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BJS7592 Original article

Liver resection for colorectal cancer metastases involving the caudate lobe R. L. Thomas1 , J. T. Lordan1 , K. Devalia1 , N. Quiney2 , W. Fawcett2 , T. R. Worthington1 and N. D. Karanjia1 Departments of 1 Hepatopancreaticobiliary Surgery and 2 Anaesthesia and Intensive Care, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK Correspondence to: Professor N. D. Karanjia, Department of Hepatopancreaticobiliary Surgery, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK (e-mail: [email protected])

Background: Up to 5 per cent of liver resections for colorectal cancer metastases involve the caudate

lobe, with cancer-involved resection margins of over 50 per cent being reported following caudate lobe resection. Methods: Outcomes of consecutive liver resections for colorectal metastases involving the caudate lobe between 1996 and 2009 were reviewed retrospectively, and compared with those after liver surgery without caudate resection. Results: Twenty-five patients underwent caudate and 432 non-caudate liver resection. Caudate resection was commonly performed as part of extended resection. There were no differences in operative complications (24 versus 21·1 per cent; P = 0·727) or blood loss (median 300 versus 250 ml; P = 0·234). The operating time was longer for caudate resection (median 283 versus 227 min; P = 0·024). Tumour size was larger in the caudate group (median 40 versus 27 mm; P = 0·018). Resection margins were smaller when the caudate lobe was involved by tumour, than in resections including tumour-free caudate or non-caudate resection; however, there was no difference in the proportion of completely excised tumours between caudate and non-caudate resections (96 versus 96·1 per cent; P = 0·990). One-year overall survival rates were 90 and 89·3 per cent respectively (P = 0·960), with 1-year recurrence-free survival rates of 62 and 71·2 per cent (P = 0·340). Conclusion: Caudate lobe surgery for colorectal cancer liver metastases does not increase the incidence of resection margin involvement, although when the caudate lobe contains metastases the margins are significantly closer than in other resections. Morbidity, mortality and long-term survival rates are similar after caudate and non-caudate resection. Presented to the Annual Meeting of the Association of Upper Gastrointestinal Surgeons, Oxford, UK, September 2010, and published in abstract form as: Br J Surg 2010; 97(Suppl 5): 28 Paper accepted 31 March 2011 Published online in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.7592

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Introduction

Liver metastases affect up to 50 per cent of patients with colorectal cancer during the course of their disease1 – 3 and up to 30 per cent of these patients are candidates for potentially curative resection2,4 . Morbidity and mortality associated with liver resection for metastatic colorectal cancer is acceptably low, with mortality rates in the region of 1–2 per cent, morbidity occurring in less than 30 per cent, and 5-year survival rates of 35–58 per cent following hepatectomy with curative intent5 – 9 . The use of  2011 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd

neoadjuvant chemotherapy before elective liver resection for colorectal metastases has also improved long-term survival expectation8 . The criteria for resectability have been revised and expanded in recent years, although there are few reported series of caudate lobe resections for colorectal metastases10 – 14 . According to Couinaud’s functional classification, the caudate lobe represents segment I of the liver, and is subdivided into right dorsal (Ir) and left (Il) segments15 . The right dorsal part is also known as the paracaval portion (Ix), as described by Kumon16 . British Journal of Surgery 2011; 98: 00–00

12 13 14 15 16 17 18 19 20 21 22

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 TS1

R. L. Thomas, J. T. Lordan, K. Devalia, N. Quiney, W. Fawcett, T. R. Worthington et al.

Surgical access to the caudate lobe is difficult and caudate resection is technically challenging. However, recent data compare favourably with those of other hepatic resections for colorectal liver metastasis10,17 – 19 . Isolated caudate lobectomy was first described by Lerut and colleagues11 , although is more commonly performed in conjunction with resection of other portions of the liver12 . Recently, Khan and co-workers10 reported their experience of caudate lobectomy for colorectal liver metastasis, reporting resection margin involvement in 57 per cent. In view of the apparent paucity of data regarding caudate lobe resection independently or as part of a more radical liver resection, this study compared caudate lobe resection in patients with colorectal liver metastases with liver resection excluding the caudate lobe.

Methods

Patients undergoing elective liver resection for colorectal liver metastases between September 1996 and February 2009 in a single centre were included in this study. Between 1996 and 2005, a single consultant hepatopancreaticobiliary surgeon performed all liver resections in the series; from 2005 onwards, liver resections were performed by two surgeons. All but two caudate lobe resections were performed by the senior surgeon. No other inpatient teams performed elective liver resection for colorectal cancer metastases during the study interval. Data were Table 1

gathered and entered prospectively into a liver surgeryspecific database (Patient Management & Analysis System 2004: Statistics Software;  2003, Practical Automation Management, London, UK). The database was maintained by a full-time clerk. Preoperative assessment was standardized, and involved computed tomography and magnetic resonance imaging to evaluate metastases before treatment; intraoperative ultrasonography was used by the surgeon when indicated. All patients were discussed at a regional multidisciplinary team (MDT) meeting. Patients with synchronous or early (within 2 years of diagnosis of the primary colorectal tumour) metachronous liver metastases were offered neoadjuvant chemotherapy. Patients presenting with metachronous liver metastases (2 years or more after diagnosis of the primary) were offered neoadjuvant chemotherapy if the resection margins were thought to be potentially involved at MDT assessment, in an effort to downstage the tumour before surgery. Those offered neoadjuvant chemotherapy underwent six to eight cycles of irinotecan-based (FOLFIRI) or oxaliplatin-based (FOLFOX) therapy. Otherwise, the patient proceeded directly to surgery. In all patients liver parenchymal division was carried out using a Cavitron UltraSonic Aspirator system (CUSA ; Valleylab, Boulder, Colorado, USA). Perioperative factors recorded included: age, sex, intraoperative blood loss, intraoperative and postoperative complications, hospital stay, histology (including resection

Patient• demographics and operative data

Median age (years)* Sex ratio (M : F) Dukes’ stage of primary colorectal cancer A B C Not recorded ASA grade I II III IV Not recorded Neoadjuvant chemotherapy Major resection Extended hemihepatectomy Left Right Operative death

Caudate (n = 25)

Non-caudate (n = 432)

P†

63·1 (28·6–76·3) 13 : 12

66·1 (30·6–89·1) 268 : 164

0·477‡ 0·060

1 (5) 5 (26) 13 (68) 6

18 (4·4) 128 (31·4) 262 (64·2) 24

0·970 0·360 0·390

6 (27) 14 (64) 2 (9) 0 (0) 3 19 (76) 22 (88) 19 (76) 13 (52) 6 (24) 0 (0)

78 (20·4) 242 (63·4) 57 (14·9) 5 (1·3) 50 338 (78·2) 252 (58·3) 58 (13·4) 2 (0·5) 56 (13·0) 10 (2·3)

0·510 0·980 0·410 0·580 0·988 < 0·001 < 0·001 < 0·001 0·120 0·440

Values in parentheses are percentages unless indicated otherwise; *values are median (range). ASA, American Society of Anesthesiologists. †χ2 test, except ‡Student’s t test.

 2011 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd

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British Journal of Surgery 2011; 98: 00–00

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Liver resection for caudate lobe colorectal metastases

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margins), tumour size, and disease-free and overall survival. Major resections were those involving removal of three or more segments. Resections were categorized as complete, R1 (resection margins tumour-positive on histological analysis) or R2 (macroscopically involved resection margins). Postoperative mortality was defined as death in hospital or within 30 days following surgery. Survival times were measured to the time of most recent follow-up from the time of liver surgery.

Statistical analysis Continuous data were analysed using Student’s t test if proven to be normally distributed, and Mann–Whitney U and Kruskal–Wallis tests otherwise. χ2 test was used for categorical variables. Survival data were analysed by the Kaplan–Meier method, with differences tested using the log rank test. P < 0·050 was considered statistically significant. Statistical analyses were carried out using the Patient Management & Analysis System 2004: Statistics Software and SPSS version 15 (SPSS, Chicago, Illinois, USA).

Results

Between January 1996 and February 2009, 457 liver resections were performed for colorectal metastases, of which 25 involved caudate resection. Patients in the caudate and non-caudate groups were of similar age (median 63·1 versus 66·1 years respectively; P = 0·477).

Extent of resection There was a significantly higher proportion of major liver resections, defined as three or more segments resected, in the caudate group (22 of 25 (88 per cent) versus 252 of 432 (58·3 per cent); P < 0·001) (Tables 1 and 2). There were 19 (76 per cent) extended liver resections in the caudate group compared with 58 (13·4 per cent) in the non-caudate group (P < 0·001). A further six patients in the caudate group underwent sectionectomy or isolated caudate lobe excision. Table 2

Operative data There was greater blood loss during surgery involving the caudate lobe, but this was not statistically significant (median 300 versus 250 ml; P = 0·234) (Table 3). Median duration of operation was longer in the caudate group (283 versus 227 min; P = 0·024). Transfusion rates were similar between groups, with one patient (4 per cent) requiring blood during caudate resection, compared with 14 (3·2 per cent) during non-caudate resection (P = 0·836). There were 108 complications in 91 patients (21·1 per cent) in the non-caudate group, compared with seven in six patients (24 per cent) in the caudate group (P = 0·727) (Table 4). Transient hepatic insufficiency occurred in eight patients in the non-caudate group. There were ten postoperative deaths (2·3 per cent) in this group, including two from liver failure and two from hepatorenal

Table 3

Perioperative data and specimen analysis

Blood loss (ml)* Patients transfused Duration of operation (min) * Hospital stay (days)* Operative death Resection margin (mm)* < 1 mm Completeness of resection R2† R1‡ Completely excised Maximum tumour size (mm)*§

Caudate (n = 25)


P¶

300 (50–2500) 1 (4) 283 (31–465)

250 (< 20 to 5000) 14 (3·2) 227 (180–420)

0·234# 0·836 0·024#

10 (6–25) 0 (0) 5 (0–25)

9 (0–53) 10 (2·3) 7 (0–150)

0·403# 0·440 0·084#

4 (16)

33 (7·6)

0·140

0 (0) 1 (4) 24 (96) 40 (15–110)

8 (1·9) 9 (2·1) 415 (96·1) 27 (0–180)

0·490 0·520 0·990 0·018#

Values in parentheses are percentages unless indicated otherwise; *values are median (range). †Macroscopically involved margins; ‡microscopically involved margins. §A tumour diameter measurement of 0 mm refers to pathological assessment of tumours undergoing complete response to chemotherapy with subsequent scar only on radiological assessment, and subsequently no malignancy demonstrated in the resected specimen. ¶χ2 test, except #Mann–Whitney U test.

Resections in caudate group Extended left hepatectomy

Extended right hepatectomy

9 4 0

4 2 1 (right portal vein sleeve resection)


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Caudate tumour Tumour-free caudate Vascular resection

Segmentectomy

Caudate lobe only

2 1 0

3 0 0


44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86

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syndrome. There were no postoperative deaths in the caudate group, and no patient experienced liver dysfunction. Twenty-four patients (5·5 per cent) in the non-caudate group developed chest sepsis or acute respiratory distress syndrome compared with one (4 per cent) in the caudate group (P = 0·740). There was no significant difference in hospital stay between the groups (10 and 9 days for caudate and non-caudate surgery respectively; P = 0·403).

Pathological data Four patients (16 per cent) in the caudate group had resection margins smaller than 1 mm compared with 33 (7·6 per cent) in the non-caudate group (P = 0·140) (Table 3). No patient had macroscopically involved margins following caudate resection, compared with eight (1·9 per cent) after non-caudate surgery. There was, however, no overall difference in the incidence of cancerinvolved margins (P = 0·990). Median resection margins were 5 (range 0–25) and 7 (0–150) mm respectively (P = 0·084). Significantly closer resection margins were demonstrated in patients undergoing resection of tumours involving the caudate than in patients undergoing caudate resection in order to secure a clear resection (median margins 4 versus 10 mm; P = 0·021) (Table 5). This difference in resection margin was also evident on further Table 4

comparison with non-caudate resections (P = 0·030). These differences, however, did not affect the incidence of cancer-involved resection margins. Median maximum tumour diameter was greater in the caudate group (40 versus 27 mm; P = 0·018) (Table 3).

Recurrence and survival At 1 year, overall survival rates after caudate and noncaudate resections were 90 and 89·3 per cent respectively (P = 0·960) (Fig. 1). Median overall survival was 19·3 (range 1·2–82·0) and 21·9 (0·2–118·0) months respectively (P = 0·320). One-year disease-free survival rates were 62 Table 5

Resection margins Caudate resections

Resection margin (mm) Mean Median

Caudate involved

Tumour-free caudate

Non-caudate resections

3·8 4

10·8 10*

12·0 7

*P = 0·021 versus caudate involved (Mann–Whitney U test). P = 0·030 (analysis of three groups, Kruskal–Wallis test). 100

Postoperative complications

Chest infection, pneumonia, ARDS Bile leak Transient hepatic insufficiency Wound infection/dehiscence Liver failure Hepatorenal syndrome Acute renal failure Pneumothorax Subphrenic collection Upper gastrointestinal bleed Hypotension Postoperative bleed Cerebral abscess Myocardial infarction Other cardiac complications Urinary tract complications Postoperative ileus/adhesional obstruction Diarrhoea Transient ischaemic attack Thomboembolic disease Total complications No. of patients with complications

Caudate (n = 25)


1 1 0 0 0 0 0 0 0 0 2 0 0 0 0 0 2 1 0 0 7 6 (24)

24 11 8 9 2 2 6 3 4 4 0 1 1 5 13 4 6 2 1 2 108 91 (21·1)*

80

60 Survival (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52


40 Caudate Non-caudate 20

0

12

24

36

Time after surgery (months) No. at risk Caudate 25 Non-caudate 432

18 420

11 408

10 396

Kaplan–Meier overall survival curves for patients who had caudate or non-caudate resections. P = 0·960 (log rank test)

Values in parentheses are percentages. ARDS, acute respiratory distress syndrome. P=0·727 versus caudate group (χ2 test).

Fig. 1


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5

100

80

Survival (%)

60

40

Caudate Non-caudate

20

0

12

24

36

Time after surgery (months) No. at risk Caudate 25 Non-caudate 432

13 423

8 412

400

Kaplan–Meier disease-free survival curves for patients who had caudate or non-caudate resections. P = 0·340 (log rank test)

Fig. 2

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

and 71·2 per cent after caudate and non-caudate resections (P = 0·340) (Fig. 2). Median disease-free survival was 15·3 (0·9–82·0) and 17·6 (0·2–118·0) months respectively (P = 0·880). The 5-year overall survival rates after caudate and noncaudate resections were 52 and 48·1 per cent respectively, and corresponding disease-free survival rates were 38 and 38·6 per cent. However, these longer-term results should be interpreted with caution, especially those for the caudate group, as this group was extremely small. Discussion

Caudate lobe excision comprises 0·5–7·5 per cent of all liver resections; isolated caudate excisions are even more infrequent10,13,18,19 . One reason for this is its relative inaccessibility and proximity to the portal triad, hepatic veins and inferior vena cava15,16 . Position restricts the feasibility of chemoembolization or radiofrequency ablation10 and therefore limits options for non-resectional management. Major hepatectomy (more than 3 segments) rates of 43–57 per cent have been reported as necessary to obtain a negative resection margin, and up to 22 per cent require a vascular resection to achieve a  2011 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd

negative margin10,14,20 . In the present series, 5·5 per cent of resections involved the caudate lobe, although 22 of the 25 caudate resections were part of major hepatectomies, with 19 involving the caudate lobe as an extension of radical right or left hemihepatectomy. The data demonstrate that major liver resection including the caudate lobe is not only feasible, but permits acceptable resection margins. The present data suggest that liver resection involving the caudate lobe is safe, with low operative morbidity and mortality rates. Previous reports suggested greater transfusion requirements and intraoperative blood loss following caudate resection10,18 than was found in this study. Despite a higher rate of extended liver resection in the caudate group, there were no episodes of mild or severe liver failure or hepatorenal syndrome, even though use of neoadjuvant chemotherapy was similar in the two groups. Previously published data demonstrated a reduction in Pringle clamp use in recent years21 , which may partly explain this low incidence of postoperative hepatic insufficiency. Recent series have also reported an increased hospital stay following resection involving the caudate lobe10 , whereas all patients in the present series experienced a rapid recovery with a median hospital stay similar to that after non-caudate resection. Resection margins of less than 1 cm were previously viewed as a relative contraindication to surgery22 – 24 . However, a number of studies have shown no differences in survival and recurrence between close and wider margins25 – 28 . A 1-cm resection margin is desirable, although not essential to secure a good oncological outcome. Although there is no firm consensus regarding the definition of R1 resection, it is often defined in terms of size of margin (1 mm or less) or according to microscopic margin involvement, as in the present study. Other studies have sought to assess the influence of close versus microscopically involved margins. Konopke and colleagues25 demonstrated reduced overall survival with margins smaller than 2 mm, defining R1 as a microscopically positive. Above this level of clearance, no further improvements in overall or disease-free survival or intrahepatic recurrence rates were shown, suggesting that 3-mm margins were oncologically sound. This was also reflected by Are et al.24 in a review of 1019 patients where, although a 1-cm margin was oncologically advantageous, poorer survival was noted where margins were microscopically involved compared with margins of less than 1 mm; involved margins were a strong predictor of poor outcome, with improved survival when margins exceeded 1 mm. Bodingbauer and co-workers28 defined R1 as margin involvement, showing a correlation with reduced survival and disease-free interval. Correlation between the number of metastases and size of resection margins was shown, www.bjs.co.uk


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although resection margin size did not affect survival in itself. Rees and colleagues29 also defined R1 as positive resection margins (in the absence of extrahepatic disease) and, again, positive resection margin adversely affected median overall and disease-free survival. There is also an effect of using the ultrasonic aspirator to transect liver parenchyma (as in all patients in this series); its use is thought to widen the resection margin by up to 5 mm as liver tissue is aspirated during use, although the exact amount of additional margin provided by the aspirator is unclear25,28,30 . Measurements of width of resection margin are therefore likely to be inaccurate as the degree of tissue aspirated during surgery cannot be evaluated clearly. The presence of microscopic disease at the resection margin, however, is clear and is therefore a more reliable indicator of incomplete resection. There is evidence that caudate lobe resection incurs a greater risk of microscopically involved margins. Khan et al.10 reported R1 resection (less than 1 mm margin) rates of 57 per cent in a series of 52 caudate resections, compared with 32 per cent in non-caudate resections. In the present study the resection margin was less than 1 mm after 16 per cent of caudate resections and 7·6 per cent of non-caudate liver resections. Furthermore, there was no significant difference in the rates of macroscopically involved (R2) resection margins and, importantly, the rates of complete excision were the same, indicating the importance of assessing complete resection with close margins as well as margin width. The proportion of extended liver resections was similar to that in Khan and co-workers’ series (76 versus 68 per cent), although median maximum tumour diameter in patients undergoing caudate resection was smaller in the present series (40 versus 50 mm). These encouragingly low rates of involved resection margins and comparatively smaller tumour diameters may be accounted for by a unit policy of offering neoadjuvant chemotherapy before liver resection to patients with synchronous or early metastases. Furthermore, a significant proportion of patients with metachronous metastases were also offered neoadjuvant chemotherapy following MDT review. In this series, threequarters of patients received neoadjuvant chemotherapy before surgery. There is conflicting evidence regarding disease recurrence and long-term survival after caudate lobe resection. Theories to explain increased recurrence following surgery for caudate metastases include a tendency for intrahepatic spread owing to the proximity of afferent vasculature and bile ducts, and increased frequency of distant spread as a result of direct drainage into the inferior vena cava or major hepatic veins10,14,20 .

Tanaka and colleagues19 suggested that caudate lobe metastases were a risk factor for early local recurrence following hepatectomy, reporting disease-free survival rates at 1 and 3 years of 40 and 40 per cent respectively in the caudate group, and 87 and 62 per cent in the noncaudate group. Sarmiento and co-workers18 demonstrated 50 per cent 5-year survival following isolated lobectomy, emphasizing that major liver resection was necessary only for large neoplasms involving the major hepatic veins or hepatic hilar structures. Khan et al.10 reported no difference in median disease-free and cancer-specific survival between caudate and non-caudate groups, whereas other reports have suggested an increased likelihood of local disease recurrence and inferior survival after caudate resection13,31 . In view of these data, the present overall and disease-free survival periods are encouraging. There was no significant difference between groups in overall and recurrence-free survival rates, providing further evidence that long-term survival and disease recurrence are not significantly reduced following liver resection involving the caudate lobe. There was, however, a weak trend towards reduced overall and recurrence-free survival after caudate resection, which may in part be explained by the high proportion of extended right hemihepatectomies in this group. Recently published data has demonstrated significantly poorer overall survival up to 5 years after extended right hemihepatectomy compared with all other types of resection32 . The number of caudate resections was small in the present study; a larger series might perhaps have shown a significant difference in long-term outcome attributable to frequent extended liver resection rather than caudate lobe resection itself.


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Acknowledgements

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