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Retrospective study of metachronous lung metastases from primary hepatocellular carcinoma Kenneth S. H. Chok, Thomas C. C. Yau, Tan To Cheung, Ronnie T. P. Poon and Chung Mau Lo Department of Surgery, The University of Hong Kong, Hong Kong, China

Key words liver, lobectomy, outcome, segmentectomy, wedge resection. Correspondence Dr Kenneth S. H. Chok, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pok Fu Lam Road, Hong Kong, China. E-mail: [email protected] K. S. H. Chok MBBS; T. C. C. Yau MBBS; T. T. Cheung MBBS; R. T. P. Poon MBBS, MS, PhD; C. M. Lo MBBS, MS. This paper was presented at the 4th Biennial Congress of the Asian Pacific Hepato-Pancreato-Biliary Association, 27–30 March 2013, Shanghai, China. Accepted for publication 7 August 2014. doi: 10.1111/ans.12859

Abstract Background: This study investigates whether there has been any survival improvement for hepatocellular carcinoma patients with resectable and unresectable lung metastases over time. Methods: The data of 280 hepatocellular carcinoma patients who developed metachronous lung metastases after hepatectomy with curative intent were analysed. Overall survival was compared in patients with resectable and unresectable lung metastases and in different periods (Era I: 1989–1995, Era II: 1996–2010). Results: The median overall survival of patients with unresectable and resectable diseases was 7.46 and 40.36 months, respectively (P < 0.0001). In Era I, the median overall survival of patients with unresectable and resectable diseases was 5.59 and 43.15 months, respectively (P < 0.0001). The corresponding figures in Era II were 8.38 and 32.90 months (P < 0.0001). The overall survival of patients with resectable disease did not differ significantly in the two eras but there was a significant improvement in survival of patients with unresectable disease in Era II. Their 1-year, 3-year and 5-year survival rates in Era I versus Era II were 11.1% versus 38.4%, 5.6% versus 9.1% and 2.8% versus 3.5%, respectively (P = 0.041). The corresponding figures for their counterparts in the resectable group were 90% versus 85.8%, 80% versus 45.9% and 40% versus 29.5%, respectively (P = 0.443). Conclusions: Patients with resectable lung metastases had better overall survival than those with unresectable lung metastases. Notably, patients with unresectable lung metastases had significant improvement in survival over the years.

Introduction Hepatocellular carcinoma (HCC) is a common malignancy in many Asian countries where hepatitis B virus infection is prevalent. It is the fourth most common cancer and the third cause of cancer-related deaths in Hong Kong.1 Its incidence is on the rise in Western countries such as the United States and the United Kingdom.2 Hepatic resection is the most common treatment of HCC. With recent advances in diagnostic modalities, perioperative management and surgical techniques, more patients can benefit from hepatic resection.3 However, the long-term prognosis after potentially curative resection remains unsatisfactory as the incidence of recurrence is high.4 Most recurrences are intrahepatic but extrahepatic metastases are also common, with the lungs being the most common site.5 A study in 1998 by our centre reported that in the treatment of lung metastases, the survival benefit of resection was significant.6 In view of the advancement of surgical techniques, imaging modalities and surveillance programmes as well as the emergence of targeted thera© © 2014 2014 Royal Royal Australasian Australasian College of Surgeons

pies over the past decade, we aim to investigate whether there has been any survival improvement for the patient population over the years.

Methods Prospectively collected data of all adult patients who were diagnosed with HCC at our centre in the period between December 1989 and December 2010 were reviewed. Patients who received previous or simultaneous treatment (e.g. transarterial chemoembolization, radiofrequency ablation, high-intensity focused ultrasound ablation) and patients whose tumours were non-HCC lesions on final histology were excluded. A total of 284 patients who had undergone curative liver resection (all with tumour-free margins) and were found to have metachronous lung metastases were retrospectively reviewed. The follow-up data of four patients were incomplete and therefore they were excluded from analysis. ANZ J Surg (2014) ••–•• ANZ J Surg 86 •• (2016) 289–293

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The cohort was divided into two groups as Era I (1989–1995) and Era II (1996–2010). The two groups were compared in terms of survival outcomes. The aforesaid study6 used 1995 as the end point, so it was used as a cut-off in this research.

Patients with unresectable disease (because of multiple recurrences or significant comorbidity) were referred to oncologists for consideration for systemic therapies or best supportive care. Resectable lung metastases were managed by surgery alone.

Surveillance for recurrences after the first hepatectomy

Management of simultaneous intrahepatic recurrences

All patients were followed-up quarterly in the first 2 years and then half-yearly, with regular monitoring for disease recurrence by serum α-fetoprotein level check and computed tomography of the liver. The diagnosis of recurrence was based on typical disease manifestations on imaging studies and a raised level of serum α-fetoprotein. Dual-phase helical computed tomography has been used since 1994. During the latest years of the study period, the use of magnetic resonance imaging and dual-tracer positron emission tomography (PET)7 became increasingly often. Needle biopsy was not performed for patients with resectable tumours to avoid needle tract seeding of tumour cells. All HCCs were subsequently confirmed by histological examination after resection. Hospital mortality was defined as death occurring within 90 days of lung resection. All resections were with curative intent.

If the extrahepatic metastasis could be treated by resection, then an aggressive approach to the intrahepatic recurrence would be adopted. Re-resection was one of the treatment options for recurrent HCCs. Selection criteria for repeat hepatectomy were the same as those for primary resection.8 Transarterial chemoembolization was offered to patients with multifocal intrahepatic recurrences. Patients who had unresectable extrahepatic metastases were referred to oncologists for consideration for systemic therapies or best supportive care.

Management of lung metastases All patients with newly diagnosed lung metastases were assessed by thoracic surgeons, anaesthesiologists, respirologists and oncologists.

Statistical analysis Pearson’s chi-squared test or Fisher’s exact test was used to compare categorical variables. Non-parametric continuous variables were compared by the Mann–Whitney U-test and presented as medians and ranges. Parametric continuous variables were compared by Student’s t-test and presented as means with standard deviation. The Kaplan–Meier method was used to analyse survival and the log-rank test was used to compare the variables. P-values of less than 0.05

Table 1 Data of the two groups of patients Unresectable (n = 234) Age (years) Sex (Male : Female) Preoperative serum α-fetoprotein level (ng/mL) Preoperative Child-Pugh grade A B Preoperative indocyanine green retention rate at 15 min (%) Tumour staging (TNM1997) I II IIIA IVA Operation duration (min) Hospital mortality Blood transfusion Post-operative complication Classification of surgical complications Clavien-Dindo class 3A Clavien-Dindo class 3B Clavien-Dindo class 4A Clavien-Dindo class 5 No simultaneous recurrence Simultaneous intrahepatic recurrence Simultaneous extrahepatic recurrence Both intrahepatic and extrahepatic recurrences First treatment for pulmonary recurrence Systemic chemotherapy Tamoxifen Nexavar Nexavar + radiation Nexavar and Tegafur Median follow-up (months)

Resectable (n = 46)

55.0 (19–82) 197:37 636 (2–133 5900)

49.5 (26–78) 41:5 475.5 (4–182 900)

225 (96.2%) 9 (3.8%) 10.4 (1.4–62.2)

46 (100.0%) 0 (0%) 9.9 (1.6–36.9)

6 (2.6%) 25 (10.7%) 106 (45.3%) 97 (41.5%) 420 (90–1349) 0 35 (76.1%) 64 (27.4%)

0 (0%) 12 (26.1%) 22 (47.8%) 12 (26.1%) 420 (150–690) 0 49 (20.9%) 12 (26.1%)

43 (18.4%) 4 (1.7%) 1 (0.4%) 0 (0%) 44 (18.8%) 97 (41.5%) 34 (14.5%) 59 (25.2%)

9 (19.6%) 0 (0%) 0 (0%) 0 (0%) 12 (26.1%) 12 (26.1%) 10 (21.7%) 12 (26.1%)

51 23 25 2 1 7.46 (0–243.08)

7 –– –– –– –– 33.08 (6.34–240.19)

P-value 0.184 0.527 0.734 0.371

0.758 0.015

0.704 ––

Retrospective study of metachronous lung metastases from primary hepatocellular carcinoma.

This study investigates whether there has been any survival improvement for hepatocellular carcinoma patients with resectable and unresectable lung me...
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