Diagnosis of HCC in medical centers

In Italy, the average number of diagnoses of HCC in public hospitals decreased in 2020 compared with 2018 and 2019 by 20% [16], and another study showed it HCC decreased by 30.4% [17]. A study of HCC which was conducted in 27 hospitals in 14 countries in Oceania and Asia found that during the COVID-19 crisis, the diagnosis of new cases of HCC decreased by 26.7% [18].

In France, the number of patients with HCC, including patients with the first diagnosis was lower in 2020 (n = 221) than in 2019 (n = 304). Although this number decreased significantly during the weeks in 2020 with a similar trend to 2019 (P = 0.034), it was not significant for those who had their first diagnosis of HCC (P = 0.083) [19]. In addition, Kempf et al. [20] have shown that the diagnosis of HCC during the period of restrictions in 2020 compared with the same period in 2018 and 2019 decreased by 29%; and, after the removal of these restrictions, this downward trend also has continued.

In the US, the number of diagnoses of liver and intrahepatic parts of the biliary tract (C24) per 100,000 patients with healthcare encounters in the early phase of COVID-19 in 2020 decreased by 34.13% and in the delayed phase continued with a 25.58% decline [21]. In Austria, the number of cases of HCC diagnosed had no difference between 2019 and 2020 [22].

Activities of diagnostic centers and pathology laboratories

Global investigation showed that the number of pathology samples for HCC diagnosis decreased from 158 in 2019 to 98 in 2020, but the percentage of the pathology samples of HCC increased from 0.14% in 2019 to 0.27% in 2020 compared to the total pathology samples [23]. Grinspan et al. [24] found that the number of diagnosed HCCs decreased in 2020 compared to 2018 and 2019, but HCC compared to other gastrointestinal cancers, was higher in 2020. Also, during the COVID-19 period, the detection rate of HCC among gastrointestinal cancers increased from 7.7% to 16.7% [24]. Some investigations in Italy demonstrated that despite a 4.3% increase in the number of referrals to the MDTM, the diagnosis of new cases of HCC has decreased from 15% in 2019 to 12% in 2020 [25].

Delay in diagnosis

In 14 countries of Oceania and Asia, the diagnosis of HCC was delayed in 48.2% of BCLC cases 0/A/B and 59.1% of BCLC C cases [18].

Screening method

During the COVID-19 pandemic, 80.9% of 76 HCC diagnostic and treatment centers around the world HCC changed their screening programs during the first wave of the corona. Furthermore, 40.8% of centers changed biopsy and imaging diagnostic procedure requests and their timing during the COVID-19 pandemic. Also, 39.5% of the centers modified magnetic resonance/computed tomography scan strategy for HCC staging or evaluation of treatment response [26].

Risk of HCC in patients with alcohol-related hepatitis

Patients admitted in the post-crisis period of COVID-19 had a higher risk for elevating incidence of HCC (OR = 1.19; 95% CI: 1.08–1.32; P < 0.001), which was attributed to delay or inconsistent standard HCC monitoring due to the prevalence of COVID-19 [27].

More details were presented in Tables 1 and 3.

Delaying or stopping treatment activities

A total of 27% of members of the Italian Liver Study Association reported that both locoregional surgical and non-surgical treatments were reduced (44% and 34%, respectively) or suspended (44% and 8%, respectively). Also, the number of patients to started treatment fell and 4% stopped systematic treatment [28]. In Italy, planning for HCC treatment was delayed for 42 patients, of which only 26% had a delay of 2 months: 2 TA, 4 TACE, 3 TARE, and 2 systemic treatments [29]. Furthermore, Martinez et al. [30] found that in 2020 the treatment of 5 patients with HCC was delayed for one month.

In France, after comparing HCC data in the first 6 weeks of a pandemic in 2020 with a similar period in 2019, it was shown that 21.5% of patients in 2020 experienced a delay of more than 1 month in treatment, while this rate in 2019, was 9.5% (P < 0.001). In the COVID-19 pandemic, a higher rate of patients requiring an interventional procedure experienced a delay of more than one month compared to those requiring medical treatment [intervention method: < 1 month, 54.3% (n = 100) vs. more than 1 month, 68.8% (n = 75); medical treatment: < 1 month, 41.8% (n = 77) vs. > 1 month, 13.8% (n = 15)] [19]. A study investigated by Gandhi et al. [18] showed that during the COVID-19 crisis, in 27 hospitals in 14 countries in Oceania and Asia, HCC treatment of 66.7% of BCLC 0/A/B cases and 63% of BCLC C was delayed. In addition, Pomej et al. [22] found that compared to 2019, the number of patients with delay in visits was 30% (n = 31) vs. 10% (n = 10) cases (P = 0.001); and the number of imaging delays was 25% (n = 25) vs. 7% (n = 7) cases (P = 0.001), which was higher in 2020.

Activities of medical centers

A total of 194 members of the Italian Liver Study Association reported that in 45% of centers, the care and follow-up of patients with HCC were limited. Also, 34% of them reported fundamental changes in their activities [28].

In three treatment centers in US, Singapore, and Japan, was found that there was generally no significant reduction in the number of visits for patients with HCC and/or cirrhosis (P trend = 0.11). Also, it was not observed in other parts of the world, although there was a significant downward trend at the US site (P trend = 0.094). However, between February 1 and March 14, 2020 and March 15 to May 1, 2020, the total number of HCC/cirrus visits decreased by 39.07% and 46.62% for the patients in the US and 26.6% for patients in Japan [31].

In Spain, 40.7% of gastrointestinal beds, 24.8% of gastroenterologists, and 58.3% of staff are dedicated to caring for patients with COVID-19, and outpatient visits; in addition, abdominal ultrasound and endoscopy decreased by 81.8–91.9%. Also, nine large university hospitals had 75% and 89% reductions in therapeutic endoscopies and surgery for HCC [32].

The results of an international study of 76 HCC diagnostic and treatment centers around the world during the COVID-19 crisis found that 73.5% of post-treatment centers changed imaging follow-up in HCC patients. A total of 63.2% of surgical treatment centers and 52.9% of locoregional treatment centers maintained their ability to perform HCC treatment in 96% of the centers. Of the 48 centers with LT programs before the COVID-19 pandemic, 58.3% did not change their LT activity. A total of 60.8% of the centers were able to perform surgical resection, 68.9% had percutaneous treatments, and 81.1% had locoregional. The option of initiating systemic treatment was maintained in 93.2% of the centers. In 50% of the centers, treatment and/or palliative care for HCC was canceled in at least one patient percenter due to SARS-CoV-2 infection [26].

In a study in China that analyzed the activity of 664 specialist physicians in 42 first-class teaching hospitals, 51.4% of physicians reported a reduction of more than 60% in regular workload, and surgeons (57.6%) announced the largest ratio of workload reduction (more than 60%). During the pandemic, regular workload decreased in 99.2% of the surveyed hospitals by varying degrees [33].

Modifying treatment method

In Nepal and Italy was shown that during the COVID-19 pandemic, surgical procedures were performed unchanged in patients with liver metastases. Local ablation for primary and metastatic tumors also has been performed regularly [34]. The results of a study in Italy revealed that in 3 patients TA was performed instead of pre-planned surgical resection [29].

In France, comparing HCC data in 2020 with 2019, it was shown that the treatment strategy changed in 13.1% of patients with no difference between the two periods [19]. Also, treatment strategy changes (between the proposed treatments during MTB and the treatments that were finally received) were reported in 13.1% of patients, with no difference between the two periods (P = 0.91). There were no differences in the distribution of treatment: neither for treatment (therapist, palliative, or BSC) nor for the group (interventional, non-interventional, or BSC). The main reasons for the alteration in treatment strategy in 2020 compared to 2019 were significantly different including COVID-19 infection, and tumor progression [19]. A study of HCC in 27 hospitals in 14 countries in Oceania and Asia demonstrated that in 33.3% of cases, BCLC 0/A /B and 18.5% of BCLC C treatment methods were changed [18].

LT in patients with HCC

In France, 2.2% of patients with HCC were excluded from the liver transplant waiting list during the COVID-19 crisis due to cancer progression [35]. Furthermore, in Italy, liver transplants for HCC dropped from three cases in 2019 to one case in 2020 [29]. A Chinese study of patients on the waiting list for liver transplants in Hong Kong (China) and Singapore predicted that by 2020, the number of cancellations of liver transplants in patients with HCC will increase significantly due to the disease progression of COVID-19 pandemic in one year (by 31.8%, 107.96%, 176.06%, and 291.00% for a 1-, 3-, 6- , and 12-disruptions respectively) [36]. In addition, HCC in Italy was shown that in 2020, compared to 2019, LT due to HCC decreased by 35.7% [25].

After the COVID-19 crisis in 55 wards in 43 Italian hospitals, preoperative assessments remained unchanged at 74.5%, and liver transplant activity reduced in 44.4% of centers. Follow-up, after LT was ineffective in 71.1% of the centers and immediate examinations, were performed in 26.3% [37].

Visiting and consulting patients

In Italy, the number of outpatient visits for HCC patients decreased from 117 in 2019 to 77 in 2020 [29]. The results of an international study HCC showed that during the COVID-19 crisis in 51.4% of centers, the telephone call service was improved, and an increase in the number of calls (more days and/or more hours per day) had the most alteration in 84% of centers, while 17.9% centers introduced telephone calls as a new method during COVID-19 pandemic [26]. In 58 centers, nurses were added to the HCC team, HCC nurses made decisions regarding face-to-face vs. phone call visits in 30.1% of the centers, and in 70.3% of cases, they organized visits. Nurses undertook telephone call visits in 62.5% to answer questions about treatment or follow-up events [26].

In another study in Italy, outpatient visits decreased by 8.9%, and out of a total of 1,416 visits to the HCC outpatient clinic, 7.2 % were done through video calling [25]. Another study in Italy revealed that face-to-face counseling for patients with HCC in multidisciplinary counseling sessions was reduced from 46 in 2019 to 42 in 2020 [29]. In France, more consultations were cancelled in 2020 compared to 2019 (7.8% vs. 1.4%, P < 0.001, respectively). The percentage of remote consultations increased during the pandemic (35.9% vs. 1.3%, P < 0.001, respectively) [19]. A study in Oceania and Asia found that face-to-face patient consultations decreased by 27.3% in hospitals, and telephone and video counseling increased by 18.3% [18].

In Austria, 56.1% of HCC patients reported less telemedical contact with their liver specialist (P < 0.001). Also, 75.6% had fewer personal visits to the hospital, and 40.9% needed acute medical care during COVID-19-related healthcare restrictions (P = 0.253). A total of 18.2% of patients reported an increase in difficulty seeking medical help compared to the situation before COVID-19. The VAS index for face-to-face contact with the treating physician was low among HCC patients (P = 0.066), and patient satisfaction with treatment of liver disease during COVID-19-related health care restrictions was minimal in patients with HCC (P = 0.159) [38]. Pomej et al. [22] found that although face-to-face visits decreased, there was an increase in telemedical counseling, and the median number of elective/non-elective admissions did not differ in different periods of 2020 and 2019. In addition, Zhao et al. [33] analyzed the activity of 664 specialist physicians in 42 first-class teaching hospitals, 82.5% of the hospitals in question provided remote counseling services to HCC patients during the COVID-19 outbreak and the majority of respondents (92.5%) used online medical counseling instead of face-to-face appointments.

Hospitalization

Iavarone et al. [29] found that the total number of HCC patients admitted to the ward decreased from 58 in 2019 to 48 in 2020.

Performing treatment methods

Iavarone et al. [29] demonstrated that liver resection due to cancer decreased from 3 cases in 2019 to 2 cases in 2020. According to another study in Italy, the number of surgeries performed to treat HCC decreased from 12 in 2019 to 7 in 2020, but the percentage of surgeries performed to treat HCC compared to all surgeries increased from 14.2% in 2019 to 18.9% in 2020 [39]. In addition, Amaddeo et al. [19] found that the number of treatments suggested or performed in active HCC patients referred to the center decreased from 56.7% in 2019 to 43.7% in 2020, which was significant in the second half of the period in 2020 (P = 0.018). In Italy, laparoscopic ablations and TACE/TARE procedures decreased by 52.6% and 20.2%, and surgical resection and percutaneous ablations increased by 43.8% and 108.3% respectively [25]. Examining the activity of 55 departments of 43 Italian hospitals the was shown that surgical or locoregional treatments for HCC, at similar rates to the first wave, were decreased or stopped in significant numbers of the centers (55.8% and 48.1%, respectively). A total of 75.5% of centers continued to prescribe systemic treatments [37].

Also, in Italy, a 27.5% and 28.3% decline was observed in the number of patients referring to MLTB and percutaneous ablations respectively, while TACE remained unchanged and SIRT increased by 64%. In 2020, 31 surgeries were performed on primary lesions (mostly HCC), compared to 14 surgeries in 2019. More than 50% of patients with HCC were in the intermediate stage (BCLC B); approximately one-third of cases were in the advanced stage (BCLC C) due to intrahepatic macrovascular invasion. No HCC patients underwent SIRT in the early stages between March and July 2020, while 3 cases were reported in 2019 (P = 0.04). The type of treatment in 2019 and 2020 was not significantly different; In 2020, the number of measures performed using the holmium-166-labeled microspheres method increased [40]. In China, oncologists were more concerned about antitumor effects, adverse drug reactions, quality of life, and the stability of treatment, prevention, and control of COVID-19 in patients with advanced HCC receiving systemic therapies. Only 34% of specialists recommended surgical resection during this period. In addition, a significant number of experts recommended non-surgical treatment strategies, including RFA and observation [33].

Pursue treatment by participating in research projects

In France in 2020, 5.4% (36/670) of patients agreed to be enrolled in the study protocol, which had no difference from the pre-COVID-19 period (P = 0.228) [19].

Therapeutic complications

Twenty-seven hospitals in 14 countries in Oceania and Asia found that in the COVID-19 crisis, treatment complications increased by 15% at all stages of BCLC [18].

Response to treatment

A study in China found that the ORR to treatment, after the last radiological treatment in the study group and the controls were 23.9% and 39.8%, respectively (P = 0.037) [41].

Follow-up treatment

A study in China showed that the mean follow-up interval (82 days) during the COVID-19 period was significantly higher than in the pre-pandemic period (66 days, P = 0.004) [41]. Among a total of 664 specialist physicians in 42 first-class teaching hospitals in China, 62.2% of surgeons, more than three months after the last examination recommended follow-up, for HCC patients who underwent routine postoperative follow-up after liver resection while 15.4% suggested postponement in either case. For patients receiving TACE, 55.4% of interventional oncologists recommend that patients can appropriately delay follow-up, but not more than six months from the previous follow-up, while 20.5% did not suggest follow-up during the pandemic. Most physicians (86.1%) recommended postponing or canceling follow-ups for patients who had completed their radiation therapy (patients did not receive adjuvant radiation therapy) [33].

Average time of performing treatment methods

In Italy, the average time for MDTM-TACE was reduced from 20 days in 2019 to 15 days in 2020 (P = 0.42), HCC treatment-radiological evaluation of response increased from 34 days in 2019 to 41 days in 2020 (P < 0.0001), and for outpatients’ visit—radiological evaluation of response increased from 64 days in 2019 to 69 days in 2020 [25].

Distribution of medicine

One year after the COVID-19 crisis, home delivery was performed by 14.5% of 55 wards in 43 Italian hospitals [37].

Please refer to Tables 2 and 4 for more details.