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Is Hepatic Resection Justified After Chemotherapy in Patients With Colorectal Liver Metastases and Lymph Node Involvement?

René Adam, Robbert J. de Haas, Dennis A. Wicherts, Thomas A. Aloia, Valérie Delvart, Daniel Azoulay, Henri Bismuth, Denis Castaing

From the Assistance Publique—Hôpitaux de Paris Hôpital Paul Brousse, Centre Hépato-Biliaire; Université Paris-Sud; and Inserm, Unité 785, F-94804 Villejuif, France; and Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands

Corresponding author: René Adam, MD, PhD, Assistance Publique—Hôpitaux de Paris Hôpital Paul Brousse, Centre Hépato-Biliaire, 12 Avenue Paul Vaillant Couturier, F-94804 Villejuif, France; e-mail: rene.adam{at}pbr.aphp.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose For patients with colorectal liver metastases (CLM), regional lymph node (RLN) involvement is one of the worst prognostic factors. The objective of this study was to evaluate the ability of a multidisciplinary approach, including preoperative chemotherapy and hepatectomy, to improve patient outcomes.

Patients and Methods Outcomes for a consecutively treated group of patients with CLM and simultaneous RLN involvement were compared with a cohort of patients without RLN involvement. Univariate and multivariate analysis of clinical variables was used to identify prognostic factors in this high-risk group.

Results Of the 763 patients who underwent resection at our institution for CLM between 1992 and 2006, 47 patients (6%) were treated with hepatectomy and simultaneous lymphadenectomy. All patients had received preoperative chemotherapy. Five-year overall survival (OS) for patients with and without RLN involvement were 18% and 53%, respectively (P < .001). Five-year disease-free survival rates were 11% and 23%, respectively (P = .004). When diagnosed preoperatively, RLN involvement had an increased 5-year OS compared with intraoperative detection, although the difference was not significant (35% v 10%; P = .18). Location of metastatic RLN strongly influenced survival, with observed 5-year OS of 25% for pedicular, 0% for celiac, and 0% for para-aortic RLN (P = .001). At multivariate analysis, celiac RLN involvement and age 40 years were identified as independent poor prognostic factors.

Conclusion Combined liver resection and pedicular lymphadenectomy is justified when RLN metastases respond to or are stabilized by preoperative chemotherapy, particularly in young patients. In contrast, this approach does not benefit patients with celiac and/or para-aortic RLN involvement, even when patients’ disease is responding to preoperative chemotherapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
For patients with colorectal liver metastases (CLM), hepatic resection remains the best treatment option, with reported 5-year survival rates between 28% and 41%.^1-5 These favorable outcomes have prompted an expansion in the indications for hepatic surgery for CLM. Technical improvements, including two-stage hepatectomy and vascular exclusion and reconstruction techniques, have made more patients with CLM eligible for surgery.^6-9 In addition, preoperative chemotherapy has been shown to convert a substantial number of cases that were initially considered unresectable to a resectable situation.^10,11

Despite this progress, the presence of regional lymph node (RLN) involvement in patients with CLM is still considered to be one of the worst prognostic factors and, for most oncologists, continues to be an absolute contraindication to surgery. Accordingly, a review of 16 reported series of patients with both CLM and RLN involvement consistently identifies poor 5-year survival rates, including 11 series reporting no 5-year survivors^3,12-26 (Table 1). Given these data, the expert consensus-based therapeutic decision model OncoSurge rated metastatic RLN involvement as a poor prognostic factor and celiac or para-aortic RLN involvement as absolute contraindications to liver surgery.²⁷ More recently, however, several studies have concluded that the presence of extrahepatic disease is not an absolute contraindication to hepatic surgery.^16,28,29 Given the limited number of patients studied and the apparent conflicts in the literature, the role of surgery in these patients remains highly controversial.

During our experience treating patients with CLM, we have not considered the presence of RLN metastases as an absolute contraindication to surgery, provided that response or stabilization during preoperative chemotherapy was observed. This experience gives us an unique opportunity to determine the impact of preoperative chemotherapy on postoperative outcomes for patients with liver and RLN involvement. The purpose of the present study was to define the role of surgery in this category of patients by systematically examining long-term outcomes and prognostic factors.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Patients
Patients who fulfilled the following criteria were included in this study: hepatectomy for CLM, presence of RLN metastases simultaneous to hepatectomy (ie, diagnosed before or during hepatectomy), preoperative chemotherapy, and resection of histologically proven RLN metastases. All study data were present in our Human Subject Committee–approved prospective database. For outcomes analysis, patients were grouped according to the location of RLN metastases: pedicular (distal to the gastroduodenal artery branch), celiac (overlying the common hepatic artery proximal to the gastroduodenal artery branch), and para-aortic RLN metastases. To determine the influence of RLN metastases on patient outcomes, additional comparisons were made to a simultaneously treated group of patients undergoing hepatectomy in the absence of RLN involvement.

Preoperative Evaluation
Before hepatectomy, all patients were radiologically staged with abdominal ultrasound and abdominopelvic and chest computed tomography (CT). In our more recent experience, selected patients were additionally staged with positron emission tomography (PET) CT. If the diagnosis of RLN involvement was made preoperatively (based on evolution of size and round shape on CT and/or hypermetabolic appearance on PET-CT), patients were initially treated with systemic chemotherapy. Furthermore, preoperative chemotherapy was considered in patients with initially unresectable disease or who presented with recurrent hepatic metastases within 1 year after the previous operation. The Response Evaluation Criteria in Solid Tumors were applied to serial imaging studies obtained every 2 months during preoperative therapy to determine chemotherapy response.⁴⁰ In cases of RLN involvement identified before surgery, hepatectomy combined with lymphadenectomy was only performed in patients with RLN involvement responding to or stabilized by chemotherapy.

Operation
All patients underwent hepatectomy with curative intent, preserving as much normal liver parenchyma as possible. Resection of three or more segments was considered a major hepatectomy.^41,42 If the estimated future remnant liver volume was less than 30% (< 40% in case of prolonged chemotherapy), portal vein embolization was performed.⁴³ When up to three lesions were deeply located in the future remnant liver, resection was combined to radiofrequency ablation and/or cryosurgery. If not all liver lesions could be completely resected in a single procedure, even when combined to radiofrequency ablation and/or cryosurgery, a two-stage procedure was performed.⁶ In patients with preoperatively identified RLN involvement, intraoperative confirmation of RLN disease by frozen-section biopsy preceded lymphadenectomy. In cases of no preoperative suspicion of RLN involvement, the intraoperative finding of macroscopically enlarged and firm nodes prompted immediate frozen-section analysis. If this was positive, hepatectomy combined with lymphadenectomy was performed when resection of all disease sites was deemed both feasible and safe. Postoperative histopathologic examination of all resection specimens was routine.

Postoperative Management
All patients were observed regularly, starting 1 month postoperatively and then every 4 months. These evaluations consisted of a history and physical examination, serum tumor markers, liver function parameters, and abdominal ultrasonography. Every 8 months, thoracoabdominal CT scans were performed. When concomitant resectable extrahepatic disease sites (except RLN metastases) were present, a resection was generally performed 2 to 3 months after hepatectomy, with intercurrent systemic chemotherapy delivered to prevent disease progression. To decrease the risk of recurrence, especially in patients with initially unresectable disease or who presented with a recurrence before, adjuvant chemotherapy was routinely recommended.

Statistical Analysis
Categoric and continuous study variables were compared between groups using the ² test, the independent-samples t test, or the one-way analysis of variance test, as appropriate. Overall and disease-free survival probabilities were estimated using the Kaplan-Meier method and were compared using log-rank tests. The log-rank tests were also used to identify variables associated with survival in univariate analysis. For multivariate analysis, all variables with a univariate P value .10 were entered in a Cox regression model to identify variables independently associated with survival. A P value .05 was considered statistically significant. Statistical analysis was performed using SPSS version 13.0 (SPSS Inc, Chicago, IL).

	RESULTS

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Patient and Tumor Characteristics
Between June 1992 and July 2006, 763 patients with CLM underwent hepatectomy at our institution. Among them, 53 patients (7%) had clinical evidence of RLN metastases simultaneous to hepatectomy. Six patients were excluded from the study because their suspected RLN disease could not be confirmed intraoperatively, leaving 47 patients (6%) available for analysis. Of these 47 study patients, 26 patients (3%) presented with pedicular, 14 patients (2%) presented with celiac, and seven patients (1%) presented with para-aortic RLN involvement. The group of patients who underwent resection and who were without simultaneous RLN metastases consisted of 710 patients (93%). Patient characteristics and liver metastases data are outlined in Table 2. The RLN group consisted of younger patients, with more advanced primary tumors (T4),⁴⁴ a higher frequency of metachronous CLM, and a higher incidence of initially unresectable CLM.

Lymph Node Metastases
Lymph node involvement was diagnosed before hepatectomy in 19 (40%) of 47 patients and intraoperatively in the remaining 28 patients (60%). Preoperatively, PET-CT was performed in six (13%) of the 47 patients, identifying RLN metastases in four patients. All patients with RLN disease diagnosed before surgery were treated with preoperative systemic chemotherapy and experienced either a response or stabilization of RLN disease. Of the patients with intraoperative diagnosis of RLN involvement, all had received preoperative chemotherapy. In all but four of these cases, liver disease responded to or was stabilized by preoperative chemotherapy (Table 4). Within the pedicular and celiac groups, all patients underwent a complete lymphadenectomy with no residual RLN disease, compared with 86% (six of seven patients) in the para-aortic group. Type of lymphadenectomy with the resected RLN areas are indicated in Table 3. Lymph node features are listed in Table 5.

The mean follow-up interval for the RLN group was 29 months, and for patients alive at last follow-up, the mean interval was 30 months. Only two patients were lost to follow-up. At the time of last follow-up, 32 patients (68%) had died of disease progression, and 15 patients (32%) were alive, seven (15%) of whom were disease free. Within the RLN group, 19 patients (40%) underwent a repeat hepatectomy, compared with 223 patients (31%) in the liver disease only group (P = .20).

Three- and 5-year overall survival rates in the RLN group and the group without RLN involvement were 38% and 18% versus 68% and 53%, respectively (P < .001; Fig 1). Median survivals were 28 months (95% CI, 21 to 34 months) and 65 months (95% CI, 55 to 75 months) from hepatectomy and 34 months (95% CI, 26 to 43 months) and 75 months (95% CI, 61 to 89 months) from CLM diagnosis, respectively. Disease-free survival rates after 3 and 5 years were significantly lower in the RLN group compared with the liver disease only group (15% and 11% v 34% and 23%; median, 9 months [95% CI, 2 to 16 months] v 20 months [95% CI, 18 to 23 months]; P = .004; Fig 2). Five-year overall survival for patients preoperatively diagnosed with RLN involvement was 35%, compared with 10% when the diagnosis was intraoperative (median survival, 43 months [95% CI, 21 to 64 months] v 27 months [95% CI, 15 to 38 months]; P = .18). When liver disease responded to chemotherapy (n = 26), 5-year survival was 26%, compared with 17% in case of stabilization or progression (n = 21; P = .08). Survival was similar whether RLN disease responded to chemotherapy (n = 12) or was only stabilized (n = 7; 5-year survival rate, 32% v 35%, respectively; P = .94).

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Overall survival for the combined liver and lymph node group versus liver disease only group.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Disease-free survival for the combined liver and lymph node group versus liver disease only group.

Prognostic Factors
Univariate analysis of potential prognostic factors within the RLN group identified three variables associated with poor outcome: age at hepatectomy (P = .04), initial carcinoembryonic antigen level (P = .02), and location of RLN metastases (P = .001; Appendix Table A1, online only). In multivariate analysis, two variables were identified as independent poor prognostic factors: celiac location of RLN metastases (hazard ratio, 4.7; P < .001) and age at hepatectomy 40 years (hazard ratio, 5.2; P = .004).

	DISCUSSION

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Although RLN involvement remains a generally poor prognostic factor, selected patients with RLN involvement seem to benefit from a multimodality treatment strategy that includes chemotherapy followed by surgical resection of both CLM and RLN disease. Specifically, the present study indicates that hepatectomy combined with lymphadenectomy could offer patients with simultaneous RLN involvement a 5-year survival rate of 18% with no operative mortality. Patients presenting with pedicular RLN involvement experienced more favorable postoperative outcomes (5-year survival rate of 25%) than those with celiac and/or para-aortic RLN involvement (no 5-year survivors). Furthermore, patients younger than 40 years experienced better long-term survival than older patients (5-year survival rate of 45% v 10%, respectively).

These results make an important contribution to the still controversial topic of hepatectomy combined with lymphadenectomy in patients with CLM. Only three of the 16 series directly addressing outcomes after combined hepatectomy and lymphadenectomy report any 5-year survivorship.^3,12-26 On the basis of this experience, RLN involvement has generally been considered a contraindication to surgery.

In contrast, our institution has maintained the indication for combined hepatectomy with lymphadenectomy. As a result of the dramatic improvements in the effectiveness of chemotherapy both in terms of response and survival,^30-39 we have continued to offer surgery to these patients, provided that no progression of RLN disease was observed and that resection was potentially curative. To our knowledge, the present study reports the largest single-institution series of patients with resected RLN and is the first one reporting on a cohort of patients all treated with preoperative chemotherapy.

As with any aggressive treatment approach, the results of this study should be assessed with regards both to the risk and to the long-term benefit of this combined approach. With regard to the risks, no patients died within 60 days of combined hepatectomy with regional lymphadenectomy. Although these results are in accordance with previous reports,^3,15,17,21 our cohort contains more patients undergoing lymphadenectomy for para-aortic RLN involvement. In our series, lymphadenectomy for para-aortic RLN disease was performed in seven patients, who represented 15% of all patients with RLN involvement. On the basis of this experience with extensive lymphadenectomy in the absence of perioperative mortality, we conclude that combined hepatectomy with lymphadenectomy can be done safely.

Regarding the potential benefit of this combined surgical procedure, a substantial 5-year survival rate of 18% was obtained for the total RLN group. As expected, when compared with patients without RLN involvement, patients with CLM and simultaneous RLN involvement shared other poor prognostic features, including more advanced T stage of the primary tumor and higher incidence of initially unresectable CLM. Accordingly, the 5-year survival rate for patients in the RLN group was lower compared with that of the control group (18% v 53%; P < .001). Despite these survival differences, the 18% 5-year survival rate observed in our series compares favorably with the outcomes reported in the majority of studies addressing this topic. Possible explanations for these better results are the systematic use of preoperative chemotherapy and the selection of surgical candidates based on the absence of progression of RLN disease before surgery.

The site of RLN metastases was strongly associated with long-term outcomes. For patients with pedicular nodal involvement, the 5-year overall survival rate was 25%, compared with 0% for either celiac or para-aortic RLN involvement. To date, the prognostic distinction between pedicular and celiac RLN involvement has only been made by Jaeck et al,¹⁸ who reported 17 patients, eight of whom presented with pedicular RLN metastases and the remaining nine patients with celiac RLN metastases. In this series, reported 3-year survival rates for the pedicular and celiac RLN groups were 38% and 0%, respectively. Although limited in the number of patients and in the duration of follow-up, these results agree with our present findings. Combined, these data suggest that although chemotherapy may have changed the spectrum of disease for patients with pedicular involvement, the prognosis continues to be poor for more distant RLN disease.

The timing of diagnosis of RLN involvement also seems to impact the efficacy of this approach. When RLN metastases were diagnosed intraoperatively, the 5-year survival rate was only 10%. In contrast, patients with preoperative identification of suspicious regional lymphadenopathy experienced a 5-year survival rate of 35% (P = .18). The difference between preoperative and intraoperative identification of RLN metastases has, to our knowledge, never been explored.

In practice, surgeons are frequently confronted with intraoperative discovery of metastatic RLN. As was the case in 60% of our study patients, these involved nodes are indeed often underdiagnosed on preoperative imaging for a variety of reasons. The proportion of patients with intraoperatively discovered RLN involvement in our experience may be explained by the limited use of [¹⁸F]fluorodeoxyglucose (FDG) PET scanning at our institution. In a recent meta-analysis, both the sensitivity and specificity of FDG-PET imaging for the detection of extrahepatic lesions exceeded 90%, compared with only 60.9% and 91.1%, respectively, for CT scanning.⁴⁵ Furthermore, a systematic review of FDG-PET imaging results in patients with CLM has determined that FDG-PET may detect extrahepatic disease not identified by other modalities in 10% to 32% of patients.⁴⁶

When diagnosed intraoperatively, there is no consensus regarding whether to proceed with hepatectomy. In our practice, when the diagnosis of RLN involvement was made intraoperatively, we used the intrahepatic tumoral response to preoperative chemotherapy as a guide. In all but four of these patients, CLM had been stabilized or responded to preoperative chemotherapy, and we proceeded with combined hepatectomy and lymphadenectomy. When RLN involvement was diagnosed preoperatively, lymphadenectomy and hepatectomy were only performed in patients with chemotherapy-induced response or stabilization of RLN disease. Regardless of diagnostic timing, only those patients in whom both the hepatectomy and lymphadenectomy could be curative underwent resection.

That patients with RLN involvement younger than 40 years experienced better outcomes after surgery was an unexpected finding of our study. Only 10% of the 38 patients with RLN involvement who were older than 40 years survived 5 years, whereas the nine patients younger than 40 years experienced a 45% 5-year survival rate. Obviously, this survival difference was not related to a decreased operative mortality, because the operative mortality in the RLN-involved group was nil. Additionally, surgical procedures did not differ between both age groups, and the rate of postoperative chemotherapy was similarly distributed (89% of patients younger than 40 years v 87% of patients 40 years of age). A slightly higher proportion of older patients had celiac or para-aortic RLN involvement (47% v 33%), which may have contributed to the observed survival difference. In addition, these outcomes data may also reflect a younger patient's ability to tolerate an aggressive multimodality regimen.

In summary, the perioperative mortality-free 5-year survival rate of 25% in patients with CLM and isolated pedicular RLN involvement justifies combined hepatectomy with lymphadenectomy. This strategy is best suited to younger patients and those with preoperatively diagnosed RLN involvement that responds to systemic chemotherapy. In contrast, it is now clear that patients with either celiac or para-aortic RLN metastases, even when responding to preoperative chemotherapy, do not benefit from this approach.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: René Adam, Robbert J. de Haas, Dennis A. Wicherts, Valérie Delvart, Denis Castaing

Administrative support: Robbert J. de Haas, Dennis A. Wicherts, Thomas A. Aloia

Provision of study materials or patients: René Adam, Daniel Azoulay, Henri Bismuth, Denis Castaing

Collection and assembly of data: Robbert J. de Haas, Dennis A. Wicherts, Thomas A. Aloia

Data analysis and interpretation: René Adam, Robbert J. de Haas, Dennis A. Wicherts, Valérie Delvart, Daniel Azoulay, Henri Bismuth

Manuscript writing: René Adam, Robbert J. de Haas, Dennis A. Wicherts, Thomas A. Aloia, Valérie Delvart, Daniel Azoulay, Henri Bismuth, Denis Castaing

Final approval of manuscript: René Adam, Robbert J. de Haas, Dennis A. Wicherts, Thomas A. Aloia, Valérie Delvart, Daniel Azoulay, Henri Bismuth, Denis Castaing

	Appendix

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	NOTES

 
Both R.A. and R.J.H. contributed equally to this work.

Presented in part at the 14th Annual European Surgical Association meeting, April 13-14, 2007, Dublin, Ireland.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted December 10, 2007; accepted February 26, 2008.

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