key: cord-0710612-eqt13h0n
authors: Brugel, Mathias; Letrillart, Léa; Evrard, Camille; Thierry, Aurore; Tougeron, David; El Amrani, Mehdi; Piessen, Guillaume; Truant, Stéphanie; Turpin, Anthony; Christelle d'Engremont; Roth, Gaël; Hautefeuille, Vincent; Regimbeau, Jean Marc; Williet, Nicolas; Schwarz, Lilian; Di Fiore, Frédéric; Borg, Christophe; Doussot, Alexandre; Lambert, Aurélien; Moulin, Valérie; Trelohan, Hélène; Bolliet, Marion; Topolscki, Amalia; Ayav, Ahmet; Lopez, Anthony; Botsen, Damien; Piardi, Tulio; Carlier, Claire; Bouché, Olivier
title: Impact of the COVID-19 pandemic on disease stage and treatment for patients with pancreatic adenocarcinoma: a French comprehensive multicentre ambispective observational cohort study (CAPANCOVID)
date: 2022-02-10
journal: Eur J Cancer
DOI: 10.1016/j.ejca.2022.01.040
sha: d48ee415ec8bf1142d784c1f223a3196bc6f42f6
doc_id: 710612
cord_uid: eqt13h0n

Background. The COVID-19 pandemic caused major oncology care pathway disruption. The CAPANCOVID study aimed to evaluate the impact on pancreatic adenocarcinoma (PA) – from diagnosis to treatment – of the reorganisation of the health care system during the first lockdown. Methods. This multicentre ambispective observational study included 833 patients diagnosed with PA between September 1(st), 2019 and October 31(st), 2020 from 13 French centres. Data were compared over three periods defined as before the outbreak of COVID-19, during the first lockdown (March 1(st) to May 11(th), 2020) and after lockdown. Results. During the lockdown, mean weekly number of new cases decreased compared with that of pre-pandemic levels (13.2 vs. 10.8, -18.2%; p=0.63) without rebound in the post-lockdown period (13.2 vs. 12.9, -1.7%; p=0.97). The number of borderline tumours increased (13.6% to 21.7%) whereas the rate of metastatic diseases rate dropped (47.1% to 40.3%) (p=0.046). Time-to-diagnosis and -treatment were not different over periods. Waiting neoadjuvant chemotherapy in resectable tumours was significantly favoured (24.7% to 32.6%) compared with upfront surgery (13% to 7.8%) (p=0.013). The use of mFOLFIRINOX preoperative chemotherapy regimen decreased (84.9% to 69%; p=0.044). After lockdown, the number of borderline tumours decreased (21.7% to 9.6%) and advanced diseases increased (59.7% to 69.8%) (p=0.046). SARS-CoV-2 infected 39 patients (4.7%) causing 5 deaths (12.8%). Conclusion. This cohort study suggests the existence of missing diagnoses and of a shift in disease stage at diagnosis from resectable to advanced diseases with related therapeutic modifications whose prognostic consequences will be known after the planned follow-up.

Inserm UMR-S1277, University of Lille, Lille, France 23 Introduction 98 Pancreatic adenocarcinoma (PA) is the most lethal gastrointestinal cancer and the 99 fourth cause of cancer-related deaths in Europe with few therapeutic perspective 1, 2 . 100

The severity of Coronavirus disease 2019 caused by Severe Acute 101

Respiratory Syndrome -Coronavirus 2 (SARS-CoV2) required most countries to take 102 measures to contain the pandemic in 2020. Health care systems were reorganised to 103 prioritise resources towards the management of critically ill patients. Patients with 104 severe medical conditions and cancer have an increased risk of severe forms of 105 COVID-19 3-6 . 106

The oncology care pathway was heavily disrupted at this time 7, 8 . Screening and 107 diagnosis of many cancers were impacted, delaying time to treatment 9 . New guidelines 108 were published proposing surgery deferral for resectable PA with waiting 109 chemotherapy, palliative chemotherapy adjustments and telemedicine promotion [10] [11] [12] [13] [14] . 110

The consequences of oncological care pathway disruption on PA patient management 111 remain unknown. 112

The CAPANCOVID study aimed to evaluate the impact of the reorganisation of the 113 health care system during the COVID-19 pandemic on the number of new cases, 114 disease stages at diagnosis and treatment of patients newly diagnosed with PA. 115

Secondary objectives were to describe COVID-19 incidence, severity and 116 consequences on management of PA patients. We performed a comprehensive multicentre ambispective (retro-prospective) 121 observational cohort study in nine French tertiary hospitals, two cancer institutes and 122 two general hospitals. To simplify the interpretation of the influence of COVID-19 123 incidence on our data, we assembled them into larger geographical areas: Grand East 124 (Reims, Nancy, Besançon, Colmar); East (Saint Etienne, Grenoble); North (Lille, 125 Amiens) and West (La Rochelle, Poitiers, Rouen) . This study followed the 126 2020, whose files were discussed in a multidisciplinary tumour board meeting (MTBM) 131 were included. As every patient's file had to be discussed in an MTBM, histological 132 proof was not mandatory in order to consider the diagnosis (association of typical 133 radiological findings and increased CA 19-9 levels). Patients under guardianship, with 134 non-malignant tumours, neuroendocrine tumours or who were opposed to the study 135

were not included. 136

137 All data were collected online from patients' medical files after being screened using 138 MTBM working lists. All data from patients diagnosed from September 1 st , 2019 to April 139 15 th , 2020 were collected retrospectively. Data from patients included after April 15 th , 140 2020 were collected both prospectively and consecutively. 141

Three periods were defined according to French COVID-19 governmental containment 142 measures. The first period (P0), prior to COVID-19, was defined from before the onset 143 of the epidemic until February 29 th , 2020. From this date, French government instituted 144 a first lockdown 16 . The second period (P1) was defined as the first epidemic wave and 145 lasted from March 1 st to May 11 th , 2020, when the first lockdown ended. A third period 146 (P2) was defined from May 12 th , 2020 to the end of the study. 147

Data collection included patient characteristics such as age, gender, weight, body 148 mass index, ECOG performance status (PS) and distance between home and care 149 centre. We also collected primary tumour location, histological type, date and type of 150 first symptom, disease stage at diagnosis (resectable, borderline, locally advanced or 151 metastatic according NCCN classification) and CA19-9 levels 1, 17 . Diagnostic 152 management was described using dates of the first specialist care consultation or 153 admission, imaging technique, biopsy, and MTBM. Times from symptoms onset to first 154 imaging, to diagnosis and to treatment, time from diagnosis to MTBM and time from 155 first imaging to treatment were calculated according to existing standards 18 . The first 156 therapeutic strategy (upfront surgery, preoperative (neoadjuvant or induction) 157 chemotherapy, palliative chemotherapy or exclusive best supportive care) was defined 158 using date of application, modalities and justification (COVID-19 guidelines or usual 159 guidelines) 1, 12 . All treatment adaptations due to the COVID-19 pandemic were 160 collected. COVID-19 infections, their complications (admission to the medical or 161 intensive care unit, death) and their impact on treatment were also assessed. 162

Ethical approval 163 As this study was non-interventional, approval by an independent ethical committee 164 was not required. The institutional review board at Reims University Hospital approved 165 the study. All analysed patients were informed and did not express their opposition to 166 the study. It was registered on ClinicalTrials.gov (NCT04406571 Although tumour (T) and node (N) stages remained steady, metastasis (M) discoveries 229 during surgery were more frequent during lockdown (from 2.2% in P0 to 13.8% in P1; 230 p=0.015). One patient out of 18 with delayed surgery had metastases discovered 231 during the surgical procedure. 232

The use of mFOLFIRINOX neoadjuvant or induction chemotherapy regimen 233 decreased significantly during P1 (from 84.9% in P0 to 69% in P1; p=0.044) ( Table 1) . 234

In palliative settings, the use of FOLFIRINOX decreased (p=0.262) during lockdown 235 (from 49.2% in P0 to 39.3% in P1), contrasting with the more frequent use of 236 gemcitabine (from 18.8% in P0 to 26.2% in P1) ( papillary mucinous neoplasm which may be the initial presentation of PA, were not 279 prioritised at pandemic's peak 24, 28, 25 . In contrast, patients with jaundice or pancreatitis, 280 considered as emergencies, may have been referred more easily 25 . In a Japanese 281 retrospective study, the number of endoscopic retrograde cholangiopancreatographies 282 was not significantly reduced as a result of urgent procedures for jaundice, but the 283 number of endoscopic ultrasonography cases was significantly reduced 24 . 284

In our study, patients were not significantly affected by the lockdown regarding times 285 to diagnosis and treatment, reflecting the maintenance of the quality of care. However, 286 from the patient's perspective, fear and anxiety about COVID-19 may have resulted in 287 reluctance to have medical contact or to perform imaging exams 25 . Although the 288 influence of time to diagnosis or treatment on PA prognosis remains unclear, a surge 289 in later disease stages at diagnosis and a poorer prognosis than expected could be 290 feared 9, 29, 30 . 291

The first treatment is determined by disease stage at diagnosis. Resectable tumours 292

should be treated with upfront surgery according to PA management guidelines 1, 17 . 293

Every patient but one (n = 20, 95.2%) treated by neoadjuvant chemotherapy for a 294 resectable PA diagnosed before COVID-19 epidemic were included in clinical trials. In 295 our study, we observed a mean 43-days postponement period for scheduled surgeries, 296 with a major switch from upfront surgery to waiting neoadjuvant chemotherapy in 297 patients with resectable disease. The diminished access to operating rooms and 298 postoperative care in intensive care units justified the use of neoadjuvant 299 chemotherapy 31-33 . Neoadjuvant chemotherapy could have improved the prognosis 300 but clinical trial results are still pending. As recommended in the guidelines, oncologists 301 switched from tri-chemotherapy to bi-or mono-chemotherapy during the first 302 lockdown 12 . ESMO recommendations in the COVID-19 era considered newly 303 diagnosed resectable and advanced PA as "high priority to treat" 11, 14 . The COVID-19 304 pandemic also had a dramatic impact on all aspects of pancreatic cancer research 34 . 305

In France, all clinical research trials were stopped for 3 months. During the second 306 wave, the improved knowledge on COVID-19 management and risk factors allowed 307 new French guidelines to step up research and treatment to their previous levels 35 . 308

Cancer patients are particularly vulnerable to SARS-CoV2 infections with a higher rate 309 of severe forms 3-6 . In our cohort, 4.7% of the patients were contaminated by SARS-310

CoV2 with a mortality rate of only 12.8%, lower compared to previous declarative 311 studies [3] [4] [5] [6] . A recent large cohort study reported a mortality rate of only 7.8% for patients 312 with recent cancer treatment 36 . SARS-CoV-2 PCR tests availability and increasing 313 expertise in the management of COVID-19 severe forms could have made mortality 314 rate estimation evolve all along previous published descriptive studies 6, 36, 37 . Our 315 ambispective setting allows us to consider these results as non-biased real-life 316 observations in a population with initial good performance status (79.6% of PS 0-1). 317

However, these infections may have disrupted patients' treatment schedules. In our 318 study, these modifications occurred in 56.4% of infected patients, with a mean delay 319 of less than two weeks. In a French monocentric study, COVID-19 management 320 caused a median 20-days delay for 41% of patients 6 . As the first French epidemic wave 321 was concentrated in the Eastern regions, we observed a majority of COVID-19 322 infections in these Eastern centres (58.8%) but no differences in PA management, 323 contrary to results reported in an Italian survey 38 . In France, a unique health policy was 324 applied to the whole national territory without considering regional epidemic situation. 325

The CAPANCOVID study has some limitations. Firstly, in this ambispective setting, the 326 first part of the study was retrospective. However, very few data are missing. Secondly, 327 despite a multicentre design, COVID-19 incidence remained very heterogeneous 328 between participating centres while the Paris area, significantly impacted by the 329 epidemic, was not represented. A study reported a higher decline of PA new cases by 330 34% in Paris 39 . In an Italian survey, a reduction in the number of PA diagnoses was 331 recorded only in the North and Centre of the country (14.1% and 4.7% respectively) 38 . 332

Thirdly, this cohort was not a population-based study. Data collection from MTBM could 333 have introduced a selection bias: some patients' files, particularly those receiving 334 exclusive supportive care, might not be addressed. Another limitation is due to the low 335 number of certain subgroups and the inability to perform multivariate analysis in these 336 specific subgroups. 

Number of new biweekly cases of pancreatic adenocarcinoma based on 542 first therapeutic decision

P0: from September 1 st

During the lockdown, the weekly number of new cases decreased by 18

 Neoadjuvant chemotherapy was favoured compared with upfront surgery (p=0.013)

 A shift in disease stage at diagnosis occurred from localised to advanced diseases

outside the submitted work. G.P. reports personal fees as a speaker and/or in an advisory role from BMS, MSD, Stryker and Medtronic, outside the submitted work. A.T. reports personal fees as a speaker and/or in an advisory role from Amgen, Merck KGaA, Servier, Mylan and Pierre Fabre and travel accommodations expenses from Pfizer and Sanofi, outside the submitted work. G.R. reports personal fees as a speaker and/or in an advisory role from Accord Healthcare, Abbvie, Amgen, Ipsen, Sanofi, Servier, and MSD, outside the submitted work. F.D.F. reports personal fees as a speaker and/or in an advisory role from Roche

M reports personal fees as a speaker and/or in an advisory role from Sanofi, outside the submitted work. A.L. reports personal fees as a speaker and/or in an advisory role from Amgen

outside the submitted work. C.C. reports personal fees as a speaker from Bristol Myers Squibb, outside the submitted work. O.B. reports personal fees as a speaker and/or in an advisory role from Merck KGaA

All other authors declared no conflicts of interest for this study