RESUMO
PURPOSE: Poorly differentiated neuroendocrine carcinoma (PDNEC) of the rectum and anus is a rare disease exhibiting aggressive biological behaviour, even if diagnosed early. Currently, there are no agreed standard treatment approaches and management of locally advanced (LA) and metastatic PDNEC usually follows treatments used in pulmonary neuroendocrine carcinomas because of the similarities with small cell lung cancer. The role of surgery in PDNEC is still debated and the benefit of chemoradiotherapy (CRT) is unknown. This report summarises the experiences of CRT application in anorectal PDNEC in a single Danish institution. METHODS: All patients with PDNEC treated with concomitant CRT between May 2019 and January 2021 at a University hospital in Denmark were evaluated. Demographics, treatment and survival outcomes were collected and analysed. RESULTS: Six patients were identified. Five patients received radiotherapy with 50.4 Gy/28 fractions, and four were eligible for curative resection after the CRT. Distant metastasis was observed in four patients at diagnosis. Two patients with synchronous liver metastases were treated with RFA, and one received a liver resection. The treatment was well tolerated with limited side effects. The median follow-up time was 17 months (range 10-36 months), and the median duration of response was 11.2 months (range 8.1 to 24.2 months). One patient achieved a complete response. CONCLUSION: A multimodal treatment approach with CRT in advanced stages of PDNEC in a highly selected patient group is well tolerated and with a high chance of achieving local control and, combined with surgery, even complete response in a single case.
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Carcinoma Neuroendócrino , Tumores Neuroendócrinos , Humanos , Canal Anal , Reto , Pelve , Quimiorradioterapia , Carcinoma Neuroendócrino/terapiaRESUMO
BACKGROUND: The optimal treatment for metastatic high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms when Ki-67 ≤55% is unknown. A prospective multi-centre phase 2 study was performed to evaluate the efficacy and safety of everolimus and temozolomide as first-line treatment for these patients. METHODS: Patients received everolimus 10 mg daily continuously and temozolomide 150 mg/m2 for 7 days every 2 weeks. Endpoints included response, survival, safety and quality of life (QoL). Histopathological re-evaluation according to the 2019 WHO classification was performed. RESULTS: For 37 eligible patients, the primary endpoint with 65% disease control rate (DCR) at 6 months (m) was reached. The response rate was 30%, the median progression-free survival (PFS) 10.2 months and the median overall survival (OS) 26.4 months. Considering 26 NET G3 patients, 6 months DCR was 77% vs. 22% among nine NEC patients (p = 0.006). PFS was superior for NET G3 vs. NEC (12.6 months vs. 3.4 months, Log-rank-test: p = 0.133, Breslow-test: p < 0.001). OS was significantly better for NET G3 (31.4 months vs. 7.8 months, p = 0.003). Grade 3 and 4 toxicities were reported in 43% and 38%. QoL remained stable during treatment. CONCLUSION: Everolimus and temozolomide may be a treatment option for selected GEP-NET G3 patients including careful monitoring. Toxicity did not compromise QoL. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NTC02248012).
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Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Everolimo/efeitos adversos , Temozolomida , Qualidade de Vida , Estudos Prospectivos , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologiaRESUMO
High-grade gastroenteropancreatic (HG-GEP) neuroendocrine neoplasms (NENs) are highly aggressive cancers. The molecular etiology of these tumors remains unclear, and the prevalence of pathogenic germline variants in patients with HG-GEP NENs is unknown. We assessed sequencing data of 360 cancer genes in normal tissue from 240 patients with HG-GEP NENs; 198 patients with neuroendocrine carcinomas (NECs) and 42 with grade 3 neuroendocrine tumors (NET G3). Applying strict criteria, we identified pathogenic germline variants and compared the frequency with previously reported data from 33 different cancer types. We found a recurrent MYOC variant in three patients and a recurrent MUTYH variant in two patients, indicating that these genes may be important underlying risk factors for HG-GEP NENs when mutated. Further, germline variants were found in canonical tumor-suppressor genes, such as TP53, RB1, BRIP1 and BAP1. Overall, we found that 4.5% of patients with NEC and 9.5% of patients with NET G3 carry germline pathogenic or highly likely pathogenic variants. Applying identical criteria for variant classification in silico to mined data from 33 other cancer types, the median percentage of patients carrying pathogenic or highly likely pathogenic variants was 3.4% (range: 0-17%). The patients with NEC and pathogenic germline variants had a median overall survival of 9 months, similar to what is generally expected for metastatic GEP NECs. A patient with NET G3 and pathogenic MUTYH variant had much shorter overall survival than expected. The fraction of HG-GEP NENs with germline pathogenic variants is relatively high, but still <10%, meaning that that germline mutations cannot be the major underlying cause of HG-GEP NENs.
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Carcinoma Neuroendócrino , Neoplasias Gastrointestinais , Neoplasias Intestinais , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Mutação em Linhagem Germinativa , Neoplasias Gastrointestinais/genética , Tumores Neuroendócrinos/patologia , Carcinoma Neuroendócrino/patologia , Neoplasias Intestinais/genética , Neoplasias Intestinais/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: Neuroendocrine neoplasms represent a diverse group of malignancies. Anatomic origin, histology and aggressiveness vary extensively, from low-grade tumours with an indolent prognosis to highly aggressive conditions with poor outcome. Surgery, with a curative intent, is the standard of treatment when possible. Other treatment regimens include local treatment, or systemic therapy. The role of radiotherapy in treating neuroendocrine neoplasms is not yet established, but studies indicate that a high rate of local control can be achieved by high-dose radiotherapy. Stereotactic body radiotherapy (SBRT) is high dose of radiation delivered to a small volume. We aimed to investigate the one-year local control rate of SBRT in patients with neuroendocrine neoplasms. MATERIAL AND METHODS: Patients with neuroendocrine neoplasms treated with SBRT between 2003 and 2021 were retrospectively identified. Patient characteristics and SBRT-details were collected by review of patient records and the radiotherapy planning charts. All types except for small cell lung cancer and brain metastases were allowed. The prescribed dose was 45-67.8 Gy in three fractions. Progression, both within the target-site and in other sites, was determined based on existing imaging reports. One-year local control rate and systemic control rate was calculated. Descriptive analyses of local response duration, progression-free survival and overall survival were performed. RESULTS: Twenty-one patients were included. The one-year local control rate was 94%. Four of the patients had local progression. All patients receiving SBRT towards their primary tumour (n = 11) had a bronchopulmonary neuroendocrine neoplasm, and a one-year local control rate of 100%. In patients treated at a metastatic target, 80% developed systemic progression but the local control remained high. CONCLUSION: Our study suggests that SBRT may offer a feasible and effective treatment of neuroendocrine neoplasms in selected cases. SBRT provides long-term local stability and may be useful in treating patients with localised disease not fit for surgery.
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Neoplasias Encefálicas , Neoplasias Pulmonares , Tumores Neuroendócrinos , Radiocirurgia , Humanos , Estudos de Coortes , Radiocirurgia/métodos , Estudos Retrospectivos , Resultado do Tratamento , Tumores Neuroendócrinos/radioterapiaRESUMO
INTRODUCTION: The European Neuroendocrine Tumor Society (ENETS) reports variables of prognostic significance in bronchopulmonary neuroendocrine neoplasms (BP-NENs). The aim of this study was to investigate prognostic factors, recurrence-free survival (RFS), and overall survival (OS) for patients with typical carcinoid (TC), atypical carcinoid (AC), and large-cell neuroendocrine carcinoma (LCNEC). Current follow-up practices vary as the evidence is sparse, and we aimed to explore the relevance of routine bronchoscopy in follow-up. METHODS: This was a cohort study of 208 patients with BP-NENs followed at Aarhus University Hospital in 2008-2019. RFS and OS were determined using the Kaplan-Meier method for the variables such as primary tumor, primary treatment, smoking status, gender, and histological subtypes. RESULTS: The study included 153 patients with TC, 29 with AC, and 26 with LCNEC. Median follow-up was 48 months. The majority of patients (n = 191) received surgical resection, of which 22 (11%) recurred over time. Seventeen patients had nonsurgical treatment, of which 10 (59%) progressed. The 5-year OS rate was 86% for operated and 9% for nonoperated patients (p < 0.05). Patients with TC had a 5-year OS of 90% compared with 63% and 39% for AC and LCNEC, respectively. As for prognostic factors, nonsmokers did not secure a significant difference in OS compared with current/previous smokers (p = 0.51). In the follow-up period, only 2 (9%) of the 22 recurrences were found on a routine bronchoscopy. Both of these recurrences were also found by diagnostic imaging. CONCLUSIONS: Surgical treatment, especially, and diagnosis of TC were associated with a good prognosis. Furthermore, our data did not support routine bronchoscopy as part of a follow-up program for bronchial carcinoids.
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Neoplasias Brônquicas , Tumor Carcinoide , Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Neoplasias Pulmonares , Tumores Neuroendócrinos , Humanos , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/terapia , Estudos de Coortes , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/terapia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Tumor Carcinoide/patologia , Prognóstico , Neoplasias Brônquicas/diagnóstico , Neoplasias Brônquicas/epidemiologia , Neoplasias Brônquicas/terapiaRESUMO
INTRODUCTION: Neuroendocrine tumors (NETs) are rare and characterized by a heterogeneous clinical course and an unmet need for better prognostic markers. Plasma cell-free DNA (cfDNA) has prognostic value in other malignancies but is not previously investigated in NETs. We studied cfDNA levels in patients with mainly low-grade small intestinal NET -(siNET) or pancreatic NET (pNET) and evaluated the prognostic potential of cfDNA. MATERIALS AND METHODS: We included 70 NET patients, siNET (n = 50) and pNET (n = 20). Plasma cfDNA levels were determined by droplet digital PCR for the beta-2-microglobulin gene every 6 months during a period of 3 years, including in a subgroup of 19 patients during peptide receptor radionuclide therapy (PRRT) therapy. RESULTS: cfDNA levels were higher in both siNET and pNET compared to a previously established healthy cohort (p < 0.0001). -cfDNA levels did not predict overall survival (crude hazard ratio [HR] 0.95 [0.57-1.58], p = 0.837, adjusted for smoking status HR 0.77 [0.51-1.17], p = 0.22). The impact of cfDNA level on progression-free survival showed different trends in siNET and pNET. There was no effect of PRRT treatment on cfDNA levels and no difference in cfDNA levels between patients with and without progressive disease after PRRT (ANOVA p = 0.66). cfDNA levels were significantly higher in never-smokers and previous smokers than in current smokers (p = 0.029). DISCUSSION/CONCLUSION: cfDNA levels are higher in NET patients than in healthy controls; however, there was no association with prognosis, and cfDNA levels were unaffected by PRRT. Our observations suggest that cfDNA levels are not associated with the disease course in low-grade NET in contrast to other malignancies.
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Biomarcadores Tumorais/sangue , Ácidos Nucleicos Livres/sangue , Neoplasias Intestinais/sangue , Neoplasias Intestinais/diagnóstico , Tumores Neuroendócrinos/sangue , Tumores Neuroendócrinos/diagnóstico , Avaliação de Resultados em Cuidados de Saúde/normas , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/diagnóstico , Radioisótopos/uso terapêutico , Neoplasias Gástricas/sangue , Neoplasias Gástricas/diagnóstico , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Neoplasias Intestinais/radioterapia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/radioterapia , Neoplasias Pancreáticas/radioterapia , Valor Preditivo dos Testes , Prognóstico , Intervalo Livre de Progressão , Receptores de Peptídeos , Neoplasias Gástricas/radioterapiaRESUMO
BACKGROUND: Stereotactic Ablative Body Radiotherapy (SABR) is a non-invasive treatment which allows delivery of an ablative radiation dose with high accuracy and precision. SABR is an established treatment for both primary and secondary liver malignancies, and technological advances have improved its efficacy and safety. Respiratory motion management to reduce tumour motion and image guidance to achieve targeting accuracy are crucial elements of liver SABR. This phase II multi-institutional TROG 17.03 study, Liver Ablative Radiotherapy using Kilovoltage intrafraction monitoring (LARK), aims to investigate and assess the dosimetric impact of the KIM real-time image guidance technology. KIM utilises standard linear accelerator equipment and therefore has the potential to be a widely available real-time image guidance technology for liver SABR. METHODS: Forty-six patients with either hepatocellular carcinoma or oligometastatic disease to the liver suitable for and treated with SABR using Kilovoltage Intrafraction Monitoring (KIM) guidance will be included in the study. The dosimetric impact will be assessed by quantifying accumulated patient dose distribution with or without the KIM intervention. The patient treatment outcomes of local control, toxicity and quality of life will be measured. DISCUSSION: Liver SABR is a highly effective treatment, but precise dose delivery is challenging due to organ motion. Currently, there is a lack of widely available options for performing real-time tumour localisation to assist with accurate delivery of liver SABR. This study will provide an assessment of the impact of KIM as a potential solution for real-time image guidance in liver SABR. TRIAL REGISTRATION: This trial was registered on December 7th 2016 on ClinicalTrials.gov under the trial-ID NCT02984566 .
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Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/radioterapia , Movimentos dos Órgãos , Radiocirurgia/métodos , Radioterapia Guiada por Imagem/métodos , Austrália , Carcinoma Hepatocelular/secundário , Dinamarca , Marcadores Fiduciais , Humanos , Neoplasias Hepáticas/secundário , Qualidade de Vida , Radiocirurgia/efeitos adversos , Radiocirurgia/instrumentação , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia Guiada por Imagem/efeitos adversos , Radioterapia de Intensidade Modulada/métodos , Respiração , Resultado do TratamentoRESUMO
Bronchopulmonary neuroendocrine tumours (BP-NET) are a heterogeneous population of neoplasms with different pathology, clinical behaviour and prognosis compared to the more common lung cancers. The management of BP-NET patients is largely based on studies with a low level of evidence and extrapolation of data obtained from more common types of neuroendocrine tumours. This review reflects our view of the current state of the art of diagnosis and treatment of patients with BP-NET.