key: cord-0829736-9p8hz30b
authors: Cantini, Luca; Mentrasti, Giulia; Lo Russo, Giuseppe; Signorelli, Diego; Pasello, Giulia; Rijavec, Erika; Russano, Marco; Antonuzzo, Lorenzo; Rocco, Danilo; Giusti, Raffaele; Adamo, Vincenzo; Genova, Carlo; Tuzi, Alessandro; Morabito, Alessandro; Gori, Stefania; La Verde, Nicla; Chiari, Rita; Cortellini, Alessio; Cognigni, Valeria; Pecci, Federica; Indini, Alice; De Toma, Alessandro; Zattarin, Emma; Oresti, Sara; Pizzutilo, Elio Gregory; Frega, Stefano; Erbetta, Elisa; Galletti, Alessandro; Citarella, Fabrizio; Fancelli, Sara; Caliman, Enrico; Della Gravara, Luigi; Malapelle, Umberto; Filetti, Marco; Piras, Marta; Toscano, Giuseppe; Zullo, Lodovica; De Tursi, Michele; Di Marino, Pietro; D'Emilio, Vittorio; Cona, Maria Silvia; Guida, Annalisa; Caglio, Andrea; Salerno, Flavio; Spinelli, Gianpaolo; Bennati, Chiara; Morgillo, Floriana; Russo, Alessandro; Dellepiane, Chiara; Vallini, Ilaria; Sforza, Vincenzo; Inno, Alessandro; Rastelli, Francesca; Tassi, Valentina; Nicolardi, Linda; Pensieri, Vittoria; Emili, Rita; Roca, Elisa; Migliore, Antonella; Galassi, Tommaso; Bruno Rocchi, Marco Luigi; Berardi, Rossana
title: Evaluation of COVID-19 impact on DELAYing diagnostic-therapeutic pathways of lung cancer patients in Italy (COVID-DELAY study): fewer cases and higher stages from a real-world scenario
date: 2022-02-03
journal: ESMO Open
DOI: 10.1016/j.esmoop.2022.100406
sha: 8fe61c04c3f916771d5ef5690b9730fefa127e6c
doc_id: 829736
cord_uid: 9p8hz30b

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has disrupted the global health care system since March 2020. Lung cancer (LC) patients (pts) represent a vulnerable population highly affected by the pandemic. This multicenter Italian study aimed to evaluate whether the COVID-19 outbreak impacted on access to cancer diagnosis and treatment for LC pts compared to pre-pandemic time. METHODS: Consecutive newly diagnosed LC pts referred to 25 Italian Oncology Departments between March and December 2020 were included. Access rate and temporal intervals between date of symptoms onset and diagnostic and therapeutic services were compared to the same period in 2019. Differences between the two years were analyzed using chi-square test for categorical variables and Mann-Whitney U test for continuous variables. RESULTS: A slight reduction (-6.9%) in newly diagnosed LC cases was observed in 2020 compared with 2019 (1523 vs 1637, p=0.09). Newly LC pts in 2020 were more likely to be diagnosed with stage IV disease (p<0.01) and to be current smokers (p<0.01). The drop in terms of new diagnoses was greater in the lockdown period (percentage drop -12% vs -3.2%) compared to the other months included. More LC pts referred to low/medium volume hospital in 2020 compared to 2019 (p=0.01). No differences emerged in terms of interval between symptoms onset and radiological diagnosis (p=0.94), symptoms onset and cytohistological diagnosis (p=0.92), symptoms onset and treatment start (p=0.40), treatment start and first radiological revaluation (p=0.36). CONCLUSIONS: Our study pointed out a reduction of new diagnoses with a shift towards higher stage at diagnosis for LC pts in 2020. Despite this, the measures adopted by Italian Oncology Departments ensured the maintenance of the diagnostic-therapeutic pathways of LC pts.

Coronavirus disease 2019 has disrupted the global health care system since March 2020. Lung cancer (LC) patients (pts) represent a vulnerable population highly affected by the pandemic. This multicenter Italian study aimed to evaluate whether the COVID-19 outbreak impacted on access to cancer diagnosis and treatment for LC pts compared to pre-pandemic time.

Consecutive newly diagnosed LC pts referred to 25 Italian Oncology Departments between March and December 2020 were included. Access rate and temporal intervals between date of symptoms onset and diagnostic and therapeutic services were compared to the same period in 2019. Differences between the two years were analyzed using chi-square test for categorical variables and Mann-Whitney U test for continuous variables.

A slight reduction (-6.9%) in newly diagnosed LC cases was observed in 2020 compared with 2019 (1523 vs 1637, p=0.09). Newly LC pts in 2020 were more likely to be diagnosed with stage IV disease (p<0.01) and to be current smokers (p<0.01). The drop in terms of new diagnoses was greater in the lockdown period (percentage drop -12% vs -3.2%) compared to the other months included. More LC pts referred to low/medium volume hospital in 2020 compared to 2019 (p=0.01). No differences emerged in terms of interval between symptoms onset and radiological diagnosis (p=0.94), symptoms onset and cytohistological diagnosis (p=0.92), symptoms onset and treatment start (p=0.40), treatment start and first radiological revaluation (p=0.36).

Since the beginning of 2020, the Coronavirus Disease 2019 (COVID-19) has abruptly spread worldwide, becoming a global health emergency. Italy was among the most affected countries in terms of COVID-19

related new cases and deaths, especially during the first pandemic wave. 1 Therefore, Italian government introduced a national lockdown between 8 th March and 4 th May 2020, to minimize the human-to-human viral transmission and to limit as far as possible pandemic incidence and mortality.

The COVID-19 pandemic overwhelmed the whole health care system that has been forced to rapidly reorganize to this unprecedented scenario. Human and economic resources have been channeled to COVID-19 patients (pts) care pathways, while many diagnostic and therapeutic services have been deferred or cancelled in non-COVID-19 related care activities. 2, 3 In the setting of cancer pts care, many efforts have been placed in order to ensure high-quality standards for diagnostic-therapeutic pathways, according to the guidelines from the major scientific societies. 4, 5 Oncologic departments have experimented a substantial reorganization in management and maintenance of life-saving treatments, such as systemic therapies and radiotherapy. [6] [7] [8] Recent studies have pointed out a remarkable reduction of new cancer diagnoses in Europe and USA during the pandemic period. 9,10 Undiagnosed cancer diseases are expected to emerge at more advanced stage and with a worst prognosis, 11 involving that a significant delay in diagnosis and access to treatment may result in a suboptimal therapeutic care of cancer pts and then in an increased mortality. 12, 13 Lung cancer (LC) represents the leading cause of cancer-related death worldwide and usually is diagnosed at advanced stage. 14 Considering clinical spectrum and potential overlap of LC symptoms and radiological findings with COVID-19 disease, the differential diagnosis may be complicated and challenging. 15 In this study, using datasets from different Italian oncologic departments, we aimed to assess whether COVID-19 outbreak impacted on new diagnoses of LC. For this purpose, we evaluated access to diagnosis and treatment for a cohort of newly diagnosed LC pts during pandemic and compared it with the pre-pandemic period, to provide a real-world picture of efficacy of the health care system response to the COVID-19.

J o u r n a l P r e -p r o o f

The COVID-DELAY ("Evaluation of COVID-19 impact on DELAYing diagnostic-therapeutic pathways of lung cancer patients in Italy") was a multicentric, observational, retrospective study. Primary objective of the study was to assess whether the COVID-19 outbreak impacted the LC pts' likelihood of receiving timely diagnosis and access to treatment in 2020, by assessing total number of new diagnoses, access rate (number of pts/month) and temporal intervals between date of symptoms onset, diagnosis, first oncological appointment, treatment start, and first radiological reassessment and comparing with those of the same Subgroup analyses were also performed by specifically looking at the lockdown period and at the infection rate of the provinces where LC pts were diagnosed (high-vs medium/low-infected provinces) 16 

To estimate the study sample size, a 20% reduction of newly diagnosed LC cases in the pandemic year (2020) compared to 2019 was postulated. Therefore, assuming a 95% confidence interval (95%CI) range of 10% 

A total of 3160 pts met our inclusion criteria (Figure 1) . A slight albeit non-significant reduction (-6.9%) in newly diagnosed LC cases was seen in 2020 (n = 1523) when compared with 2019 (n = 1637). The mean monthly access rates were 163.7 vs 152.3, respectively (access rate ratio = 0.93, p = 0.09) (Figure 2 Similarly, the pandemic did not impact the multidisciplinary management of LC pts, with 44% of the cases being discussed in multidisciplinary meetings in 2020, compared to 45% in 2019. However, a slight reduction of LC pts treated in the context of clinical trials was seen during 2020 (5% vs 7%, p = 0.07). Demographic, clinicopathological and treatment characteristics by year of treatment are summarized in Table 1 .

J o u r n a l P r e -p r o o f

Looking at access to cancer diagnosis, staging and treatment for LC pts after March 2020, no major differences emerged compared to pre-pandemic time ( Table 2 access to treatment) stands firm despite the gap in disaster preparedness. 17, 18 Since the first pandemic wave with a Health Care System close to collapse and limited experience-based guidelines to keep the cancer care ship afloat, medical oncologists' associations had to elaborate a prompt as much as needed response. Conflicting measures have been adopted to effectively exit the crisis, such as patient-tailored reconsideration of treatment schedules to reduce avoidable hospital admissions, visits'

conversion to telehealth encounters and multidisciplinary boards rearrangement following specialists' reallocation to COVID-19 units.

The scientific community now wonders which effects on the expected cancer incidence and mortality rates we are going to reap in the near future. 11, 19 Despite the earliest establishment of experts' consensus and the implementation of these recommendations in daily clinical practice, the outcome of the efforts made to prevent diagnostic delays and the much-feared "upstaging effect" are still a matter of speculation and might affect the years to come. 4, 6, 20 Although a growing number of publications has focused on continuum of care impairment during the first peaks of coronavirus spread, 21, 22 there is still a great deal of uncertainty on how COVID-19 has impacted on cancer diagnosis, staging and time to treatment initiation after March 2020.

To our knowledge this is the first report to provide a thorough insight on whether the measures adopted by the Italian Oncology Departments in response to COVID-19 outbreak were able to optimally address quality J o u r n a l P r e -p r o o f of care issues and impact LC pts' likelihood of receiving timely diagnosis and treatment compared to prepandemic time.

According to previous findings that revealed an upsetting drop in the number of new incidence cancers globally, 9,10,23 our study confirmed a reduction (-6.9%) in LC diagnoses in 2020 (n=1523) compared to 2019 (n=1637) in Italy. Pandemic's challenges considered, this decline in the rate of newly diagnosed LC is and COVID-19 were current or former smokers, but only smoking history in the multivariate analysis was associated with increased risk of death. 25 Strikingly relevant from our data is the significant difference in the clinical stage at diagnosis between the two years. Unprecedentedly, our results demonstrate that LC pts were more likely detected at stage IV in 2020 compared to pre-pandemic time (72% vs 67%, p < 0.01). Although the consequent impact of such postpandemic later stage diagnosis on survival is still to be determined, some concerning predictions from a large UK modelling study have estimated an increase in LC mortality rate around 5% up to 5 years after diagnosis. 12, 26 Our analysis shows that, despite great difficulties, no flaw in the multidisciplinary management system has been exposed during the pandemic (44% of cases discussed in 2020 tumor boards vs 45% in 2019).

Specifically, looking at temporal intervals in the diagnostic-therapeutic pathway (date of symptoms onset, radiological diagnosis, cytohistological diagnosis, treatment start and first radiological revaluation), no gaps J o u r n a l P r e -p r o o f at any level emerged from our data. The absence of a difference between symptom onset and the first radiological examination, despite higher stages at diagnosis, could have been partially influenced by the interindividual variability in reporting symptoms onset. According to our findings, also the Italian COVINT study observed a small rate (8.9%) of deferred anti-cancer treatment because of the pandemic. 27 Our study has revealed a setback in LC pts' participation in clinical trials after COVID-19 (5% vs 7%, p = 0.07).

While it is too soon to tell how the slowdowns within the cancer research community will affect the progress in cancer care, an extensive analysis supported by the National Institutes of Health (NIH) confirmed that coronavirus has globally hampered the enrollment in clinical studies with a drop of trials completion rate between 13% and 23% from April to October 2020. 28 Since the present study represents the joint effort of a nationwide cooperation, it also accounts for regional variations in the response to the pandemic. Therefore, it should not resent differences in cancer incidence throughout the country. Of note, we observed a reverse migration from high-volume cancer centers to lowvolume Oncology Departments in 2020 compared to the previous year, irrespective of the spatial heterogeneity of the infection spread. As an adjustment to a pandemic context, this proved decentralization of cancer care might represent the epiphenomenon of lockdowns institution and confinement measures after COVID-19.

We acknowledge that our work has potential limitations as a retrospective study. As our analysis did not include all centers and LC patients in Italy, the observed reduction in newly diagnosed LC might for example merely reflect an additional shift of patients towards (low) volume centers not participating in the study.

However, gathering broad national collaboration and extensive case series, we consider these results as an Including advanced, neoadjuvant and adjuvant disease, all characterized by very distinct clinical presentation and outcomes, our study was expected to overcome this limit. 6, 11 From our results we can conclude that, while COVID-19 repercussions on cancer care will likely be felt for decades to come, Italian Medical Oncologists set a virtuous example to address quality of care issues and J o u r n a l P r e -p r o o f ensure timely diagnosis and treatment for LC pts after March 2020. As the pandemic shows no sign of abating, the strategy developed to answer the emergency may prove even more valuable to take further steps towards maintaining high-quality standards for diagnostic-therapeutic pathways. More importantly, our findings stress the value of keeping the performance bar high for cancer patients in order to avoid the dire consequences of a cancer pandemic once the COVID-19 pandemic would be over. Future investigations will offer a more exhaustive and long-term picture on the effectiveness of the efforts made to contain the coronavirus tidal wave also in other cancer settings. 

COVID Live Update: 156,719,262 Cases and 3,270,225 Deaths from the Coronavirus -Worldometer

Delays and Disruptions in Cancer Health Care Due to COVID-19 Pandemic: Systematic Review

Cancer care during the spread of coronavirus disease 2019 (COVID-19) in Italy: Young oncologists' perspective

Cancer Patient Management During the COVID-19 Pandemic | ESMO

Managing Cancer Care during the COVID-19 Pandemic: Agility and Collaboration Toward a Common Goal

Managing cancer patients during the COVID-19 pandemic: an ESMO multidisciplinary expert consensus

Scientia Potentia Est: How the Italian World of Oncology Changes in the COVID-19 Pandemic

Social distress among medical oncologists and other healthcare professionals during the first wave of COVID-19 pandemic in Italy

Changes in the Number of US Patients With Newly Identified Cancer Before and During the Coronavirus Disease 2019 (COVID-19) Pandemic

Fewer cancer diagnoses during the COVID-19 epidemic in the Netherlands

The impact of the COVID-19 pandemic on cancer deaths due to delays in diagnosis in England, UK: a national, population-based, modelling study

Assessment of Time-to-Treatment Initiation and Survival in a Cohort of Patients With Common Cancers

Global cancer statistics 2020: GLOBOCAN estimates of incidence J o u r n a l P r e -p r o o f and mortality worldwide for 36 cancers in 185 countries

Coronavirus Disease 2019 Infection in a Patient Population with Lung Cancer: Incidence, Presentation, and Alternative Diagnostic Considerations

Epidemiological characteristics of COVID-19 cases in Italy and estimates of the reproductive numbers one month into the epidemic. medRxiv

Lung Cancer Early Diagnosis: The Sooner, the Better" -Prof

Seroprevalence of SARS-CoV-2-Specific Antibodies in Cancer Patients Undergoing Active Systemic Treatment: A Single-Center Experience from the Marche Region, Italy

Pausing cancer screening during the severe acute respiratory syndrome coronavirus 2pandemic: Should we revisit the recommendations?

Cancer has not gone away: A primary care perspective to support a balanced approach for timely cancer diagnosis during COVID-19

COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: A prospective cohort study

Patient-reported treatment delays in breast cancer care during the COVID-19 pandemic

Impact of the COVID-19 pandemic on the symptomatic diagnosis of cancer: the view from primary care

Effects of the COVID-19 Pandemic on Cancer-Related Patient Encounters

COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study

Effect of delays in the 2-week-wait cancer referral pathway during the COVID-19 pandemic on cancer survival in the UK: a modelling study

COVID-19 risk for patients undergoing anticancer treatment at the outpatient clinic of the National Cancer Institute of Milan: The COVINT study

Assessing the Impact of COVID-19 on Registered Interventional Clinical Trials

The Authors thank the patients, the investigators and their teams who took part in this study.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-forprofit sectors.

J o u r n a l P r e -p r o o f