Surgery combined with oncological treatments in liver metastases from colorectal cancer

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1 Scandinavian Journal of Surgery 100: 35 41, 2011 Surgery combined with oncological treatments in liver metastases from colorectal cancer H. Isoniemi 1, 3, P. Österlund 2, 3 1 Transplantation and Liver Surgery Clinic, Helsinki University Central Hospital, Helsinki, Finland 2 Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland 3 University of Helsinki, Helsinki, Finland Abstract The patients with colorectal liver metastases used to have a rather disappointing prognosis in the past. At present there is moderate possibility for cure with liver resection. In addition more patients are accessible for liver resection and potential cure when modern chemotherapy combined with biological agents is used. At the time of diagnosis liver metastases of 10 20% of patients are resectable. Potentially unresectable metastases can be converted to resectable in 10 15% of patients with advances in surgery together with improved oncological therapy. Resection rate increases linearly with the response rate to chemotherapy. In this century the 5-year survival rates after resection have improved remarkably being around 50% in many reports. Multidisciplinary management of metastatic colorectal cancer has increased the number of patients with potentially curative treatment and has improved patient survival. Key words: Colorectal cancer; liver metastases; liver resection; liver surgery; thermoablation; neoadjuvant chemotherapy; adjuvant chemotherapy Introduction Colorectal cancer (CRC) is the third most frequent cancer in the Western world and the liver is the most common site of metastases. About half of the patients will develop metastases at some point, either synchronous metastases at the time of diagnosis of colorectal cancer or will develop metachronous metastasis during the later course of the disease. If liver metastases are not treated, the median patient survival is only some months. Combination chemotherapy increases survival to about 18 months and when biologics are added the median survival is around 24 months without surgery (1). Correspondence: Helena Isoniemi, M.D. Transplantation and Liver Surgery Clinic Helsinki University Central Hospital PO Box 340 FI HUS, Finland helena.isoniemi@hus.fi This review will concentrate on the current possibility to treat liver metastases with surgery which still is the only chance for cure, and also to discuss the present role of neoadjuvant and adjuvant treatment combined with liver resection. Surgery How to define resectability About 10 20% of liver metastases in patients with CRC have been resectable at the time of diagnosis (2). The suitability for liver resection of CRC liver metastases has changed substantially since the eighties. The definition of resectability was simple, but has become extremely difficult with advances both in surgery and in other treatments, especially in chemotherapy combined with biologics. Earlier hepatic resection was considered contraindicated if there were more than three metastases, diameter of metastases was over five centimetres and resection margins were less than one centimetres. Now these are not con-

2 36 H. Isoniemi, P. Österlund traindications anymore and the only goal is to achieve histologically tumour free resection margins (R0 resection) with functionally sufficient remaining liver parenchyma (3). How to define what is functionally sufficient liver remnant? The operative approach is determined by the anatomic location of the metastases in relation to main branches of vessels and bile ducts in the liver. Instead, the extent of resection is a balance between complete removals of metastases while preserving as much liver parenchyma as possible. Resectability depends also very much on the experience and skills of the surgeon. Functionally sufficient remaining liver is commonly considered 30% of the initial liver volume and at least 40% if the patient has received chemotherapy, or at least two segments (3). Patients with complex multiple metastases require good collaboration between surgeon, radiologist and oncologist to achieve this. Furthermore many lesions that were previously condemned unresectable are now convertible to R0 resection with the help of neoadjuvant treatment, so that initially unresectable liver metastases can be potentially curatively resected (2, 4). Even extra-hepatic disease in CRC patients should no longer be an absolute contraindication for liver resection, provided that all lesions can be completely treated with resection or ablation (5 6). Selected patients with both lung and liver metastases can achieve long-term survival after surgery (7). Reresection Recurrence after liver resection appears in half to two thirds of patients, and half of the recurrences are solely hepatic (8 9). Reresection should be considered with the same indications as the first resection with curative intent. In a study of 166 patients with recurrence after resection, 71 had isolated hepatic metastases, 25 had isolated pulmonary metastases, 13 had hepatic plus pulmonary metastases, and 57 had metastases in other organs. Repeated resections were conducted in 85% of the patients with isolated hepatic recurrence and in 69% with both hepatic and pulmonary recurrence (8). The 5-year survival rates after repeated resection were 39% for isolated hepatic metastases, and 20% for hepatic plus pulmonary metastases. In experienced centres operative mortality or morbidity is not higher in reresection than in the first liver resection (9). Improved technique Optimized surgical dissecting techniques with better intra- and postoperative care have enabled more challenging resections without impairing the results or increasing mortality. Before the eighties mortality in liver surgery was high, from 10 to 20%. Since then it is reduced steadily. In the nineties 5% was acceptable mortality. Postoperative mortality has decreased even further, although liver resections have become more extensive and complicated, being as low as 1 2% in a single centre (10). Today, even in a multicenter trial, under 1% 30-day mortality has been achieved in surgery of colorectal cancer metastases (11). Preoperative diagnostic accuracy has improved with the use of modern types of computer tomography (CT) and magnetic resonance imaging. PET-CT is valuable in detection of extrahepatic disease reducing futile laparotomies (12). Understanding the segmental anatomy of the liver and selecting the proper transection plane using intraoperative ultrasound, are prerequisites for safe liver surgery. Intraoperative ultrasound has been used since the eighties and now contrast-enhanced intraoperative ultrasound has improved the diagnostic sensitivity even further (13). Liver surgery is always team work. The anaesthesiologist has an important role. Low central venous pressure anaesthesia has been shown to reduce bleeding remarkably (14). A randomized controlled trial showed that low central venous pressure at 2 4 mmhg led to significantly reduced blood loss and shortened length of hospital stay compared to patients with normal central venous pressure (15). Parenchymal division was historically performed with the so called finger fracture technique (16). This very robust and brutal technique was replaced by a variety of clamping and crushing methods using different instruments. Newer technologies are CUSA (cavitron ultrasound surgical aspirator) and waterjet (with high pressure jet of water) which are used for parenchymal division. With CUSA liver parenchymal cells are destroyed with ultrasonic energy and aspirated, but leaving intact fibrous vascular and ductal structures, which can be ligated, coagulated or clipped. Waterjet is principally similar, but the energy is a high pressure jet of water. CUSA is more popular than waterjet. Our own experience is that waterjet is easier to use, but CUSA allows exacter dissection when operating close to tumours and main trunks of hepatic veins. The surgeon s experience with the particular technique determines which is clinically the best. Few randomized trials have been performed and have not shown superiority of any specific technique (17). However it is noteworthy that the randomized study showing no difference between clamp crushing and CUSA techniques is from a Japanese group which has abundant experience with clamp crushing techniques (18,19). New instruments for liver dissection using different types of energy for coagulation or sealing of vessels have been developed. These include radiofrequency devices, Harmonic Scalpel, Ligasure and TissueLink dissecting sealer. These instruments allow faster dissection than CUSA but as of today the precision of the dissection is much greater with CUSA and whether these new instruments improve the safety of liver dissection has not been demonstrated (19). Radiofrequency thermoablation devices have been used for liver dissection. Recently a device consisting of multiple parallel electrodes has been developed. Radiofrequency-assisted liver dissection is a fast technique. However, main concern for this method is the risk of thermal injury to major bile ducts and its use is probably restricted to minor resections (19).

3 Liver resection in colorectal metastases 37 Vascular staplers are replacing the conventional technique with vascular clamping followed by suturing the major vascular trunks in the liver. Vascular staplers are especially useful in division of major hepatic vein trunks. In many centres Pringle s manoeuvre, which is selective portal clamping, has been used to reduce bleeding during liver surgery. A recent randomized trial did not show any difference in bleeding in resection with or without hepatic pedicle clamping (20). Many centres, including ours, rarely use the Pringle s manoeuvre today. Surgery combined with other techniques If the remaining liver is considered functionally insufficient there are different ways to overcome this. One is portal venous embolization, which was first described to increase the safety of major hepatectomy for hilar cholangiocarcinoma (21). This technique has later been introduced also in patients with liver metastases. Portal venous embolization causes atrophy on the affected liver parenchyma and provokes compensatory hypertrophy on the contralateral side. It is usually performed to increase the liver volume of the left side and is recommended if liver volume is estimated to be less than 25 30%, or less than 40% in patients who have received chemotherapy (22 23). Usually the remnant liver volume can be increased by 30% in few weeks (24). With this technique the number of major hepatectomies performed safely can be increased. In specialized hepatobiliary centres bilobar multiple metastases can be approached by staged liver resection. Limited resections are first performed in one lobe and after a recovery period a major resection is done in a second procedure. To this portal embolization can be combined and results are comparable with simpler resections (25). Combination of resection and radiofrequency thermoablation has also extended the definition of resectability (26). In some cases resection of all multiple metastases is not safe in one procedure, but can be done with the combination of resection and thermoablation. Prognostic factors Factors which were recently considered contraindications for liver resection, are now considered only as adverse prognostic factors. The size and the number of liver metastasis do not count any more if R0 resection line can be achieved (27 28). A tumour free R0 resection margin remains the most important prognostic factor and the width in millimetres no longer counts (28 29). However the amount of metastases still correlates with the possibility of achieving tumour free margins (29). There are no good preoperative parameters or scoring systems that discriminate benefitting patients from those that do not benefit, even if both have had tumour free resection margins. The prognostic scores available do not predict long term survival or the risk of recurrence on the individual level (30). The chance of long-term survival decreases when the amount of usual risk factors increases (31). In many studies lack of response to neoadjuvant chemotherapy have been associated with worse prognosis after resection (32). If there is disease progression during chemotherapy the prognosis after resection has been the same as without resection, causing discussion if these patients should be operated (32). Today there are also opposite results showing survival benefit of liver resection even with tumour progression during preoperative chemotherapy (33). Recently the histologic response to preoperative chemotherapy has been reported as an independent prognostic factor (34). Staged or combined liver and colon resections The surgical strategy for resectable synchronous colorectal liver metastases remains controversial and there is no consensus of timing of liver resection. There is a recent report of similar surgical outcome in staged, combined, or reverse surgical strategies in patients with synchronous liver metastases (35). Generally resection of only one segment has been recommended in simultaneous resections (36). Many authors have also recommended postponed resection, to test if occult metastases become detectable, and thus patients with unresectable disease can be spared from surgery. A recent study presented significantly better survival rates in patients with delayed hepatic resection compared with simultaneous resection (37), and especially hepatic disease free survival was better in staged group. Efficacy of neoadjuvant chemotherapy may render some inoperable liver metastases resectable The efficacy of chemotherapy has improved substantially over the past ten years (1). In 2000 the combination of irinotecan or oxaliplatin to 5-fluorouracil and leucovorin showed more and longer lasting responses. Combinations of oxaliplatin to 5-fluorouracil early showed that 16% of initially unresectable liver metastases became resectable (38) and that increased resectability and also improved survival (1). In Fig. 1 an unresectable tumour was treated to resectable with neoadjuvant chemotherapy. Resection of initially unresectable liver metastases has been debated over the past 10 years but remains the patient s only chance for cure (39). The main concerns have been residual cancer cells at the lateral borders of the diminished metastases and liver damage due to cytostatics (40). Irinotecan induces steatosis and steatohepatitis, and oxaliplatin causes sinus dilatation (41). Postoperative morbidity has been the major concern with chemotherapy, but fortunately mortality has not increased. Morbidity correlates with the cumulative dose of che-

4 38 H. Isoniemi, P. Österlund a b c Fig. 1. Example of one large central metastasis which originally was unresectabe (a) and converted to resectable with six month neoadjuvant treatment (b). Three month control CT showed liver regenaration without recidive (c). After three years the patient is still disease free. motherapy before surgery, but not with the type of chemotherapy (42). Targeted drugs have improved the response rates further and Folprecht has elegantly showed that higher response rates linearly lead to increased resectability (2). In large randomized studies with targeted drugs versus combination chemotherapy alone some 5 11% of initially unresectable tumours have achieved a R0 resection, but this was not a primary endpoint of the studies (39). In most studies the trend is that with targeted drugs combined to chemotherapy some more patients may be amenable with surgery. Three phase II studies have specifically addressed liver resectability with combination chemotherapy and targeted drugs. Cetuximab combinations are known to give high response rates in KRAS wild type patients and in the CELIM study high resectability rates were proven (4). Bevacizumab combinations may in theory impair wound healing and liver regeneration, and were initially feared in conjunction with liver resection (43), but on the contrary were shown to be safe and even protective against liver damage (44). Gruenberger and Wong have shown that high resectability rates can safely be achieved also with bevacizumab combinations (45 46). There is data suggesting that bevacizumab can be safely administered until 5 weeks before liver resection without increasing the rate of surgical complications or disturbing liver regeneration (45) and it does not increase morbidity or mortality after liver resection (47 48). Neoadjuvant chemotherapy in conjunction with targeted therapy is generally recommended in borderline resectable metastatic colorectal cancer and adjuvant therapy is generally recommended after the resection (NCCN: 50). The role of disappearing metastases during chemotherapy Effective neoadjuvant chemotherapy has triggered the problem of disappearing metastases. Lesions which were originally present radiologically cannot be identified by imaging after some cycles of chemotherapy. But complete radiological response does not mean pathologic complete response, and thus not cure. Residual disease or early recurrence in situ has been observed in 83% of cases (51). It is recommended that corresponding parenchyma of radiologically disappeared metastases is resected using landmarks of vascular structures. Sometimes it is advisable to follow the patient and to resect or thermoablate later when the lesion is again visualized radiologically. Based on small patient series, there is also a contrary opinion that obligatory resection of the initially affected part of the liver is no longer needed (52). Role of adjuvant therapy in the resection of liver metastases Resection is the only possibility for cure in metastatic colorectal cancer. However, recurrence is common after liver resection. With surgery alone 55 65% of patients will have a recurrence within 5 years, although systemic therapy reduces the recurrence rates (53). When treating metastatic disease with surgery, only metastases visualized by radiologic means are addressed. Microscopic residual disease is more often the site of failure, than local relapse in the resected area. Microscopic disease is an attractive target for chemotherapy with the potential for cure. Adjuvant 5-fluorouracil based chemotherapy reduces relapses with 22 34% in stage III (and II) colorectal cancer disease and with the addition of oxaliplatin to approximately 40 48% (54) 5-fluorouracil based adjuvant therapy after liver resection has been studied in small randomized studies and in patient series (55). Two of these studies have been combined by Mitry et al and showed that intravenous 5-fluorouracil and leucovorin non-significantly increased progression-free survival (27.9 vs months, HR = 1.32; CI 95% ; P =.058) and median overall survival (62.2 vs months (HR = 1.32; 95% CI 95% ; P =.095; Table 1) (56).

5 Liver resection in colorectal metastases 39 Table 1 Randomized studies with postoperative or perioperative chemotherapy in conjunction with liver resection for colorectal cancer metastases Study Number of patients Random assignment (chemotherapy + surgery v surgery) DFS at 4 years* (chemo v surgery) OS at 4 years* (chemo v surgery) Follow-up (months) % P % P Langer (65) 107 FU/LV NR Surgery Portier (66) 171 FU/LV Surgery ECOG (58) 075 FUDR HAI + systemic Surgery German/Austrian (57) 226 FU/LV HAI 13.7** mths 40.8** mths Surgery 14.2 mths NS 34.5 mths NS 018 MSKCC (59 60) 156 FUDR/Dex HAI + systemic Surgery + systemic EORTC (11) 364 Perioperative oxaliplatin+ FU/LV 35 NA Surgery NA 045 Abbreviations: DFS, disease-free survival; OS, overall survival; HAI, hepatic arterial infusion; FU, fluorouracil; LV, leucovorin; FUDR, floxuridine; Dex, dexamethasone; NA, not available; NS, not significant ** Estimated from Kaplan-Meier curves for DFS and OS. ** Four-year DFS not reported. Figures reported are median (intention to treat). Ten-year OS. The third study gave 5-fluorouracil and leucovorin via hepatic arterial infusion (HAI) which was too toxic and additionally only 30% of the allocated patients received the short adjuvant therapy (57). This HAI treatment had a detrimental effect on survival (Table 1). The Kemeny sisters have published two randomized studies comparing floxuridine (FUDR) given as HAI with resection alone or with systemic chemotherapy and resection (Table 1). In both studies the predefined relapse endpoints were positive (58 60). In a Cochrane review including four additional HAI studies intrahepatic relapses were reduced, but no survival advantage from HAI was noted (61). In the study published by Nordlinger et al, perioperative chemotherapy, with 5-fluorouracil and leucovorin combined with oxaliplatin (FOLFOX), was administered for three months pre- and postresection and compared with resection alone (11). In this study a significant survival advantage was seen in resected patients (33.2% to 42.4%; HR 0.73 CI 95% ; p=.025), but was borderline significant in the intention to treat population (Table 1). International guidelines recommend adjuvant therapy with oxaliplatin and 5-fluorouracil, based on these small randomized studies (NCCN: guidelines.asp) (49 50, 62). Survival after resection Liver resection offers the only chance for cure in colo rectal cancer with liver metastases. The five year survival was long time around 30%, but is now increased to 45 50% and even beyond 50% (53, 63 64). 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Liver resection Liver resection Years Fig. 2. Survival after resection of colorectal cancer liver metastases in Helsinki. Two consecutive periods, 71 patients resected between and 277 patients resected between All patients have at least one year follow-up. Many cases considered non-resectable can now be resected, due to neoadjuvant chemotherapy, with similar results as in primarily resectable (4, 8 9). Concurrent complete resection of hepatic and extrahepatic disease in well-selected patients is associated with a possibility of long-term survival. In a recent single centre 5-year survival was 49% in patients resected for hepatic metastases and 25% with resectable hepatic and extrahepatic disease (6). Survival has improved in this century due to many factors. Recent results are favourable also in our own centre (Fig. 2). This is not only due to improved surgical and anaestesiologic techniques, but above all due to improved diagnostics and modern chemotherapy. After all, the most important factor for improved results is a multidisciplinary approach in the treatment of colorectal cancer liver metastases.

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