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Original Investigation |

Long-term Outcomes Following Tumor Ablation for Treatment of Bilateral Colorectal Liver Metastases FREE

Paul J. Karanicolas, MD, PhD1,3; William R. Jarnagin, MD1; Mithat Gonen, PhD2; Scott Tuorto, BA1; Peter J. Allen, MD1; Ronald P. DeMatteo, MD1; Michael I. D’Angelica, MD1; Yuman Fong, MD1
[+] Author Affiliations
1Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
2Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York
3Department of Surgery, Sunnybrook Health Sciences Center, University of Toronto, Toronto, Canada
JAMA Surg. 2013;148(7):597-601. doi:10.1001/jamasurg.2013.1431.
Text Size: A A A
Published online

Importance  Ablative therapies extend the capability of delivering potentially curative treatment for bilateral hepatic colorectal metastases.

Objective  To compare the long-term effectiveness of ablation with that of resection in patients with bilateral hepatic colorectal metastases.

Design  Review of a prospective database of 2123 operative cases of hepatic colorectal metastases.

Setting  A large institution with expertise in ablation and resection.

Patients  Patients with bilateral colorectal liver metastases undergoing operation with a curative intent. A total of 141 patients had been treated with bilateral resection (BR) and 95 had undergone ablation.

Interventions  Radiofrequency or microwave ablation alone or in combination with resection (A/R) compared with BR.

Main Outcomes and Measures  We compared tumor characteristics and operative and postoperative outcomes using χ2 or Wilcoxon tests as appropriate and assessed overall survival differences between the 2 groups using the log-rank test.

Results  During the study, 141 patients were treated with BR and 95 patients with A/R. The A/R group was a significantly poorer prognostic group than the BR group as judged by the Clinical Risk Score (P < .01). There was no difference in median operative time (A/R: 280 minutes, BR: 282 minutes; P = .52), but a lower blood loss (A/R: 300 mL, BR: 500 mL; P < .01) and a shorter length of stay (A/R: 7 days, BR: 9 days; P < .01) was achieved in the A/R group. Long-term outcome was not significantly different between the groups (5-year overall survival, A/R: 56%, BR: 49%; P = .16).

Conclusions and Relevance  Treatment of bilateral, multiple hepatic metastases with combined resection and ablation was associated with improved perioperative outcomes without compromising long-term survival compared with bilateral resection. Ablative therapies extend the capability of delivering potentially curative treatment for bilateral hepatic colorectal metastases.

Figures in this Article

Resection of colorectal metastases confined to the liver improves the overall survival of patients and offers the potential for cure.15 Patients with bilateral liver metastases are less likely to be resectable with conventional techniques. Strategies for managing patients with bilateral liver metastases include multiple simultaneous liver resections, staged approaches to resection (with or without portal vein embolization), or attempts at reducing tumor burden using systemic or local chemotherapy.6,7

In the past decade, ablative techniques have emerged as an option to locally treat liver tumors including colorectal liver metastases. The role of ablation in patients with colorectal liver metastases is unclear. Previous series have suggested that ablation yields an improvement in survival compared with chemotherapy alone for unresectable metastases but is inferior to resection for resectable metastases.8 A recent attempt to establish clinical practice guidelines concluded that there was insufficient evidence on which to base guidelines, with wide variability in 5-year survival (15%-55%) and a compelling need for more research to determine the efficacy and usefulness of ablation.9

Given the challenges to treating patients with bilateral colorectal liver metastases, ablative techniques may increase the number of patients eligible to be treated with a potentially curative intent. The objective of this study was to compare perioperative and long-term outcomes in patients with bilateral colorectal liver metastases treated with ablation with or without resection (A/R) to patients treated with the historical gold standard of bilateral resection (BR).

Patients operatively treated for bilateral, multiple colorectal liver metastases between 1999 and 2008 were identified from a prospectively maintained database containing demographic, clinical, operative, pathologic, and follow-up data. Prior to 2004, patients with resectable bilateral colorectal metastases underwent bilateral resection in either a 1-stage or 2-stage approach. Surgeons at our institution began using ablation (primarily radiofrequency ablation) more frequently in 2004. In general, patients with bilateral colorectal metastases undergo BR if sufficient parenchyma can be safely preserved. Patients with borderline resectable metastases or with unresectable metastases amenable to complete treatment with ablation undergo ablation alone or in combination with resection.

To minimize the bias from patient selection that has occurred in the more contemporary period, we compared patients treated by ablation alone or in combination with resection from 2004-2008 (A/R group) with cases treated by conventional BR from 1999-2003 (BR group). Some of the patients in this study were included in prior reports on outcomes of metastatic colorectal cancer at our institution. The institutional review board at Memorial Sloan-Kettering Cancer Center approved this study.

We calculated the Clinical Risk Score (CRS) for each patient included in the analysis.10 The CRS is a prediction tool consisting of 5 clinical variables: node-positive primary cancer, disease-free interval less than 12 months, multiple liver metastasis, largest diameter of any liver metastasis greater than 5 cm, and preoperative serum carcinoembryonic antigen level greater than 200 ng/mL. Based on CRS, patients were grouped into 2 categories: low CRS (0, 1, or 2) and high CRS (3, 4, or 5).

We compared baseline patient and tumor characteristics, operative time, blood loss, length of hospital stay, and 30-day mortality between patients in the 2 groups using the χ2 test for categorical variables and the Wilcoxon test for continuous variables. We assessed overall survival differences between the 2 groups using the log-rank test. All statistical tests were 2 sided, and we considered P < .05 indicative of statistically significant differences.

During the defined study periods, 141 patients were treated with BR and 95 patients underwent ablation, either alone (n = 9) or in combination with resection (n = 86). The median age was 62 years, with no difference between groups (Table 1). More patients treated with the combined approach had colon primary cancers compared with the resected group, and patients treated with ablation were more likely to undergo simultaneous colorectal resection (23% vs 4%). Patients treated with a combined strategy in general had a higher CRS, primarily attributed to shorter disease-free intervals (Figure 1). In contrast, patients treated with resection had higher carcinoembryonic antigen (CEA) levels, number of tumors, and size of largest tumor.

Table Graphic Jump LocationTable 1.  Characteristics of Patients Included in the Study
Place holder to copy figure label and caption
Figure 1.
Risk Score Distribution

Distribution of Clinical Risk Score among patients treated with bilateral resection or ablation with or without resection (P = .002).

Graphic Jump Location

Operative time was similar between the 2 groups, while blood loss was significantly greater in patients treated with BR (Table 2). Three patients (2.1%) died within 30 days of operation in the resection group compared with 1 patient in the A/R group. The median length of stay was 9 days following resection and 7 days following ablation with or without resection (P < .001).

Table Graphic Jump LocationTable 2.  Operative and Perioperative Outcomes in Patients Treated With Bilateral Resection or Ablation ± Resection

The median follow-up in patients treated with resection was 44 months and 23 months in patients treated with the combined approach. Overall survival at 3 years was 67% in the BR group and 77% in the A/R group; after 5 years, overall survival was 49% and 56%, respectively (P = .16, Figure 2).

Place holder to copy figure label and caption
Figure 2.
Probability of Survival

Overall survival in patients treated with bilateral resection or ablation with or without resection (P = .16).

Graphic Jump Location

This comparative analysis of patients with bilateral colorectal liver metastases demonstrates the perioperative and long-term safety of a combined ablative strategy compared with the conventional gold standard of BR. Patients treated with ablation, either alone or in combination with resection, had less intraoperative blood loss, similar perioperative mortality, shorter length of hospitalization, and similar overall 5-year survival.

The long-term survival in patients treated with the combined approach in this study is particularly encouraging given their high-risk clinical characteristics. More than half of patients in the A/R group presented with a CRS of 3 or greater compared with 31% of patients who underwent BR. This difference was predominantly driven by the shorter disease-free interval in patients who underwent ablation. The median disease-free interval in this group was zero, indicating that most patients presented with synchronous liver metastases. In contrast, patients who underwent BR had larger tumor burden, evidenced by the higher number of metastases, size of the largest metastasis, and CEA level. In the more contemporary time frame, patients with high tumor burden were appropriately selected for resection rather than ablation; therefore, they were noticeably absent from this group.

This study is strengthened by the high quality of the data. All patients were treated at a single institution with extensive experience caring for patients with colorectal liver metastases. Data were prospectively collected and follow-up was complete. We chose to focus on overall survival as an indicator of long-term efficacy because it is objective and of most importance to patients.

The conclusions from this study are most limited by the selection bias inherent in this comparison. The optimal study design to address this question would be a prospective, randomized clinical trial. Unfortunately, surgeons have been relatively unsuccessful at assessing the efficacy of new technologies with randomized trials and this technology is no exception. Technologies instead are generally introduced into general practice and rapidly adopted as part of standard care. A randomized trial would be particularly difficult to conduct in this setting because the selection of patients for ablation or resection seems intuitive. In general, patients with multiple tumors confined to one region of the liver or with large solitary metastases should undergo resection. Ablation in these settings would be, at best, inefficient and, at worst, ineffective. In contrast, ablation may play a role for patients with a limited number of small metastases deep within the hepatic parenchyma. In this scenario, ablation allows for optimal parenchymal preservation and extends potentially curative treatment to patients who might otherwise be deemed unresectable.

We attempted to address the inherent selection bias as much as possible by selecting patients who underwent BR from the time frame prior to the adoption of ablation at our institution. As a result, this group represents a broadly representative group of patients with bilateral metastases, rather than patients who were specifically selected not to receive ablation. Although the 2 groups are not perfectly matched (Table 1), the higher CRS in the ablation group suggests that, if anything, the long-term results should favor the resection group. The comparable long-term survival despite this potential bias is reassuring. Furthermore, although systemic treatment of patients with colorectal liver metastases has improved during this period, the incremental benefit has been modest, with overall survival in the absence of surgery between 20% and 30% at 3 years.11,12 The 3-year survival in patients who underwent ablation in this study was 77%, 3 times that of these contemporary patients treated with chemotherapy only. Follow-up in the ablation group was shorter than in the resection group given the different periods, thus, longer follow-up ideally including patterns of recurrence would be beneficial.

This study contributes to the growing body of literature confirming the safety and efficacy of ablation in the treatment of colorectal liver metastases. Abdalla and colleagues8 from the MD Anderson Cancer Center reported their experience in a series of patients with metastases confined to the liver. With a median follow-up of 21 months, patients who underwent resection achieved better 3-year survival than patients who underwent ablation (73% vs 40%). However, the authors reserved ablative strategies for patients deemed unresectable at the time of laparotomy, making it difficult to compare outcomes in these heterogeneous groups. In a similar study from the Cleveland Clinic, 234 patients who were not candidates for resection underwent laparoscopic ablation.13 Five-year survival in this group of patients was only 18%; however, a significant proportion of patients had extrahepatic disease and most patients had been treated extensively with chemotherapy prior to operation. The authors concluded that survival in these patients would be near zero and that the use of ablation in this group achieves a survival advantage. Our study builds on these findings by limiting inclusion to patients with bilateral liver metastases in whom ablation was more liberally adopted with excellent long-term outcomes. Future research may compare these patients with a larger group of patients treated with ablation alone, perhaps including a percutaneous ablation group.

In summary, treatment of bilateral hepatic colorectal metastases with a combined ablative strategy yields good perioperative outcomes and does not compromise long-term overall survival. Ablative therapies may extend the capability of delivering potentially curative treatment for patients with bilateral hepatic colorectal metastases.

Corresponding Author: Yuman Fong, MD, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (fongy@mskcc.org).

Accepted for Publication: November 21, 2012.

Published Online: May 8, 2013. doi:10.1001/jamasurg.2013.1431

Author Contributions:Study concept and design: Karanicolas, Tuorto, DeMatteo, and Fong.

Acquisition of data: Jarnagin and Tuorto.

Analysis and interpretation of data: Karanicolas, Gonen, Allen, and D’Angelica.

Drafting of the manuscript: Karanicolas, Gonen, Tuorto, Allen, D’Angelica, and Fong.

Critical revision of the manuscript for important intellectual content: Karanicolas, Jarnagin, DeMatteo, and D’Angelica.

Statistical analysis: Karanicolas and Gonen.

Administrative, technical, and material support: Tuorto.

Study supervision: Allen, DeMatteo, D’Angelica, and Fong.

Conflict of Interest Disclosures: None reported.

Previous Presentation: This study was presented at the American College of Surgeons Hepatobiliary Paper Session; October 6, 2010; Washington, DC.

Choti  MA, Sitzmann  JV, Tiburi  MF,  et al.  Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg. 2002;235(6):759-766.
PubMed   |  Link to Article
House  MG, Ito  H, Gonen  M,  et al.  Survival after hepatic resection for metastatic colorectal cancer: trends in outcomes for 1,600 patients during two decades at a single institution. J Am Coll Surg. 2010;210(5):744-752, 752-755.
PubMed   |  Link to Article
Nordlinger  B, Guiguet  M, Vaillant  JC,  et al; Association Française de Chirurgie.  Surgical resection of colorectal carcinoma metastases to the liver: a prognostic scoring system to improve case selection, based on 1568 patients. Cancer. 1996;77(7):1254-1262.
PubMed   |  Link to Article
Scheele  J, Stang  R, Altendorf-Hofmann  A, Paul  M.  Resection of colorectal liver metastases. World J Surg. 1995;19(1):59-71.
PubMed   |  Link to Article
Tomlinson  JS, Jarnagin  WR, DeMatteo  RP,  et al.  Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol. 2007;25(29):4575-4580.
PubMed   |  Link to Article
Gold  JS, Are  C, Kornprat  P,  et al.  Increased use of parenchymal-sparing surgery for bilateral liver metastases from colorectal cancer is associated with improved mortality without change in oncologic outcome: trends in treatment over time in 440 patients. Ann Surg. 2008;247(1):109-117.
PubMed   |  Link to Article
Kornprat  P, Jarnagin  WR, Gonen  M,  et al.  Outcome after hepatectomy for multiple (four or more) colorectal metastases in the era of effective chemotherapy. Ann Surg Oncol. 2007;14(3):1151-1160.
PubMed   |  Link to Article
Abdalla  EK, Vauthey  JN, Ellis  LM,  et al.  Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg. 2004;239(6):818-825, discussion 825-827.
PubMed   |  Link to Article
Wong  SL, Mangu  PB, Choti  MA,  et al.  American Society of Clinical Oncology 2009 clinical evidence review on radiofrequency ablation of hepatic metastases from colorectal cancer. J Clin Oncol. 2010;28(3):493-508.
PubMed   |  Link to Article
Fong  Y, Fortner  J, Sun  RL, Brennan  MF, Blumgart  LH.  Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230(3):309-318, discussion 318-321.
PubMed   |  Link to Article
Falcone  A, Ricci  S, Brunetti  I,  et al; Gruppo Oncologico Nord Ovest.  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.
PubMed   |  Link to Article
Hurwitz  H, Fehrenbacher  L, Novotny  W,  et al.  Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335-2342.
PubMed   |  Link to Article
Siperstein  AE, Berber  E, Ballem  N, Parikh  RT.  Survival after radiofrequency ablation of colorectal liver metastases: 10-year experience. Ann Surg. 2007;246(4):559-565, discussion 565-567.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Risk Score Distribution

Distribution of Clinical Risk Score among patients treated with bilateral resection or ablation with or without resection (P = .002).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Probability of Survival

Overall survival in patients treated with bilateral resection or ablation with or without resection (P = .16).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Characteristics of Patients Included in the Study
Table Graphic Jump LocationTable 2.  Operative and Perioperative Outcomes in Patients Treated With Bilateral Resection or Ablation ± Resection

References

Choti  MA, Sitzmann  JV, Tiburi  MF,  et al.  Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg. 2002;235(6):759-766.
PubMed   |  Link to Article
House  MG, Ito  H, Gonen  M,  et al.  Survival after hepatic resection for metastatic colorectal cancer: trends in outcomes for 1,600 patients during two decades at a single institution. J Am Coll Surg. 2010;210(5):744-752, 752-755.
PubMed   |  Link to Article
Nordlinger  B, Guiguet  M, Vaillant  JC,  et al; Association Française de Chirurgie.  Surgical resection of colorectal carcinoma metastases to the liver: a prognostic scoring system to improve case selection, based on 1568 patients. Cancer. 1996;77(7):1254-1262.
PubMed   |  Link to Article
Scheele  J, Stang  R, Altendorf-Hofmann  A, Paul  M.  Resection of colorectal liver metastases. World J Surg. 1995;19(1):59-71.
PubMed   |  Link to Article
Tomlinson  JS, Jarnagin  WR, DeMatteo  RP,  et al.  Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol. 2007;25(29):4575-4580.
PubMed   |  Link to Article
Gold  JS, Are  C, Kornprat  P,  et al.  Increased use of parenchymal-sparing surgery for bilateral liver metastases from colorectal cancer is associated with improved mortality without change in oncologic outcome: trends in treatment over time in 440 patients. Ann Surg. 2008;247(1):109-117.
PubMed   |  Link to Article
Kornprat  P, Jarnagin  WR, Gonen  M,  et al.  Outcome after hepatectomy for multiple (four or more) colorectal metastases in the era of effective chemotherapy. Ann Surg Oncol. 2007;14(3):1151-1160.
PubMed   |  Link to Article
Abdalla  EK, Vauthey  JN, Ellis  LM,  et al.  Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg. 2004;239(6):818-825, discussion 825-827.
PubMed   |  Link to Article
Wong  SL, Mangu  PB, Choti  MA,  et al.  American Society of Clinical Oncology 2009 clinical evidence review on radiofrequency ablation of hepatic metastases from colorectal cancer. J Clin Oncol. 2010;28(3):493-508.
PubMed   |  Link to Article
Fong  Y, Fortner  J, Sun  RL, Brennan  MF, Blumgart  LH.  Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230(3):309-318, discussion 318-321.
PubMed   |  Link to Article
Falcone  A, Ricci  S, Brunetti  I,  et al; Gruppo Oncologico Nord Ovest.  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.
PubMed   |  Link to Article
Hurwitz  H, Fehrenbacher  L, Novotny  W,  et al.  Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335-2342.
PubMed   |  Link to Article
Siperstein  AE, Berber  E, Ballem  N, Parikh  RT.  Survival after radiofrequency ablation of colorectal liver metastases: 10-year experience. Ann Surg. 2007;246(4):559-565, discussion 565-567.
PubMed   |  Link to Article

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