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COVID‐19 outbreak in Lombardy: Impact on reducing solid cancer diagnoses in 2020

Abstract Our aim was to analyse, on a population level, the year‐long decline in cancer diagnoses in the region of Lombardy (Italy), and to characterise the tumours with the greatest reduction in diagnosis by patient age, sex and tumour stage at diagnosis. We used the health care utilisation databases of the Lombardy region to identify cancer patients' characteristics (eg, sex, age) and cancer‐related information (eg, cancer site, stage at diagnosis). The frequency of new cancer diagnoses in 2019 and 2020 were compared in terms of percentage differences in undiagnosed cases. We observed two peaks in the decline in cancer diagnoses: March to May 2020 (−37%) and October to December 2020 (−19%). The decline persisted over the course of 2020 and was higher in males and patients aged 74+. Diagnoses of all four common cancers analysed (female breast, lung, colorectal and prostate) remained below pre‐pandemic levels. For breast and colorectal cancers, the decline in diagnoses was high in the age groups targeted by population‐based screening programmes. We observed a reduction in localised stage cancer diagnoses for all four cancers. Our data confirm that timely monitoring of cancer diagnoses and interventions to prevent disruption of routine diagnostic services are needed to mitigate the impact of emergencies on cancer patients.

negatively impacted by the COVID-19 pandemic. Timely monitoring of cancer diagnoses and interventions to prevent disruption of routine diagnostic services are needed to mitigate the impact of public health emergencies on cancer patients.

| INTRODUCTION
Following its outbreak in China in December 2019, the COVID-19 pandemic spread rapidly, with Italy being the first Western country to experience a massive outbreak of the virus. The Italian government imposed strict measures to counteract the spread of SARS-CoV-2. 1,2 The Healthcare System reorganised or reduced many activities in order to adapt to the emergency, and routine diagnostic procedures, including cancer screening, were either halted or postponed. [3][4][5] Italian oncological societies recommended limiting follow-up appointments and second opinions and established a priority scale designed to optimise available resources while continuing to offer the best possible care to cancer patients. 6 However, the impact of these measures on cancer diagnoses and treatment has become a widespread source of concern.
Disruption of activities also affected surveillance systems, such as population-based cancer registration. 7 As a result, population-based data on the decline in cancer diagnoses are limited. [8][9][10][11][12] Dutch, Danish and USA studies reported a notable decrease in cancer diagnoses during the early months of the COVID-19 pandemic (February to April 2020). The decline was observed in males and females, and at nearly all cancer sites. [9][10][11] In Northern Ireland, a 23% reduction was observed in diagnosed cancer cases during the 6-month peak of the first wave of the pandemic. 12 In Belgium, Peacock 8 and colleagues observed the whole of 2020 and reported a steep decline in cancer diagnoses in the first wave of the pandemic (À44% in April 2020 compared to April 2019) and a small 2% dip in diagnoses during the second wave, in November 2020.
Data on the impact of the COVID-19 pandemic on cancer detection in Italy come mainly from mono-or multicentre studies. [13][14][15] Our goal is to analyse, at a population level, the year-long decline in cancer diagnoses in Lombardy, that is, the epicentre of the Italian COVID-19 pandemic. 16 Specifically, we aim to characterise the tumours with the greatest overall reduction in diagnoses, according to patients' age and sex, and tumour stage at diagnosis. The latter is particularly important since early diagnosis is known to improve cancer patient prognosis, but currently available population-based evidence does not report any data disaggregated by stage. To our knowledge, this is the first time such a study has been conducted in Italy at a population level. The data used for the present study were retrieved from the health care utilisation databases of Lombardy, the second Italian region by resident population, with around 10 million inhabitants. 17 All Italian citizens have equal access to health care services as part of the NHS. The NHS guarantees partly or entirely free of charge access to a number of health care services to all Italian citizens. In Lombardy, this has been associated since late 1990s with an automated system of health care utilisation databases including: hospital discharge (inpatient and day-hospital) database containing information about primary diagnosis, coexisting conditions, provided procedures (coded according to the ICD-9CM) 18 and clinical condensed stage (1: tumour confined to organ of origin; 2: tumour beyond organ of origin; 3: metastases to regional lymph node; 4: tumour beyond organ of origin + metastases to regional lymph nodes; 5: distant metastases; 6: distant lymph nodes; 7: not confined to organ of origin but unknown if 2, 3, 4, 5 or 6; 8: no distant organs invasions but unknown if 1, 2, 3 or 4; 9: unknown); drug prescription database providing information on all the drugs reimbursed by the NHS (coded according to the ATC classification system); outpatient database, including visits in specialist ambulatories and diagnostic laboratories accredited from the NHS (coded according to the regional outpatients services coding); and copayment exception database, including exception for chronic disease (coded according to the national exceptions coding). Pathological reports are not included in the healthcare utilisation databases. These various types of data are interconnected, since a single individual identification code is used by all databases for each citizen enrolled. Further details of the databases of health care use in Lombardy have been described in previous studies. 19

| Case definition
To identify cancer patients, we used the hospital discharge records database. The hospital discharge records are fed from the medical records for all patients discharged from public and private healthcare    discharge was classified as localised (tumour confined to organ of origin), locally advanced (tumour beyond organ of origin; metastases to regional lymph node; tumour beyond organ of origin + metastases to regional lymph nodes), metastatic (distant metastases; distant lymph nodes) or unknown (not confined to organ of origin but unknown if locally advanced or metastatic; no distant organs invasions but unknown if localised or locally advanced; unknown). When staging information was missing at the index date, we searched for it in patients' hospital discharge records for up to 6 months after cancer diagnosis.
All analyses were performed using SAS Studio software.

| Overall changes over 2020
We observed a significant reduction of approximately À20% in   Figure 1A,B).
The percentage difference varied widely over the course of the year ( Figure 1A,B and the second in the second wave (October-December 2020; 10 797 vs 13 288 cancer cases, À19%).  Figure 1A). Young people (<50 years old), on the other hand, had the smallest reduction in newly diagnosed cancers. However, a reduction of À37% was observed for them too in April 2020. The summer months showed the lowest reduction in newly diagnosed cancers. Notably, the greatest decline in these months was observed for younger patients (both <50 and 50-74 age groups).

| Changes over 2020 by sex
We observed a sex-based difference in the reduction in new cancer diagnoses: À22% in men and À18% in women ( Figure 1B). The sex

| Changes over 2020 by cancer site and age groups
During the first wave of the pandemic (March-May 2020), the percentage difference in cancer diagnoses was greater in elderly (aged >74 years) than in younger (aged <50 years) patients for both colorectal and female breast cancer: À37% vs À6% in colorectal and À42% vs À15% in female breast cancer (Figure 3). After the first wave, the largest reduction in new cancer diagnoses for colorectal and female breast cancer was found in the screening-target age group (À21%;

50-74 years).
For lung and prostate cancer, the overall decrease was similar across the age groups. However, after the first wave, the reduction was higher at older ages for lung cancer (À14% and À13% at age 50-74 and >74 years, respectively, vs À5% at <50 years) and highest in young patients for prostate cancer (À20% in those aged <50 years; Figure 3).

| Changes over 2020 by cancer site and sex
In colorectal cancer, we observed a lower decline in new cancer diagnoses in women compared to men, in both the younger (<50 years old) and older age groups (>74 years old). In terms of lost new cancer diagnoses, there were no major differences between women and men either overall or in the screening-target age group (50-74 years old) ( Table 1).
For lung cancer, we observed a higher decline in new cancer diagnosis in young women (<50 years old) compared to young men (Table 1). No substantial differences were observed between males and females for the other age groups.

| Changes over 2020 by cancer site and stage
In all four cancers considered, localised stage diagnoses presented the largest reduction: À22%, À27%, À27% and À31% in female breast, colorectal, lung and prostate cancers, respectively ( Figure 4). The largest reduction in localised stage diagnoses was observed during the first wave of the pandemic: À34%, À41%, À46% and À64% in female breast, colorectal, lung and prostate cancers, respectively. The smallest reduction for the whole period was observed for metastatic breast cancer patients.
Stage distribution did not change substantially between 2019 and 2020 for all cancers considered (Table S1).

| DISCUSSION
Two key findings of our study were the reduction in cancer diagnoses, which persisted over the course of 2020-although some recovery did were more common among the elderly and patients with comorbidities (eg, diabetes mellitus, hypertension and cardiovascular disease). 26 Elderly men were also at higher risk of complications and death from COVID-19, 27 so it is conceivable that older men are the least likely to see a doctor. Additionally, as deaths were higher among the elderly, 27 it is also likely that some cancer diagnoses in this age group were missed by dying from COVID-19 before being diagnosed with cancer. Although elderly were particularly impacted by the COVID-19, there was still a 15% drop in cancer diagnoses in young patients (<50 years old).
Our results confirmed a high reduction in diagnoses of breast, colorectal and prostate cancers, and a lower, but relevant decline in diagnoses for lung cancer. 8,9,12 Belgian data previously showed that poor prognosis cancers were less impacted. In the case of lung cancer, symptoms mimicking those of COVID-19 may have contributed to keeping the diagnosis rate higher compared to other cancers. 8 A slight reduction in newly diagnosed lung cancer cases was observed in 2020 compared to 2019 in several other studies. [28][29][30][31] However, some studies have observed relevant decrease in lung cancer diagnoses 32,33 likely due to the disruption of lung cancer screening [34][35][36] or to the different setting of the study (hospital vs population-based). Lung cancer screening is not available in Italy.
We observed a major decline in cancer diagnoses for colon and breast cancers in the age groups targeted by population-based screening programmes. Italian national data showed a significant decline in the number of screening tests performed in 2020 compared to 2019.
For breast cancer, there was a À54% reduction in the number of screening tests performed between January and May 2020 and a À24% fall between September and December 2020. In Lombardy, the reduction was À62% and À25% in the first and last months of 2020, respectively. 4 For colorectal cancer, the decrease in the number of screening tests performed was À58% between January and May 2020 and À24% between September and December 2020. In Lombardy, the reduction was À69% and À55% in the first and last months of 2020, respectively. This can again be explained by patients' fear of being infected during hospital access and the recommendation to limit primary and secondary care access to more fragile patients, including the elderly. Our study demonstrates the substantial effect that the  22 The breast cancer screening programme was disrupted, leading to a significant decrease in in situ breast cancer diagnoses and an increase in node-positive and stage III tumours. 39 Furthermore, waiting times on list and times between biopsy/cytological examination and surgery were significantly longer during lockdown and were associated with an increase in pathological node involvement. 40 In any event, despite observing a differential relative decrease in localised stage cancer diagnoses, stage distribution did not change substantially between 2019 and 2020 for any of the cancers considered (Table S1). This could be due to the limited follow-up (December 2020), which did not allow us to observe the long-term impact of the two COVID-19 waves, and to the cancer stage grouping, which prevented us from observing detailed changes such as tumour size. The large reduction in prostate cancer diagnoses with missing stage information may be explained by the decline in PSA testing during the first wave of the pandemic.
Our study has several limitations which need to be acknowledged. We used hospital discharge database, which are claims data collected for administrative, not epidemiological purposes, so they are not completely precise, especially in terms of diagnostic codes, and only include procedures performed in hospital. This could also explain some observed differences between our data and those reported by CRs which are based on different sources of information, including pathological reports. To address these issues, we focused on solid tumours that can be adequately retrieved via the ICD-9CM codes used in the hospital discharge database, limiting more in-depth analyses to the four tumours with a clear hospital pathway, which can be identified without losing cases via the hospital discharge database.
However, we were unable to report on haematological cancers and skin melanomas, which were heavily impacted by the emergency.
Another limitation is that our follow-up ended in December 2020, preventing us from assessing the full impact of the second wave of the pandemic and full retrieval of cancer diagnoses. However, we did have access to the latest updated data as of December 31, 2020.
Although the number of diagnoses increased in several countries 12,41 in 2021, the pandemic and COVID-19 restrictions differed substantially across EU countries, hence their impact on cancer detection across countries could likewise differ. 42 Despite the weaknesses mentioned above, our study has the merit of supporting the use of health care utilisation database to study the impact of emergency situations on cancer detection (and beyond) when population cancer registries cannot promptly contribute. This is the first population-based study performed in Lombardy, the Italian region most hit by the COVID-19 pandemic.
To conclude, our data confirm a strong, not yet fully recovered