Improved survival in patients with thyroid function test abnormalities secondary to immune-checkpoint inhibitors.

Immune-checkpoint inhibitors (ICI) are monoclonal antibodies which target molecules to enhance antitumor response. Several adverse events have been described and the major ICI-related endocrinopathies are thyroid dysfunction and hypophysitis. Its occurrence has been associated with improved outcomes, but it is still to be proven. We performed a retrospective study of patients treated with ICI between 2014 and 2019 at an oncologic center to characterize thyroid function test abnormalities (TFTA) and to evaluate clinical outcomes. We excluded patients without regular monitoring of thyroid function, with previous thyroid or pituitary disease, previous head/neck radiotherapy and who performed only one ICI cycle. We included 161 of 205 patients treated with pembrolizumab, nivolumab or ipilimumab for several neoplasms, with a median duration of 18.9 weeks (9.1-42.6) of ICI treatment and 49.4 weeks (26.5-75.8) of follow-up. New-onset TFTA was diagnosed in 18% of patients (n = 29), in median at 10.6 weeks (6.1-31.1) of ICI therapy. On the whole, 8.7% had primary hypothyroidism, 4.3% central hypothyroidism, 2.5% biphasic thyroiditis and 2.5% thyrotoxicosis. Patients who experienced primary or central thyroid dysfunction had a significantly improved overall response rate (58.6% vs 34.2%, p = 0.015) and overall survival (3.27 vs 1.76 years, p = 0.030), compared to the control group. The risk of mortality was two times higher for control group (adjusted HR = 2.43, 95% CI 1.13-5.23, p = 0.023). This study recognizes that primary and central thyroid dysfunction can be a predictive clinical biomarker of a better response to ICI across several neoplasms.

68Ga-DOTANOC and 18F-FDG PET/CT in metastatic medullary thyroid carcinoma: novel correlations with tumoral biomarkers.

OBJECTIVE: Metastatic disease is common in medullary thyroid carcinoma (MTC) and it is usually detected by raising calcitonin and carcinoembryonic antigen (CEA) levels. Nuclear medicine imaging has an important role in lesion identification/characterisation. We aim to compare 68Ga-DOTANOC PET/CT and 18F-FDG PET/CT performance and to explore the correlations between tumoral markers and functional imaging. METHODS: This a retrospective cross-sectional study including 13 patients with MTC and high calcitonin/CEA levels that underwent both 68Ga-DOTANOC PET/CT and 18F-FDG PET/CT. RESULTS: 68Ga-DOTANOC PET/CT identified MTC metastases in 2twopatients that were 18F-FDG-negative (sensitivity of 69.2% vs. 53.9%, respectively). 68Ga-DOTANOC PET/CT also detected a higher number of lesions than 18F-FDG PET/CT in seven patients, with only one patient showing the opposite pattern. Both differences lacked statistical significance (p = 0.50 and p = 0.86, respectively) but 68Ga-DOTANOC PET/CT better performance allowed changes in patients' management. 68Ga-positive/18F-FDG-negative patients were the ones with the lowest calcitonin doubling time and presented a CEA doubling time >24 months, while the patient with more 18F-FDG-positive lesions was the one with the highest CEA/calcitonin ratio. The number of lesions found in 68Ga-DOTANOC PET/CT were correlated with calcitonin levels (r = 0.73; p < 0.01) but not with CEA ones (r = 0.42; p = 0.15). The number of 18F-FDG hypermetabolic focus were correlated with CEA levels (r = 0.60; p < 0.05) but not with calcitonin (r = 0.48; p = 0.09). CONCLUSIONS: This is the first study to describe a positive correlation between 68Ga-positive lesions and calcitonin levels and between 18F-FDG-positivity and CEA levels. Tumoral markers pattern in metastatic MTC could help clinicians to decide which exam to perform first.

[Treatment of Gastroenteropancreatic Neuroendocrine Tumors with 177Lu-DOTA-TATE: Experience of the Portuguese Institute of Oncology in Porto]. / Tratamento de Tumores Neuroendócrinos Gastroenteropancreáticos com 177Lu-DOTA-TATE: Experiência do Instituto Português de Oncologia do Porto.

INTRODUCTION: The purpose of this article is to report the experience of the Portuguese Institute of Oncology - Porto in the treatment of gastroenteropancreatic neuroendocrine tumors with 177Lu-DOTA-TATE, regarding the safety and efficacy of this treatment modality. MATERIAL AND METHODS: A retrospective analysis of clinical reports of patients with gastroenteropancreatic neuroendocrine tumors undergoing treatment with 177Lu-DOTA-TATE between April 2011 and November 2013 was performed. RESULTS: Thirty six cases were reviewed and 30 completed all 3 cycles of 177Lu-DOTA-TATE (83.3%). In these patients it was registered: acute side effects in 8.9% of cycles; grade 3 CTCAE liver toxicity in 13.3% of patients (all with previous abnormal liver function); absence of significant renal or hematologic toxicity; symptomatic improvement in 71.4% of patients; median overall time to progression of 25.6 months; median overall survival from diagnosis of 121.7 months. Patients with higher expression of somatostatin receptors had longer progression-free survival and overall survival times (p < 0.05). DISCUSSION: Peptide receptor radionuclide therapy with 177Lu-DOTA-TATE is an effective, safe and well-tolerated treatment, as evidenced in our study by the following findings: symptomatic improvement in most patients and increased time to disease progression and survival (especially in those with higher sstr expression), with acute and significant subacute/chronic side effects reported only in a minority of cases. CONCLUSION: Peptide receptor radionuclide therapy with 177Lu-DOTA-TATE is a promising treatment for patients with gastroenteropancreatic neuroendocrine tumors, with demonstrated benefits in terms of safety and efficacy.

Introdução: O objetivo deste artigo é rever a experiência do Instituto Português de Oncologia do Porto na terapêutica de tumores neuroendócrinos gastroenteropancreáticos com 177Lu-DOTA-TATE, tendo como principais pontos de análise a segurança e eficáciaterapêutica. Material e Métodos: Foi realizada uma análise retrospetiva dos processos clínicos de doentes com tumores neuroendócrinos gastroenteropancreáticos, submetidos a terapêutica com 177Lu-DOTA-TATE entre abril de 2011 e novembro de 2013. Resultados: Dos 36 casos revistos, 30 completaram os três ciclos de 177Lu-DOTA-TATE (83,3%). Nesses doentes foram registados: efeitos colaterais agudos em 8,9% dos ciclos; toxicidade hepática grau 3 CTCAE em 13,3% dos doentes (todos com alterações prévias da função hepática); ausência de toxicidade renal ou hematológica significativa; melhoria sintomática em 71,4% dos doentes; tempo mediano global desde o início da terapêutica até progressão de doença de 25,6 meses; tempo mediano global de sobrevivência desde o diagnóstico de 121,7 meses. Verificou-se um maior tempo livre de progressão de doença e de sobrevivência nos doentes com expressão elevada de recetores da somatostatina (p < 0,05). Discussão: A peptide receptor radionuclide therapy com 177Lu-DOTA-TATE apresenta respostas clínicas favoráveis com segurança e boa tolerabilidade terapêutica, conforme evidenciado no nosso estudo pelos seguintes achados: melhoria dos sintomas na maioria dos doentes e aumento significativo do tempo livre de progressão de doença e da sobrevivência (sobretudo nos doentes com expressão elevada de sstr), com efeitos colaterais agudos e subagudos/crónicos significativos numa minoria de doentes. Conclusão: A peptide receptor radionuclide therapy com 177Lu-DOTA-TATE é uma terapêutica promissora, com benefícios reais em termos de eficácia e segurança nos doentes com tumores neuroendócrinos gastroenteropancreáticos.