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BACKGROUND: Cisplatin/gemcitabine is standard first-line treatment for patients with advanced biliary tract cancer (ABC). NUC-1031 (phosphoramidate transformation of gemcitabine) is designed to enhance efficacy by maximizing intratumoral active metabolites. METHODS: Patients with untreated ABC, Eastern Cooperative Oncology Group performance status 0-1 received NUC-1031 (625 or 725 mg/m2 ) and cisplatin (25 mg/m2 ) on days 1 and 8, every 21 days. Primary objectives were safety and maximum tolerated dose; secondary objectives were objective response rate (ORR), pharmacokinetics, progression-free survival (PFS), and overall survival (OS). RESULTS: Twenty-one patients (median age 61 years, n = 13 male; 17 cholangiocarcinoma, 2 ampullary, and 2 gallbladder cancer) received NUC-1031 625 mg/m2 (n = 8 and expansion n = 7; median six cycles) or 725 mg/m2 (n = 6; median 7.5 cycles). Treatment was well tolerated; most common treatment-emergent grade 3-4 adverse events occurring in more than one patient with 625 mg/m2 NUC-1031 were increased gamma-glutamyl transferase (GGT), 40%; alanine aminotransferase, 20%; bilirubin, 13%; neutropenia, 27%; decreased white cell count, 20%; thrombocytopenia, 13%; nausea, 13%; diarrhea, 13%; fatigue, 13%; and thrombus, 20% and with 725 mg/m2 , increased GGT, 67%, and fatigue, 33%. NUC-1031 725 mg/m2 was selected as the recommended dose with cisplatin in ABC. ORR was 33% (one complete response, six partial responses), DCR was 76%, median PFS was 7.2 months (95% confidence interval [CI], 4.3-10.1), and median OS was 9.6 months (95% CI, 6.7-13.1). The median estimates of area under the plasma concentration-time curve from time 0 to last measurable time and maximum concentration were highest for NUC-1031 (218-324 µgâ¢h/mL and 309-889 µg/mL, respectively) and lowest for di-fluoro-deoxycytidine (0.47-1.56 µgâ¢h/mL and 0.284-0.522 µg/mL, respectively). CONCLUSION: This is the first study reporting on the combination of NUC-1031 with cisplatin in ABC and demonstrated a favorable safety profile; 725 mg/m2 NUC-1031 in combination with cisplatin is undergoing phase III trial evaluation in ABC. (ClinicalTrials.gov ID: NCT02351765; EudraCT ID: 2015-000100-26). IMPLICATIONS FOR PRACTICE: The prognosis for patients with advanced biliary tract cancer (ABC) is approximately 1 year, and new treatment options are required. The cisplatin/gemcitabine combination is standard first-line treatment for patients with ABC. NUC-1031 is a phosphoramidate transformation of gemcitabine and is designed to enhance efficacy by maximizing intratumoral active metabolites. This phase Ib study (ABC-08) demonstrated a favorable safety profile of NUC-1031 in combination with cisplatin for the first-line treatment of patients with ABC, and 725 mg/m2 NUC-1031 was recommended in combination with cisplatin for phase III trial evaluation; the NuTide:121 global randomized study is currently enrolling.
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Neoplasias dos Ductos Biliares , Neoplasias do Sistema Biliar , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Ductos Biliares Intra-Hepáticos , Neoplasias do Sistema Biliar/tratamento farmacológico , Cisplatino/uso terapêutico , Monofosfato de Citidina/análogos & derivados , Intervalo Livre de Doença , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: TG01 is the first cancer immunotherapy targeting KRAS oncogenic mutations. This study assessed the safety and efficacy of TG01/GM-CSF in patients with resected pancreatic adenocarcinoma. METHODS: Patients with stage I or II pancreatic adenocarcinoma who had undergone surgical resection (R0 or R1) received adjuvant gemcitabine with TG01/GM-CSF using two schedules of vaccination. Immune response was defined as a positive delayed-type hypersensitivity (DTH) response and/or positive T-cell proliferation assay. RESULTS: Thirty-two patients were enrolled between February 2013 and May 2016. Nineteen were treated with the high antigen burden, with four serious adverse reactions considered possibly related to TG01 treatment, including three allergic reactions. On this basis, a further 13 patients received a modified vaccination schedule with reduced antigen burden, with no serious adverse events related to TG01. Ninety-five percent patients in the main cohort and 92% in the modified cohort had a positive immune response. Median overall survival (OS) was 33.1 months, and median disease-free survival (DFS) was 13.9 months for the main cohort. For the modified cohort, the median OS was 34.3 months and median DFS was 19.5 months. CONCLUSIONS: TG01/GM-CSF with gemcitabine was well tolerated, with high levels of immune activation. OS and DFS compare favourably with published data for adjuvant gemcitabine. CLINICAL TRIAL REGISTRATION: This clinical trial was registered at ClinicalTrials.gov (NCT02261714).
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Adenocarcinoma/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/patologia , Idoso , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Gencitabina , Neoplasias PancreáticasRESUMO
BACKGROUND/AIMS: To assess health-related quality of life (HRQoL), treatment patterns, and clinical outcomes of adult (≥18 years) patients with advanced (unresectable or metastatic) pancreatic neuroendocrine neoplasms (PanNENs) treated with everolimus in routine clinical practice. METHODS: In a prospective, non-interventional, multi-center study patients administered at least one 10 mg dose of everolimus were evaluated for change in HRQoL (EORTC QLQ-C30 Global Health Status scale) from baseline after 6 months treatment (primary endpoint). Secondary endpoints included disease-specific HRQoL measures (EORTC QLQ-G.I.NET21), clinical outcomes, everolimus treatment patterns, and safety. RESULTS: Forty-eight patients were recruited (between August 2013 and March 2015); the median treatment duration was 27.8 months. EORTC QLQ-C30 Global Health score was not significantly different from baseline after 6 months of treatment (mean difference -1.9 points, p = 0.660, n = 30). In pairwise analyses, the only significant changes in HRQoL from baseline were for EORTC QLQ-C30 physical functioning score at month 3 (adjusted mean difference -8.8 points, p = 0.002, n = 36) and the EORTC QLQ-G.I.NET21 disease-related worries scores at months 1 and 2 (adjusted mean differences: -11.5 points [p = 0.001, n = 44] and -8.8 points [p = 0.017, n = 43], respectively). Disease progression or death was recorded in 44.4% (n = 20/45) patients during follow-up; median progression-free survival was 25.1 months and the cumulative survival rate at 3 years was 71%. No new safety signals were detected. CONCLUSIONS: The OBLIQUE study demonstrates that HRQoL is maintained in patients with PanNENs during treatment with everolimus in a UK real-world setting. This study adds to the limited HRQoL data available in this patient group.
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Antineoplásicos/uso terapêutico , Everolimo/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Adulto , Idoso , Antineoplásicos/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Everolimo/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Inquéritos e Questionários , Taxa de SobrevidaRESUMO
BACKGROUND: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. METHODS: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m2 oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. FINDINGS: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group. INTERPRETATION: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.
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Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Capecitabina/administração & dosagem , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/efeitos adversos , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/cirurgia , Quimioterapia Adjuvante , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: Previous observations suggest suboptimal 'real world' survival outcomes for advanced pancreatic adenocarcinoma. We hypothesized that centralisation of advanced pancreatic adenocarcinoma management would improve chemotherapy treatment and survival from the disease. METHODS: The data was prospectively collected on all cases of advanced pancreatic adenocarcinoma reviewed through Clatterbridge Cancer Centre according to two groups; 1 October 2009-31st Dec 2010 (devolved care) or 1 January 2013-31 March 2014 (centralised care). Analysis included treatment received, 30-day chemotherapy mortality rate and overall survival (OS). RESULTS: More patients received chemotherapy with central care (67.0% (n=115) vs 43.0% (n=121); P=2.2 × 10-4) with no difference in 30-day mortality (20.8% vs 25%; P=0.573) but reduced time to commencement of chemotherapy (18 vs 28 days, P=1.0 × 10-3). More patients received second-line chemotherapy with central care (23.4% vs 1.9%, P=1.4 × 10-4), while OS was significantly increased with central care (median: Five vs three months, HR 0.785, P=0.045). Exploratory analysis suggested that it was those with a poorer performance status, elderly or with metastatic disease who benefited the most from transition to central care. CONCLUSIONS: A centralised clinic model for advanced pancreatic cancer management resulted in prompt, safe and higher use of chemotherapy compared with devolved care. This was associated with a modest survival benefit. Prospective studies are required to validate the findings reported and the basis for improved survival with centralised care.
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Adenocarcinoma/terapia , Institutos de Câncer/organização & administração , Acessibilidade aos Serviços de Saúde/organização & administração , Neoplasias Pancreáticas/terapia , Equipe de Assistência ao Paciente/organização & administração , Programas Médicos Regionais/organização & administração , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Análise de Sobrevida , Cuidado Transicional/organização & administração , Resultado do TratamentoRESUMO
Polymorphisms in the vascular endothelial growth factor (VEGF)/angiogenesis pathway have been implicated previously in cancer risk, prognosis and response to therapy including in esophageal adenocarcinoma. Prior esophageal adenocarcinoma studies focused on using candidate polymorphisms, limiting the discovery of novel polymorphisms. Here, we applied the tagSNP (single nucleotide polymorphism) approach to identify new VEGF pathway polymorphisms associated with esophageal adenocarcinoma prognosis and validated them in an independent cohort of esophageal adenocarcinoma patients. In 231 esophageal adenocarcinoma patients of all stages/treatment plans, 58 genetic polymorphisms (18 KDR, 7 VEGFA and 33 FLT1) selected through tagging and assessment of predicted function were genotyped. Cox-proportional hazard models adjusted for important socio-demographic and clinico-pathological factors were applied to assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then validated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis and median OS and PFS were 20 and 12 months, respectively. KDR rs17709898 was found significantly associated with PFS (adjusted hazard ratio, aHR = 0.69, 95% confidence interval (CI): 0.53-0.90; P = 5.9E-3). FLT1 rs3794405 and rs678714 were significantly associated with OS (aHR = 1.44, 95% CI: 1.04-1.99; P = 0.03 and aHR = 1.50, 95% CI: 1.01-2.24; P = 0.045, respectively). No VEGFA polymorphisms were found significantly associated with either outcome. Upon validation, FLT1 rs3794405 remained strongly associated with OS (aHR = 1.59, 95% CI: 1.04-2.44; P = 0.03). FLT1 rs3794405 is significantly associated with OS in esophageal adenocarcinoma, whereby each variant allele confers a 45-60% increased risk of mortality. Validation and evaluation of this association in other cancer sites are warranted.
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Adenocarcinoma/genética , Neoplasias Esofágicas/genética , Neovascularização Patológica/genética , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Neoplasias Esofágicas/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
There are very few xenograft models available for the study of esophageal (E) and gastro-esophageal junction (GEJ) cancer. Using a NOD/SCID model, we implanted 90 primary E and GEJ tumors resected from patients and six endoscopic biopsy specimens. Of 69 resected tumors with histologically confirmed viable adenocarcinoma or squamous cell carcinoma, 22 (32%) was engrafted. One of 11 tumors, considered to have had a complete pathological response to neo-adjuvant chemo-radiation, also engrafted. Of the 23 patients whose tumors were engrafted, 65% were male; 30% were early stage while 70% were late stage; 22% received neo-adjuvant chemo-radiation; 61% were GEJ cancers. Engraftment occurred in 18/54 (33%) adenocarcinomas and 5/16 (31%) squamous cell carcinomas. Small endoscopic biopsy tissue had a 50% (3/6) engraftment rate. Of the factors analyzed, pretreatment with chemo-radiation and well/moderate differentiation showed significantly lower correlation with engraftment (P<0.05). In the subset of patients who did not receive neo-adjuvant chemo-radiation, 18/41 (44%) engrafted compared with those with pretreatment where 5/29 (17%, P=0.02) engrafted. Primary xenograft lines may be continued through 4-12 passages. Xenografts maintained similar histology and morphological characteristics with only minor variations even after multiple passaging in most instances.
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Adenocarcinoma/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Neoplasias Experimentais/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Sobrevivência de Enxerto , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Transplante de NeoplasiasRESUMO
Phase 3 trials have established standard first-line (1L) and 2L systemic therapy options for patients with advanced biliary cancer (ABC). However, a standard 3L treatment remains undefined. Clinical practice and outcomes for 3L systemic therapy in patients with ABC were therefore evaluated from three academic centres. Included patients were identified using institutional registries; demographics, staging, treatment history, and clinical outcomes were collected. Kaplan-Meier methods were used to assess progression-free survival (PFS) and overall survival (OS). Ninety-seven patients, treated between 2006 and 2022, were included; 61.9% had intrahepatic cholangiocarcinoma. At the time of analysis, there had been 91 deaths. Median PFS from initiating 3L palliative systemic therapy (mPFS3) was 3.1 months (95%CI 2.0-4.1), while mOS3 was 6.4 months (95%CI 5.5-7.3); mOS1 was 26.9 months (95%CI 23.6-30.2). Among patients with a therapy-targeted molecular aberration (10.3%; n = 10; all received in 3L), mOS3 was significantly improved versus all other included patients (12.5 vs. 5.9 months; p = 0.02). No differences in OS1 were demonstrated between anatomical subtypes. Fourth-line systemic therapy was received by 19.6% of patients (n = 19). This international multicentre analysis documents systemic therapy use in this select patient group, and provides a benchmark of outcomes for future trial design.
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Background: The prognosis for patients with poorly-differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC) is poor. A recognised first-line (1L) treatment for advanced disease is etoposide/platinum-based chemotherapy with no standard second-line (2L) treatment. Methods: Patients with histologically-confirmed PD-EP-NEC (Ki-67 > 20%; Grade 3) received IV liposomal irinotecan (nal-IRI) (70 mg/m2 free base)/5-FU (2400 mg/m2)/folinic acid, Q14 days (ARM A), or IV docetaxel (75 mg/m2), Q21 days (ARM B), as 2L therapy. Primary endpoint was 6-month progression-free survival (PFS) rate (80% power to demonstrate one-sided 95% lower confidence interval excluded 15% (target level of efficacy: 30%)). Secondary endpoints: objective response rate (ORR), median PFS, overall survival (OS), toxicity and patient-reported quality-of-life (QoL) (ClinicalTrials.gov: NCT03837977). Findings: Of 58 patients (29 each arm); 57% male, 90% ECOG PS 0/1, 10% PS 2, 89.7% Ki-67 ≥ 55%, primary site: 70.7%-gastrointestinal, 18.9%-other, 10.3%-unknown, 91.4%/6.9%/1.7% were resistant/sensitive/intolerant to 1L platinum-based treatment, respectively. The primary end-point of 6-month PFS rate was met by ARM A: 29.6% (lower 95% Confidence-Limit (CL) 15.7), but not by ARM B: 13.8% (lower 95%CL:4.9). ORR, median PFS and OS were 11.1% (95%CI:2.4-29.2) and 10.3% (95%CI:2.2-27.4%); 3 months (95%CI:2-6) and 2 months (95%CI:2-2); and 6 months (95%CI:3-10) and 6 months (95%CI:3-9) in ARMS A and B, respectively. Adverse events ≥ grade 3 occurred in 51.7% and 55.2% (1 and 6 discontinuations due to toxicity in ARMS A and B), respectively. QoL was maintained in ARM A, but not ARM B. Interpretation: nal-IRI/5-FU/folinic acid, but not docetaxel, met the primary endpoint, with manageable toxicity and maintained QoL, with no difference in OS. ORR and median PFS were similar in both arms. This study provides prospective efficacy, toxicity and QoL data in the 2L setting in a disease group of unmet need, and represents some of the strongest evidence available to recommend systemic treatment to these patients. Funding: Servier.
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With its significant contribution to cancer mortality globally, advanced colorectal cancer (CRC) requires new treatment strategies. However, despite recent good results for mismatch repair (MMR)-deficient CRC and other malignancies, such as melanoma, the vast majority of MMR-proficient CRCs are resistant to checkpoint inhibitor (CKI) therapy. MMR-proficient CRCs commonly develop from precursor adenomas with enhanced Wnt-signalling due to adenomatous polyposis coli (APC) mutations. In melanomas with enhanced Wnt signalling due to stabilized ß-catenin, immune anergy and resistance to CKI therapy has been observed, which is dependent on micro-environmental myelomonocytic (MM) cell depletion in melanoma models. However, MM populations of colorectal adenomas or CRC have not been studied. To characterize resident intestinal MM cell populations during the early stages of tumorigenesis, the present study utilized the ApcMin/+ mouse as a model of MMR-proficient CRC, using enhanced green fluorescent protein (EGFP) expression in the mouse lysozyme (M-lys) lys-EGFP/+ mouse as a pan-myelomonocytic cell marker and a panel of murine macrophage surface markers. Total intestinal lamina propria mononuclear cell (LPMNC) numbers significantly decreased with age (2.32±1.39×107 [n=4] at 33 days of age vs. 1.06±0.24×107 [n=8] at 109 days of age) during intestinal adenoma development in ApcMin/+ mice (P=0.05; unpaired Student's t-test), but not in wild-type littermates (P=0.35). Decreased total LPMNC numbers were associated with atrophy of intestinal lymphoid follicles and the absence of MM/lymphoid cell aggregates in ApcMin/+ mouse intestine, but not spleen, compared with wild-type mice. Furthermore, during the early stage of intestinal adenoma development, there was a two-fold reduction of M-lys expressing cells (P=0.05) and four-fold reduction of ER-HR3 (macrophage sub-set) expressing cells (P=0.05; two tailed Mann-Whitney U test) in mice with reduced total intestinal LPMNCs (n=3). Further studies are necessary to determine the relevance of these findings to immune-surveillance of colorectal adenomas or MMR-proficient CRC CKI therapy resistance.
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BACKGROUND: The pathogenesis of brain metastasis as a relatively rare complication of epithelial ovarian cancer is poorly understood. Some observations suggest that brain metastases from ovarian cancer are becoming more common and that ovarian cancers, which metastasize to the brain, may have a different biological pattern. METHODS: Data were extracted from the Edinburgh Ovarian Cancer Database on a cohort of patients managed at the Edinburgh Cancer Centre (UK) between 1998 and 2004. The incidence of brain metastases was compared between patients with previous treatment for early breast cancer and patients without previous treatment for early breast cancer. Baseline characteristics, the time to cancer antigen 125 relapse, the time to brain metastasis, and the radiological pattern of relapse were also compared between these patients. RESULTS: We demonstrate a higher incidence of serous histology (P = 0.02) in patients in remission from early breast cancer and that the incidence of brain metastases in this group is 11.6% compared with 1.1% in patients without prior breast cancer (relative risk = 10.5, P < 0.001). Brain metastases were clinically evident after 45.6 months in patients with previous breast cancer compared with 21 months in patients without previous breast cancer (P = 0.008). Among the patients who developed brain metastases, isolated retroperitoneal lymph node recurrence was noticed in patients in remission from early breast cancer but rarely in other patients. CONCLUSIONS: Ovarian cancer patients with a history of early breast cancer have a higher incidence of brain metastases and a different pattern of disease recurrence. We speculate that a higher incidence of breast cancer early onset mutations in patients with previous early breast cancer underlies these observed differences.
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Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/secundário , Neoplasias da Mama/epidemiologia , Carcinoma/epidemiologia , Idoso , Neoplasias da Mama/patologia , Carcinoma/patologia , Carcinoma Epitelial do Ovário , Estudos de Coortes , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/epidemiologia , Neoplasias Epiteliais e Glandulares/patologia , Segunda Neoplasia Primária/epidemiologia , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologia , Recidiva , Risco , Fatores de TempoRESUMO
BACKGROUND: The safety of conservative surgery and the benefit of additional interventions after surgery for borderline ovarian tumours are unknown. OBJECTIVES: To evaluate the benefits and harm of different treatment modalities offered for borderline ovarian tumours. SEARCH STRATEGY: We searched the Cochrane Gynaecological Cancer Group Trials Register to 2009, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 4), MEDLINE and EMBASE to 2009. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared different interventions in adult women diagnosed with borderline ovarian tumours of any histological variant. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data and assessed risk of bias. MAIN RESULTS: We identified seven RCTs that enrolled 372 women. We could not pool results of trials as the treatment comparisons differed.Six RCTs (n = 340) conducted over 15 years ago, evaluated adjuvant therapy (chemotherapy, pelvic external irradiation or intra-peritoneal radioactive isotope therapy) after radical surgery; over 87% of participants had Stage I tumours. Most participants were followed up for over 10 years. Overall and recurrence-free survival were similar between both arms of these trials, except that one trial (n = 66) showed a significantly lower survival (P = 0.03) in women who received chemotherapy (thio-TEPA). Adverse effects of treatment were incompletely reported and all six trials were at high risk of bias.One further trial (n = 32) that recruited participants with bilateral serous tumours who were wishing fertility preservation, revealed a significantly increased chance of pregnancy (hazard ratio (HR) = 3.3, 95% CI 1.4 to 8.0) but non-significantly earlier disease recurrence (HR = 1.5, 95% CI 0.6 to 3.8) in the women who had ultra-conservative surgery (bilateral cystectomy) than in those who had conservative surgery (cystectomy and contralateral oophorectomy). This trial was at low risk of bias.Quality of life (QoL) was not documented in any included trial. We did not find any trials that compared radical with conservative surgery or laparoscopy with laparotomy. AUTHORS' CONCLUSIONS: We did not find evidence to support the use of any specific type of adjuvant therapy for borderline ovarian tumours. RCTs evaluating the benefit of adjuvant therapy with optimally dosed chemotherapy and newer targeted drugs are necessary, particularly for advanced borderline ovarian tumours. The low mortality from borderline ovarian tumours should make recurrence-free survival, time to recurrence and morbidity important end points in such trials.Bilateral cystectomy may be offered to women with bilateral borderline ovarian tumours diagnosed intra-operatively who are wishing to preserve their fertility. Similarly, women who had RCTs comparing radical with conservative surgery and comparing laparoscopy with laparotomy are needed.
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Neoplasias Ovarianas/terapia , Adulto , Quimioterapia Adjuvante , Feminino , Humanos , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Gravidez , Qualidade de Vida , Radioterapia Adjuvante , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
INTRODUCTION: Poorly differentiated (PD), extrapulmonary (EP), neuroendocrine carcinomas (NECs) are rare but aggressive neuroendocrine neoplasms. First-line treatment for advanced disease is an etoposide and platinum-based chemotherapy combination. There is no established second-line treatment for patients with PD-EP-NEC, and this is an area of unmet need. METHODS AND ANALYSIS: NET-02 is a UK, multicentre, randomised (1:1), parallel group, open-label, phase II, single-stage selection trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients with progressive PD-EP-NEC. One hundred and two eligible participants will be randomised to receive either nal-IRI/5-FU/folinic acid or docetaxel. The primary objective is to determine the 6-month progression-free survival (PFS) rate. The secondary objectives of this study are to determine PFS, overall survival, objective response rate, toxicity, quality of life and whether neuron-specific enolase is predictive of treatment response. If either treatment is found to have a 6-month PFS rate of at least 25%, that treatment will be considered for a phase III trial. If both treatments meet this target, prespecified selection criteria will be applied to establish which treatment to take forward. ETHICS AND DISSEMINATION: This study has ethical approval from the Greater Manchester Central Research Ethics Committee (reference no. 18/NW/0031) and clinical trial authorisation from the Medicine and Healthcare Products Regulatory Agency. Results will be published in peer-reviewed journals and uploaded to the European Union Clinical Trials Register. TRIAL REGISTRATION NUMBERS: ISRCTN10996604, NCT03837977, EudraCT Number: 2017-002453-11.
Assuntos
Carcinoma Neuroendócrino , Docetaxel/uso terapêutico , Fluoruracila/uso terapêutico , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto , Humanos , Estudos Multicêntricos como Assunto , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Importance: The patterns of disease recurrence after resection of pancreatic ductal adenocarcinoma with adjuvant chemotherapy remain unclear. Objective: To define patterns of recurrence after adjuvant chemotherapy and the association with survival. Design, Setting, and Participants: Prospectively collected data from the phase 3 European Study Group for Pancreatic Cancer 4 adjuvant clinical trial, an international multicenter study. The study included 730 patients who had resection and adjuvant chemotherapy for pancreatic cancer. Data were analyzed between July 2017 and May 2019. Interventions: Randomization to adjuvant gemcitabine or gemcitabine plus capecitabine. Main Outcomes and Measures: Overall survival, recurrence, and sites of recurrence. Results: Of the 730 patients, median age was 65 years (range 37-81 years), 414 were men (57%), and 316 were women (43%). The median follow-up time from randomization was 43.2 months (95% CI, 39.7-45.5 months), with overall survival from time of surgery of 27.9 months (95% CI, 24.8-29.9 months) with gemcitabine and 30.2 months (95% CI, 25.8-33.5 months) with the combination (HR, 0.81; 95% CI, 0.68-0.98; P = .03). The 5-year survival estimates were 17.1% (95% CI, 11.6%-23.5%) and 28.0% (22.0%-34.3%), respectively. Recurrence occurred in 479 patients (65.6%); another 78 patients (10.7%) died without recurrence. Local recurrence occurred at a median of 11.63 months (95% CI, 10.05-12.19 months), significantly different from those with distant recurrence with a median of 9.49 months (95% CI, 8.44-10.71 months) (HR, 1.21; 95% CI, 1.01-1.45; P = .04). Following recurrence, the median survival was 9.36 months (95% CI, 8.08-10.48 months) for local recurrence and 8.94 months (95% CI, 7.82-11.17 months) with distant recurrence (HR, 0.89; 95% CI, 0.73-1.09; P = .27). The median overall survival of patients with distant-only recurrence (23.03 months; 95% CI, 19.55-25.85 months) or local with distant recurrence (23.82 months; 95% CI, 17.48-28.32 months) was not significantly different from those with only local recurrence (24.83 months; 95% CI, 22.96-27.63 months) (P = .85 and P = .35, respectively). Gemcitabine plus capecitabine had a 21% reduction of death following recurrence compared with monotherapy (HR, 0.79; 95% CI, 0.64-0.98; P = .03). Conclusions and Relevance: There were no significant differences between the time to recurrence and subsequent and overall survival between local and distant recurrence. Pancreatic cancer behaves as a systemic disease requiring effective systemic therapy after resection. Trial Registration: ClinicalTrials.gov identifier: NCT00058201, EudraCT 2007-004299-38, and ISRCTN 96397434.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/cirurgia , Recidiva Local de Neoplasia/etiologia , Neoplasias Pancreáticas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Capecitabina/administração & dosagem , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/mortalidade , Quimioterapia Adjuvante , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Estudos Prospectivos , Resultado do Tratamento , GencitabinaRESUMO
PURPOSE: Brahma (BRM) is a critical catalytic subunit of the SWI/SNF chromatin remodeling complex; expression of BRM is commonly lost in various cancer types. BRM promoter polymorphisms (BRM-741; BRM-1321) are associated with loss of BRM expression, and with cancer risk/survival. We evaluated these two polymorphisms in the overall survival (OS) of esophageal adenocarcinoma (EAC) patients. RESULTS: Of 270 patients, 37% were stage IV. Minor allele frequencies were 47-49%; 15% were double-homozygotes. When compared to the wild-type genotype, the homozygous variant of BRM-741 carried an adjusted OS hazard ratio (aHR) of 1.64 (95% CI:1.1-2.4); for BRM-1321, the aHR was 2.09 (95% CI:1.4-3.0). Compared to the double wild-type, carrying homozygous variants of both promoter polymorphisms (double-homozygote) yielded an aHR of 2.21 (95% CI:1.4-3.6). Directions/magnitudes of associations were similar in subsets by age, gender, smoking status, use of platinum agents, and disease stage, and for progression-free survival. MATERIALS AND METHODS: In a cohort of EAC patients of all stages (84% male; median age of 64 years), two BRM polymorphisms were genotyped. Cox proportional hazards models, adjusted for known prognostic variables, estimated the association of polymorphisms with OS. CONCLUSIONS: BRM polymorphisms were associated with OS in EAC in this study. Validation studies are warranted.
Assuntos
Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo Genético , Regiões Promotoras Genéticas , Fatores de Transcrição/genética , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Terapia Combinada , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de SobrevidaRESUMO
Polymorphisms in miRNA and miRNA pathway genes have been previously associated with cancer risk and outcome, but have not been studied in esophageal adenocarcinoma outcomes. Here, we evaluate candidate miRNA pathway polymorphisms in esophageal adenocarcinoma prognosis and attempt to validate them in an independent cohort of esophageal adenocarcinoma patients. Among 231 esophageal adenocarcinoma patients of all stages/treatment plans, 38 candidate genetic polymorphisms (17 biogenesis, 9 miRNA targets, 5 pri-miRNA, 7 pre-miRNA) were genotyped and analyzed. Cox proportional hazard models adjusted for sociodemographic and clinicopathological covariates helped assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then evaluated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis, and median OS and PFS were 20 and 12 months, respectively. GEMIN3 rs197412 (aHR = 1.37, 95%CI: [1.04-1.80]; P = 0.02), hsa-mir-124-1 rs531564 (aHR = 0.60, 95% CI: [0.53-0.90]; P = 0.05), and KIAA0423 rs1053667 (aHR = 0.51, 95% CI: [0.28-0.96]; P = 0.04) were found associated with OS. Furthermore, GEMIN3 rs197412 (aHR = 1.33, 95% CI: [1.03-1.74]; P = 0.03) and KRT81 rs3660 (aHR = 1.29, 95% CI: [1.01-1.64]; P = 0.04) were found associated with PFS. Although none of these polymorphisms were significant in the second cohort, hsa-mir-124-1 rs531564 and KIAA0423 rs1053667 had trends in the same direction; when both cohorts were combined together, GEMIN3 rs197412, hsa-mir-124-1 rs531564, and KIAA0423 rs1053667 remained significantly associated with OS. We demonstrate the association of multiple miRNA pathway polymorphisms with esophageal adenocarcinoma prognosis in a discovery cohort of patients, which did not validate in a separate cohort but had consistent associations in the pooled cohort. Larger studies are required to confirm/validate the prognostic value of these polymorphisms in esophageal adenocarcinoma.