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Originally published as JCO Early Release 10.1200/JCO.2005.04.4669 on November 21 2005 © 2005 American Society of Clinical Oncology.
Improving Long-Term Outcomes for Patients With Liver Metastases From Colorectal CancerRoyal Marsden Hospital, London and Surrey, United Kingdom Despite improved screening and adjuvant therapy for primary colorectal cancers, synchronous and metachronous liver metastases remain a significant problem for patients with this disease. Approximately 40% of patients who develop metastatic disease have tumor confined to the liver, which has driven interest in regional therapies targeting the liver. These include chemotherapy delivered via hepatic arterial infusion (HAI), destructive therapies such as radiofrequency ablation (RFA), and surgical metastasectomy. Surgical techniques for liver resection have improved significantly during the last decade; therefore, this has become an attractive method for rendering suitable patients macroscopically disease free. Studies showing prolonged disease-free survival, overall survival—and possibly cure—in selected patients have demonstrated the efficacy of this approach.1,2 Systemic chemotherapy has been shown to downsize a proportion of initially unresectable liver metastases to the point of resectability. Adam et al3 reported a single-institution series of 872 patients with colorectal liver metastases who were assessed for resectability: 171 (19.6%) had resectable disease initially and underwent immediate surgery; 701 patients who had unresectable disease initially were treated with preoperative chemotherapy, which was mainly oxaliplatin based. After restaging, 95 patients (13.6%) were considered resectable, and underwent surgery. The actuarial 5-year survival for this downstaged group was 34%, with the survival curve almost exactly replicating that of patients who had initially resectable disease who underwent immediate surgery.4 This nonrandomized, yet innovative comparison has been a major rationale in support of surgery for patients with initially unresectable disease that responds adequately to preoperative chemotherapy. Response to this therapy is also predictive for long-term outcome. Adam et al5 found that patients who had liver metastasectomy after tumor progression on preoperative chemotherapy had significantly poorer survival than responders or those with tumor stabilization. Postoperative therapy is an accepted and rational component of treatment for patients requiring preoperative downsizing before resection. However, even patients with initially resectable liver metastases may benefit from postoperative therapy. The largest study was performed by the Fédération Francophone de Cancérologie Digestive, which randomly assigned 167 patients to intravenous fluorouracil (FU)/leucovorin (LV) or observation after complete liver metastasectomy.6 Preliminary results suggested a nonstatistically significant trend toward improved disease-free and overall survival. An Intergroup study of 109 patients compared postoperative HAI floxuridine plus continuous-infusion intravenous FU versus observation.7 Although there was no difference in overall survival, both time to recurrence and time to recurrence in the liver were prolonged in the postoperative therapy arm. Additional support for the notion of more intensive postoperative therapy was provided by a study that demonstrated improved 2-year survival for patients randomly assigned to postoperative HAI floxuridine plus systemic FU versus systemic FU alone.8 Long-term follow-up has confirmed superior progression-free survival and a trend to improved overall survival for the combination arm.9 There are few prospective trials of preoperative systemic chemotherapy for patients with unresectable liver-only metastases. Pozzo et al10 conducted a single-institution nonrandomized study that comprised 40 patients with unresectable disease defined by local criteria. These criteria were more than six metastases (or > three per lobe; 14 patients); more than 5 cm diameter of at least one lesion if six metastases (or three per lobe; 10 patients); and contiguity with at least two hepatic veins, inferior vena cava or liver hilum (14 patients). The response rate to irinotecan/FU/LV) was 47.5%, and 13 (32.5%) patients underwent R0 liver resection. Six cycles of postoperative chemotherapy were administered to all patients who underwent resection except one. The median disease-free interval was 14.3 months for patients who underwent resection and the median survival was not reached at a median follow-up time of 19 months. Retrospective analyses of multicenter randomized studies have also demonstrated the efficacy of systemic chemotherapy in downsizing unresectable liver metastases. The N9741 study was a large randomized trial which compared oxaliplatin/FU/LV (FOLFOX4) versus irinotecan/FU/LV (IFL) and irinotecan/oxaliplatin in non-pretreated patients with advanced colorectal cancer.11 Although resection of liver metastases was not mandated in the protocol, 16 patients (2%) did undergo liver metastasectomy.12 Five patients received postoperative chemotherapy via the hepatic arterial or intravenous routes. After a median 32 months follow-up, four of these patients were alive and disease free. Pooled survival figures, which included eight patients who had liver RFA or pulmonary metastasectomy, showed a median time to progression of 18.4 months, and a median survival of 42.4 months. Interestingly, 42 patients who achieved complete response with chemotherapy alone, and did not undergo resection, had a similar median time to progression and survival of 14.8 and 39.2 months, respectively. In this issue of the Journal of Clinical Oncology, Alberts et al13 report on a study that is significant because it is both prospective and multicenter. Forty-four patients with unresectable liver metastases were enrolled, of whom two were deemed ineligible because of extrahepatic disease. The study was conducted at 13 centers of the North Central Cancer Trials Group. Criteria for unresectability were predefined; actual reasons for unresectability were as follows: number of lesions (19 patients), location (three patients), size (three patients), and combination of factors (15 patients). Subsequent central review by a single liver surgeon found that 10% of patients actually could have undergone resection initially, highlighting the issue of intersurgeon variation. Patients received FOLFOX4 as preoperative therapy and the response rate (complete and partial responses) was 50%. Patients who obtained a favorable response (complete, partial, or minor response) were reassessed for surgery. Fourteen (33%) of 42 patients went on to have successful surgical resection and 10 of these received postoperative FOLFOX4. As expected, pre- and postoperative chemotherapy was well tolerated, but postsurgical complications were not documented. Eleven patients experienced recurrence within a median postsurgical follow-up of 22 months, and the median time to progression for resected patients was 19 months. However, 67% of resected patients were alive at a median follow-up of 36 months. The outcomes of this prospective, multicenter series lend additional support for a preoperative strategy of downsizing followed by resection. So how can we advance the management of unresectable colorectal liver-only metastases? The definition of initial unresectability is the most critical aspect for trials designed to assess conversion to resectability; the lack of widely accepted guidelines hampers the construction and interpretation of such trials. A recent consensus statement defining absolute unresectability appears disarmingly simple: nontreatable extrahepatic disease, unfitness for surgery, or involvement of more than 70% of the liver or six segments.14 However, although there is clarity regarding absolute unresectability, there is variation among individual liver surgeons regarding borderline cases, as illustrated in the study by Alberts et al.13 Additional progress is needed to ensure consistency of patient selection for clinical trials. Clinicians should not be confused by the randomized European Organisation for Research and Treatment of Cancer 40983 study that is evaluating the efficacy of perioperative FOLFOX4 for patients with initially resectable colorectal liver metastases.15 The patient population being studied in that trial is one in which liver metastases are considered to be technically operable without the need for prior chemotherapy—as opposed to the more challenging group of patients whose disease technically is unresectable without prior downsizing. An issue closely related to patient selection is that of early identification of patients with liver metastases before the development of gross extrahepatic disease. A key goal of follow-up after resection and adjuvant therapy for a primary colorectal cancer is to identify such patients who may be amenable to surgical resection. In a retrospective analysis of a single-institution series of 154 relapses after adjuvant chemotherapy for primary colorectal cancer, carcinoembryonic antigen measurement and computed tomography scanning detected 13 asymptomatic patients with liver metastases who subsequently underwent potentially curative liver resection.16 Only one patient with symptomatic recurrence in the liver was able to proceed to metastasectomy, suggesting that surveillance carcinoembryonic antigen and computed tomography scans are useful in identifying candidates for resection of liver metastases. Can we improve on FOLFOX4 as a preoperative regimen for downsizing liver metastases? Not surprisingly, higher response rates to chemotherapy are associated with higher resectability rates, both in trials of liver-only metastases and nonselected patients.17 Thus, optimization of the preoperative regimen to achieve a high probability of response is critical to the success of surgical resection. Such a regimen might involve chemotherapy administered both systemically and by HAI to both downsize liver lesions and control extrahepatic micrometastases. Kemeny et al18 recently reported a phase I study where a total of 36 patients with unresectable liver metastases received either HAI floxuridine and intravenous oxaliplatin plus irinotecan (group A), or HAI floxuridine and intravenous oxaliplatin/FU/LV (group B). Most patients had received prior chemotherapy for metastatic disease, yet encouraging response rates of 90% and 87% were achieved, respectively. Seven patients in group A subsequently went on to receive liver metastasectomy. Although the results are intriguing, interest in HAI therapy has not been universal because of the high response rates achieved with modern systemic chemotherapy and the prospect of additional gains from targeted therapies. The pursuit of higher response rates needs to be tempered by awareness of hepatic toxicity caused by preoperative treatment. Chemotherapy-associated steatohepatitis can occur with many chemotherapy agents, and may compromise the liver's tolerance of resection.19 Oxaliplatin is associated with development of hepatic sinusoidal obstruction and fibrosis.20 Hepatic toxicity is therefore an important consideration in the development of new preoperative regimens. Can targeted therapies such as bevacizumab and cetuximab improve outcomes without compromising tolerability for patients with unresectable liver metastases? The addition of bevacizumab to chemotherapy improves objective response and prolongs survival in both first- and second-line therapy for metastatic colorectal cancer.21,22 Cetuximab resensitizes a proportion of irinotecan-refractory tumors to irinotecan in second- and third-line settings.23 The phase II ACROBAT study demonstrated a response rate of 72% using FOLFOX plus cetuximab for treatment-naïve, epidermal growth factor receptor–positive, but otherwise unselected patients with metastatic colorectal cancer.24 Of 42 assessable patients, eight patients went onto liver metastasectomy. Clearly, the higher response rates achieved by the combination of targeted agents and chemotherapy are attractive for a preoperative approach for patients with unresectable liver metastases.25 Currently, fluoropyrimidine-based chemotherapy plus bevacizumab is a first-line standard of care for metastatic colorectal cancer. We might therefore expect that a greater proportion of patients with initially unresectable liver-only disease to become resectable as a result of bevacizumab. However, at present there are few data describing the effect of anti–vascular endothelial growth factor therapy on surgical wound healing, or on hepatic regeneration after liver resection. Analysis of the randomized trial comparing IFL to IFL plus bevacizumab found a higher incidence (five of 55 patients) of postoperative wound healing complications in patients in the bevacizumab-containing arms compared with those in the IFL-only arm (zero of 25 patients).26 Many of these operations were emergencies, especially for bowel obstruction. For the patients developing complications in this small series, the median time from their last bevacizumab dose was 39 days. It is difficult to extrapolate these findings to patients undergoing planned liver metastasectomy, although caution clearly would be required for patients receiving preoperative bevacizumab. On the basis of allowing bevacizumab clearance over 2.5 to 3 half-lives, an 8-week interval between the last dose of bevacizumab and surgery has been recommended.27 In addition to improving pre- and postoperative therapy, there may also be scope to improve the surgical component of therapy for unresectable liver metastases. Elias et al28 described a cohort of patients with unresectable disease who were treated in a multidisciplinary fashion with systemic chemotherapy, surgical resection, and RFA. Sixty-three patients, some of whom also required resection of extrahepatic metastases, obtained a 36-month median survival with this aggressive, multidisciplinary strategy. Although 71% of patients experienced recurrence in the liver, the impressive median survival suggests that RFA may play an integral part in treatment of unresectable liver metastases. Patients who present with primary colorectal cancer and synchronous liver metastases are a prognostically poor subgroup who may also benefit from an aggressive strategy of perioperative chemotherapy and resection of all disease sites. Roth et al29 recently described a series of 20 patients with colon or rectal cancer who also had advanced synchronous liver metastases. After treatment with oxaliplatin-based chemotherapy, a total of 16 patients were able to have resection of both liver metastases and primary colorectal tumors. Eight of 10 patients with rectal cancer also had preoperative radiation. The actuarial 3-year survival rate was 89%. Although resection of liver-only metastases arising from colorectal cancer has become a standard of care, there is still much room for improvement, particularly for patients with initially unresectable disease. Patient selection criteria need to be standardized to deliver appropriate preoperative therapy and to facilitate design and interpretation of clinical trials. Superior pre- and postoperative regimens incorporating vascular/epidermal growth factor receptor targeting agents are being developed. As liver-specific therapies improve, attention needs to be paid to the early identification of patients with potentially resectable disease. Continuing multidisciplinary collaboration will further improve outcomes for patients with metastatic colorectal cancer confined to the liver. Authors' Disclosures of Potential Conflicts of Interest
The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
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Results of an intergroup phase III study (trial FFCD-ACHBTH-AURC 9002). Proc Am Soc Clin Oncol 20:528, 2002 (abstr) 7. Kemeny MM, Adak S, Gray B, et al: Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: Surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy–an intergroup study. J Clin Oncol 20:1499-1505, 2002 8. Kemeny N, Huang Y, Cohen AM, et al: Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 341:2039-2048, 1999 9. Kemeny NE, Gonen M: Hepatic arterial infusion after liver resection. N Engl J Med 352:734-735, 2005 10. Pozzo C, Basso M, Cassano A, et al: Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol 15:933-939, 2004 11. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004 12. Delaunoit T, Alberts SR, Sargent DJ, et al: Chemotherapy permits resection of metastatic colorectal cancer: Experience from Intergroup N9741. Ann Oncol 16:425-429, 2005 13. Alberts SR, Horvath WL, Sternfeld WC, et al: Oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX4) for patients with unresectable liver-only metastases from colorectal cancer: A North Central Cancer Treatment Group (NCCTG) phase II study. J Clin Oncol 23:9243-9249, 2005 14. Poston GJ, Haller D, Kahan J, et al: Individualize the treatment of liver metastases from colorectal cancer using RAND appropriateness method: Oncosurge decision model—Results of a consensus detecting from the international taskforce group. J Clin Oncol 22:268, 2004 (suppl; abstr 3595) 15. Nordlinger B, Sorbye H, Debois M, et al: Feasibility and risks of pre-operative chemotherapy with Folfox 4 and surgery for resectable colorectal cancer liver metastases. Interim results of the EORTC Intergroup randomized phase III study 40983. J Clin Oncol 23:253, 2005 (suppl; abstr 3528) 16. Chau I, Allen MJ, Cunningham D, et al: The value of routine serum carcinoembryonic antigen measurement and computed tomography in the surveillance of patients after adjuvant chemotherapy for colorectal cancer. J Clin Oncol 22:1420-1429, 2004 17. Folprecht G, Grothey A, Alberts S, et al: Neoadjuvant treatment of unresectable colorectal liver metastases: Correlation between tumour response and resection rates. Ann Oncol 16:1311-1319, 2005 18. Kemeny N, Jarnagin W, Paty P, et al: Phase I trial of systemic oxaliplatin combination chemotherapy with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer. J Clin Oncol 23:4888-4896, 2005 19. Leonard G, Curran SD, Kemeny N, et al: A comparative assessment of the incidence of steatohepatitis seen with modern chemotherapy agents. J Clin Oncol 23:741, 2005 (suppl; abstr 8051) 20. Rubbia-Brandt L, Audard V, Sartoretti P, et al: Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 15:460-466, 2004 21. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 22. Giantonio BJ, Catalano PJ, Meropol NJ, et al: High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200. J Clin Oncol 23:1, 2005 (suppl; abstr 2) 23. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004 24. Diaz Rubio E, Tabernero J, Van Cutsem E, et al: Cetuximab in combination with oxaliplatin/5-fluorouracil/folinic acid (FOLFOX-4) in the first-line treatment of patients with epidermal growth factor receptor-expressing metastatic colorectal cancer: An international phase II study. J Clin Oncol 23:254, 2005 (suppl; abstr 3535) 25. Leonard GD, Brenner B, Kemeny NE: Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol 23:2038-2048, 2005 26. Hurwitz H, Fehrenbacher L, Cartwright T, et al: Wound healing/bleeding in metastatic colorectal cancer patients who undergo surgery during treatment with bevacizumab. J Clin Oncol 22:294, 2004 (suppl; abstr 3702) 27. Ellis LM, Curley SA, Grothey A: Surgical resection after downsizing of colorectal liver metastasis in the era of bevacizumab. J Clin Oncol 23:4853-4855, 2005 28. Elias D, Baton O, Sideris L, et al: Hepatectomy plus intraoperative radiofrequency ablation and chemotherapy to treat technically unresectable multiple colorectal liver metastases. J Surg Oncol 90:36-42, 2005[CrossRef][Medline] 29. Roth AD, Rubbia-Brandt L, Majno P, et al: Results of inverse strategy using systemic chemotherapy first, liver resection second, and primary tumor resection last for patients with advanced synchronous liver metastases from colorectal cancer. J Clin Oncol 23:291, 2005 (suppl; abstr 3683) Related Article
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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