Local Treatment for Recurrent Colorectal Hepatic Metastases after Partial Hepatectomy
- 498 Downloads
The objective of the study was to identify patients who may benefit from local treatment in recurrent colorectal liver metastases.
Materials and methods
A total of 51 consecutive patients were treated for hepatic recurrence(s) after an initial partial hepatic resection. Surgery was considered as the primary treatment option for eligible patients. Patients with a small liver remnant after major hepatectomy were treated with radiofrequency ablation (RFA) or stereotactic body radiation therapy (SRx). SRx was given as an outpatient, emerging local treatment option for patients with intra-hepatic recurrences not eligible for surgery or RFA. Partial liver resection was performed in 36 patients (70%), RFA in ten patients (20%), and SRx in five patients (10%).
Median hospital stay was 7 (range, 3–62) days with a morbidity of 16% without in-hospital death. None of the patients received adjuvant chemotherapy. There was no difference in recurrence or survival between the three treatment modalities. Overall 5-year survival was 35% with an estimated median survival of 37 months. Patients with a disease-free interval between first hepatectomy and hepatic recurrence less than 6 months did not survive 3 years.
Resection, RFA, and SRx can be performed safely in patients with recurrent colorectal liver metastases and offer a survival that seems comparable to primary liver resections of colorectal liver metastases.
KeywordsColorectal liver metastases Recurrent hepatic metastases Hepatic resection Radiofrequency ablation Stereotactic body radiation
Colorectal cancer is one of the most common malignancies and a leading cause of death. Liver metastases develop in 50–60% of patients,1,2 and surgical resection currently represents the best treatment for long-term survival and even cure in patients with colorectal liver metastases. Despite the curative intent, more than 60% will suffer from recurrence after liver resection, the liver being the most common location.3 Since liver resection has become safer through improvements in surgical techniques and per-operative management, repeat hepatic resection is being more frequently performed in patients with hepatic recurrences. Several studies on repeat hepatic resection have been reported in the last decade.4, 5, 6, 7, 8, 9 Recent technologic advances have also made local ablative treatments for liver tumors accessible.10 Patients with small central recurrences after a prior major liver resection and patients who are poor candidates for surgery are often treated by radiofrequency ablation (RFA). Stereotactic body radiation therapy (SRx) is another emerging local treatment option for patients with intrahepatic malignancies not eligible for surgery or RFA.11
Unfortunately, most patients who develop a recurrence after colorectal liver surgery cannot undergo secondary procedures. Systemic chemotherapy (CTx) is used in these patients with increasing median survival rates with current multimodality treatments.12,13 Approximately 5% to 10% of patients who develop hepatic recurrence after liver resection are amenable to a second resection or local ablative treatment. Most reports are based on small populations or on combined populations from several centers. In this article, we report our experience in a single center with local treatment for recurrent liver disease. The purpose of this study was to evaluate prognostic factors for overall, disease-free survival and to identify patients who might benefit most from secondary local treatment.
Patients and Methods
Between March 1988 and October 2007, 520 partial liver resections were performed in our center because of colorectal liver metastases. Fifty-one patients were treated for hepatic recurrences after a first partial hepatic resection for colorectal liver metastases.
Criteria for repeat liver treatment were similar to those for first hepatectomy: the presence of technically removable metastases (preserving at least two segments of the liver parenchyma), and the possibility of an oncological radical procedure. Surgery was considered as the primary treatment option for eligible patients. Nowadays, surgery provides the best outcome for the treatment of colorectal liver metastases. To date, no randomized trial has been performed between resection versus local ablation. Therefore, in colorectal metastases, surgery is still the gold standard.14,15 For patients with a small liver remnant after major hepatectomy, RFA or SRx were alternatives if the metastases were <3 cm.10,11 RFA was first treatment option, but in case of ill location of the metastases (nearby main vessel and/or bile ducts), SRx was the alternative.
Patients with extrahepatic disease that was resectable were also included in this study.
RFA was performed with a 200-W RF generator and the cluster RF electrode was introduced into the hepatic malignancies during laparotomy or by imaging guidance percutaneously.10 SRx was mostly given in three fractions of 15 Gy, and the prescription isodose was 65%.11
Data analyzed included demographics, pathological tumor–node–metastases stage of the primary tumor, maximum size and number of metastases on computed tomography (CT), plasma carcinoembryonic antigen (CEA) level, type of liver surgery, overall duration of hospital stay, complications, radicality, site, and treatment of recurrence.
Overall survival and disease-free survival (DFS) were measured from the start of treatment of hepatic recurrence. The nomenclature and extent of hepatic resection were recorded according to the terminology defined by Couinaud.16 We defined a positive surgical margin as the presence of exposed tumor along the line of transaction.
After partial hepatectomy, patients routinely underwent a physical examination and determination of CEA level and abdominal/chest CT or ultrasonography every 4 months for the first year, every 6 months the second year, and once a year thereafter. Endoscopic surveillance was performed after 1 year and thereafter depending on the findings.
The nonparametric log-rank test was used to identify prognostic variables associated with survival after the second liver resection, with significance at p = 0.05.
First Partial Liver Resection
Clinical Data on the First and Second Local Treatment
First hepatectomy N = 51
Second local treatment N = 51
No. of tumorsa
Size of tumor (cm)a
Preoperative CEA-level (μg/L)a
Hospital stay (days)
Positive surgical margin (%)
Clinical data of the 51 patients who underwent treatment for recurrent metastases are depicted in Table 1. The median interval between first hepatectomy and recurrent hepatic metastases was 11 (range, 3–78) months. Partial liver resection was performed in 36 patients (70%), RFA in ten patients (20%, two open and eight percutaneous procedures) and SRx in five patients (10%). One patient showed peritoneal disease, and the omentum was resected. One patient showed ingrowth of the diaphragm, and a partial resection of the diaphragm was performed. Two patients received additional SRx for solitary lung metastases and one patient for a solitary costal metastasis. There was no in-hospital death. Eight patients had per-operative complications without surgical intervention, and median hospital stay for patients who underwent resection or open RFA was 7 (range, 3–65) days. None of the patients were treated with adjuvant CTx.
Median follow-up from secondary treatment for recurrences were 22 (3–115) months. Thirty-two patients (63%) developed a secondary recurrence. Five patients underwent palliative systemic CTx for pulmonary metastases. One patient developed a local recurrence in the pelvis and underwent resection. Of the 26 patients with intra-hepatic recurrence, 14 patients were treated with palliative CTx or analgesic treatment and 12 patients with repeat local treatment. Disease-free survival after treatment of hepatic recurrence was 47% at 1 year, and estimated median DFS was 11 months.
Univariate Analysis of Prognostic Factors for Survival after Repeat Treatment for Recurrence of Intrahepatic Disease
Survival 3 years (%)
Site of primary tumor
pT primary tumor
pN primary tumor
Interval (months) of first hepatectomy to date of recurrence
No. of tumors
Size of tumor (cm)
Distribution of metastases
Type of treatment
Positive lymph nodes
Margin of hepatectomy
Literature Review of Large Series (>50 pts) of Repeat Local Treatment in Patients with Recurrent Colorectal Liver Metastases in the Last 10 Years
No. of centers
No. of patients
Median survival (months)
Improvements in surgical techniques and per-operative management increase the number of repeat hepatic resection in patients with isolated hepatic recurrence.20 A reduction of blood loss, which is associated with preoperative morbidity and mortality, was obtained over the past decade with a corresponding decrease of transfusion requirements. This was related to an increase in parenchymal-sparing resection, performing of resections with a low central venous pressure, and with the advent of portal pedicle ligation maneuvers.21 The extent of liver resection depends on the size, location, distribution, and the relation of the major afferent and efferent vasculatures and bile ducts to liver metastases. More wedge resections can be performed because several recent studies have indicated that a margin less than 1 cm is not a contraindication to resection of colorectal liver metastases.22, 23, 24, 25 Moreover, a margin of 1 mm seems to be appropriate, despite the fact that the pathological report will define the procedure as a microscopic irradical resection.24 Current techniques with ultrasonic dissectors aspirate a part of the liver parenchyma interposed between the specimen and the normal liver, making assessment of the true margin difficult.
The rate of wedge resection in our study was higher in repeat hepatectomies than in the initial hepatectomies because the extent of resection at repeat hepatectomy depended on the amount of remnant liver after first hepatectomy. It seems that the extent of hepatic resection does not influence the outcome of secondly resected patients, providing that all metastatic tissue is removed, which is in agreement with the results of Zorzi et al.26 A deeper knowledge of the segmental anatomy of the liver16 and the routine use of intraoperative ultrasonography has eliminated the need of “blind” extensive resection, therefore limiting the amount of resected parenchyma.
The present study shows that 3-year survival rate is significantly better for those patients with an interval of more than 6 months between first hepatectomy and hepatic recurrence. Patients who had an interval shorter than 6 months did not survive longer than 3 years (median estimated survival 27 months). This is in agreement with the results of Bhattacharjya et al. who suggest that tumors recurring early following liver resection are less likely to be amenable to re-resection because of adverse tumor characteristics and a higher potential for spread of disease.27 They concluded in their study that aggressive follow-up during the first 6 months was not advisable because none of the patients could benefit from local treatment. Together with our results, it may be concluded that patients with intra-hepatic recurrences within 6 months after partial hepatectomy should be offered systemic CTx because the median survival of patients who were treated with modern systemic chemotherapy also may exceed 20 months.28
The other significant factor was synchronicity of the metastases of the primary tumor. Patients with synchronous metastases showed a significantly (p = 0.006) improved survival after intra-hepatic recurrences that could be treated by local treatment than patients with metachronous disease. A clear explanation cannot be given besides the fact that the number of patients is small.
Despite favorable results of repeat hepatic resection for patients with recurrent colorectal liver metastases, there remains controversy regarding the optimal treatment for such patients. The advent of minimally invasive therapies such as RFA or SRx may offer less procedure-associated morbidity and mortality. A concern is the variable rate of local recurrence that can follow such targeted therapies. Lesions treated with RFA have local recurrence rates of 4% to 55%.10,29Crude local control rates of 78–100% are reported in tumor-based analysis after SRx.30 RFA has achieved an important role for patients unfit for surgery with small (<3 cm) liver metastases. Some authors even stated that the time has come to perform a randomized trial between resection and other local ablative methods.31 In our center, resection is still the gold standard.15 The treatment failure rate after radiofrequency ablation even in small tumors is higher than local recurrence rates after definitive resection. Again, the results of the local ablative treatments are promising, and therefore, local ablation therapies may be applied in patients not suitable for surgery because of ill location of the tumor and/or the physical state of the patients.
These repeat local treatments can be performed safely, without greater risk than first liver resections, and offer a survival rate as good as first liver resections. Resection should be the preferred approach, but RFA and SRx are good alternatives with a beneficial outcome. Patients with intra-hepatic recurrences within 6 months after first partial hepatectomy should be offered systemic chemotherapy.
This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
- 18.Falcone A, Ricci S, Brunetti I et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 2007;25(13):1670–1676. doi:10.1200/JCO.2006.09.0928.PubMedCrossRefGoogle Scholar
- 19.Dols LF, Verhoef C, Eskens FA, Schouten O, Nonner J, Hop WC, Méndez Romero A, De Man RA Van der Linden, Dwarkasing R, IJzermans JN. Improvement of survival after resection of colorectal liver metastases. Ned Tijdschr Geneeskd. 2008; in press.Google Scholar
- 20.DeMatteo RP, Fong Y, Jarnagin WR, Blumgart LH. Recent advances in hepatic resection. Semin Surg Oncol 2000;19(2):200–207. doi:10.1002/1098-2388(200009)19:2<200::AID-SSU11>3.0.CO;2-M.PubMedCrossRefGoogle Scholar
- 23.Figueras J, Burdio F, Ramos E et al. Effect of subcentimeter nonpositive resection margin on hepatic recurrence in patients undergoing hepatectomy for colorectal liver metastases. Evidences from 663 liver resections. Ann Oncol 2007;18(7):1190–1195. doi:10.1093/annonc/mdm106.PubMedCrossRefGoogle Scholar
- 27.Bhattacharjya S, Aggarwal R, Davidson BR. Intensive follow-up after liver resection for colorectal liver metastases: results of combined serial tumour marker estimations and computed tomography of the chest and abdomen—a prospective study. Br J Cancer 2006;95(1):21–26. doi:10.1038/sj.bjc.6603219.PubMedCrossRefGoogle Scholar