population for prevention clinical trials was the most commonly cited barrier to prevention clinical trials among oncologists. Nearly half (45%) of first-degree relatives had not heard of cancer prevention clinical trials, but 68% expressed interest in learning more, and 55% expressed willingness to participate. In the proportional odds model, greater information source seeking/responsiveness (i.e., interest in learning more about clinical prevention trials from more information sources) (p = 0.04), and having fewer psychosocial barriers (p = 0.02) were associated with a greater willingness to participate. CONCLUSIONS: Many individuals who may be at greater risk for developing cancer because of having a first-degree relative with cancer are unaware of the availability of clinical cancer prevention trials. Nonetheless, many perceive low personal risk associated with these studies, and are interested in learning more.
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Atitude do Pessoal de Saúde , Ensaios Clínicos como Assunto , Família , Neoplasias/prevenção & controle , Seleção de Pacientes , Médicos/estatística & dados numéricos , Prevenção Primária , Adulto , Família/psicologia , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Medicina Interna , Masculino , Oncologia , Pessoa de Meia-Idade , Razão de Chances , PennsylvaniaRESUMO
Gastrointestinal (GI) malignancies are among the most commonly diagnosed cancers worldwide. Despite the introduction of targeted and immunotherapy agents in the treatment landscape, cytotoxic agents, such as fluoropyrimidines and irinotecan, remain as the cornerstone of chemotherapy for many of these tumors. Pharmacogenetics (PGx) is a rapidly evolving field that accounts for interpatient variability in drug metabolism to predict therapeutic response and toxicity. Given the significant incidence of severe treatment-related adverse events associated with cytotoxic agents, utilizing PGx can allow clinicians to better anticipate drug tolerability while minimizing treatment interruptions or delays. In this review, the PGx profiles of drug-gene pairs with potential impact in GI malignancy therapy - DPYD-5-fluorouracil/capecitabine and UGT1A1-irinotecan - and the available clinical evidence of their roles in reducing severe adverse events are discussed. Considerations for clinical implementation, such as optimal laboratory workflows, electronic health record integration, and stakeholder engagement, as well as provider education, are addressed. Last, exploratory PGx markers in GI malignancy treatment are described. As the PGx knowledge base rapidly evolves, pharmacists will be vital in leveraging their pharmacology knowledge and clinical skills to implement PGx testing in the clinic.
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Antineoplásicos/uso terapêutico , Di-Hidrouracila Desidrogenase (NADP)/genética , Neoplasias Gastrointestinais/tratamento farmacológico , Glucuronosiltransferase/genética , Humanos , Farmacogenética , Testes FarmacogenômicosRESUMO
Asymptomatic patients with metastatic colorectal cancer do not routinely need to undergo resection of the primary tumor. Although several retrospective analyses suggest that patients who undergo resection of the primary tumor live longer, most of these reviewed data prior to the advent of modern polychemotherapy and are subject to considerable bias, as patients who were considered able to undergo surgery likely had better overall prognoses than those who were not. In addition to significant prolongation of overall survival, current combinations of systemic chemotherapeutic agents and targeted agents have allowed improved local and distant tumor control, decreasing the likelihood of local tumor-related complications requiring colon resection.
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Neoplasias Colorretais/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Colectomia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Humanos , Obstrução Intestinal/etiologia , Obstrução Intestinal/cirurgia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Metástase Neoplásica , Cuidados Paliativos , Seleção de Pacientes , Complicações Pós-Operatórias , Prognóstico , Estudos Retrospectivos , Medição de Risco , Taxa de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of liposome-entrapped paclitaxel easy-to-use (LEP-ETU) and to characterize the relationship between LEP-ETU concentrations and the time course of neutropenia in cancer patients. EXPERIMENTAL DESIGN: LEP-ETU was administered to 88 patients and 63 were evaluable for pharmacokinetic/pharmacodynamic (PK/PD) analysis following 1.5- and 3-h infusions every 3 weeks (q3w; dose range, 135-375 mg/m(2)). MTD was identified using a 3 + 3, up-and-down dose-finding algorithm. PK/PD modeling was done to describe the temporal relationship between paclitaxel concentrations and neutrophil count. Simulations assessed the influence of dose and schedule on neutropenia severity to help guide dose selection. RESULTS: The MTD of LEP-ETU was identified as 325 mg/m(2). DLTs occurring at 375 mg/m(2) consisted of febrile neutropenia and neuropathy. The C(max) and area under the plasma concentration-time curve of LEP-ETU were less than proportional with increasing dose. The PK/PD model showed that LEP-ETU inhibition of neutrophil proliferation was 9.1% per 10 mug/mL of total paclitaxel concentration. The incidence of grade 4 neutropenia increased from 33% to 42% across the dose range of 275 to 325 mg/m(2) q3w. For a dose of 110 mg/m(2) given weekly, grade 4 neutropenia was estimated to be 16% compared with 42% for the same total dose administered q3w. CONCLUSIONS: LEP-ETU can be administered safely at higher doses than Taxol. Modeling and simulation studies predict that 325 mg/m(2) LEP-ETU q3w provides acceptable neutropenic events relative to those observed at 175 mg/m(2) Taxol q3w. A 275 mg/m(2) dose may offer an improved therapeutic index.
Assuntos
Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamente , Paclitaxel/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Feminino , Humanos , Lipossomos/administração & dosagem , Lipossomos/farmacocinética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Modelos Biológicos , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinéticaRESUMO
Hepatocellular carcinoma (HCC) is a challenging to treat malignancy with few available systemic therapies. Angiogenesis has been implicated in the pathogenesis of HCC and prior studies have suggested a role for anti-VEGF therapy. Prior to FDA approval of second-line therapy for advanced HCC, from 2008 until 2017, we initiated bevacizumab monotherapy (5-10 mg/kg every 2-3 weeks) in 12 patients with intolerance of or progression during sorafenib therapy. Bevacizumab therapy was well tolerated with only 1/12 patients experiencing a grade 3-4 treatment-related adverse event (transient ischemic attack) and only 2/12 patients discontinued the therapy due to adverse events. Median overall survival was 20.2 months (IQR, 7.0-43.5), with a median time to radiologic progression of 10.4 months (IQR, 2.8-16.1) and a disease control rate of 54%. Taken together, our experience provides rationale for further prospective investigation of bevacizumab for the treatment of advanced HCC.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Bevacizumab/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Idoso , Inibidores da Angiogênese/efeitos adversos , Bevacizumab/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Uso Off-Label , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , VeteranosRESUMO
BACKGROUND: Concurrent chemoradiotherapy is an established component of the nonoperative management of locally advanced head and neck squamous cell carcinoma (HNSCC), but the standard dose of 100 mg/m2 cisplatin every 3 weeks is associated with clinically significant toxicity. Interest in a more tolerable regimen has led to the widespread use of weekly lower dose cisplatin, but few randomized trials have compared these approaches. METHODS: We examined outcomes of patients with stage III-IVb HNSCC treated with definitive intent chemoradiotherapy using either high-dose cisplatin (HDC) or low-dose cisplatin (LDC), using population-based Veterans Affairs data. In an intent-to-treat analysis, patients were assigned to the HDC vs LDC group according to the dose of their first cycle. Variables potentially influencing treatment decisions including cancer site, stage, smoking/alcohol use, and comorbidities were used to generate propensity scores (PS) for the use of HDC. We compared overall survival (OS) by treatment group using Cox regression, adjusting for PS. We then determined the risk of toxicities using PS-adjusted logistic regression. RESULTS: A total of 2901 patients were included in the analysis; 2200 received HDC (mean initial dose 100 mg/m2). The mean initial dose of LDC was 40 mg/m2. After PS adjustment, HDC was not associated with improved OS over LDC (hazard ratio = 0.94, 95% confidence interval = 0.80 to 1.04). Adjusting for PS, HDC was associated with an increased risk of acute kidney injury, neutropenia, dehydration/electrolyte disturbance, and hearing loss. CONCLUSION: In this large, population-based study of US military veterans, LDC was associated with similar survival to HDC in the nonoperative definitive management of locally advanced HNSCC of the oral cavity, oropharynx, and hypopharynx/larynx. HDC was associated with statistically significantly more toxicity than LDC. Adoption of LDC may reduce toxicity burden while maintaining OS.
Assuntos
Antineoplásicos/administração & dosagem , Quimiorradioterapia/métodos , Cisplatino/administração & dosagem , Neoplasias de Cabeça e Pescoço/terapia , Radiossensibilizantes/administração & dosagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Injúria Renal Aguda/induzido quimicamente , Idoso , Antineoplásicos/efeitos adversos , Quimiorradioterapia/efeitos adversos , Intervalos de Confiança , Esquema de Medicação , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Radiossensibilizantes/efeitos adversos , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Resultado do Tratamento , VeteranosRESUMO
OBJECTIVES: An integrated protocol combining capecitibine-temozolomide with yttrium-90 radioembolization (CapTemY90) for liver-dominant grade 2 neuroendocrine tumors (NETs) was designed in the hope of achieving synergistic improvement in liver disease control with no more than additive toxicities. This report describes the feasibility and safety of this regimen. METHODS: Twenty-one patients with unresectable grade 2 NET liver-dominant metastases without contraindications to radioembolization or to CapTem initiated therapy with capecitabine 600 mg/m twice daily for 14 days and temozolomide 150 to 200 mg/m in 2 divided doses on days 10 to 14, with 14 days between cycles. During the first cycle, simulation angiography was performed. The dominant lobe was radioembolized on day 7 of the second cycle. In patients with bilobar disease, the other lobe was treated on day 7 of the third or fourth cycle. RESULTS: Nineteen of 21 patients completed the protocol. Adverse events were as expected. Objective response rate was 74% in the liver and 55% for extrahepatic tumor. Median progression-free survival was not reached. Progression-free survival at 3 years was 67%, with 74% progression-free in the liver. CONCLUSIONS: CapTemY90 is feasible and safe for grade 2 NETs. Toxicities were additive. Oncologic outcomes suggest synergy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Embolização Terapêutica/métodos , Neoplasias Hepáticas/terapia , Tumores Neuroendócrinos/terapia , Radioisótopos de Ítrio/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Embolização Terapêutica/efeitos adversos , Estudos de Viabilidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Temozolomida/administração & dosagem , Temozolomida/efeitos adversos , Trombocitopenia/induzido quimicamente , Radioisótopos de Ítrio/efeitos adversosRESUMO
Physical activity is associated with a lower risk of disease recurrence among colon cancer survivors. The pathways through which physical activity may alter disease outcomes are unknown, but may include changes in metabolic growth factors, such as insulin. Between January 2015 and August 2015, 39 stage I-III colon cancer survivors were randomized to one of the three groups: usual care control, 150 min/week of aerobic exercise (low-dose) and 300 min/week of aerobic exercise (high-dose) for six months. The pre-specified key metabolic growth factor outcome was fasting insulin. Insulin resistance was quantified using the homeostatic model assessment. Mean age was 56.5 ± 10.0 years, 51% had stage III disease, 72% were treated with chemotherapy and the mean time since finishing treatment was 10.9 ± 6.1 months. Over six months, the low-dose group completed 141.5 ± 9.9 min/week of aerobic exercise, and the high-dose group completed 247.2 ± 10.7 min/week of aerobic exercise. Fasting insulin concentrations decreased 7.4 ± 9.4 pmol/L in the control group, 28.0 ± 8.3 pmol/L in the low-dose group and 20.7 ± 9.3 pmol/L in the high-dose group (nonlinear Ptrend = 0.042). Insulin resistance decreased 0.11 ± 0.20 in the control group, 0.63 ± 0.17 in the low-dose group and 0.43 ± 0.19 in the high-dose group (nonlinear Ptrend = 0.012). Aerobic exercise reduces insulin concentrations and insulin resistance among patients with stage I-III colon cancer. Prescribing 150 min/week of aerobic exercise may be sufficient for reducing insulin concentrations and insulin resistance, which may partially mediate the relationship between physical activity and colon cancer prognosis.