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1.
Br J Cancer ; 125(10): 1350-1355, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34526664

RESUMO

BACKGROUND: Advanced hepatocellular carcinoma (HCC) is commonly diagnosed using non-invasive radiological criteria (NIRC) defined by the European Association for the Study of the Liver or the American Association for the Study of Liver Diseases. In 2017, The National Institute for Clinical Excellence mandated histological confirmation of disease to authorise the use of sorafenib in the UK. METHODS: This was a prospective multicentre audit in which patients suitable for sorafenib were identified at multidisciplinary meetings. The primary analysis cohort (PAC) was defined by the presence of Child-Pugh class A liver disease and performance status 0-2. Clinical, radiological and histological data were reported locally and collected on a standardised case report form. RESULTS: Eleven centres reported 418 cases, of which 361 comprised the PAC. Overall, 76% had chronic liver disease and 66% were cirrhotic. The diagnostic imaging was computed tomography in 71%, magnetic resonance imaging in 27% and 2% had both. Pre-existing histology was available in 45 patients and 270 underwent a new biopsy, which confirmed HCC in 93.4%. Alternative histological diagnoses included cholangiocarcinoma (CC) and combined HCC-CC. In cirrhotic patients, NIRC criteria had a sensitivity of 65.4% and a positive predictive value of 91.4% to detect HCC. Two patients (0.7%) experienced mild post-biopsy bleeding. CONCLUSION: The diagnostic biopsy is safe and feasible for most patients eligible for systemic therapy.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia/estatística & dados numéricos , Carcinoma Hepatocelular/tratamento farmacológico , Colangiocarcinoma , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Imageamento por Ressonância Magnética/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Reino Unido , Adulto Jovem
2.
Lancet ; 389(10073): 1011-1024, 2017 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-28129987

RESUMO

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.


Assuntos
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 , Gencitabina
3.
Lancet Oncol ; 18(3): 357-370, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28163000

RESUMO

BACKGROUND: Peri-operative chemotherapy and surgery is a standard of care for patients with resectable oesophagogastric adenocarcinoma. Bevacizumab, a monoclonal antibody against VEGF, improves the proportion of patients responding to treatment in advanced gastric cancer. We aimed to assess the safety and efficacy of adding bevacizumab to peri-operative chemotherapy in patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. METHODS: In this multicentre, randomised, open-label phase 2-3 trial, we recruited patients aged 18 years and older with histologically proven, resectable oesophagogastric adenocarcinoma from 87 UK hospitals and cancer centres. We randomly assigned patients 1:1 to receive peri-operative epirubicin, cisplatin, and capecitabine chemotherapy or chemotherapy plus bevacizumab, in addition to surgery. Patients in the control group (chemotherapy alone) received three pre-operative and three post-operative cycles of epirubicin, cisplatin, and capecitabine chemotherapy: 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 and 1250 mg/m2 oral capecitabine on days 1-21. Patients in the investigational group received the same treatment as the control group plus 7·5 mg/kg intravenous bevacizumab on day 1 of every cycle of chemotherapy and for six further doses once every 21 days following chemotherapy, as maintenance treatment. Randomisation was done by means of a telephone call to the Medical Research Council Clinical Trials Unit, where staff used a computer programme that implemented a minimisation algorithm with a random element to establish the allocation for the patient at the point of randomisation. Patients were stratified by chemotherapy centre, site of tumour, and tumour stage. The primary outcome for the phase 3 stage of the trial was overall survival (defined as the time from randomisation until death from any cause), analysed in the intention-to-treat population. Here, we report the primary analysis results of the trial; all patients have completed treatment and the required number of primary outcome events has been reached. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 46020948, and with ClinicalTrials.gov, number NCT00450203. FINDINGS: Between Oct 31, 2007, and March 25, 2014, 1063 patients were enrolled and randomly assigned to receive chemotherapy alone (n=533) or chemotherapy plus bevacizumab (n=530). At the time of analysis, 508 deaths were recorded (248 in the chemotherapy alone group and 260 in the chemotherapy plus bevacizumab group). 3-year overall survival was 50·3% (95% CI 45·5-54·9) in the chemotherapy alone group and 48·1% (43·2-52·7) in the chemotherapy plus bevacizumab group (hazard ratio [HR] 1·08, 95% CI 0·91-1·29; p=0·36). Apart from neutropenia no other toxic effects were reported at grade 3 or worse severity in more than 10% of patients in either group. Wound healing complications were more prevalent in the bevacizumab group, occurring in 53 (12%) patients in this group compared with 33 (7%) patients in the chemotherapy alone group. In patients who underwent oesophagogastrectomy, post-operative anastomotic leak rates were higher in the chemotherapy plus bevacizumab group (23 [10%] of 233 in the chemotherapy alone group vs 52 [24%] of 220 in the chemotherapy plus bevacizumab group); therefore, recruitment of patients with lower oesophageal or junctional tumours planned for an oesophagogastric resection was stopped towards the end of the trial. Serious adverse events for all patients included anastomotic leaks (30 events in chemotherapy alone group vs 69 in the chemotherapy plus bevacizumab group), and infections with normal neutrophil count (42 events vs 53). INTERPRETATION: The results of this trial do not provide any evidence for the use of bevacizumab in combination with peri-operative epiribicin, cisplatin, and capecitabine chemotherapy for patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. Bevacizumab might also be associated with impaired wound healing. FUNDING: Cancer Research UK, MRC Clinical Trials Unit at University College London, and F Hoffmann-La Roche Limited.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Junção Esofagogástrica/patologia , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Bevacizumab/administração & dosagem , Capecitabina/administração & dosagem , Estudos de Casos e Controles , Cisplatino/administração & dosagem , Epirubicina/administração & dosagem , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Assistência Perioperatória , Prognóstico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida
4.
Liver Int ; 36(12): 1821-1828, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27214151

RESUMO

BACKGROUND & AIMS: The Albumin-Bilirubin (ALBI) grade was proposed as an objective means to evaluate liver function in patients with Hepatocellular Carcinoma (HCC). ALBI grade 1 vs 2 were proposed as stratification factors within the Child Pugh (CP) A class. However, the original publication did not provide comparison with the subclassification by points (5-15) within the CP classification. METHODS: We retrospectively analysed data from patients treated with sorafenib for HCC from 17 centres in United Kingdom and France. Overall survival (OS) was analysed using the Kaplan-Meier method and a Cox regression model. Discriminatory abilities of the classifications were assessed with the log likelihood ratio, Harrell's C statistics and Akaike information criterion. RESULTS: Data from 1019 patients were collected, of which 905 could be assessed for both scores. 92% of ALBI grade 1 were CP A5 while ALBI 2 included a broad range of CP scores of which 44% were CP A6. Median OS was 10.2, 7.0 and 3.6 months for CP scores A5, A6 and >A6, respectively (P < 0.001), Hazard Ratio (HR) = 1.60 (95%CI: 1.35-1.89, P < 0.001) for A6 vs A5. Median OS was 10.9, 6.6 and 3.0 months for ALBI grade 1, 2 and 3, respectively (P < 0.001), HR = 1.68 (1.43-1.97, P < 0.001) for grade 2 vs 1. Discriminatory abilities of CP and ALBI were similar in the CP A population, but better for CP in the overall population. CONCLUSIONS: Our findings support the use CP class A as an inclusion criterion, and ALBI as a stratification factor in trials of systemic therapy.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Bilirrubina/análise , Feminino , França , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Niacinamida/uso terapêutico , Prognóstico , Estudos Retrospectivos , Albumina Sérica/análise , Sorafenibe , Análise de Sobrevida , Reino Unido , Adulto Jovem
5.
Gynecol Oncol ; 112(1): 155-60, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19019416

RESUMO

OBJECTIVE: The term gestational trophoblastic neoplasia (GTN) encompasses a variety of uncommon neoplastic conditions arising from the placental trophoblast. Staging of GTN using the FIGO 2000 system divides patients into low and high risk groups and treatment of these patients depends on the risk score achieved. Chest x-ray (CXR) is recommended to assess lung metastases; however the significance of lung metastases seen on computed tomography (CT) scan of the chest is uncertain. The aim of this study is to determine whether or not CT scan significantly influences outcome of patients with GTN in terms of a need to change to second line chemotherapy or time to remission. METHODS: 96 patients with low risk metastatic GTN and 102 patients with low risk non-metastatic GTN who had been staged at Weston Park Hospital, Sheffield were identified. Staging according to the FIGO 2000 system was retrospectively calculated to assess what impact using CT scan would have had on the scores of those patients. Rates of first line treatment failure and time to remission were assessed and comparisons made. RESULTS: There was no significant difference in the need to change to second line chemotherapy or in time to remission in those patients with metastatic GTN whose score or risk was changed when CT scan was used in place of CXR. Low risk patients with metastatic disease were, however, significantly more likely to need to change to second line chemotherapy than patients with non-metastatic GTN although there was no significant difference in time to remission between these groups. CONCLUSIONS: CT scan of the chest used instead of CXR in the staging of GTN does not alter outcome.


Assuntos
Doença Trofoblástica Gestacional/diagnóstico por imagem , Doença Trofoblástica Gestacional/patologia , Adulto , Feminino , Doença Trofoblástica Gestacional/tratamento farmacológico , Doença Trofoblástica Gestacional/cirurgia , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Estadiamento de Neoplasias , Gravidez , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos , Adulto Jovem
6.
JAMA Oncol ; 5(8): 1181-1187, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31219517

RESUMO

IMPORTANCE: Perioperative chemotherapy and surgery are a standard of care for operable gastroesophageal adenocarcinoma. Anti-HER2 therapy improves survival in patients with advanced HER2-positive disease. The safety and feasibility of adding lapatinib to perioperative chemotherapy should be assessed. OBJECTIVES: To assess the safety of adding lapatinib to epirubicin, cisplatin, and capecitabine (ECX) chemotherapy and to establish a recommended dose regimen for a phase 3 trial. DESIGN, SETTING, AND PARTICIPANTS: Phase 2 randomized, open-label trial comparing standard ECX (sECX: 3 preoperative and 3 postoperative cycles of ECX with modified ECX plus lapatinib (mECX+L). This multicenter national trial was conducted in 29 centers in the United Kingdom in patients with histologically proven, HER2-positive, operable gastroesophageal adenocarcinoma. Registration for ERBB/HER2 testing took place from February 25, 2013, to April 19, 2016, and randomization took place between May 24, 2013, and April 21, 2016. Data were analyzed May 10, 2017, to May 25, 2017. INTERVENTIONS: Patients were randomized 1:1 open-label to sECX (3 preoperative and 3 postoperative cycles of 50 mg/m2 of intravenous epirubicin on day 1, 60 mg/m2 intravenous cisplatin on day 1, 1250 mg/m2 of oral capecitabine on days 1 through 21) or mECX+L (ECX plus lapatinib days 1 through 21 in each cycle and as 6 maintenance doses). The first 10 patients in the mECX+L arm were treated with 1000 mg/m2 of capecitabine and 1250 mg of lapatinib per day, after which preoperative toxic effects were reviewed according to predefined criteria to determine doses for subsequent patients. MAIN OUTCOMES AND MEASURES: Proportion of patients experiencing grade 3 or 4 diarrhea with mECX+L. A rate of 20% or less was considered acceptable. No formal comparison between arms was planned. RESULTS: Between February 2013, and April 2016, 441 patients underwent central HER2 testing and 63 (14%) were classified as HER2 positive. Forty-six patients were randomized; 44 (24 sECX, 20 mECX+L) are included in this analysis. Two of the first 10 patients in the mECX+L arm reported preoperative grade 3 diarrhea; thus, no dose increase was made. The primary endpoint of preoperative grade 3 or 4 diarrhea rates were 0 of 24 in the sECX arm (0%) and 4 of 20 in the mECX+L arm (21%). One of 24 in the sECX arm and 3 of 20 in the mECX+L arm stopped preoperative treatment early, and for 4 of 19 in the mECX+L arm, lapatinib dose was reduced. Postoperative complication rates were similar in each arm. CONCLUSIONS AND RELEVANCE: Administration of 1250 mg of lapatinib per day in combination with ECX chemotherapy was feasible with some increase in toxic effects, which did not compromise operative management. TRIAL REGISTRATION: ISRCTN.org identifier: 46020948; clinicaltrialsregister.eu identifier: 2006-000811-12.

7.
JAMA Surg ; 154(11): 1038-1048, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31483448

RESUMO

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 , Gencitabina
8.
Int J Oncol ; 26(4): 1093-9, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15754007

RESUMO

We evaluated clinical features, management and survival of patients with localised (stage 1E or 2E) testicular non-Hodgkin lymphoma (NHL) presenting to the Sheffield Lymphoma Group between 1972 and 2002. Thirty consecutive eligible patients were identified from the lymphoma database and clinical records of all were reviewed. Survival data were statistically analysed. The median age of patients was 74 years (range 38-87). Sixty-three percent were >70 years of age. The median duration of follow-up was 15 months (range 2.1-211). All patients had orchidectomy. Eleven (37%) had orchidectomy alone. Twelve (40%) had orchidectomy and chemotherapy, 4 (13%) had orchidectomy and radiotherapy. Three (10%) had orchidectomy, chemotherapy and radio-therapy. Five (17%) had immediate disease progression following orchidectomy or whilst on treatment. A complete response was seen in the remaining 25 (84%) irrespective of treatment modality. Seven (23%) of patients remain alive, with a median follow-up of 73 months (range 9.9-211). Six (20%) died of causes not related to their lymphoma. Twelve (40%) relapsed following a complete response and median time to relapse was 9 months. Only 1 of these relapses was in the central nervous system; 1 in bone, 1 in skin, 2 in the contralateral testis. The majority of relapses (58%) occurred in the lymph nodes. Primary testicular lymphoma is an uncommon and poor prognosis disease usually affecting older men. The data and experience available to guide the treatment strategies for testicular lymphoma are limited. However, the evidence points to a combined modality approach being the most likely effective treatment, comprising surgery, anthracycline-containing combination chemotherapy with or without prophylactic contralateral testis and regional lymph node irradiation.


Assuntos
Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/cirurgia , Recidiva Local de Neoplasia , Orquiectomia , Neoplasias Testiculares/patologia , Neoplasias Testiculares/cirurgia , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Humanos , Metástase Linfática/radioterapia , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/radioterapia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/radioterapia
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