key: cord-1001894-ju0jubcd
authors: Fazio, Nicola; Gervaso, Lorenzo; Halfdanarson, Thorvadur R.; La Salvia, Anna; Hofland, Johannes; Hernando, Jorge; Sonbol, Mohamad B.; Garcia-Carbonero, Rocio; Capdevila, Jaume; de Herder, Wouter W.; Koumarianou, Anna; Kaltsas, Gregory; Rossi, Maura; Grozinsky-Glasberg, Simona; Oleinikov, Kira; Boselli, Sabrina; Tamayo, Darina; Bagnardi, Vincenzo; Laffi, Alice; Rubino, Manila; Spada, Francesca
title: COVID-19 in patients with neuroendocrine neoplasms: Preliminary results of a worldwide survey (The INTENSIVE study)
date: 2021-06-30
journal: Eur J Cancer
DOI: 10.1016/j.ejca.2021.06.029
sha: 8cb21a148f2965a5aa57b7ddd037feff4891c82e
doc_id: 1001894
cord_uid: ju0jubcd

BACKGROUND: Specific data regarding COVID-19 in patients with neuroendocrine neoplasms (NEN) are lacking. This aim of this study is to describe the characteristics of NEN patients who tested SARS-CoV-2 positive. MATERIAL AND METHODS: This is a worldwide study collecting cases of NEN patients with a positive nasopharyngeal swab RT-PCR for SARS-CoV-2 between June 1, 2020, and March 31, 2021. Centers treating NEN patients were directly contacted by the principal investigator. Patients with NEN of any primary site, grade, and stage were included, excluding small-cell lung carcinoma and mixed adeno-neuroendocrine carcinoma. RESULTS: Among 81 centers directly contacted 88.8% responded and 48.6% of them declined due to lack of cases or interest. On March 31(st), 2021, eight recruiting centers enrolled 89 patients. Median age was 64 years at the COVID-19 diagnosis. Most patients had metastatic, non-functioning, low/intermediate grade gastro-entero-pancreatic (GEP) NEN, on treatment with somatostatin analogs (SSA) and radioligand therapy (RLT). Most of them had comorbidities. Only 8% of patients had high grade NEN and 12% were receiving chemotherapy. Most patients had symptoms or signs of COVID-19, mainly fever and cough. Only 3 patients underwent sub-intensive treatment, whereas the majority received medical therapies, mostly antibiotics. In two third of cases, no changes occurred for the anti-NEN therapy. More than 80% of patients completely recovered without sequelae whereas 7.8% patients died due to COVID-19. CONCLUSIONS: Patients included in this study reflect the typical NEN population regardless of SARS-CoV-2. In the majority of cases they overcome COVID-19 without need of intensive care, short-term sequelae and discontinuation of systemic oncological therapy.

Coronavirus disease (COVID)-19 is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that emerged in Wuhan, China, in late 2019 and rapidly spread all over the world causing a pandemic 1 .

On 30 December 2019, a previously unknown beta-coronavirus was identified with RT-PCR of samples from a bronchoalveolar lavage of a patient with pneumonia of unknown etiology in Wuhan Jinyintan Hospital 2 . This new coronavirus, named 2019-nCoV, was later named SARS-CoV-2 due to its association with severe acute respiratory syndrome (SARS). The related disease, mainly involving the respiratory system, initially was named coronavirus disease .

Information on the epidemic was notified to WHO on 3 January 2020. After that the outbreak spread outside China and on 30 January 2020, the WHO declared COVID-19 as the sixth public health emergency of international concern (PHEIC). On 11 March 2020 the WHO general director, Dr Tedros Adhanom Ghebreyesus, declared that SARS-CoV-2 outbreak could be characterized as a pandemic. Thus far, the pandemic has resulted in a large number of excess deaths compared to recent years 3 .

As cancer patients have historically been considered to beat higher risk of infection and related complications, largely secondary to the immunosuppressive effects of the malignancies and the cancer-directed therapies, the main oncological societies published general guidances to aim cancer patients on their websites. Moreover, an international collaborative group proposed some practical measures for the management of cancer patients based on the available data 4 .

It was also reported that cancer patients are more susceptible to viral infections, particularly those related to SARS-CoV-2 5 . Furthermore, according to data originating from a Chinese cohort, patients with cancer had a significantly higher risk of developing severe COVID-19-related events, mainly intensive care unit (ICU) admissions, compared with patients without cancer (39% vs 8%, p=0.0003) 6 . A higher COVID-19 mortality has also been reported in patients with cancer compared J o u r n a l P r e -p r o o f with those without cancer [7] [8] [9] [10] [11] . Multiple other studies have reported high mortality rates in cancer patients who acquired COVID-19 11-13 . In line with this some types of cancers, including thoracic cancers, and clinical underlying conditions, such as concomitant immunosuppressive concurrent therapies and/or immune-related comorbidities, put cancer patients at a higher risk for infection and complications of COVID-19 14 We searched PubMed on April 05, 2021, using the search terms ("novel coronavirus" OR "SARS-CoV2" OR "COVID-19") AND ("neuroendocrine tumors" OR "neuroendocrine tumours" OR "neuroendocrine neoplasms" OR "neuroendocrine carcinomas" OR "carcinoids") for articles in English that documented the COVID-19 in patients with NENs. Sixteen articles appeared, including three case reports, 12 recommendations or consensus statements and one only mini-series of four cases among a large thoracic cancers series 19,22-24 17,18,20,25-33 .

Therefore, and based on the rarity of NEN patients, we conducted a worldwide collection of data through an international database to characterize the clinical course of NEN patients with COVID- 19 . This study aims to generate a large dataset to evaluate the frequency of events, clinical 

This is a retrospective/prospective, observational, international, multicentric study on consecutive SARS-CoV-2 positive NEN patients. Established centers known to be involved in national or international NEN clinical networks or European Neuroendocrine Tumor Society (ENETS) Centers of Excellence (CoE) were directly invited by email to join this study. After obtaining permission from local institutional review boards (IRBs), data were uploaded in a web application (REDCap) which reported the clinical characteristics of patients with NEN and COVID-19. 

Descriptive statistics were used to summarized patients' characteristics. To evaluate the association between age, sex, and type of NEN with the risk of death, the non-parametric test for trend and the Fisher exact test were used for ordinal and nominal variable, respectively.

For this initial analysis, data from consecutive patients entered into the database between June 01, 2020, and March 31, 2021, with complete reports, were collected.

Other than IEO, 81 total centers were directly contacted by the principal investigator of the study. Even when different types of cancers were correlated with COVID-19 mortality, NEN cases were not reported 16 . In one of the largest investigation of SARS-CoV-2 in patients with cancer which was the first focused specifically on patients receiving antitumor treatment, among around 60,000 cancer patients analyzed, no NEN were reported 35 .

Our series represents the result of a worldwide data collection among centers dealing with NEN patients. Most patients had a well differentiated GEP NET reflecting the real world NEN scenario.

This could be surprising if we consider that GEP NET are usually slow-growing and not treated with chemotherapy. Moreover, therapies like everolimus or RLT, which are often used in NEN patients, may produce immuno-suppression and lymphopenia, both considered to favor COVID-19

infection.

The 7.8% of mortality observed in our study is much lower than the 33% reported for lung cancer with the TERAVOLT study 23 , reflecting the different populations studied and the seemingly increased risk of death among patients with lung cancer and COVID-19 23 

Platinum and etoposide regimen is a chemotherapy usually administered to patients with NECs. In our study eight patients with NEC were included and two of them were on platinum-etoposide. A recent publication of probably the largest series of cancer patients with COVID-19 reported that platinum-etoposide was one of the risk factors correlated with higher COVID-19 mortality rate 38 .

Other studies have similarly reported worse outcomes in patients receiving cytotoxic chemotherapy 39, 40 , but not all studies support that recent chemotherapy administration is associated with higher risk of death 12, 41 .

Our study has several limitations. First, the selection of the participant centers was arbitrary and it is unclear if they were the right context to check NEN patients with SARS-CoV-2. They were primarily larger academic ones with substantial expertise in managing patients with NEN and potentially with more resources to handle critically ill COVID-19 patients. Nevertheless, it is possible that they may not accurately reflect the care provided to NEN patients with COVID-19 in the community or, more simply, that COVID-19 was managed at non-NEN-referral centers, and therefore our analysis could have missed a proportion of them. Moreover, the outcomes of hospitalized patients in the U.S. have improved over the last 12 months, presumably with the advent of better antiviral therapy and improved supportive care 42 . Although it is probable that most patients suffering from NEN are managed by NEN-referral institutions. Second, although more than 80 patients are a relatively high number, considering the rarity of NEN it is still relatively low in absolute, given the high prevalence of patients with NEN in the community at any given time, and the probability that COVID-19 occurred in NEN patients frequently, especially in high-risk areas.

Third, our survey was more focused on the NEN rather than COVID-19 context, as it mainly regarded NEN-referral centers. Therefore, even though it was quite spread across the world, we cannot be sure that these data are representative of the topic as it is not clear whether it is more probable to capture this information in the COVID-19 context or in the NEN context. Some knowledge about NEN coming from the COVID-19 context could be reported soon with the CCC-five continents this analysis reported data about six European, one USA and one Middle East centers. Notably areas like India, Brazil, UK, Russia, and Mexico, that were highly impacted in terms of COVID-19 mortality, declared not to have specific information about NEN cases.

Likewise, it is notable that Chinese centers (the Guangzhou and Wuhan Centers and the Chinese Study group for NET, CSNET, were contacted) did not have any NEN patients with COVID-19 although they managed a very high number of NEN cases. Unfortunately, other highly affected areas, such as Chile (Pontifical Catholic University of Chile) and Brazil (Camargo Cancer Center, Sao Paulo), did not join the survey due to logistic/bureaucratic issues. A further limitation of our study is the lack of information about the actual incidence of COVID-19 in this population.

However, the major strength of this study is being the only one to date that specifically focused on COVID-19 and NEN and involved many NEN centers worldwide. Furthermore, the high response rate to the survey (88.8%) is promising in terms of worldwide representation.

Although the specific incidence, morbidity and mortality related to COVID-19 among NEN patients remain to be defined, our analysis is the first to specifically capture data about morbidity and mortality in a similar population. However, but most NEN patients with COVID-19 infection present with a relatively mild illness, although mortality was increased over what it is seen in the 

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We thank all the patients and their families. We thank all the researchers involved in this study.This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. 

All authors disclose any actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within that could inappropriately influence (bias) this work.J o u r n a l P r e -p r o o f