Colonization with multidrug-resistant organisms impairs survival in patients with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related death globally and the most common malignant primary liver cancer disease. HCC usually develops as a result of chronic liver disease due to chronic viral hepatitis, alcohol abuse and in fast increasing numbers from non-alcoholic steatohepatitis (nASH). The risk of HCC development increases with the stage of liver fibrosis. The cumulative risk for HCC development in patients with established cirrhosis ranges from 5 to 30% within 5 years (Villanueva 2019). HCC treatment is performed according to the BCLC (Barcelona Clinic Liver Cancer) stages (European Association for the Study of the Liver 2018). Curative HCC treatment with local ablative procedures, surgical resection or liver transplantation is reserved for patients in early stages with sufficient liver function (European Association for the Study of the Liver 2018). For HCC patients with unresectable advanced stages palliative treatment with transarterial chemoembolization (TACE) or sorafenib has been standard of care in the past decade. In 2020 immunotherapy with the combination of atezolizumab and bevacizumab has become the favored first line treatment for these patients (Finn et al. 2020).

The global spread of multidrug-resistant organisms (MDRO), namely, vancomycin-resistant Enterococcus faecalis/faecium (VRE), methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Gram-negative bacteria (MDRGN) complicates treatment and isolation measures in health care (2013). MDRO-colonization has been shown to especially impair survival in patients with hematological malignancies and solid tumors as well as in patients with liver disease (Ballo et al. 2019; Ferstl et al. 2017, 2021; Stratmann et al. 2020; Arvaniti et al. 2010; Waidmann et al. 2015). Apart from the cancer disease itself, most HCC patients also suffer from relevant chronic liver disease. Infectious complications, mostly by bacteria belong to the predominant causes of acute on chronic liver failure leading to high rates of death (Waidmann et al. 2015; Ferstl et al. 2021). As MDRO severely narrow antibiotic treatment options higher mortality rates in patients with liver disease and MDRO are reported (Waidmann et al. 2015; Ferstl et al. 2021; Fernandez et al. 2016a). Despite the knowledge of MDRO-colonization adversely affecting survival in these patients, no studies are available investigating the impact of MDRO-colonization in patients with HCC. Considering that many HCC patients do not die due to uncontrolled tumor growth but due to complications of cirrhosis (e.g., sepsis) there is a need to improve supportive measures, e.g., by avoiding MDRO-colonization and lethal infections (Couto et al. 2007).

We conducted this retrospective analysis to determine the incidence of MDRO-colonization in HCC patients and to evaluate its impact on the clinical course.

Several studies have shown that MDRO-colonization adversely affects the clinical course of patients with hematological malignancies and solid tumors as well as in patients with liver disease (Ballo et al. 2019; Ferstl et al. 2017; Stratmann et al. 2020; Arvaniti et al. 2010). Although HCC is a leading cause of cancer‐related death globally, to our knowledge this is the first study investigating the clinical impact of MDRO-colonization on patients with HCC.

Due to strict exclusion criteria (exclusion of HCC patients that never received MDRO screening and HCC patients who acquired MDRO-colonization later than 90 days after HCC diagnosis) we were able to define two clearly separated HCC patient cohorts (Fig. 1). By excluding HCC patients that were never screened for MDRO-colonization the risk of false-negative or occult positive noncolonized HCC patients was minimized. Excluded HCC patients that acquired MDRO-colonization later than 90 days after diagnosis of HCC prevented bias and confounders, as in these patients the clinical course is not primarily or at least not in the beginning determined by MDRO-colonization.

After exclusion of the above patients we found 59 (6%) of 954 HCC patients to be MDRO-colonized and 895 (94%) HCC patients to be noncolonized. The most frequent MDRO detected in colonized HCC patients was ESBL/ ± FQ with 59%, followed by VRE with 37%. The finding of ESBL as the most frequent MDRO in HCC patients is not surprising, since other studies analyzing the epidemiology of MDRO in Europe already described ESBL as a frequently isolated MDRO in hepatological patients (Fernandez et al. 2016b; Merli et al. 2015). A dominant prevalence of VRE-colonization was also expected. Germany has one of the highest VRE prevalence in Europe and again Hesse, North Rhine-Westphalia, Thuringia and Saxony have the highest proportion of VRE-colonization within Germany (Gastmeier et al. 2014). Surprisingly, colonization with CRE—known to cause untreatable lethal infections in patients with liver and other diseases—was only found in one HCC patients (Ballo et al. 2019; Ferstl et al. 2017).

Colonized patients with HCC had strongly impaired prognosis with a median OS of 189 days (6.3 months) compared to a median OS of 1001 days (33.4 months) in noncolonized HCC patients. The vast difference in survival for colonized and noncolonized HCC patients is due to different reasons. As shown in Table 3 cirrhosis and cancer disease were significantly more advanced in colonized HCC patients. Patients suffering from more severe cirrhosis and/or more severe HCC do often not qualify for systemic treatment and have impaired survival regardless of MDRO-colonization. They are more likely to receive antibiotic treatment, they are more often hospitalized and treated on intensive care unit and in turn more often provided with invasive devices (e.g., urinary catheter, central venous catheter etc.). All these factors impair survival and are likewise known to be risk factors for MDRO-colonization (Buul et al. 2012). Therefore, highest importance is attached to the multivariate analysis of factors associated with survival in this study. All relevant characteristics collected in our large HCC data base that potentially affect survival were included. Here, besides BCLC stage C or D, ALBI grade 3, AFP > 400 ng/ml and resection as HCC treatment, MDRO-colonization was identified as an independent prognostic factor in HCC patients. As causes for death in HCC patients vary amongst infectious complications, liver or multiple organ failure (Arroyo et al. 2020), uncontrolled tumor growth, lethal bleeding events and more (each of them possibly leading to one another), unambiguously determining the leading cause for death in HCC patients is difficult in a retrospective study setting and needs to be addressed in future prospective studies. We found, however, that only 6 (18.2%) HCC patients died in a setting of uncontrolled tumor disease. In at least 8 (24.2%) colonized HCC patients, death events were associated with infectious complications. Couto et al. showed that up to 43% of HCC patients do not die as a result of cancer progression, but from complications of the underlying cirrhosis (sepsis, bleeding etc.) (Couto et al. 2007). The fact that many HCC patients die in the absence of uncontrolled tumor growth emphasizes the importance of our finding in clinical practice even more.

At our hospital it was already reported that MDRO-colonization adversely affects survival in patients with hematological malignancies and solid tumors as well as in patients with liver disease (Ballo et al. 2019; Ferstl et al. 2017; Stratmann et al. 2020; Arvaniti et al. 2010). This is the first study proving a similar impact of MDRO-colonization on patients with HCC. Hospital antibiotic stewardship programs have shown to reduce colonization and infection with MDRO (Baur et al. 2017). Thus, clinicians should carefully balance the risks and benefits of intensive antibiotic agents to reduce incidence of MDRO colonization and infection. In summary, this study highlights the importance of MDRO screening, appropriate isolation measures as well as interdisciplinary antibiotic steward-ship programs in the context of HCC treatment, as these patients are highly susceptible to infections due to cancer and liver disease.