Liver resection for colorectal liver metastases in older patients

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1 Critical Reviews in Oncology/Hematology 67 (2008) Liver resection for colorectal liver metastases in older patients Nicola de Liguori Carino a,, Barbara L. van Leeuwen b, Paula Ghaneh a, Andrew Wu a, Riccardo A. Audisio b, Graeme J. Poston a a Supra-Regional Hepatobiliary Unit, University Hospital Aintree, Liverpool L9 7AL, UK b SIOG Surgical Task Force, Whiston Hospital, University of Liverpool, Prescot L35 5DR, UK Accepted 15 May 2008 Contents 1. Introduction Methods Statistical analysis Results Postoperative outcomes Overall- and disease-free survival Discussion Conflict of interest statement Reviewers References Biography Abstract Introduction: Seventy-six percentages of patients with a newly diagnosed colorectal carcinoma are between 65 and 85 years old. A substantial proportion will develop liver metastases, for which resection is the only potential curative treatment. This study was conducted to investigate both the feasibility, and short- and long-term outcomes of liver resection for colorectal liver metastases in elderly patients. Methods: Between August 1990 and April 2007 data were prospectively collected on patients over 70 years of age who underwent a liver resection for colorectal liver metastases in a single centre. Results: One hundred and eighty-one liver resections were performed in 178 consecutive patients (median age 74 years). Thirty-four patients (18.8%) received neoadjuvant chemotherapy (all FOLFOX) prior to liver surgery and the majority (57.5%) of liver resections involved more than two Couinaud s segments. Median hospital stay was 13 days, 70 (38.5%) patients had postoperative complications, and overall in hospital mortality was 4.9% (9 patients). Overall- and disease-free survival rates at 1, 3 and 5 years were 86.1%, 43.2% and 31.5% and 65.8%, 26% and 16%, respectively. In multivariate analysis: T3 primary staging; major liver resections; more than three liver lesions; and the occurrence of postoperative complications were associated with inferior overall survival. Conclusions: Liver resection for colorectal liver metastases in elderly patients is safe and may offer long-time survival to a substantial percentage of patients. We strongly recommend considering senior patients for surgical treatment whenever possible Elsevier Ireland Ltd. All rights reserved. Keywords: Colorectal liver metastases; Liver resection; Elderly; Neoadjuvant chemotherapy 1. Introduction Corresponding author at: Supra-Regional Hepatobiliary Unit, Directorate of General Surgery, University Hospital Aintree, Lower Lane, Liverpool L9 7AL, UK. Tel.: ; fax: address: Nicola.dlc@gmail.com (N. de Liguori Carino). Life expectancy has increased dramatically over the last 100 years, and is now years for men and years for women in western society [1]. The demographics of these changes have important consequences for health care professionals in oncology. Currently, over half of all cancers /$ see front matter 2008 Elsevier Ireland Ltd. All rights reserved. doi: /j.critrevonc

2 274 N. de Liguori Carino et al. / Critical Reviews in Oncology/Hematology 67 (2008) are diagnosed in elderly patients, and 76% of all colorectal cancer patients are diagnosed between 65 and 85 years old [2,3]. Although the prevalence of colorectal cancer in elderly patients is increasing, survival in this patient category has not improved accordingly. Age standardised survival rates are lower for elderly patients with colorectal cancer compared to younger ones, especially during the first year after diagnosis [2]. Elderly patients are less likely to undergo curative surgery, and less likely to be offered the option of metastasectomy when liver metastases are present [4]. Synchronous liver metastases are present in about 20% of patients found to have carcinoma of the colon and rectum [5], and metachronous liver metastases will subsequently appear in approximately 20 50% of patients [6 9]. Hepatic resection is the only treatment offering long-term survival for these patients [8,10,11]. However, in studies reporting resection of colorectal liver metastases, only 8 20% [11,12] of the patients are older than 70 years [13]. When balancing the benefits of surgical resection of liver metastases against the potential risks of surgery, many clinicians are still reluctant to advise in favour of surgical treatment in the elderly. Although such a minimalist approach might seem unacceptable, it is likely that concerns about postoperative morbidity and mortality in the elderly may have influenced the decision to not offer surgery to these patients. Recent improvements in techniques of hepatic resection and anaesthetic interventions have evolved dramatically. Postoperative mortality has decreased over the past decades, and nowadays peri-operative care has improved with mortality rates varying between 0% and 11%, even for procedures combining colon resection with metastasectomy [14]. In addition, neoadjuvant chemotherapy is being used increasingly with the intention of improving disease-free survival post-liver resection, and also to bring patients with initially unresectable liver disease to potentially curative surgery. This study was therefore conducted to investigate the feasibility, short- and long-term outcomes of liver resection for colorectal liver metastases in patients over the age of Methods Out of a consecutive series of 654 liver resections for colorectal metastases collected between August 1990 and April 2007 at our Unit, all patients over 70 years old were included in this study. Preoperative radiological investigations and clinical details of all patients were discussed at the hepatobiliary (HB) multidisciplinary team (MDT) meeting before proceeding to surgery data were collected prospectively, including: age, sex, site and staging of primary tumour, administration of neoadjuvant chemotherapy, distribution, number and maximum size of liver lesions, type of liver resection, surgical clearance, use of pedicle clamping (Pringle manoeuvre), duration of in-hospital stay and the occurrence of postoperative complications, including death. Primary outcome parameters included postoperative morbidity and mortality; secondary outcome parameters were overall and disease-free survival. The extent of hepatic resection was classified according to Goldsmith and Woodburne [15]. For the purpose of further analysis in these elderly patients, a liver resection that involved more than two Couinaud segments was considered major, and those involving one or only two segments were considered minor resections. Those patients who underwent combined procedures (with synchronous colorectal resection, or resection of other intra-abdominal disease) were classified as other resections. A liver resection was defined as having clear margins when no extrahepatic disease was present, and the resection margin clearance was greater than 1 mm. Patients who received neoadjuvant chemotherapy had a median number of six cycles (2 10) of 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX)-based regimens. All patients were admitted to the High Dependency Unit for the first 24 postoperative hours as per hospital protocol, and then if well transferred to the ward. Postoperative mortality was defined as all death occurring within the same hospital admission. Data on follow-up were registered during out patient consultations in the HPB unit with the liver surgeons and/or by the referring physicians: oncologist, gastroenterologist, or general practitioner Statistical analysis Chi-square test was used to test for differences between groups. Overall survival and disease-free survival were estimated by the Kaplan Meier method. For the analysis of the influence of individual variables on survival Log-Rank and Gehan s Wilcoxon tests were performed. The Cox proportional hazard ratio was used to compare the effect of multiple variables on survival. p < 0.05 was considered statistically significant for all tests. A hazard ratio of 1 indicates that the presence or absence of this variable had no influence on outcome. A hazard ratio above or below 1 indicates that survival was worse or better in the presence of a certain variable. Statistical analysis was performed using Statistica software version 7 (StatSoft, Tulsa, OK, USA). 3. Results Within the 17-year study period 181 liver resections were performed in 178 consecutive patients. The American Association of Anesthesiologists (ASA) grade was less than IV for all patients included. The median age of patients was 74 years (range years). Patient characteristics are shown in Table 1. Thirty-four patients (18.8%) received neoadjuvant chemotherapy prior to liver surgery. No patients received neoadjuvant chemotherapy prior to 2000, and all of those who received it thereafter were treated using oxaliplatin-based regimens (the majority using FOLFOX-4, but more recently,

3 N. de Liguori Carino et al. / Critical Reviews in Oncology/Hematology 67 (2008) Table 1 Patient characteristics N (%) Patients 178 Resections performed 181 Median age (years) (range) 74 (70 82) Gender Male 115 (64.6) Female 63 (35.4) Localisation of primary tumour Colon 92 (51.7) Rectum 75 (42.1) Unknown 11 (6.2) Primary tumour T1 6 (3.4) T2 45 (25.3) T3 50 (28.1) T4 66 (37.1) Unknown 11 (6.1) Neoadjuvant chemotherapy given Yes 34 (18.8) No 147 (81.2) Metastases Synchronous 66 (36.5) Metachronous 110 (60.7) Recurrence 3 (1.7) Unknown 2 (1.1) Unilobar 137 (75.6) Bilobar 44 (24.4) Mean size dominant lesion (mm)(range) 50 (10 190) Percentages in brackets unless otherwise specified. FOLFOX-6). Of the patients who received chemotherapy prior to liver surgery, six were in the EORTC EPOC trial of peri-operative FOLFOX-4 versus surgery alone. Four patients were initially considered unresectable but became suitable candidates for surgery after very good responses (>50% reduction in tumour volume) after chemotherapy. The other 24 received chemotherapy prior to surgery since although considered resectable at the time of diagnosis of their liver disease, the radiologic morphology of their disease was such (bilobar metastases, >3 metastases, <1 cm predicted resection margins based on CT scanning, suspiciously enlarged portal lymph node) that resection would only be offered following a documented response/stabilisation of their disease following chemotherapy. The median number of cycles of FOLFOX given was 6 (2 10) over a median of 12 (4 24) weeks. There was a minimum break of 4 weeks between completion of chemotherapy and liver resection. The majority (57.5%) of the liver resections were considered major (involving more than two Couinaud segments) (Table 2). Pedicle clamping (Pringle manoeuvre) was recorded for 146 (80.2%) patients Postoperative outcomes The median length of in-hospital stay was 13 days (range 6 60). 70 (38.5%) patients experienced postoperative com- Table 2 Characteristics of liver resection Variables N (%) Type of liver resection Segmentectomy 39 (21.6) Bisegmentectomy 31 (17.1) Left hemihepatectomy 9 (5) Right hemihepatectomy 40 (22.1) Left extended hemihepatectomy 8 (4.5) Right extended hemihepatectomy 29 (16) Combined procedure left and right lobe 18 (9.9) Others 7 (3.8) Resection margins Clear 166 (91.7) Not clear 15 (8.3) Pedicle clamping performed during surgery No 77 (42.6) Yes 69 (38.1) Unknown 35 (19.3) Percentages in brackets. plications, with 27 (14.9%) patients suffering surgical complications, and 43 (23.8%) with medical complications. Surgical complications included wound infections, bile leak, intra-abdominal collections, paralitic ileus, haemorrhage, sepsis, duodenal ulcer and adhesional small bowel obstructions while confusion, chest infections, decompensate diabetes, atrial fibrillation, congestive cardiac failure, renal failure and liver failure accounted for the medical complications. Among those who suffered complications were seven patients with transient liver failure, and three (1.7%) with fatal liver failure. Liver failure only occurred after resection of four or more liver segments There was no significant difference in the postoperative complication rate among patients who underwent minor, compared to those who underwent major liver resections (p = 0.383). The postoperative complication rate was not increased in those receiving neoadjuvant chemotherapy (p = 0.954). The overall postoperative mortality rate was 4.9% (9 patients) in the over 70 years of age patients, with five patients dying within the first, and four within the second postoperative months. All but 1 death occurred after a major resection Overall- and disease-free survival Median follow-up is presently 17.5 months (range months). Overall- and disease-free survival rates at 1, 3 and 5 years were 86.1%, 43.2% and 31.5%, and 80.4%, 31.6%, and 17.4%, respectively. Tumour recurred in 84 (46.4%) patients and the most common site of recurrence was in the liver (Table 3). Among patients suffering recurrence, clear resection margins had not been achieved in 15 (17.9%) patients. The majority of patients experiencing recurrence had undergone a major liver resection (59.5%) compared to 34.5%, and 5% of patients having undergone a minor or other liver resection, respectively (Fig. 1).

4 276 N. de Liguori Carino et al. / Critical Reviews in Oncology/Hematology 67 (2008) Table 3 Tumour recurrence after hepatic resection N (%) No recurrence 97 (53.6) Recurrence 84 (46.4) Recurrence site Liver 36 (42.8) Lungs 21 (25) Bones 3 (3.6) Pelvis/local 3 (3.6) Multiple sites 16 (19) Others 3 (3.6) Unknown 2 (2.4) Percentages in brackets. Table 5 Cox regression on variables influencing overall survival Variable Overall survival HR (95% CI) Significance Primary tumour T (1,12 3,17) p = 0.02 Number of lesions > (1.01 3,40) p = 0.05 Neoadjuvant chemotherapy given 1.13 (0,57 2,24) NS Major liver resection 1.67 (1.01 2,76) p = 0.05 Postoperative complications 1.80 (1,14 2,81) p = 0.01 HR = hazard ratio; CI = confidence interval. The presence of more than three liver lesions and interestingly, the use of neoadjuvant chemotherapy also decreased overall survival, but these factors had no influence on diseasefree survival (Table 4). Hepatic pedicle clamping did not significantly influence overall and/or disease-free survival (p > 0.05). Similarly, no difference has been noticed when patients with bi-lobar liver metastases were compared to unilobar ones (p > 0.05). Cox regression analysis showed that T3 primary tumours, major liver resections, more than three liver lesions, and the occurrence of postoperative complications to be associated with a decrease in overall survival, while none of these factors influenced disease-free survival (Table 5). 4. Discussion Fig. 1. Overall survival by resection type. Age, sex, primary tumour staging, characteristics of liver metastases, use of neoadjuvant chemotherapy, extent of liver resection, whether or not pedicle clamping was employed during surgery, and the occurrence of postoperative complications were compared in a univariate analysis of factors associated with overall and disease-free survival. T3 colorectal cancers, major liver resection and the occurrence of postoperative complications were shown to negatively influence both overall and disease-free survival. Even with the recent advances in chemotherapy, 5-year survival in patients with colorectal liver metastases receiving only palliative chemotherapy is 0 4% and none are cured [16,17]. The active treatment of elderly patients with metastatic colorectal cancer disease, with the intention of increasing life expectancy, presents us with a dilemma between the benefits and risks of surgery. Most studies reporting outcome after hepatic resection in the elderly deal with mixed caseloads (including a substantial number of patients with hepatocellular carcinoma) and different types of resection, making informed conclusions difficult. The present study is the largest single centre series of liver resections for colorectal liver metastases in patients older than 70 years, and Table 4 Univariate analysis of variables influencing overall and disease-free survival Variable N (at baseline) Overall survival (p) Disease-free survival Primary tumour T3 = p = 0.04 Others = 118 Number of lesions 3 = NS >3=19 Neoadjuvant chemotherapy given No = NS Yes=34 Extension of resection 2 Segments = p = 0.05 >2 Segments = 111 Postoperative complications No = p = 0.02 Yes=70

5 N. de Liguori Carino et al. / Critical Reviews in Oncology/Hematology 67 (2008) it is the first single centre study which attempts to evaluate the impact of neoadjuvant chemotherapy in elderly patients undergoing liver resection. Our measured postoperative morbidity and mortality rates (38.5%, and 4.9%, respectively) are in line with previous series in both older and younger patients, confirming that there is no significantly increased operative risk among elderly patients [13,18 20]. Liver failure is a worrying but thankfully rare complication after liver resection. Some authors have found elderly patients to be more at risk than younger ones of developing this complication, resulting in a more conservative surgical selection policy [21,22]. Ettorre et al. findings however, showed no difference in postoperative liver function after right hepatectomy when comparing 24 patients aged 65 years or more to 22 patients aged younger than 40 [23]. This is in accordance with reports that showed that using donor livers from elderly patients resulted in comparable outcomes in orthotopic liver transplantation [24,25]. In the present study liver failure occurred in 3.9% of patients. Although this series reports on a cohort of patients undergoing liver surgery over an 18-year period, pre-operative chemotherapy was not adopted for these patients until 2000 (for the last 7 years of the study). Prior to 2000, the standard chemotherapy regimen for adjuvant chemotherapy following surgery for Stage 3 colorectal cancer and palliation of inoperable Stage 4 colorectal cancer in the UK was based on regimens of 5-fluorouracil and folinic acid. After 2000, irinotecan and then oxaliplatin-based regimens were increasingly adopted. However, at that time (2000 onwards) peri-operative oxaliplatin was used exclusively in the scenario of possible subsequent liver resection in our centre because of the absence of data to support the use of irinotecan in this particular setting. During the course of the period , our centre was a major contributor to the EORTC EPOC Phase III trial of peri-operative FOLFOX versus surgery alone [29], and therefore while recruiting into the study, we increasingly adopted the use of adjuvant chemotherapy for patients whose disease was predicted to have a high chance of recurrence after hepatectomy (see above). This is the first single centre study to specifically report the feasibility of neoadjuvant chemotherapy before liver resection in patients over the age of 70. Treatment with FOLFOX has been shown to successfully prolong survival (with a median survival of 22 months), and delay progression of disease in patients with advanced colorectal cancer [26,27]. Even in patients over the age of 70 years FOLFOX-based regimens have proven to be a safe treatment. In theory, giving neoadjuvant chemotherapy to patients undergoing resection of colorectal liver metastases has several advantages; reduction of tumour size may allow for easier resection, and an increased rate of negative surgical margins [28]. Recent data from the EORTC EPOC peri-operative chemotherapy trial has shown a significant improvement in 3-year disease-free survival in patients who actually underwent liver resection [29]. Responsiveness to chemotherapy can be used as a negative selection criterion, as resection of liver metastases in nonresponders has been proven to result in poorer outcomes [30]. In elderly patients, with reduced hepatic functional reserve and other possible comorbidties, hepatotoxicity (sinusoidal congestion and thrombosis) caused by oxaliplatin could prove to be a problem [28]. Among the 34 patients who received neoadjuvant FOLFOX chemotherapy in our series, only 1 developed liver failure after resection, and died on postoperative day 10. This observation accounts for the 3% mortality in this group, and is comparable to mortality to the overall study population, therefore not increasing the postoperative mortality risk after major liver resection in the elderly. When postoperative complication rates were compared among the subgroups who did or did not receive neoadjuvant chemotherapeutic treatment, there was no difference between the groups. This is in accordance with findings of Parikh et al. who showed that after treatment using 5FU, leucovorin and irinotecan regimens in younger patients there was no increase in peri-operative morbidity in patients resected for liver metastases [31]. In our study, neoadjuvant chemotherapy was found to correlate with increased overall survival, but not with disease-free survival. However, results on survival analysis in the present study should be interpreted with some care, because of the relatively small numbers and short median follow up of patients. Overall survival rates at 3 and 5 years were 43.2% and 31.5% which are comparable to those reported by Fong et al. [18] and Adam and colleagues (Adam R, Laurent C, Poston GJ, et al. Liver resection of colorectal metastases in elderly patients: is it worthwhile and is there an age limit? Annual Meeting European Surgical Association; 2007) but lower than those reported by Menon et al. [20] in a series with a mixed disease caseload. An important factor in our study that influenced postoperative survival was primary tumour category: surprisingly patients with a T3 primary tumour showed inferior overall and disease-free survival compared to T4 tumours. This may suggest an increased tendency for early metastatic spread in T3 tumours compared to the relatively more locally progressive T4 tumours. Both overall- and disease-free survival were better in patients who had undergone resection of one or two liver segments when compared to those undergoing major liver resection. Although no significant difference in morbidity between the two groups was found, 8 of the 9 postoperative deaths occurred after a major resection, and this observation will certainly have influenced long-term survival. However, there was a trend for lower recurrence rates after minor resections compared to major resections, suggesting that favourable long-term outcomes in patients after limited liver resections may be related to a less aggressive liver disease at the time of presentation, rather than a different surgical approach. In view of these findings it is advisable to consider a limited liver resection whenever possible from the oncologic perspective, rather than extended surgery.

6 278 N. de Liguori Carino et al. / Critical Reviews in Oncology/Hematology 67 (2008) In conclusion this study provides further evidence that resection of colorectal liver metastases in elderly patients can be performed with low mortality and acceptable morbidity rates, and offers long-time survival advantage to many of these patients. Liver failure remains a serious but rare complication after major liver resection in the elderly and reliable techniques for the estimation of functional hepatic reserve will be essential to reduce this risk of postoperative hepatic failure. Neoadjuvant chemotherapy can be used safely prior to such surgery in these elderly patients. We strongly recommend considering senior patients for surgical treatment whenever possible. Conflict of interest statement No funding sources have been employed and there is no conflict of interest to be declared. Reviewers Professor Nicolas Demartines, Head, Department of Visceral Surgery, Centre Hospitalier Universitaire Vaudois CHUV, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland. References [1] World Health Organisation. World Health Statistics. Anonymous. WHO Library Cataloguing-in-Publication Data, [2] Quaglia A, Capocaccia R, Micheli A, et al. A wide difference in cancer survival between middle aged and elderly patients in Europe. Int J Cancer 2007;120(10): [3] Petrowsky H, Clavien PA. Should we deny surgery for malignant hepato- pancreatico-biliary tumors to elderly patients? World J Surg 2005;29(9): [4] Temple LK, Hsieh L, Wong WD, et al. Use of surgery among elderly patients with stage IV colorectal cancer. J Clin Oncol 2004;22(17): [5] Gilbert HA, Kagan AR. Metastases:incidence, detection and evaluation without histologic confirmation. In: Weiss L, editor. Fundamental aspects of metastases. Amsterdam: North-Holland; p [6] Bengmark S, Hafstrom L. 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Ann Surg 2004;240(6): [31] Parikh AA, Gentner B, Wu TT, et al. Perioperative complications in patients undergoing major liver resection with or without neoadjuvant chemotherapy. J Gastrointest Surg 2003;7(8): Biography Nicola de Liguori Carino, M.D., Degree in Medicine and Surgery at University of Tor Vergata in Rome. Currently Surgical Senior Clinical Fellow in HPB and Transplant at St. James University Hospital, Leeds, UK.