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PURPOSE: Somatostatin receptor (SSTR) imaging features are predictive of treatment outcome for neuroendocrine tumor (NET) patients receiving peptide receptor radionuclide therapy (PRRT). However, comprehensive (all metastatic lesions), longitudinal (temporal variation), and lesion-level measured features have never been explored. Such features allow for capturing the heterogeneity in disease response to treatment. Furthermore, models combining these features are lacking. In this work we evaluated the predictive power of comprehensive, longitudinal, lesion-level 68GA-SSTR-PET features combined with a multivariate linear regression (MLR) model. METHODS: This retrospective study enrolled NET patients treated with [177Lu]Lu-DOTA-TATE and imaged with [68Ga]Ga-DOTA-TATE at baseline and post-therapy. All lesions were segmented, anatomically labeled, and longitudinally matched. Lesion-level uptake and variation in uptake were measured. Patient-level features were engineered and selected for modeling of progression-free survival (PFS). The model was validated via concordance index, patient classification (ROC analysis), and survival analysis (Kaplan-Meier and Cox proportional hazards). The MLR was benchmarked against single feature predictions. RESULTS: Thirty-six NET patients were enrolled and stratified into poor and good responders (PFS ≥ 25 months). Four patient-level features were selected, the MLR concordance index was 0.826, and the AUC was 0.88 (0.85 specificity, 0.81 sensitivity). Survival analysis led to significant patient stratification (p<.001) and hazard ratio (3⨯10-5). Lastly, in a benchmark study, the MLR modeling approach outperformed all the single feature predictors. CONCLUSION: Comprehensive, lesion-level, longitudinal 68GA-SSTR-PET analysis, combined with MLR modeling, leads to excellent predictions of PRRT outcome in NET patients, outperforming non-comprehensive, patient-level, and single time-point feature predictions. MESSAGE: Neuroendocrine tumor, peptide receptor radionuclide therapy, Somatostatin Receptor Imaging, Outcome Prediction, Treatment Response Assessment.
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BACKGROUND: HER2 is an actionable target in metastatic colorectal cancer. We assessed the activity of tucatinib plus trastuzumab in patients with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer. METHODS: MOUNTAINEER is a global, open-label, phase 2 study that enrolled patients aged 18 years and older with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer at 34 sites (clinics and hospitals) in five countries (Belgium, France, Italy, Spain, and the USA). Initially, the study was designed as a single-cohort study, which was expanded following an interim analysis to include more patients. Initially, patients were given tucatinib (300 mg orally twice daily) plus intravenous trastuzumab (8 mg/kg as an initial loading dose, then 6 mg/kg every 21 days; cohort A) for the duration of treatment (until progression), and after expansion, patients were randomly assigned (4:3), using an interactive web response system and stratified by primary tumour location, to either tucatinib plus trastuzumab (cohort B) or tucatinib monotherapy (cohort C). The primary endpoint was confirmed objective response rate per blinded independent central review (BICR) for cohorts A and B combined and was assessed in patients in the full analysis set (ie, patients with HER2-positive disease who received at least one dose of study treatment). Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03043313, and is ongoing. FINDINGS: Between Aug 8, 2017, and Sept 22, 2021, 117 patients were enrolled (45 in cohort A, 41 in cohort B, and 31 in cohort C), of whom 114 patients had locally assessed HER2-positive disease and received treatment (45 in cohort A, 39 in cohort B, and 30 in cohort C; full analysis set), and 116 patients received at least one dose of study treatment (45 in cohort A, 41 in cohort B, and 30 in cohort C; safety population). In the full analysis set, median age was 56·0 years (IQR 47-64), 66 (58%) were male, 48 (42%) were female, 88 (77%) were White, and six (5%) were Black or African American. As of data cutoff (March 28, 2022), in 84 patients from cohorts A and B in the full analysis set, the confirmed objective response rate per BICR was 38·1% (95% CI 27·7-49·3; three patients had a complete response and 29 had a partial response). In cohorts A and B, the most common adverse event was diarrhoea (55 [64%] of 86), the most common grade 3 or worse adverse event was hypertension (six [7%] of 86), and three (3%) patients had tucatinib-related serious adverse events (acute kidney injury, colitis, and fatigue). In cohort C, the most common adverse event was diarrhoea (ten [33%] of 30), the most common grade 3 or worse adverse events were increased alanine aminotransferase and aspartate aminotransferase (both two [7%]), and one (3%) patient had a tucatinib-related serious adverse event (overdose). No deaths were attributed to adverse events. All deaths in treated patients were due to disease progression. INTERPRETATION: Tucatinib plus trastuzumab had clinically meaningful anti-tumour activity and favourable tolerability. This treatment is the first US Food and Drug Administration-approved anti-HER2 regimen for metastatic colorectal cancer and is an important new treatment option for chemotherapy-refractory HER2-positive metastatic colorectal cancer. FUNDING: Seagen and Merck & Co.
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Neoplasias do Colo , Neoplasias Retais , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Trastuzumab/efeitos adversos , Receptor ErbB-2/genética , Estudos de Coortes , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias do Colo/tratamento farmacológico , Diarreia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: The aim of this study was to investigate the antitumour activity, safety, and tolerability of pamiparib plus tislelizumab in patients with previously treated advanced solid tumours. METHODS: In this study, patients were enrolled into eight arms by tumour type. All received pamiparib 40 mg orally twice daily plus tislelizumab 200 mg intravenously every 3 weeks. The primary endpoint was objective response rate (ORR), assessed by the investigator per Response Evaluation Criteria in Solid Tumours v1.1. Secondary endpoints included duration of response (DoR), safety, and tolerability. RESULTS: Overall, 180 patients were enrolled. In the overall population, the ORR was 20.0% (range: 0-47.4 across study arms), with median DoR of 17.1 months (95% confidence interval [CI]: 6.2, not estimable [NE]). The highest ORR was observed in the triple-negative breast cancer (TNBC) arm (patients with BRCA1/2 mutations and/or homologous recombination deficiency) (ORR: 47.4%; median DoR: 17.1 months [95% CI: 3.0, NE]). Treatment-emergent adverse events (TEAEs) of ≥Grade 3 occurred in 61.7% of patients. Serious TEAEs occurred in 50.0% of patients. CONCLUSIONS: Pamiparib plus tislelizumab showed a variable level of antitumour activity in patients with advanced solid tumours, with the highest ORR in TNBC and was associated with a manageable safety profile. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov: NCT02660034.
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Proteína BRCA1 , Neoplasias de Mama Triplo Negativas , Humanos , Proteína BRCA2 , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.
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Adenocarcinoma , Ampola Hepatopancreática , Neoplasias do Ducto Colédoco , Neoplasias Duodenais , Humanos , Neoplasias do Ducto Colédoco/diagnóstico , Neoplasias do Ducto Colédoco/terapia , Neoplasias Duodenais/diagnóstico , Neoplasias Duodenais/terapia , Adenocarcinoma/diagnóstico , Adenocarcinoma/terapia , Neoplasias PancreáticasRESUMO
BACKGROUND: First-line therapy for advanced oesophageal cancer is currently limited to fluoropyrimidine plus platinum-based chemotherapy. We aimed to evaluate the antitumour activity of pembrolizumab plus chemotherapy versus chemotherapy alone as first-line treatment in advanced oesophageal cancer and Siewert type 1 gastro-oesophageal junction cancer. METHODS: We did a randomised, placebo-controlled, double-blind, phase 3 study across 168 medical centres in 26 countries. Patients aged 18 years or older with previously untreated, histologically or cytologically confirmed, locally advanced, unresectable or metastatic oesophageal cancer or Siewert type 1 gastro-oesophageal junction cancer (regardless of PD-L1 status), measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, and Eastern Cooperative Oncology Group performance status of 0-1, were randomly assigned (1:1) to intravenous pembrolizumab 200 mg or placebo, plus 5-fluorouracil and cisplatin (chemotherapy), once every 3 weeks for up to 35 cycles. Randomisation was stratified by geographical region, histology, and performance status. Patients, investigators, and site staff were masked to group assignment and PD-L1 biomarker status. Primary endpoints were overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 combined positive score (CPS) of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients. This trial is registered with ClinicalTrials.gov, NCT03189719, and is closed to recruitment. FINDINGS: Between July 25, 2017, and June 3, 2019, 1020 patients were screened and 749 were enrolled and randomly assigned to pembrolizumab plus chemotherapy (n=373 [50%]) or placebo plus chemotherapy (n=376 [50%]). At the first interim analysis (median follow-up of 22·6 months), pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more (median 13·9 months vs 8·8 months; hazard ratio 0·57 [95% CI 0·43-0·75]; p<0·0001), oesophageal squamous cell carcinoma (12·6 months vs 9·8 months; 0·72 [0·60-0·88]; p=0·0006), PD-L1 CPS of 10 or more (13·5 months vs 9·4 months; 0·62 [0·49-0·78]; p<0·0001), and in all randomised patients (12·4 months vs 9·8 months; 0·73 [0·62-0·86]; p<0·0001). Pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for progression-free survival in patients with oesophageal squamous cell carcinoma (6·3 months vs 5·8 months; 0·65 [0·54-0·78]; p<0·0001), PD-L1 CPS of 10 or more (7·5 months vs 5·5 months; 0·51 [0·41-0·65]; p<0·0001), and in all randomised patients (6·3 months vs 5·8 months; 0·65 [0·55-0·76]; p<0·0001). Treatment-related adverse events of grade 3 or higher occurred in 266 (72%) patients in the pembrolizumab plus chemotherapy group versus 250 (68%) in the placebo plus chemotherapy group. INTERPRETATION: Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved overall survival in patients with previously untreated, advanced oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients regardless of histology, and had a manageable safety profile in the total as-treated population. FUNDING: Merck Sharp & Dohme.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Fluoruracila/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , SobrevidaRESUMO
In this phase I, dose-escalation study, we sought to determine the maximum tolerated dose (MTD) of the anaplastic lymphoma kinase/c-ROS oncogene 1 receptor (ALK/ROS1) inhibitor ceritinib in combination with gemcitabine-based chemotherapy in patients with advanced solid tumors. Secondary objectives were characterization of the safety profile, pharmacokinetics and preliminary efficacy of these combinations, and identification of potential biomarkers of efficacy. Ceritinib was combined with gemcitabine (Arm 1), gemcitabine/nab-paclitaxel (Arm 2) or gemcitabine/cisplatin (Arm 3). Drug concentrations in plasma were measured by tandem mass spectrometric detection (LC-MS/MS). We analyzed archival tumor tissue for ALK, ROS1, hepatocyte growth factor receptor (c-MET) and c-Jun N-terminal kinase (JNK) expression by immunohistochemistry. Arm 2 closed early secondary to toxicity. Twenty-one patients were evaluable for dose-limiting toxicity (DLT). There was one DLT in Arm 1 (grade 3 ALT increase) and three DLTs in Arm 3 (grade 3 acute renal failure, grade 3 thrombocytopenia, grade 3 dyspnea). The MTD of ceritinib was determined to be 600 mg (Arm 1) and 450 mg orally daily (Arm 3). Main toxicities were hematologic, constitutional and gastrointestinal as expected by the chemotherapy backbone. The apparent clearance for ceritinib decreased substantially after repeated dosing; cisplatin did not significantly affect the pharmacokinetics of ceritinib. The overall response rate was 20%; the median progression-free survival was 4.8 months. Three out of five response-evaluable cholangiocarcinoma patients had clinical benefit. Increased expression of c-MET was associated with a lack of clinical benefit. Ceritinib in combination with gemcitabine and gemcitabine/cisplatin has a manageable toxicity profile. Further development of this strategy in tumors with ALK or ROS1 fusions is warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/análogos & derivados , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Sulfonas/administração & dosagem , Adulto , Idoso , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/farmacocinética , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/mortalidade , Neoplasias/patologia , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Sulfonas/efeitos adversos , Sulfonas/farmacocinética , GencitabinaRESUMO
Pancreatic acinar cell carcinoma (PACC) is a rare pancreatic exocrine malignancy. Compared with the more common pancreatic ductal adenocarcinoma (PDAC), PACC is more common in younger White men, has earlier stages and a lower mean age (56 vs 70 years) at the time of presentation, and has a better prognosis. In addition to differences in demographic, histologic, and clinical characteristics, PACC has a genomic profile distinct from PDAC, with only rare mutations in TP53, KRAS, and p16 that are commonly found in PDAC. This case report presents a man aged 81 years who presented with a pancreatic body mass with peripancreatic lymph node enlargement. Biopsy of the mass showed acinar cell carcinoma. The patient underwent upfront surgical resection, followed by one cycle of adjuvant gemcitabine, with stoppage of therapy due to poor tolerance. Lower-dose gemcitabine was reintroduced after disease progression 6 months later. Nab-paclitaxel was added to gemcitabine after 6 cycles because of a continued increase in the size of peripancreatic lymph nodes. Combination chemotherapy was stopped after 4 cycles because of further disease progression with new liver metastasis. Molecular testing showed the presence of an SEL1L-NTRK1 fusion. Targeted therapy was started with the oral neurotrophic tropomyosin receptor kinase (NTRK) inhibitor larotrectinib at a dosage of 100 mg twice daily. At the time of writing, the patient has been on therapy for 13 months with an exceptional radiographic response and has not experienced any grade 3 adverse effects. To our knowledge, this is the first clinical report of an NTRK gene fusion in a patient with PACC. This case study highlights the significance of tumor molecular profiling in patients with pancreatic tumors, especially rare histologies.
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Carcinoma de Células Acinares , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Acinares/tratamento farmacológico , Carcinoma de Células Acinares/genética , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Humanos , Masculino , Proteínas de Fusão Oncogênica/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas/genética , Receptor trkA/genéticaRESUMO
Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients' advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.
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Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/diagnóstico , Adenocarcinoma/terapia , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapiaRESUMO
BACKGROUND: Antiangiogenic-targeting agents have low response rates in patients with nonpancreatic neuroendocrine tumors (NETs). Nintedanib is an oral antiangiogenic agent that has inhibitory effects on the fibroblast growth factor receptor, which is highly expressed in NETs. The authors hypothesized that nintedanib would be active in patients with nonpancreatic NETs. METHODS: Patients with advanced, grade 1 or 2, nonpancreatic NETs who were receiving a stable dose of somatostatin analogue were enrolled. Nintedanib was administered at a dose of 200 mg twice daily in 28-day cycles. The primary endpoint was progression-free survival (PFS) at 16 weeks. RESULTS: Thirty-two patients were enrolled, and 30 were evaluable for the primary outcome. Most had radiographic disease progression within 12 months before enrollment. The 16-week PFS rate was 83%, and the median PFS and overall survival were 11.0 months and 32.7 months, respectively. Nintedanib was well tolerated and delayed deterioration in quality of life. The baseline serotonin level had a strong, positive correlation with activated but exhausted T cells. CONCLUSIONS: Nintedanib is active in nonpancreatic NETs. The immunosuppressive effect of serotonin should be targeted in future clinical trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Indóis/administração & dosagem , Neovascularização Patológica/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Idoso , Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Progressão da Doença , Feminino , Humanos , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neovascularização Patológica/patologia , Intervalo Livre de Progressão , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is a major cause of cancer-related death. It is a highly vascular tumour with multiple angiogenic factors, most importantly vascular endothelial growth factor (VEGF), involved in HCC progression. Tivozanib is an oral inhibitor of VEGFR-1/2/3 with promising activity against HCC in vivo. METHODS: We conducted a phase 1b/2 study of tivozanib in patients with advanced HCC. The safety, dosing, pharmacokinetics, pharmacodynamics, and preliminary antineoplastic efficacy of tivozanib were evaluated. RESULTS: Twenty-seven patients received at least one dose of tivozanib. Using a 3+3 design, the recommended phase 2 dose (RP2D) of tivozanib was determined to be 1 mg per os once daily, 21 days on-7 days off. The median progression-free and overall survival were 24 weeks and 9 months, respectively, for patients treated at RP2D. The overall response rate was 21%. Treatment was well tolerated. A significant decrease in soluble plasma VEGFR-2 was noted, assuring adequate target engagement. CONCLUSIONS: Although this study did not proceed to stage 2, there was an early efficacy signal with a very favourable toxicity profile. A phase 1/2 trial of tivozanib in combination with durvalumab is currently underway. TRIAL REGISTRATION: ClinicalTrials.gov NCT01835223, registered on 15 April 2013.
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Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/mortalidade , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/farmacologia , Quinolinas/farmacologia , Análise de Sobrevida , Adulto JovemRESUMO
The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights discuss important updates to the 2019 version of the guidelines, focusing on postoperative adjuvant treatment of patients with pancreatic cancers.
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Adenocarcinoma/diagnóstico , Adenocarcinoma/terapia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia , Gerenciamento Clínico , HumanosRESUMO
BACKGROUND: Calcitriol, the active analogue of vitamin D, is antiproliferative and enhances the cytotoxicity of several anticancer agents, including gemcitabine. The vitamin D receptor (VDR) is expressed in the tumor stroma and treatment with VDR ligands results in stromal remodeling and increased intratumoral gemcitabine delivery. Furthermore, calcitriol can decrease the activity of the gemcitabine deactivating enzyme cytidine deaminase (CDD). Because hypercalcemia has been the most worrisome calcitriol-related adverse event, the less hypercalcemic agent paricalcitol may be preferred for further investigation. METHODS: The authors undertook a phase 1 study of gemcitabine in combination with escalating doses of paricalcitol administered weekly intravenously in patients with advanced cancers. A standard 3+3 dose escalation schema was used. Pharmacokinetic assessment of gemcitabine and its metabolite 2',2'-difluorodeoxyuridine (dFdU) was performed. Pharmacodynamic assessment of paricalcitol was performed by measurement of CDD activity in peripheral blood mononuclear cells. RESULTS: A total of 44 patients were enrolled. Somnolence was the main dose-limiting toxicity. The highest dose of paricalcitol administered was 10.5 µg/kg. Hypercalcemia was infrequent and mild in severity. Paricalcitol did not appear to affect the pharmacokinetics of gemcitabine and dFdU. Evaluation of CDD activity was available for 9 patients; no clear trend for CDD activity after treatment with paricalcitol was established. The overall response rate was 4%; the rate of disease control was 67% in patients who were pretreated with gemcitabine. Progression-free and overall survival were 3.4 months and 6.5 months, respectively. CONCLUSIONS: Paricalcitol can be administered safely in doses up to 7 µg/kg weekly with fixed dose rate gemcitabine without dose-limiting hypercalcemia. To the best of the authors' knowledge, the maximum tolerated dose has not been formally established to date. Preliminary clinical activity deserves further exploration.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/análogos & derivados , Ergocalciferóis/administração & dosagem , Neoplasias/tratamento farmacológico , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/farmacocinética , Progressão da Doença , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ergocalciferóis/efeitos adversos , Ergocalciferóis/farmacocinética , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia , Resultado do Tratamento , GencitabinaRESUMO
Hereditary predisposition accounts for approximately 10% of all breast cancers and is mostly associated with germline mutations in high-penetrance genes encoding for proteins participating in DNA repair through homologous recombination (BRCA1 and BRCA2). With the advent of massive parallel next-generation DNA sequencing, simultaneous analysis of multiple genes with a short turnaround time and at a low cost has become possible. The clinical validity and utility of multi-gene panel testing is getting better characterized as more data on the significance of moderate-penetrance genes are collected from large, cancer genetic testing studies. In this chapter, we attempt to provide a general guide for interpretation of panel gene testing in breast cancer and use of the information obtained for clinical decision-making.
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Neoplasias da Mama/genética , Testes Genéticos , Neoplasias da Mama/terapia , Detecção Precoce de Câncer , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
Introduction The goal of organ dysfunction Phase I trials is to characterize the safety and pharmacokinetics of novel agents in cancer patients with liver or kidney dysfunction, but the clinical benefit is not well established. Methods We reviewed 170 patients across 15 liver dysfunction studies at our institution, grouped based on the NCI-Organ Dysfunction Working Group criteria or Child-Pugh Score. Results The median survival for the entire cohort was two months and just one month amongst patients with severe liver dysfunction. Patients with normal or mild liver dysfunction, absence of tumor in liver, good performance status, higher serum albumin and lower bilirubin, aspartate transaminase and alkaline phosphatase had improved survival by univariate analysis. Serum albumin and liver function classification remained significant by multivariate analysis. Conclusion Given poor survival of patients with liver dysfunction, we need better criteria, such as albumin levels, for optimally selecting patients for liver dysfunction studies.
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Ensaios Clínicos Fase I como Assunto , Hepatopatias , Seleção de Pacientes , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Análise de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Nintedanib is a tyrosine kinase inhibitor with efficacy in bevacizumab-resistant colorectal cancer models. This phase I/II study evaluated the recommended phase II dose and efficacy of nintedanib and capecitabine in refractory metastatic colorectal cancer. METHODS: Key eligibility criteria included refractory metastatic colorectal cancer and ECOG performance status of 1 or lower. The primary endpoint was 18-week progression-free survival (PFS). A 1-sided binomial test (at α = .1) compared the observed 18-week PFS with a historic control of .25. RESULTS: Forty-two patients were enrolled, including 39 at the recommended phase II dose. The recommended phase II dose was established to be nintedanib 200 mg by mouth twice daily and capecitabine 1000 mg/m2 by mouth twice daily. The protocol was evaluated for efficacy in 36 patients. The 18-week PFS was 42% (15/36 patients; P = .0209). Median PFS was 3.4 mo. Median overall survival was 8.9 mo. Sixteen (44%) patients experienced a grade 3/4 adverse event, most commonly fatigue (8%), palmoplantar erythrodysesthesia (8%), aspartate aminotransferase elevation (6%), asthenia (6%), pulmonary embolus (6%), and dehydration (6%). Osteopontin levels at cycle 1, day 1 and cycle 3, day 1 as well as ΔCCL2 levels correlated to disease control at 18 weeks. CONCLUSIONS: The combination of nintedanib and capecitabine is well tolerated. Clinical efficacy appears to be superior to regorafenib or tipiracil hydrochloride monotherapy. Further investigation of similar combinations is warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT02393755.
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Protocolos de Quimioterapia Combinada Antineoplásica , Capecitabina , Neoplasias Colorretais , Indóis , Intervalo Livre de Progressão , Humanos , Capecitabina/administração & dosagem , Capecitabina/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Indóis/uso terapêutico , Indóis/administração & dosagem , Indóis/efeitos adversos , Idoso , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Fadiga/induzido quimicamente , Síndrome Mão-Pé/etiologia , Idoso de 80 Anos ou mais , Resistencia a Medicamentos Antineoplásicos , Bilirrubina/sangueRESUMO
The tumor-suppressor p53 is commonly inactivated in colorectal cancer and pancreatic ductal adenocarcinoma, but existing treatment options for p53-mutant (p53Mut) cancer are largely ineffective. Here, we report a therapeutic strategy for p53Mut tumors based on abnormalities in the DNA repair response. Investigation of DNA repair upon challenge with thymidine analogs reveals a dysregulation in DNA repair response in p53Mut cells that leads to accumulation of DNA breaks. Thymidine analogs do not interrupt DNA synthesis but induce DNA repair that involves a p53-dependent checkpoint. Inhibitors of poly(ADP-ribose) polymerase (PARPis) markedly enhance DNA double-strand breaks and cell death induced by thymidine analogs in p53Mut cells, whereas p53 wild-type cells respond with p53-dependent inhibition of the cell cycle. Combinations of trifluorothymidine and PARPi agents demonstrate superior anti-neoplastic activity in p53Mut cancer models. These findings support a two-drug combination strategy to improve outcomes for patients with p53Mut cancer.
Assuntos
Neoplasias Colorretais , Neoplasias Pancreáticas , Humanos , Proteína Supressora de Tumor p53/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Reparo do DNA , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , DNA/uso terapêutico , Timidina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genéticaRESUMO
The efficacy and safety of olaratumab plus nabpaclitaxel and gemcitabine in treatment-naïve participants with metastatic pancreatic ductal adenocarcinoma was evaluated. An initial phase 1b dose-escalation trial was conducted to determine the olaratumab dose for the phase 2 trial, a randomized, double-blind, placebo-controlled trial to compare overall survival (OS) in the olaratumab arm vs. placebo arms. In phase 1b, 22 participants received olaratumab at doses of 15 and 20 mg/kg with a fixed dose of nabpaclitaxel and gemcitabine. In phase 2, 159 participants were randomized to receive olaratumab 20 mg/kg in cycle 1 followed by 15 mg/kg in the subsequent cycles (n = 81) or the placebo (n = 78) on days 1, 8, and 15 of a 28-day cycle, plus nabpaclitaxel and gemcitabine. The primary objective of the trial was not met, with a median OS of 9.1 vs. 10.8 months (hazard ratio [HR] = 1.05; 95% confidence interval [CI]: 0.728, 1.527; p = 0.79) and the median progression-free survival (PFS) was 5.5 vs. 6.4 months (HR = 1.19; 95% CI: 0.806, 1.764; p = 0.38), in the olaratumab vs. placebo arms, respectively. The most common treatment-emergent adverse event of any grade across both arms was fatigue. Olaratumab plus chemotherapy failed to improve the OS or PFS in participants with metastatic PDAC. There were no new safety signals.
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PURPOSE: Metastatic pancreatic adenocarcinoma (mPC) remains a difficult-to-treat disease. Fluorouarcil, oxaliplatin, irinotecan, and leucovorin (FFX) is a standard first-line therapy for mPC for patients with a favorable performance status and good organ function. In a phase I study, devimistat (CPI-613) in combination with modified FFX (mFFX) was deemed safe and exhibited promising efficacy in mPC. METHODS: The AVENGER 500 trial (ClinicalTrials.gov identifier: NCT03504423) is a global, randomized phase III trial conducted at 74 sites across six countries to investigate the efficacy and safety of devimistat in combination with mFFX (experimental arm) compared with standard-dose FFX (control arm) in treatment-naïve patients with mPC. Treatment, administered in once-every-2-weeks cycles until disease progression or intolerable toxicity, included intravenous devimistat at 500 mg/m2 total per day on days 1 and 3 in the experimental arm. The primary end point of the study was overall survival (OS). RESULTS: Five hundred and twenty-eight patients were randomly assigned (266 in the experimental arm and 262 in the control arm). The median OS was 11.10 months for devimistat plus mFFX versus 11.73 months for FFX (hazard ratio [HR], 0.95 [95% CI, 0.77 to 1.18]; P = .655) and median progression-free survival was 7.8 months versus 8.0 months, respectively (HR, 0.99 [95% CI, 0.76 to 1.29]; P = .94). Grade ≥3 treatment-emergent adverse events with >10% frequency in the devimistat plus mFFX arm versus the FFX arm were neutropenia (29.0% v 34.5%), diarrhea (11.2% v 19.6%), hypokalemia (13.1% v 14.9%), anemia (13.9% v 13.6%), thrombocytopenia (11.6% v 13.6%), and fatigue (10.8% v 11.5%), respectively. CONCLUSION: Devimistat in combination with mFFX did not improve long- and short-term mPC patient outcomes compared with standard FFX. There were no new toxicity signals with the addition of devimistat.
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PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) upregulates CD73, potentially contributing to immune surveillance evasion. Combining oleclumab (CD73 inhibitor) and durvalumab with chemotherapy may identify an effective treatment option. PATIENTS AND METHODS: Multicenter Phase 1b/2 randomized clinical trial in patients with metastatic PDAC, untreated (Cohort A) or previously received gemcitabine-based chemotherapy (Cohort B) (NCT03611556). During escalation, patients received oleclumab 1500 or 3000 mg, durvalumab 1500 mg, and gemcitabine plus nab-paclitaxel (GnP) (Cohort A; n=14) or modified FOLFOX (Cohort B; n=11). During expansion, Cohort A patients (n=170) were randomized to: GnP (Arm A1), oleclumab (recommended Phase 2 dose; RP2D) with GnP (Arm A2), or oleclumab (RP2D) with durvalumab plus GnP (Arm A3). Primary objectives were safety (escalation) and objective response rate (ORR) (expansion). Secondary objectives included progression-free survival (PFS) and overall survival (OS). RESULTS: During escalation, 1/11 patients from Cohort B (oleclumab 3000 mg) experienced two dose-limiting toxicities. Oleclumab RP2D was 3000 mg. During expansion, Grade ≥3 treatment-related adverse events occurred in 67.7% (42/62) of patients in A1, 73.7% (28/38) in A2, and 77.1% (54/70) in A3. ORR was 29.0%, 21.1%, and 32.9% in A1, A2, and A3, respectively (A1 vs A3; p=0.650). PFS (hazard ratio [HR]=0.72; 95% confidence interval [CI]: 0.47, 1.11) and OS (HR=0.75; 95% CI: 0.50, 1.13) were similar for A3 versus A1. Patients with high CD73 expression had improved PFS and OS in A3 versus A1, although this should be interpreted with caution. CONCLUSIONS: Although the safety profile was acceptable, this study did not meet its primary efficacy endpoint.
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Pancreatic cancer (PanCa) is a highly fatal malignancy with few modifiable risk and prognostic factors. This study investigates the association between cola, diet cola, and non-cola soft drink consumption and PanCa risk and mortality. A retrospective study was conducted using data from the Patient Epidemiology Data System (1982-1998) at Roswell Park Comprehensive Cancer Center (Buffalo, NY, USA), including 213 PanCa patients and 852 cancer-free controls. Data were collected using a self-administered questionnaire, including a 46-item food frequency questionnaire (FFQ). Multivariable logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) of cola, diet cola, and non-cola soft drink consumption and PanCa risk. Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% CIs of cola, diet cola, and non-cola soft drink consumption and PanCa mortality. Stratified analyses were conducted by sex, body mass index (BMI), and smoking status. We observed significant 55% increased odds of PanCa among patients consuming ≥1 regular cola per day (OR: 1.55, 95% CI: 1.01-2.39). We also observed non-significant 38% increased hazard of mortality among patients consuming ≥1 regular cola per day (HR: 1.38, 95% CI: 0.91-2.07). We conclude that regular cola consumption is a modifiable lifestyle that may be associated with PanCa risk and mortality following diagnosis.