Efficacy and cost of a hepatocellular carcinoma screening program at an Australian teaching hospital

Authors


Dr Paul Gow, Austin Hospital, Department of Gastroenterology, 145 Studley Rd, Heidelberg, VIC 3084, Australia. Email: paul.gow@austin.org.au

Abstract

Background and Aim:  Western countries are seeing an increasing prevalence of chronic viral hepatitis and a subsequent rise in the incidence of hepatocellular carcinoma (HCC). Screening patients at high risk of HCC has become standard practice. The aim of this study was to assess the efficacy and cost of screening high-risk individuals for HCC in an Australian tertiary hospital.

Methods:  A retrospective review was performed of all patients who underwent HCC screening at the Austin Hospital in Melbourne between 1 October 1998 and 31 August 2004. HCC screening was carried out in all cirrhotic patients and male non-cirrhotic patients with chronic hepatitis B virus. Screening consisted of 6-monthly alpha fetoprotein (AFP) measurements and ultrasounds (US). Outcomes of those who had HCC detected were followed up until 15 February 2007. Patients who had HCC satisfying the Milan criteria for liver transplantation were considered to have potentially curable tumor. Costs for the diagnostic tests were obtained from the 2004 Australian Medicare Benefits Schedule.

Results:  A total of 268 patient records were reviewed as part of the study. Chronic viral hepatitis accounted for 63% of the patients (n = 167). US screening was carried out at a median of 6.5 months and AFP measurements at a median of 4.0 months. HCC was detected in 22 patients (8.2%) at an incidence of 2.7% per year. These patients had a mean follow up of approximately 5.0 years after tumor detection. At the time of diagnosis, 17 patients had potentially curable tumor and 10 were alive at the conclusion of follow up. Of these 10 patients, six were successfully transplanted, three were successfully treated with radiological therapies and one was awaiting transplantation. The total cost of the screening program over the study period, including secondary investigations, was $A300 568. The cost per HCC detected was $13 662 and cost per potentially curable HCC was $17 680.

Conclusion:  An effective HCC screening program can be provided through a multi-disciplinary outpatient facility in an Australian teaching hospital. Further stratification of the high risk patient cohort may improve the cost effectiveness of this screening program.

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and its incidence as a complication of cirrhosis is on the rise in Australia and many other Western countries.1,2 Unfortunately the outcome for patients with advanced disease remains poor. However, over the last two decades a number of therapies have been developed for the treatment of early stage HCC. As a result, screening of ‘high-risk’ patients to detect early stage HCC is now widely practised and has become standard policy in some countries.3

It is now well recognized that alpha-fetoprotein (AFP) testing and abdominal ultrasound (US) scanning have the ability to detect small, potentially curable tumors.4 In addition, a recent randomized controlled trial has, for the first time, shown a survival advantage for patients at high risk of HCC who participate in a screening program.5

The last two decades have seen a significant increase in the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) in Australia and other western countries, and this has contributed to an increase in the incidence of HCC.6–9 As yet, however, there have been no studies examining the success of implementing HCC screening programs in this country. The aims of this study were to assess the efficacy of providing an HCC screening service in an Australian tertiary hospital. Within a cohort of high-risk patients attending a public hospital liver clinic, we assessed HCC detection rates using 6-monthly AFP and liver US testing, the cost of the program and the outcome of patients who have HCC detected.

Methods

The Austin Hospital is a tertiary teaching hospital providing health care to the north-eastern region of Melbourne. In addition, it provides adult liver transplantation services for the states of Victoria and Tasmania. The current study was performed as a single-centre, retrospective observational study based at the Austin Hospital.

Since the mid-1990s, it has been the policy of the Gastroenterology Unit at the Austin Hospital to screen for HCC in all patients with cirrhosis and in male non-cirrhotic patients with HBV who are over 40 years of age. Screening for HCC consists of AFP and liver US every 6 months. The study encompassed all patients who underwent screening for HCC at the Austin Hospital between 1 October 1998 and 31 August 2004. Outcome of patients who had HCC detected were followed up until 15 February 2007. Retrospective anonymous database reviews, which preserve confidentiality and do not provide identifiable data, are considered as equivalents of audits. The Austin Health Ethics Committee did not require informed consent for such studies.

The study population was identified from two computer-based searches of all patients who had had at least two AFP measures and at least two US examinations during the study period. These two lists were cross-referenced to obtain a final group of patients fulfilling both criteria. Medical records were then reviewed to ensure the patients who had had AFP and US performed had these tests as part of screening for HCC. The patients needed to have at least one normal screening episode to be included in the study.

Data collected from the medical records consisted of age at the end of the study period, gender, ethnicity, etiology of liver disease, dates of US and AFP evaluation, nature of abnormalities identified on US, AFP results, dates and modalities of radiological secondary investigations, treatment of HCC(s) and patient outcome.

The follow-up period was defined as the interval between the initial screening test and the earliest of either, the first secondary investigation performed, death, or conclusion of study period. For the purposes of the study, patients with HCC satisfying the Milan criteria for transplantation (single HCC less than 5 cm in diameter, or no more than three tumors of maximal diameter 3 cm each)10 were defined as having ‘potentially curable’ tumor.

Statistical analysis

Data are presented as mean ± standard deviation unless otherwise stated. Median and inter-quartile ranges were used for screening intervals as results demonstrated positive skewing. Calculations were performed using Microsoft Excel 2000. Costs for the diagnostic imaging tests were obtained from the Australian Medicare Benefits Schedule (1 November 2004 revision, Department of Health and Ageing, Australian Government). Individual item costs are listed in Table 1. All costs are reported in Australian dollars.

Table 1.  Diagnostic tests used in hepatocellular carcinoma (HCC) screening program
TestFull cost (A$)
  • Additional $75 if Lipiodol injected.

α-fetoprotein24.75
Ultrasound (abdomen)111.30
Doppler ultrasound (abdomen)169.50
Magnetic resonance imaging (liver)400.00
Computed tomography with contrast (abdomen/pelvis)480.05
Computed tomography angiography (abdomen)510.00
Digital subtraction angiography (abdomen)564.00

Results

During the study period, 466 patients had at least two US examinations and two AFP measures. Of these, 198 were excluded from the study for a variety of reasons. They were: performing tests for clinical indications other than HCC screening (n = 78); pre-existing HCC (n = 58); patients not fulfilling HCC screening criteria (n = 44) and unavailable medical records (n = 18). Thus, 268 patients fulfilled the criteria for inclusion in the study.

The mean age of the study population was 57.1 ± 11.5 years. There were 186 males (mean age 57.1 ± 11.4 years) and 82 females (mean age 57.0 ± 11.8 years). The majority of patients were of Anglo-Celtic origin (39.9%). Other significant ethnic minorities included Italian (16.8%), Chinese (7.8%), Greek (7.5%), Vietnamese (4.1%), Egyptian (4.1%), Macedonian (2.6%) and German (1.9%). Figure 1 documents the etiology of liver disease in the screened population. HCV cirrhosis was the most common cause of liver disease, accounting for 34.3% of the study population. Alcoholic cirrhosis and HBV cirrhosis accounted for 22.0% and 18.7%, respectively. In total, 53% of patients had chronic viral hepatitis.

Figure 1.

Etiology of liver disease in screened population. inline image, hepatitis C virus (HCV) cirrhosis; inline image, alcoholic cirrhosis; inline image, hepatitis B virus (HBV) cirrhosis; inline image, chronic HBV carrier; inline image, cryptogenic cirrhosis; inline image, NASH, non-alcoholic steatohepatitis cirrhosis; inline image, PSC, primary sclerosing cholangitis; inline image, PBC, primary biliary cirrhosis; inline image, cirrhosis—other.

The mean follow-up period for the screened population was 3.0 ± 1.7 years. The total follow-up period was 812 patient-years. Ultrasound screening was performed at a median interval of 196 days (6.5 months; interquartile range [IQR] 167–255 days) and AFP at 119 days (4.0 months; IQR 76–189 days).

In 13% of patients, the mean frequency of US scanning was > 12 months. In this group, the largest contributors to prolonged intervals between US were patient non-attendance (n = 16) and the reviewing doctor's failure to recognize requirement for screening (n = 9). Other factors included clerical errors, use of other imaging modalities and patients being lost to follow up. However, there was no difference in this group compared with the group as a whole in terms of frequency of HCC detection or mortality.

Of the 1294 ultrasounds performed, 113 areas of abnormal echogenicity that required further investigation were detected in 99 patients. Of these 99 patients, 19 underwent at least two sets of secondary investigations, prompted by two separate abnormal screening tests on different occasions.

A total of 68 lesions were confirmed and characterized using additional investigations of which 34 were HCCs (22 patients), 30 were benign liver lesions (26 patients) and four were renal lesions (four patients). In the remaining 45 cases the US-detected lesions could not be detected on subsequent investigations and were assumed to represent benign nodular areas in the cirrhotic liver. A summary of all of the lesions characterized during the study period is listed in Table 2. Four solid renal lesions were found on screening and confirmed by computed tomography (CT). In three patients these were renal cell carcinomas (RCCs) and all three died during the follow-up period. The fourth lesion was a complicated renal cyst.

Table 2.  Lesions characterized during hepatocellular carcinoma (HCC) screening
Lesions characterizedNumber
Hepatocellular carcinoma34
Renal cell carcinoma3
Benign lesions31
 Regenerative nodule14
 Hemangioma5
 Enlarged lymph nodes3
 Liver cyst2
 Liver granuloma2
 Arterio-portal shunt1
 Focal fatty sparing1
 Focal fatty infiltration1
 Cholelithiasis1
 Renal cyst1
Total68

The finding of HCC in 22 of the 268 study patients during the screening period gave an incidence of 2.7% per year. The mean age of patients with HCC was 62.0 ± 11.5 years and 18 of the 22 were male. The details of each patient with HCC detected are shown in Table 3. The initial abnormality was detected with US in 17 patients, by raised AFP in four patients and with both modalities in one patient. The majority of HCCs occurred in patients with cirrhosis secondary to HCV (n = 10) or HBV (n = 8). The annual incidence of HCC in these populations was 3.2% per year and 2.2% per year, respectively. At the time of detection, 17 of the 22 HCC patients had tumor that was within the Milan criteria10 and defined as curable. There was no significant difference in the frequency of US scanning or AFP testing between patients who had a potentially curable tumor compared with patients whose tumor was incurable at diagnosis (US frequency every 6.9 ± 4.2 vs 7.9 ± 4.6 months; AFP every: 4.4 ± 2.7 vs 4.6 ± 2.8 months, respectively).

Table 3.  Characteristics of patients with hepatocellular carcinoma (HCC)
PatientAgeGenderEtiology of cirrhosisNumber of HCC nodulesSize (cm)MetastasesPotentially curable?Initially suspicious on:Status after follow upTransplanted?
  1. AFP, alpha fetoprotein; HBV, hepatitis B virus; HCV, hepatitis C virus; US, ultrasound.

 151MHCV12 YUSAliveYes
 251MHCV53.5/2.5/2/1.5/1YesNUS/AFPDeadNo
 357MHBV31.0/1.6/1.2 YUSAliveNo
 473FCryptogenic13.8 YUSAliveNo
 577MHCV12 YUSDeadNo
 652FHCV19 NAFPDeadNo
 780MAlcohol11.8 YUSAliveNo
 857FHCV11.9 YUSDeadYes
 978MHBV22/0.4 YUSDeadNo
1070MHBV112YesNUSDeadNo
1150MAlcohol21/0.6 YAFPAliveNo
1255MHCV32.8/2.2/1.2 YUSAliveYes
1361MHBV11 YAFPAliveYes
1459MHCV11.4 YUSAliveYes
1574MHCV11.9 YUSDeadNo
1668FHBV13.5 YUSDeadNo
1751MHBV13.7 YUSDeadYes
1845MHCV12.6 YUSAliveYes
1955MHBV113.5YesNAFPDeadNo
2058MAlcohol11.5 YUSDeadNo
2148MHCV32.5/2.3/1.5 YUSAliveYes
2248MHBV13.8YesNUSLost to F/UNo

The mean follow up of the 22 patients with HCC detected was 5.0 ± 2.1 years after tumor detection. The group outcomes of screened patients and patients diagnosed with HCC are documented in Figures 2 and 3. At the conclusion of the follow-up period, 11 of the 22 had died and one had been lost to follow up. The remaining 10 patients were alive for a mean of 4.7 ± 1.4 years after detection of HCC. Of these 10 patients, six had undergone successful liver transplantation with one currently listed and awaiting liver transplantation. The other three developed recurrence or new HCC and had a variety of non-transplant therapies for their tumors. They continued to be monitored and were alive at the end of the follow-up period.

Figure 2.

Outcome of screened patients.

Figure 3.

Outcome of patients with hepatocellular carcinoma (HCC).

Of the 11 patients that died, seven were as a consequence of progression of tumor and/or liver decompensation. In particular, this included the two patients with both HCC and RCC. Both were concurrently treated with nephrectomy and radiological interventions but died following HCC recurrence and progression. Of the remaining four, two succumbed to sepsis in the setting of chronic liver failure and two died following transplantation. Regarding the two post-transplant deaths, one developed rapidly progressive fibrosing cholestatic hepatitis B and was not re-transplanted. The other developed pulmonary metastases from HCC 9 months post-transplantation and died from sepsis. Five of the 11 patients had potentially curable HCC but were not suitable transplant recipients due to a combination of advanced age, ongoing alcohol intake and/or medical co-morbidities.

In addition to the eight transplants, most patients with HCC received treatments as outlined in Table 4. Three of the 11 patients who died received palliation only (one of which was lost to follow up), while the remaining eight patients received a total of 19 sessions of treatment. By comparison, the 10 patients who remained alive at the end of follow up received a total of 26 sessions. Seven of the eight patients who went on to transplant received at least one treatment with either transarterial-chemoembolization (TACE) or radio-frequency ablation (RFA) while awaiting transplant.

Table 4.  Treatments administered to hepatocellular carcinoma (HCC) patients
TreatmentTotal sessionsDeceased patientsAlive patients
  1. OLTx, liver transplantation; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation; TACE, transarterial chemoembolization.

PEI1248
TACE1468
RFA844
OLTx826
Chemotherapy33
Total451926

All abnormalities found on screening were subjected to further investigation. During the study period 165 secondary investigations were performed, 79% of which were triple-phase CT scans (Table 5). The total cost of the program over the study period was $300 568 (Table 6). This included screening tests ($222 408) and secondary investigations ($78 160). The cost per HCC detected was calculated to be $13 662. The cost per potentially curable HCC was $17,680.

Table 5.  Secondary investigations
Modality of secondary investigationNumber (%)
  1. CT, computed tomography; CTHA, computed tomography hepatic angiography; DSA, digital subtraction angiography; MRI, magnetic resonance imaging; US, ultrasound.

CT130 (78.8)
US12 (7.3)
MRI6 (3.6)
Doppler US4 (2.4)
DSA/CTHA+ Lipiodol4 (2.4)
DSA/CTHA3 (1.8)
CTHA+ Lipiodol2 (1.2)
DSA+ Lipiodol2 (1.2)
CTHA1 (0.6)
DSA1 (0.6)
Total165 (100)
Table 6.  Cost of hepatocellular carcinoma (HCC) screening program23
TestNumberUnit cost (A$)Total cost (A$)
  1. AFP, alpha fetoprotein; CT, computed tomography; DSA, digital subtraction angiography; MRI, magnetic resonance imaging; US, ultrasound.

Screening   
 AFP192224.7547 569.50
 US1074111.30119 536.20
 Doppler US162169.5027 459.00
 Contrast CT58480.0527 842.90
 Total  222 407.60
Secondary investigations   
 US12111.301 335.60
 Doppler US4169.50678.00
 MRI6400.002 400.00
 Contrast CT130480.0562 406.50
 CT Angiography1510.00510.00
 CT Angiography with Lipiodol2585.001170.00
 DSA1564.00564.00
 DSA with Lipiodol2639.001 278.00
 CT Angiography + DSA31074.003 222.00
 CT Angiography + DSA with Lipiodol41149.004 596.00
 Total  78 160.10
Grand total  300 567.70

Discussion

Hepatocellular carcinoma is a major cause of death in patients with cirrhosis11,12 and screening of high-risk patients has become standard practice. The current study reveals that in Australian patients at high risk of HCC it was possible to provide an effective screening program which detects tumor at a potentially curable stage in the majority of cases. Screening was arranged and acted upon according to protocol in the vast majority of patients. However, there was a significant minority of patients in whom it was performed at an unacceptable frequency. The main reasons why tests were performed at an unacceptable frequency in these patients were failure to attend scheduled appointments and physicians failing to order appropriate investigations. A formal computer-based system of patients recall and follow up may help to minimize both of these potential flaws in the screening process.

The epidemiology of HCC in Australia has changed noticeably over the last three decades. In the 1970s HCC most often occurred in the setting of cirrhosis secondary to alcohol. This study confirmed the findings of another recent Australian series,6 which showed that HBV and HCV now account for almost two thirds of cases. The prevalence of chronic HBV and HCV has increased dramatically in Australia over recent years. It is currently estimated that approximately 120 000 Australians are chronically infected with HBV,13 250 000 with HCV14 and that the rates of HCC resulting from chronic viral hepatitis will at least double over the forthcoming decade.15 Screening programs that allow for early detection and treatment of HCC may improve outcomes for this disease. However, the greatest impact in reducing deaths from liver disease will come from public health measures aimed at detecting and treating chronic viral hepatitis before patients develop cirrhosis.

The broad range of therapies available for HCC cross a wide array of disciplines and include: percutaneous ethanol injection, radiofrequency ablation, surgical resection, liver transplantation, transarterial chemoembolization, selective internal radiotherapy and chemotherapy. The most important parameter in evaluating the tumor yield of an HCC surveillance program is the proportion of early tumors detected that the patients can go on to receive treatment with curative intent. If the tumors found were too large to be cured, screening would confer little if any benefit. In our study, 77% of HCCs fell within Milan guidelines for transplantation, a parameter we used to define ‘potentially curable’. This is comparable with rates described in the literature of 61% to 75%.16–18 Medium term outcomes for these patients were encouraging with 60% alive at a median of 4.7 years from diagnosis. All nine patients identified as suitable transplant candidates were assessed and most were transplanted with one patient on the waiting list at the end of follow up. The other eight patients were found to have one or more factors limiting their suitability for transplantation. However, three of these patients were treated successfully using localized radiological therapies and remained alive at the end of follow up. It is perhaps remarkable that of the 22 patients diagnosed with HCC, not a single patient underwent surgical resection. This fact reflects the increased efficacy of radiological therapies for HCC—most notably radiofrequency ablation, along with a wish to avoid surgery in patients with ‘transplantable’ disease, as it is recognized that transplantation after previous resection is associated with increased morbidity.

Due to the increasing array of potential available treatments, decision-making in individual patients requires expert input across multiple medical specialties. In our institution we have run a multidisciplinary HCC clinic for 10 years and all of the patients diagnosed with HCC in this series were managed through this clinic. Given the complexity of decision-making and many treatment options available, there is an increasingly strong argument that HCCs should be managed in multidisciplinary clinics involving hepatologists, surgeons, oncologists and interventional radiologists. Liver transplantation has emerged as one of the cornerstones of treatment for selected patients with multifocal HCC, although its role in patients with single lesions and compensated cirrhosis who are potential resection candidates is still debated.19 In the last decade in Australia, the proportion of patients undergoing liver transplantation for HCC has increased threefold, whereas the number of organ donors has remained relatively unchanged. It is likely the next decade will see this disparity between organ demand and organ donation widen leading to a corresponding increase in waiting list deaths or de-listing from tumor progression in Australian patients with liver cancer. It is hoped that a recent Federal Government funding initiative will boost Australia's very low organ donation rate.20

This study was not designed to be a cost efficacy study but a cost evaluation of screening Australian patients with cirrhosis for HCC. Based on our data we estimate that the cost of detecting one potentially curable HCC is in the order of $17 680. This is similar to an estimated cost of $13 817 per cancer detected for the national breast screening program.21 Costs could be reduced by focusing screening on a core group of high-risk patients, as suggested by Ryder in 2003.22 We recommended that screening should be confined to patients with cirrhosis due to HBV, HCV or hemochromatosis and male patients with cirrhosis due to alcohol or primary biliary cirrhosis (PBC) for semi-annual HCC screening. The results of our study support this, with 21 out of 22 HCC patients fitting these criteria.

Conclusion

Hepatocellular carcinoma is an increasingly common cancer in Australia and screening high risk patients for this tumor through a public hospital facility is both effective and relatively cost efficient. However, the challenges in this area are many. Initiatives to minimize new infections with HCV and HBV need to be expanded, as does the availability of anti-viral therapies. Multidisciplinary hepatocellular carcinoma clinics are available in the larger tertiary institutions but are still not readily available to many patients and this deficit needs to be addressed with some urgency. In addition, the organ donation rate in Australia will need to rise significantly as the demand for liver transplantation to treat this disease increases.

Ancillary