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Benefits and Risks of Neoadjuvant Therapy for Liver Metastases

Assistance Publique-Hôpitaux de Paris, Hôpital Ambroise Paré, Boulogne; and Université Versailles Saint Quentin en Yvelines, Versailles, France

Colorectal cancer ranks second in Europe and third in the United States among the most common causes of death caused by cancer. Approximately 50% of patients with colorectal cancer will develop liver metastases during the course of their disease. Surgical resection is the only treatment and can currently ensure long-term survival in 25% to 40% of patients. However, using the current indications for surgery, only 15% to 20% of patients with colorectal cancer liver metastases are suitable for surgical resection. In the majority of patients, metastases are considered to be unresectable, and chemotherapy is the treatment of choice, but 5-year survivors with chemotherapy alone are rare.

Recent progress, including more efficient chemotherapy regimens and targeted agents, has opened new perspectives in the treatment of both resectable and nonresectable colorectal liver metastases. In patients with unresectable liver metastases, emerging data have shown that neoadjuvant chemotherapy can render some metastases resectable, hence opening up the possibility of prolonged survival. In patients with initially resectable liver metastases, neoadjuvant chemotherapy is often administered, although the benefits in terms of long-term disease control have not yet been formally proven. Thus, many patients receive neoadjuvant chemotherapy before liver resection but without direct proof of benefit. Recently, the enthusiasm over the potential positive effects of neoadjuvant chemotherapy has been cooled down somewhat by the awareness of toxicity to the remnant liver caused by preoperative treatment, which could increase the risks of surgery and even preclude liver resection.

There are now accumulating data showing that preoperative chemotherapy is associated with pathologic changes of liver parenchyma.^1-7 The following two main types of chemotherapy-associated liver injuries have been reported: vascular changes and chemotherapy-associated steatohepatitis (CASH). The vascular changes include sinusoidal dilation with erythrocytic congestion, occasionally accompanied by perisinusoidal fibrosis and fibrotic venous occlusion, which could result in sinusoidal obstruction syndrome as observed in veno-occlusive disease.² CASH is defined as the association of severe steatosis, lobular inflammation, and ballooning of hepatocytes.⁶ Few studies have evaluated the correlation between the type of liver injury and the neoadjuvant chemotherapy regimen. In this issue, Aloia et al⁸ assess the relationship between systemic chemotherapy and hepatoxicity by comparing 92 patients who received preoperative chemotherapy with 17 patients who received surgery without chemotherapy. Preoperative chemotherapy included fluorouracil (FU) plus leucovorin, either alone or combined with oxaliplatin. This study confirms, as suggested in other reports,^2,6 that the oxaliplatin-based combination regimen is associated with an increased risk of vascular lesions of the liver. It is uncertain from this report whether this is specific for oxaliplatin or caused by the effects of more intensive combination chemotherapy. In other reports, irinotecan-containing regimens have also been associated with increased risks of steatosis and steatohepatitis.^3,4,6,7 Steatohepatitis is observed more frequently after chemotherapy in patients with a higher body mass index.⁴ This could explain why CASH is more frequently reported in US studies,¹ whereas vascular lesions are more often reported in studies from Europe.^2-5 Therefore, it is possible that specific chemotherapy regimens do not automatically predispose to steatosis but can aggravate it when it already exists.¹

That chemotherapy can be associated with liver injury is now well recognized. The main question is whether collective damages to the liver induced by preoperative chemotherapy have any clinical significance. Do they increase the risks of complications after surgery and lead to a change in treatment strategy? The article by Aloia et al⁸ in this issue of the Journal of Clinical Oncology addresses this question. It shows that perioperative mortality and morbidity rates were not significantly increased in patients who had received preoperative chemotherapy. However, patients who had received more than 12 cycles of preoperative chemotherapy had a higher risk of reoperation and a longer hospital stay. The safety data of European Organisation for Research and Treatment of Cancer (EORTC) study 40983, which compared perioperative chemotherapy with FU, leucovorin, and oxaliplatin (six cycles before surgery and six cycles after) with surgery alone in 364 patients, were presented at the 41st Annual Meeting of the American Society of Clinical Oncology in 2005.⁹ The results showed that the mortality rate was low (close to 1%) in the two treatment arms and that the rate of reversible complications was acceptable.⁹ Thus, administration of six cycles of FU, leucovorin, and oxaliplatin before surgery seems feasible. Another report by Karoui et al⁵ brought another insight into the relationship between duration of preoperative chemotherapy and perioperative morbidity and showed that administration of more than six cycles of neoadjuvant systemic chemotherapy increased morbidity after major liver resection but did not increase mortality. Some studies have looked at the relationship between the type of lesions induced by chemotherapy and their potential clinical consequences. Kooby et al³ showed that steatosis was associated with an increased risk of complications, in particular infections, but had no significant impact on mortality. In the report by Vauthey et al,⁶ steatohepatitis was observed in 20% of patients and was considered responsible for death as a result of postoperative liver failure in 7% of patients with steatohepatitis. In the same study, vascular injury increased the risk of operative bleeding but not perioperative morbidity or mortality.⁶ The study by Aloia et al⁸ published in this issue provides further details on vascular injuries, showing that among vascular lesions observed after neoadjuvant chemotherapy, only hemorrhagic centrilobular necrosis and regenerative nodular hyperplasia were correlated with intraoperative transfusion requirements.

We have now learned that neoadjuvant chemotherapy, as with all other treatment procedures, has both positive and negative impacts, and we must deal with both. Thus, both the drugs and the duration of treatment must be decided with care. Patients with initially unresectable liver metastases can receive chemotherapy to render their metastases resectable, provided treatment is carefully monitored. In these patients, surgery should be performed as soon as the metastases become resectable without waiting for best radiographic response to chemotherapy. Delaying surgery and continuing chemotherapy with excessive numbers of cycles may result in increased damage to the liver and the potential loss of the opportunity to do surgical resection. Only a close collaboration among medical oncologists, surgeons, and radiologists can allow for the determination of the optimal timing of treatment at presentation and after treatment has been initiated.

For patients with resectable metastases, neoadjuvant chemotherapy can be considered pending the results of EORTC 40983, but these patients also should not be overtreated to avoid chronic and progressive chemotherapy-induced liver damage, which could preclude curative surgery.

Preoperative liver biopsy has been suggested in patients who have received prolonged systemic chemotherapy to evaluate the degree of chemotherapy-induced liver injury.¹ The interest of such an approach is uncertain because of the problems with intra- and interobserver variations in the evaluation of CASH⁶ and the heterogeneity of lesions as a result of chemotherapy in the liver. Using such information to deny resection of resectable liver metastases, based only on the results of biopsies, may not prove easy. The best alternative would be to be able to identify other factors that could predict, before the start of treatment, which patients are at risk of developing chemotherapy-induced liver injury.

The integration of novel targeted agents is now transforming the treatment of patients with advanced colorectal cancer. Bevacizumab, an anti–vascular endothelial growth factor (VEGF) agent, has been considered responsible for increased risk of organ perforation, bleeding, and decreased wound healing.¹⁰ Because VEGF plays a critical role in liver regeneration, it is also possible that hepatic regeneration could be impaired in patients who undergo surgery after having received VEGF blockers. Until further evidence is obtained, it is reasonable to allow a 6- to 8-week interval (two half-lives of bevacizumab) between the last administration of bevacizumab and surgery.¹¹ New clinical studies are necessary to determine if and how surgery is feasible after administration of novel systemic targeted agents. Such a study has been organized by the EORTC and will evaluate the feasibility and safety of liver surgery for metastases in patients who had received neoadjuvant chemotherapy with FU, oxaliplatin, and cetuximab, with or without bevacizumab.

In the fast-moving field of combined treatment of patients with colorectal cancer liver metastases, multidisciplinary discussion and repeated evaluations are more indispensable than ever. If neoadjuvant chemotherapy is well chosen and well monitored and surgery is planned at the right moment, liver metastases can be resected safely.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

Author Contributions

Conception and design: Bernard Nordlinger, Stéphane Benoist Manuscript writing: Bernard Nordlinger, Stéphane Benoist Final approval of manuscript: Bernard Nordlinger

 

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3. Kooby DA, Fong Y, Suriawinata A, et al: Impact of steatosis on perioperative outcome following hepatic resection. J Gastrointest Surg 7:1034-1044, 2003[CrossRef][Medline]

4. Fernandez FG, Ritter J, Goodwin JW, et al: Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg 200:845-853, 2005[CrossRef][Medline]

5. Karoui M, Penna C, Amin-Hashem M, et al: Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg 243:1-7, 2006[CrossRef][Medline]

6. Vauthey JN, Pawlik TM, Ribero D, et al: Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 24:2065-2072, 2006[Abstract/Free Full Text]

7. Parikh AA, Gentner B, Wu TT, et al: Perioperative complications in patients undergoing major liver resection with or without neoadjuvant chemotherapy. J Gastrointest Surg 7:1082-1088, 2003[CrossRef][Medline]

8. Aloia T, Sebagh M, Plasse M, et al: Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol 24:4983-4990, 2006[Abstract/Free Full Text]

9. Nordlinger B, Sorbye H, Debois M, et al: Feasibility and risks of pre-operative chemotherapy with FOLFOX 4 and surgery for resectable colorectal liver metastases: Interim results of the EORTC Intergroup randomized phase III study 4093. J Clin Oncol 23:253s, 2005 (suppl 16, abstr 3528)

10. Scappaticci FA, Fehrenbacher L, Cartwright T, et al: Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol 91:173-180, 2005[CrossRef][Medline]

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