Erratum: METNET: a phase II trial of metformin in patients with well-differentiated neuroendocrine tumours.

[This corrects the article on p. 1 in vol. 16.].

METNET: a phase II trial of metformin in patients with well-differentiated neuroendocrine tumours.

Background: Preclinical studies have suggested that metformin has anti-tumour effects, likely due to blockage of mammalian target of rapamycin pathway through adenosine monophosphate-activated protein kinase and decreased insulin levels. A retrospective study showed that metformin added to everolimus to treat type 2 diabetes mellitus offered longer progression-free survival (PFS) in patients with pancreatic neuroendocrine tumours (NET). Aims: To evaluate the efficacy and safety of metformin monotherapy in patients with advanced/metastatic well-differentiated NET (WD-NET) of gastroenteropancreatic (GEP) or pulmonary origin. Patients and methods: Single-arm phase II trial of metformin 850 mg PO twice daily until progression or intolerance for patients with progressive metastatic well-differentiated GEP or pulmonary NET. The primary endpoint was disease control rate (DCR) by RECIST 1.1 at 6 months. Secondary endpoints were response rate, PFS, toxicity and variations in glycaemic profiles (glycaemia, glycated haemoglobin and peptide C and insulin) at baseline, at 30 and 90 days. Results: From 2014 to 2019, 28 patients were enrolled: median age was 50 years; 84% had non-functional NET, 86% were of GEP origin and 62% had G2 NET. At the time of last follow-up, 26 patients had progression, with 13 (46%) presenting DCR at 6 months and a median PFS of 6.3 months (95% confidence interval: 3.2-9.3). There was no objective response, but one patient with refractory carcinoid syndrome had complete symptom relief, lasting for more than 5 years. Variations in glycaemic profiles were not associated with DCR at 6 months. Diarrhoea was the most common adverse event, being grade 3 or 4 in 10% of the cases. Conclusion: Metformin monotherapy offers modest anti-tumour activity in well-differentiated GEP or lung NET.

Malignant bowel obstruction: effectiveness and safety of systemic chemotherapy.

OBJECTIVES: Although systemic chemotherapy is often administered to patients with malignant bowel obstruction (MBO), its benefit remains unknown. This study assessed the outcomes of patients who received systemic chemotherapy as part of MBO treatment. METHODS: For this retrospective cohort study, data were extracted from records of patients hospitalised due to MBO in a tertiary cancer centre from 2008 to 2020. Eligible patients were not candidates for surgery and received systemic chemotherapy targeting the underlying malignancy causing MBO. Primary objective was to assess patient outcomes after chemotherapy; secondary objectives were rates of intestinal function recovery, hospital discharge and grade ≥3 toxicities. The primary endpoint was overall survival (OS). RESULTS: A total of 167 patients were included: median age was 55 (18-81) years, 91% had an Eastern Cooperative Oncology Group (ECOG) performance status ≥2, 75.5% had gastrointestinal tumours and 70% were treatment-naive. The median OS after chemotherapy was 4.4 weeks (95% CI 3.4 to 5.5) in the overall population. No OS difference was observed according to treatment line (p=0.24) or primary tumour (p=0.13). Intestinal function recovery occurred in 87 patients (52%), out of whom 21 (24.1%) had a reobstruction. Hospital discharge was possible in 74 patients (44.3%). Grade≥3 adverse events occurred in 26.9% of the patients, and a total of 12 deaths (7%) attributed to toxicities were observed after chemotherapy. CONCLUSIONS: MBO was associated with a dismal prognosis in this mostly treatment-naive population. The administration of chemotherapy yielded a significant risk of toxicities, whereas it did not appear to provide any relevant survival benefit in this scenario.

Adjuvant chemotherapy in biliary tract cancer patients: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The role of adjuvant chemotherapy in biliary tract cancer is controversial. We performed a systematic review and meta-analysis to assess the effect of adjuvant chemotherapy in biliary tract cancer patients. METHODS: A literature search was performed to identify randomized controlled trials (RCTs) comparing adjuvant chemotherapy versus observation, and a pooled analysis was conducted using the random-effect model. RESULTS: Three RCTs (N = 866) were included. No difference was observed between chemotherapy and observation in terms of OS (HR 0.91; 95 %CI, 0.75-1.09; p = 0.295), whereas a significant improvement in RFS was shown (HR 0.83; 95 %CI, 0.69-0.99; p = 0.040). No subgroup that benefited most from adjuvant chemotherapy was identified, although a trend was observed in N+ patients (HR 0.83; 95 %CI, 0.65-1.08; p = 0.165). DISCUSSION: Adjuvant chemotherapy yields a significant RFS benefit in biliary tract cancer patients and should be considered for those who are able to tolerate additional treatment after surgery.

Regorafenib in Patients with Antiangiogenic-Naïve and Chemotherapy-Refractory Advanced Colorectal Cancer: Results from a Phase IIb Trial.

BACKGROUND: Regorafenib is a multikinase inhibitor with antiangiogenic effects that improves overall survival (OS) in metastatic colorectal cancer (mCRC) after failure of standard therapies. We investigated the efficacy and safety of regorafenib in antiangiogenic therapy-naïve chemotherapy-refractory advanced colorectal cancer. PATIENTS AND METHODS: This single-center, single-arm, phase IIb study (NCT02465502) enrolled adults with mCRC whose disease had progressed on, or who were intolerant to, standard therapy, but who were antiangiogenic therapy-naïve. Patients received regorafenib 160 mg once daily for 3 weeks per 4-week cycle. The primary endpoint was progression-free survival (PFS) rate at week 8. RESULTS: Of 59 treated patients, almost half had received at least four prior lines of therapy. Patients received a median of 86% of the planned dose. The week 8 PFS rate was 53% (95% confidence interval [CI], 39.1-64.3); median PFS was 3.5 months (95% CI, 1.8-3.6). Median OS was 7.4 months (95% CI, 5.3-8.9). Tumor response (RECIST version 1.1) was 2%, and metabolic response rate (criteria from the European Organisation for Research and Treatment of Cancer) was 41%. The most frequently reported regorafenib-related grade ≥3 adverse events were hypertension (36%), hand-foot skin reaction (HFSR, 25%), and hypophosphatemia (24%). There were no regorafenib-related deaths. An exploratory analysis showed that patients with grade ≥2 HFSR had longer OS (10.2 months) with regorafenib treatment versus those with grades 0-1 (5.4 months). CONCLUSION: These findings support the antitumor activity of regorafenib in antiangiogenic-naïve patients with chemotherapy-refractory mCRC. IMPLICATIONS FOR PRACTICE: The multikinase inhibitor regorafenib improved overall survival in the phase III CORRECT and CONCUR trials in heavily pretreated patients with treatment-refractory metastatic colorectal cancer (mCRC). Exploratory subgroup analysis from CONCUR suggested that regorafenib treatment prior to targeted therapy (including bevacizumab) may improve outcomes. In this single-center, single-arm phase IIb study, regorafenib demonstrated antitumor activity in 59 antiangiogenic-naïve patients with chemotherapy-refractory mCRC. Further studies should assess the efficacy of regorafenib in this patient population, as well as explore the reasons behind improved outcomes among patients who had a metabolic response and those who developed hand-foot skin reaction.

Carcinoid syndrome: update on the pathophysiology and treatment.

Approximately 30-40% of patients with well-differentiated neuroendocrine tumors present with carcinoid syndrome, which is a paraneoplastic syndrome associated with the secretion of several humoral factors. Carcinoid syndrome significantly and negatively affects patients' quality of life; increases costs compared with the costs of nonfunctioning neuroendocrine tumors; and results in changes in patients' lifestyle, such as diet, work, physical activity and social life. For several decades, patients with neuroendocrine tumors and carcinoid syndrome have been treated with somatostatin analogues as the first-line treatment. While these agents provide significant relief from carcinoid syndrome symptoms, there is inevitable clinical progression, and new therapeutic interventions are needed. More than 40 substances have been identified as being potentially related to carcinoid syndrome; however, their individual contributions in triggering different carcinoid symptoms or complications, such as carcinoid heart disease, remain unclear. These substances include serotonin (5-HT), which appears to be the primary marker associated with the syndrome, as well as histamine, kallikrein, prostaglandins, and tachykinins. Given the complexity involving the origin, diagnosis and management of patients with carcinoid syndrome, we have undertaken a comprehensive review to update information about the pathophysiology, diagnostic tools and treatment sequence of this syndrome, which currently comprises a multidisciplinary approach.

Carcinoid syndrome: update on the pathophysiology and treatment

Approximately 30-40% of patients with well-differentiated neuroendocrine tumors present with carcinoid syndrome, which is a paraneoplastic syndrome associated with the secretion of several humoral factors. Carcinoid syndrome significantly and negatively affects patients' quality of life; increases costs compared with the costs of nonfunctioning neuroendocrine tumors; and results in changes in patients' lifestyle, such as diet, work, physical activity and social life. For several decades, patients with neuroendocrine tumors and carcinoid syndrome have been treated with somatostatin analogues as the first-line treatment. While these agents provide significant relief from carcinoid syndrome symptoms, there is inevitable clinical progression, and new therapeutic interventions are needed. More than 40 substances have been identified as being potentially related to carcinoid syndrome; however, their individual contributions in triggering different carcinoid symptoms or complications, such as carcinoid heart disease, remain unclear. These substances include serotonin (5-HT), which appears to be the primary marker associated with the syndrome, as well as histamine, kallikrein, prostaglandins, and tachykinins. Given the complexity involving the origin, diagnosis and management of patients with carcinoid syndrome, we have undertaken a comprehensive review to update information about the pathophysiology, diagnostic tools and treatment sequence of this syndrome, which currently comprises a multidisciplinary approach.

Guidelines for the management of neuroendocrine tumours by the Brazilian gastrointestinal tumour group.

Neuroendocrine tumours are a heterogeneous group of diseases with a significant variety of diagnostic tests and treatment modalities. Guidelines were developed by North American and European groups to recommend their best management. However, local particularities and relativisms found worldwide led us to create Brazilian guidelines. Our consensus considered the best feasible strategies in an environment involving more limited resources. We believe that our recommendations may be extended to other countries with similar economic standards.

Carbamazepine for prevention of chemotherapy-induced nausea and vomiting: a pilot study.

CONTEXT AND OBJECTIVE: Nausea and vomiting are major inconveniences for patients undergoing chemotherapy. Despite standard preventive treatment, chemotherapy-induced nausea and vomiting (CINV) still occurs in approximately 50% of these patients. In an attempt to optimize this treatment, we evaluated the possible effects of carbamazepine for prevention of CINV. DESIGN AND LOCATION: Prospective nonrandomized open-label phase II study carried out at a Brazilian public oncology service. METHODS: Patients allocated for their first cycle of highly emetogenic chemotherapy were continuously recruited. In addition to standard antiemetic protocol that was made available, they received carbamazepine orally, with staggered doses, from the third day before until the fifth day after chemotherapy. Considering the sparseness of evidence about the efficacy of anticonvulsants for CINV prevention, we used Simon's two-stage design, in which 43 patients should be included unless overall complete prevention was not achieved in 9 out of the first 15 entries. The Functional Living Index-Emesis questionnaire was used to measure the impact on quality of life. RESULTS: None of the ten patients (0%) presented overall complete prevention. In three cases, carbamazepine therapy was withdrawn because of somnolence and vomiting before chemotherapy. Seven were able to take the medication for the entire period and none were responsive, so the study was closed. There was no impact on the patients' quality of life. CONCLUSION: Carbamazepine was not effective for prevention of CINV and also had a deleterious side-effect profile in this population.

Carbamazepine for prevention of chemotherapy-induced nausea and vomiting: a pilot study / Carbamazepina para prevenção de náusea e vômito induzidos por quimioterapia: um estudo piloto

CONTEXT AND OBJECTIVE: Nausea and vomiting are major inconveniences for patients undergoing chemotherapy. Despite standard preventive treatment, chemotherapy-induced nausea and vomiting (CINV) still occurs in approximately 50% of these patients. In an attempt to optimize this treatment, we evaluated the possible effects of carbamazepine for prevention of CINV. DESIGN AND LOCATION: Prospective nonrandomized open-label phase II study carried out at a Brazilian public oncology service. METHODS: Patients allocated for their first cycle of highly emetogenic chemotherapy were continuously recruited. In addition to standard antiemetic protocol that was made available, they received carbamazepine orally, with staggered doses, from the third day before until the fifth day after chemotherapy. Considering the sparseness of evidence about the efficacy of anticonvulsants for CINV prevention, we used Simon's two-stage design, in which 43 patients should be included unless overall complete prevention was not achieved in 9 out of the first 15 entries. The Functional Living Index-Emesis questionnaire was used to measure the impact on quality of life. RESULTS: None of the ten patients (0%) presented overall complete prevention. In three cases, carbamazepine therapy was withdrawn because of somnolence and vomiting before chemotherapy. Seven were able to take the medication for the entire period and none were responsive, so the study was closed. There was no impact on the patients' quality of life. CONCLUSION: Carbamazepine was not effective for prevention of CINV and also had a deleterious side-effect profile in this population. .

CONTEXTO E OBJETIVO: Náusea e vômito são inconvenientes importantes para pacientes submetidos a quimioterapia. A despeito do tratamento preventivo padrão, náuseas e vômitos induzidos por quimioterapia (NVIQ) ocorrem em aproximadamente 50% dos pacientes. Na tentativa de otimizar este tratamento, avaliamos os possíveis efeitos da carbamazepina na prevenção de náuseas e vômitos induzidos por quimioterapia. TIPO DE ESTUDO E LOCAL: Estudo fase II, prospectivo, não randomizado, aberto, realizado em um serviço público brasileiro de oncologia. MÉTODOS: Recrutaram-se continuamente pacientes alocados para o primeiro ciclo de quimioterapia altamente emetogênica. Além do protocolo anti-emético padrão disponibilizado, os pacientes receberam carbamazepina, por via oral, em doses escalonadas, a partir do terceiro dia anterior até o quinto dia após a quimioterapia. Dada a escassa evidência de eficácia dos anticonvulsivantes na prevenção de NVIQ, adotamos o desenho de Simon em duas fases, que deveria incluir 43 pacientes a não ser que prevenção completa global não fosse alcançada em 9 dos primeiros 15 participantes. O questionário "Functional Living Index-Emesis" foi usado para avaliar o impacto na qualidade da vida. RESULTADOS: Nenhum dos 10 pacientes (0%) apresentou prevenção completa global. Três tiveram a carbamazepina suspensa por sonolência e vômito antes da quimioterapia. Sete foram capazes de tomar a medicação por todo o período proposto e nenhum obteve resposta, sendo então interrompido o estudo. Não houve impacto na qualidade da vida. CONCLUSÃO: Carbamazepina não foi efetiva para prevenção de NVIQ e apresentou perfil deletério de efeitos adversos nesta população. .

Carcinoma da mama metastático para o olho, pálpebra e órbita: análise de quatro casos tratados em hospital escola / Metastatic breast carcinoma to the eye, eyelid and orbit: analysis of four cases treated in hospital school

Introdução: Pacientes com neoplasia de mama desenvolvem metástases oculares em 10% dos casos. As metástases são a forma mais comum de neoplasia ocular; as orbitárias representam 1% a 13% dos tumores desta região e para a pálpebra são raras, responsáveis por 1% das malignidades. Câncer da mama é o principal primário. Relato dos casos: Todas pacientes possuem doença RH+, Her-2 negativo. Caso 1, 65 anos, CDI G2 metastático (pulmão, fígado, ossos, retina). Em anastrozol há dez meses, mantém doença estável. Caso 2, 49 anos, CDI G2 metastático que evoluiu com doença cerebral e em coroide. Houve melhora dos sintomas visuais após cinco ciclos de capecitabina e termoterapia transpupilar. Teve progressão de doença óssea, evoluiu a óbito devido à doença metastática. Caso 3, 36 anos e CDI G2, estádio IV (osso e pelve) que após três linhas de quimioterapia evoluiu com metástases cerebrais e orbitária. Recebeu radioterapia em crânio, porém evoluiu a óbito um mês após. Caso 4, 47 anos, carcinoma coloide G2, metástase pulmonar. Após três linhas de quimioterapia evoluiu com doença em pálpebra. Recebeu cisplatina/gemcitabina, cinco ciclos, manteve lesão estável. Atualmente em radioterapia paliativa na pálpebra. Discussão: Metástases oculares são consideradas pouco frequentes e são pouco investigadas. Cerca de 25% dos pacientes com metástase ocular são assintomáticos. A melhora na terapêutica da neoplasia de mama avançada leva a maior longevidade desta população que, com isso, passa a ser suscetível à manifestação de sintomas visuais. O diagnóstico deve ser precoce, pois o tratamento permite controle dos sintomas e melhora da qualidade de vida.

Prevalence of the burnout syndrome among Brazilian medical oncologists.

INTRODUCTION: Burnout syndrome which is prevalent among oncologists is characterized by three aspects: emotional exhaustion, depersonalization and low personal accomplishment. The purpose was to evaluate prevalence of the burnout syndrome among Brazilian medical oncologists and the variables that correlate with its presence. METHODS: A survey was conducted with members of the Brazilian Society of Medical Oncology (SBOC) who received three questionnaires (general, Maslach burnout questionnaire and an opinion survey) mailed to all 458 members. RESULTS: Response rate was of 22.3%. According to the criteria proposed by Grunfeld, which consider burnout present when at least one of the aspects is severely abnormal, prevalence of this syndrome was 68.6% (95% confidence interval, CI: 58.68% to 77.45%). By multivariate analysis having a hobby/physical activity, a religious affiliation, older age, living with a companion and rating vacation time as sufficient were correlated significantly and independently with burnout syndrome. CONCLUSIONS: The burnout syndrome is prevalent among Brazilian oncologists. Oncologists having sufficient personal and social resources to engage in a hobby, physical activity, have enough vacation time and religious activities are at lower risk of developing burnout.

Prevalence of the burnout syndrome among Brazilian medical oncologists

INTRODUCTION: Burnout syndrome which is prevalent among oncologists is characterized by three aspects: emotional exhaustion, depersonalization and low personal accomplishment. The purpose was to evaluate prevalence of the burnout syndrome among Brazilian medical oncologists and the variables that correlate with its presence. METHODS: A survey was conducted with members of the Brazilian Society of Medical Oncology (SBOC) who received three questionnaires (general, Maslach burnout questionnaire and an opinion survey) mailed to all 458 members. RESULTS: Response rate was of 22.3 percent. According to the criteria proposed by Grunfeld, which consider burnout present when at least one of the aspects is severely abnormal, prevalence of this syndrome was 68.6 percent (95 percent confidence interval, CI: 58.68 percent to 77.45 percent). By multivariate analysis having a hobby/physical activity, a religious affiliation, older age, living with a companion and rating vacation time as sufficient were correlated significantly and independently with burnout syndrome. CONCLUSIONS: The burnout syndrome is prevalent among Brazilian oncologists. Oncologists having sufficient personal and social resources to engage in a hobby, physical activity, have enough vacation time and religious activities are at lower risk of developing burnout.

INTRODUÇÃO: A Síndrome da Estafa Profissional (SEP) é considerada uma doença caracterizada por três componentes básicos: exaustão emocional (EE), despersonalização (DP) e reduzida realização pessoal (RP), sendo identificada em oncologistas. OBJETIVO: Analisar a prevalência da SEP entre oncologistas clínicos e possíveis fatores relacionados. MÉTODOS: Foram enviados três questionários (Questionário Geral, Questionário Maslach de Burnout e Questionário de Opinião) para 458 cancerologistas cadastrados na Sociedade Brasileira de Oncologia Clínica (SBOC). RESULTADOS: A taxa de resposta foi de 20 por cento. 43,3 por cento dos entrevistados demonstraram nível baixo de EE, 57,8 por cento apresentaram nível alto de DP e 55,5 por cento alta RP. Para avaliarmos a presença da SEP, utilizamos o critério de Ramirez, que considera as três dimensões em nível grave (8,9 por cento) e o de Grunfeld que considera pelo menos um dos três domínios em nível grave (68,9 por cento). Pelos critérios de Ramirez, houve correlação negativa com praticar exercícios/hobby (p=0,0007) e crer em uma religião (p=0,0445) com SEP. Já por Grunfeld, se correlacionou positivamente com morar com o companheiro (p=0,0054) e considerar o tempo de férias insuficiente (p=0,0037). Por ambos os critérios, foi constatada uma correlação positiva entre ter a síndrome e não optar por oncologia novamente se tivesse essa oportunidade. CONCLUSÃO: A SEP é muito prevalente entre os oncologistas clínicos. Porém, a maioria destes profissionais optaria novamente por essa especialidade. Prática de exercícios/hobby, tempo de férias suficiente e crer em uma religião surgiram como possíveis fatores para prevenir esta síndrome.