Staged liver resection for colorectal metastases: a valuable strategy or a waste of time?

Raaj Chandra, Charles HC Pilgrim and Val Usatoff

Melbourne, Australia

Staged liver resection for colorectal metastases: a valuable strategy or a waste of time?

Raaj Chandra, Charles HC Pilgrim and Val Usatoff

Melbourne, Australia

BACKGROUND:The use of staged liver resections for colorectal metastases has been increasing in recent times. The aim of this study was to determine the practices and outcomes of those surgeons attending the Australia and New Zealand Hepatic, Pancreatic and Biliary Association (ANZHPBA) meeting in 2008 who perform staged resections.

METHODS:A questionnaire was sent to all members of the ANZHPBA and the international faculty who were invited to attend the annual meeting held in Coolum, Queensland, Australia in October 2008.

RESULTS:There were 30 responses from 7 centres across the UK, Germany and Australia. Twenty-eight patients completed treatment. The study population was predominantly male (n=20, 67%), with an average age of 59.4 years. All patients had bilobar disease. A right-sided first resection was planned in 39% of cases. Seventeen percent of patients underwent portal vein embolization prior to first resection. A second operation was performed at an average of 2.8 months from the first resection. Overall, 50% (n=14) of patients eventually achieved a complete (R0) staged procedure. Twelve complications after the first resection were seen in 32% patients (n=9). Twentythree patients underwent a second liver resection. Twenty-five complications after the second resection were present in 57% (n=13).

CONCLUSIONS:Two-stage liver resections are beneficial if both stages are completed and an R0 resection is achieved. While there is increased morbidity and mortality, we believe that staged liver resection for colorectal metastases is a valuable strategy in selected cases.

(Hepatobiliary Pancreat Dis Int 2010; 9: 600-604)

liver resection; colorectal cancer; liver metastases

Introduction

As many as 70% of patients with colorectal cancer develop liver metastases. There is no long-term survival without surgery and if left untreated, survival ranges from 6 to 18 months.[1-3]We now know that chemotherapy is extending the palliative survival of these patients and down-staging many others to make surgery possible. Over the past 10 years, there have been great advances in chemotherapeutic agents, which have resulted in improved survival in patients with colorectal metastases. Patients receiving chemotherapy alone without surgery have a median survival of approximately 20 months. Of these, 40%-50% have a measurable tumor response.[4]Only 15%-20% of patients with colorectal liver metastases are eligible for surgery. Those undergoing surgical resection have a 5-year survival ranging from 15%-67% with a median of 35%. Surgical resection is considered safe with a mortality rate of <5%.[5]In selected patients with initially unresectable multiple and bilobar colorectal liver metastases, twostage liver resection can be achieved safely with longterm survival similar to that observed in patients with initially resectable liver metastases.[6]This study was undertaken to determine the practices and outcomes of those surgeons attending the Australia and New Zealand Hepatic, Pancreatic and Biliary Association (ANZHPBA) meeting in 2008 who perform staged resections, and to see whether this was consistent with current practice around the world.

Methods

A questionnaire and data sheet were sent to all members of the ANZHPBA and the international faculty invited to attend the annual meeting held in Coolum, Queensland, Australia in October 2008 (Fig.). The data sheet includedpatient demographics, reason for a planned staged resection, plan for first and second operations, actual operation performed, planned delay to second operation and whether or not the second operation was delayed longer than planned. Postoperatively, was an R0 resection achieved? Was systemic therapy used pre- or post-operatively and what type? Morbidity and mortality after the first and second procedures as well as survival from the time of the first operation was also requested. Time to recurrence, if any, was recorded as was how those recurrences were treated.

Fig. Data sheet questionnaire of HPBA.

Results

The data of 30 patients were collected from 7 centres across the UK, Germany and Australia. The study population was predominantly male (n=20, 67%), with an average age of 59.4 years. The indication for staged resection was "bilobar disease" in all patients. The "total number of lesions" was also cited in 11 (37%) of the patients as an additional indication, as was "size" in 7 (23%) and "presence of synchronous disease" in 4 (13%) of the patients. The alternative to staged resection was palliative chemotherapy in 11 of the patients (but was not specified in 12 patients). Radiofrequency ablation (RFA) was a possible alternative in 2 patients, the combination of RFA and chemotherapy was possible in 1, thermic ablation in the form of laser-induced thermal therapy in 1, and chemotherapy and selective internal radiation therapy in 1 further patient.

A right-sided first resection was planned in 39% of the patients. Seventeen percent of them underwent portal vein embolisation (PVE) prior to the first resection. All PVEs were performed percutaneously, however, no information regarding volumetry or size increase was given by the contributors. Of the 28 patients in the study group, all but one of these first planned resections proceeded as planned (this case was abandoned because an additional lesion was found in segment 3, which would have required a full segmental resection, leaving an inadequate remnant, even after PVE). A second resection was undertaken in 25 patients at an average of 2.8 months from the first resection (median 2 months, range 1.25 to 8 months). Due to contributions from multiple centres, there was no uniform policy on the time interval between the first and second liver resection. In all patients, positron emission tomography and computed tomography (CT) were used in staging for the first resection. Re-staging prior to the second operation was routinely performed with CT.

One patient declined a second operation, and 2 were not offered a second resection because of interval disease progression on preoperative imaging, meaning 89% of the patients proceeded to a second resection. Two more patients did not complete a second resection, because of disease progression detected at time of second laparotomy (92% of those reaching second laparotomy proceeded to resection as planned). Five patients had an alteration to their intended second resection, three patients had their operation upsized, and two had downsizing. The upsized patients consisted of one who underwent an extended right hemihepatectomy (rather than the planned right hemihepatectomy), one who had a resection extended to include segment 1, and the one who had a right hemihepatectomy extended to include an atypical resection of segments 2 and 3. In the last patient, the term "atypical" means a non-anatomical wedge or liver-sparing resection which purely aims to make clear margins. The patients whose operation was downsized had a change of plan from a formal left hemihepatectomy to 3 atypical resections of segments 3, 4a and 4b as all these lesions were superficial and one planned right hemihepatectomy was converted to segmental resection of segments 1, 5 and 8 only. Sixty-one percent of those patients undergoing resection underwent an R0 procedure, indicating that overall, 50% (14 patients) of those patients initially for staged resection eventually achieved a complete R0 staged procedure.

Twelve complications following the first resection were seen in 9 of 28 patients (32%). They consisted of intra-abdominal collection, anastomotic leak, fluid collection, subphrenic abscess, pressure sore, pneumonia, cardiac insufficiency, pleural effusion, atelectasis, non-ST-elevation myocardial infarction (NSTEMI), intraabdominal abscess, collection at the resection margin of the liver. Following the second operation, 25 complications were observed in 13 (57%) of 23 patients. These included hepatic insufficiency, bile leak/ascites, bile fistula, bile duct stenosis requiring stent, biloma/ ileus, portal vein thrombosis, post-operative bleeding, biloma with biliary fistula, biloma, biliobronchial fistula, wound infection, ascites, non-infectious biloma, cholangitis, ascites, fluid collection, gastrointestinal bleeding, respiratory insufficiency, renal failure, noninfected hematoma, ascites, wound infection, and abdominal fluid collection at resection margin.

There were no perioperative deaths except 4 patients died at 4, 8, 13 and 18 months after first liver operation due to disease progression. Only one of these 4 patients had received an R0 resection.

Nine patients were alive without recurrence between 2 and 21 months post-operatively. The remaining 12 patients developed recurrent disease. Ten patients had recurrence recorded at between 4 and 15 months postoperatively and 2 were alive but with recurrence at 15 and 33 months. There is no follow up data on 3 patients.

Discussion

Traditionally there were exclusions for liver surgery involving colorectal metastases, particularly the number of liver metastases. This surgical dogma is challenged as the probability of survival is similar in patients with 1-3 metastases compared to those with >4 metastases, unilobar or bilobar.[7,8]In addition, about one third of patients who are initially deemed unresectable can be down-staged with chemotherapy to be resectable with excellent 5-year survival rates.[5]Caution should be taken that chemotherapy-induced hepatotoxicity can be a problem, especially if a major resection is planned with a small functional liver remnant.[9]This highlights the risks of over-aggressive neoadjuvant chemotherapy. Clear resection margins are vital for long-term survival, but insisting on a margin >10 mm is probably no longer necessary as long as the operation is completed, thus allowing the boundaries of resectability to be pushed further. The overall survival is clearly poor if margins are positive.[5,7]

A bi-institutional analysis[9]showed that repeat liver resection for colorectal liver metastases is safe and patients with a low tumor load are the best candidates for a repeat resection. The conclusion of the analysis was that in well-selected patients further resection of the liver can provide prolonged survival after recurrence of colorectal liver metastases.

In addition, tumors can be downstaged with chemotherapy and multiple lesions can be resected with close margins in both lobes. Technically a second resection, i.e. re-resection, is possible and safe. This has led to a change in paradigm from a focus on exclusion criteria such as what is removed, number of lesions, size of lesions, position in the liver, and extent of margin, towards a focus on inclusion criteria. Features such as volume of liver remnant, its inflow and outflow, as well as its function post-chemotherapy and whether or not an R0 resection are of utmost importance in selecting patients for resection. There has been a shift from focusing on exclusion criteria to satisfying inclusion criteria for surgery.

Two-stage liver resection was first described by Adam et al[10]in 2000 as a planned approach to achieve an R0 resection leaving an adequate future liver remnant and involving two liver directed operations. This is often combined with PVE and/or RFA and chemotherapy. It excludes bilobar resections. The aim of the resection is to strike a balance between removal of a tumor and preservation of the remaining liver. As most of metastases occur in the right liver, there are 2 possible approaches to staged resections. First, to resect the bulk of the tumor on the right and then "clean-up" the left side, or to "clean-up" the less invaded left liver and then resect the right side. The latter is the "standard approach". The principles of the "standard approach" include clearance of the left liver which is the future liver remnant (+/- RFA), avoidance of unnecessary dissection of the porta hepatis or right liver, PVE and interval short course chemotherapy. Recent evidence suggests that short-course chemotherapy does not interfere with regeneration. This is followed later by a major right liver resection.[11]There are a number of advantages to this method, including doing the "easy side" first,encountering fewer adhesions when performing a second major resection, and eliminating the effect of tumor growth factors on the future liver remnant. In addition, the "minor" first resection can be performed with less resultant liver injury, hence chemotherapy can be started earlier postoperatively. The first minor resection may even be performed with a synchronous primary bowel tumor resection.

Case selection is very important in determining which patients are suitable for a staged liver resection. The use of staged resections has been increasing in recent years.[11]Adam et al[10]have demonstrated a 5-year survival rate of 35%. Jaeck et al[3]also reported a significantly higher survival in patients who had undergone two-stage resections. However, worldwide there are a small number of patients undergoing staged liver resections and despite high success rates, there is significant morbidity.[12]

In a recent study,[11]41 patients were treated over 15 years. The 5-year survival in the intention to treat group was 31%. The 5-year survival after the second resection was 42% with a mean follow up of 24 months. In this series, 27% were alive and disease-free at the last followup.

Our survey suggests that surgeons are increasingly performing a two-staged resection for multiple bilobar colorectal metastases. Interestingly, 5 (17%) of our patients underwent PVE prior to the first resection, and 11 (39%) were planned to receive a right-sided first resection. It would be arguable that operation on the left lobe first is easier to approach staged resections. In addition, the use of PVE in 17% of the patients was lower than the reported in the literature. A second operation was performed in 25 patients at an average of 2.8 months from the first resection (median 2 months, range 1.25 to 8 months). Complications occurred in 32% of the patients after the first resection. In comparison, 57% of the patients had complications after the second resection, indicating that this is not a straightforward operation. However, there were no perioperative deaths. Thirtytwo percent of the patients were alive at various stages of follow-up and the remaining 43% developed recurrent disease, showing that there is potential benefit when R0 resection is completed, but many patients may still develop recurrent disease.

Limitations of our study, in particular, include the lack of controls. Because of the low number of staged resections, this is inavoitable. In addition, our study is to assess trends in the use of staged liver resections.

Case selection is important and difficult. Hence multidisciplinary assessment is compulsory. The response to chemotherapy is very important although the timing and duration of chemotherapy is unclear. It is also important to minimise unnecessary dissection and mobilization especially during the first operation. PVE is very useful, and RFA is beneficial. While there is increased (cumulative) morbidity and mortality, good results can be obtained. We believe that staged liver resections for colorectal metastases are a valuable strategy in selected cases.

Acknowledgements

We wish to acknowledge the following surgeons for their contribution of cases to this study: M. Buechler, F. Chu, R. Finch, H. Friess, S. Gallinger, T. John, G. Maddern, R. Myrddin, R. Padbury, M. Rees, J. Schmidt, A. Wei, J. Weitz, F. Welsh.

Funding:None.

Ethical approval:Not needed.

Contributors:UV proposed the study. CR wrote the first draft. PCHC analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. CR is the guarantor.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received February 22, 2010

Accepted after revision June 13, 2010

Fate is a word of the weak-willed and an excuse of a fault. Fate is never accepted by the strong-willed.

patient

additional systemic treatment, and 20 had this as neoadjuvant therapy. Thirteen patients had further chemotherapy following the first operation, and 14 patients (from 23 where this data was available) received chemotherapy after the second operation. No other adjuvant therapies other than systemic chemotherapy were offered.

Author Affiliations: The Alfred Hospital, Upper Gastrointestinal/Hepatobiliary Surgery Unit, Melbourne, Australia (Chandra R, Pilgrim CHC and Usatoff V)

Dr. Raaj Chandra, 93/8 Wells St, South Melbourne, Victoria, Australia 3205 (Tel: +61413945073; Email: raajchandra@hotmail. com)

This paper was presented at the Royal Australasian College of Surgeons Annual Scientific Meeting, Brisbane, May 2009. Presenter: Mr. Val Usatoff (Invited speaker)-Wednesday 6th May 2009.

? 2010, Hepatobiliary Pancreat Dis Int. All rights reserved.