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Journal of Clinical Oncology, Vol 23, No 36 (December 20), 2005: pp. 9073-9078 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.2334
Neoadjuvant Chemotherapy for Metastatic Colon Cancer: A Cautionary NoteJohn Wayne Cancer Institute at St John’s Health Center, Santa Monica, CA
Royal Liverpool and Aintree University Hospitals, Liverpool, UK
The University of Texas M.D. Anderson Cancer Center, Houston, TX
Siteman Cancer Center at Washington University in St Louis, St Louis, MO
Memorial Sloan Kettering Cancer Center, New York, NY
Paul Brousse Hospital, Paris, France
Paul Brousse Hospital, Paris, France
John Wayne Cancer Institute at St John’s Health Center, Santa Monica, CA Surgical management of resectable hepatic metastases of colorectal cancer has become standard treatment, with 5-year survival rates in carefully selected patients now approaching 60%.1-3 Unfortunately, most hepatic metastases are inoperable because of tumor number, size, or location. Historically, palliative treatment of metastatic colorectal cancer with fluorouracil (FU) and leucovorin (LV) yielded response rates of only 10% to 20%, with a median overall survival time of approximately 6 to 12 months. Tumor reduction to the point that would permit surgical resection was rare. During the last decade, however, the introduction of the newer agents irinotecan, oxaliplatin, cetuximab, and bevacizumab as components of standard treatment for metastatic colorectal cancer has improved response rates and survival considerably. The greater degree of activity seen with these multidrug regimens has led a number of investigators to explore the use of preoperative or neoadjuvant chemotherapy both for resectable metastases, in an attempt to improve the cure rate, and for unresectable metastases, in an attempt to convert some of these patients to a resectable state (although it should be noted that the definition of unresectable has not been definitively established or been uniform between reported studies). Although we are optimistic about the potential utility of this neoadjuvant approach, we offer here a cautionary note regarding the unanticipated hepatotoxicity issues that neoadjuvant chemotherapy imposes and provide some recommendations for dealing with this toxicity. For more than a decade, adjuvant treatment of stage III colon cancer patients with FU-based chemotherapy has been an accepted standard practice because this has been shown in randomized trials to improve both the disease-free and overall survival.4 More recently, use of oxaliplatin-based regimens has been shown to yield superior 3-year disease-free survival compared with FU/LV alone in stage II and III colon cancer patients.5,6 The fact that adjuvant chemotherapy improves the cure rate (historically accepted as equivalent to the 5-year disease-free survival rate) in these earlier stages of colon cancer indicates that it can eradicate residual microscopic disease in some patients. Because residual microscopic metastases, and not resected liver metastases, are the source of ultimately fatal recurrence in patients who experience disease relapse after liver surgery, the logic of extrapolating the stage II and III experience with adjuvant therapy to the resected stage IV setting is sound. Some have suggested that this adjuvant approach is invalid because no adequately powered, randomized study has examined chemotherapy after liver resection. The limited, small trials undertaken in this area have not realistically tested the hypothesis. Largely because of its significant activity in both the metastatic and adjuvant settings, oxaliplatin, most commonly administered in the oxaliplatin, LV, and FU (FOLFOX) regimen,5-8 has been widely used in postresection adjuvant treatment of hepatic metastases and has been evaluated by a number of investigators in the preoperative or neoadjuvant setting for its ability to increase the cure rate in resectable tumors and to convert some unresectable metastases to resectability. There are several theoretical advantages to a preoperative chemotherapy strategy. First, it allows an introduction of full-dose chemotherapy early in the course of the patient's management, when micrometastases are likely to be at their smallest and before any potential debilitation from surgery that might decrease tolerance of chemotherapy. Additionally, a neoadjuvant approach permits radiologic and pathologic assessment of the regimen's efficacy in a particular patient and can guide the decisions regarding selection of further postoperative chemotherapy. The use of FOLFOX, in this particular case in a chronomodulated regimen, to downstage unresectable tumors was first introduced in 1998 by Bismuth and Adam.9 In their study, tumors were downsized and became resectable in 16% of patients; the 5-year postoperative survival rate in these resected patients was 40%. In a larger study,10 1,104 patients with tumors deemed unresectable received oxaliplatin; 335 (23%) subsequently underwent primary hepatic resection, with a survival rate similar to the rate after primary hepatectomy in patients presenting with resectable disease. More recently, Delaunoit et al11 reported curative resection in 24 (3.3%) of 795 randomly assigned patients who had received neoadjuvant chemotherapy for initially unresectable metastatic colon cancer; most of these patients (92%) received an oxaliplatin-based regimen. The median overall survival time in the resected group was 42.4 months, and the median time to relapse was 18.4 months. In unresectable stage IV disease, the addition of bevacizumab, a recombinant monoclonal antibody that inhibits vascular endothelial growth factor, to a regimen of irinotecan, FU, and LV significantly prolonged survival.12 The addition of bevacizumab to FU and LV in patients who were believed to be unable to tolerate an irinotecan-containing regimen also significantly improved disease-free and overall survival.13 In a separate study, the addition of bevacizumab to FOLFOX significantly improved the survival of patients previously treated with irinotecan, FU, and LV.14 These results are encouraging, and bevacizumab has been rapidly incorporated (appropriately we believe) into the routine management of stage IV colorectal cancer. The higher response rates and longer survival seen with bevacizumab in unresectable patients have generated enthusiasm for the use of bevacizumab-containing chemotherapy regimens as preoperative treatment for patients with liver metastases that are resectable and for patients whose metastases have the potential for conversion to resectability. However, this enthusiasm should be tempered with caution because we do not yet fully understand the potential toxicity of an antiangiogenesis agent like bevacizumab, and it is not clear how this drug's long circulating half-life might affect liver regeneration and wound healing. Preclinical studies in rats have demonstrated that the inhibition of angiogenesis impaired wound healing,15 and it has been suggested that the inhibition of vascular endothelial growth factor receptors on endothelial cells may regulate liver regeneration.16 Hence, we do not adequately understand how the cumulative effects of any of the earlier-mentioned chemotherapy agents or combinations might impact surgical morbidity or hepatic regeneration after a major hepatectomy. Recently, hepatic surgeons in Europe and the United States have reported an increased incidence of vascular changes17 and steatohepatitis18 in livers of patients treated with chemotherapy. Most of the reports involve oxaliplatin; however, this may simply reflect the wide use of this agent in this setting. Steatohepatitis also seems to occur in patients treated with irinotecan.18 Effects specific to bevacizumab have not been reported thus far, but experience with this agent is quite limited. The changes seen with chemotherapy can have a profound effect on the safe performance of standard liver resection and, therefore, on the management of patients with hepatic metastases of colorectal cancer. The vascular alterations result in bluish discoloration, edema, and a spongiform consistency similar to that seen with early cirrhosis (Fig 1). This blue liver syndrome increases the potential for operative bleeding and decreases hepatic functional reserve. Corresponding pathologic characteristics have not been clearly defined. Rubbia-Brandt et al17 reported hepatic sinusoidal abnormalities similar to those of veno-occlusive disease in 44 (51%) of 87 hepatectomy specimens from patients who had received neoadjuvant chemotherapy; 34 specimens (77%) were from patients treated with FOLFOX. In severe cases, the degree of congestion and sinusoidal dilation was characterized by disruption of the sinusoidal membrane and collagenization of the perisinusoidal space (the so-called sinusoidal obstruction syndrome).19 Rubbia-Brandt et al17 hypothesized that FOLFOX caused a toxic injury to the endothelial cells, which resulted in sinusoidal wall disruption, collagen deposition, and fibrosis (Fig 2). None of these changes occurred in 66 patients who did not receive neoadjuvant chemotherapy. Although the impact of the histopathologic changes on postoperative complications was not evaluated, the authors suggested that these liver-specific complications be included in the list of adverse effects of systemic chemotherapy and, in particular, oxaliplatin. Similarly, Tisman et al20 reported a case of perisinusoidal obstruction and fibrotic venular occlusion in a patient who received capecitabine and oxaliplatin. This patient, who did not have hepatic metastases and had not undergone surgical intervention, developed portal hypertension and succumbed to liver failure. In a recent retrospective study of 92 patients undergoing resection of colorectal liver metastases, Adam et al21 reported that neoadjuvant FOLFOX produced hepatic vascular changes that increased the risk of operative bleeding but not mortality or morbidity. Only prolonged chemotherapy (> 12 cycles) was related to a longer duration of hospital stay. Pathologic review of liver specimens revealed that FOLFOX-treated patients had less steatosis and fibrosis but more centrilobular necrosis than patients treated with FU plus LV.
Fernandez et al18 described an association between the neoadjuvant administration of oxaliplatin and/or irinotecan and the development of steatohepatitis, which is one type of nonalcoholic fatty liver disease (NAFLD). NAFLD represents a continuum of liver injury associated with fat in the liver; its earliest phase is steatosis. Steatohepatitis (nonalcoholic steatohepatitis22) is a considerably more severe intermediate phase characterized by the development of inflammation and hepatocyte ballooning.23,24 Later stages of NAFLD include hepatocyte necrosis and, finally, cirrhosis of the liver (Table 1). Because the liver's protective mechanisms against oxidative stress are significantly impaired by the development of steatosis, a steatotic liver is much more susceptible to drug-induced oxidative stress. This may explain the steatohepatitis induced by oxaliplatin and irinotecan in the study by Fernandez at al.18 The authors reported that both body mass index and oxaliplatin/irinotecan administration were independent risk factors for development of steatohepatitis. The generally higher body mass index in the North American population compared with European populations might explain why the US study reported steatohepatitis,18 whereas the European studies reported vascular changes.17,19
Do oxaliplatin and irinotecan also act earlier in the continuum of NAFLD? Several reports have linked chemotherapy to the development of steatosis. In a study of computed tomography findings, Peppercorn et al25 reported a 47% incidence of hepatic steatosis in patients who received FU and LV. Although unenhanced helical hepatic computed tomography scans have demonstrated high accuracy for the detection of steatosis, there does not seem to be any correlation between laboratory results, drug dosing, and the degree of steatosis.26 Hepatic steatosis has also been reported in women receiving hormone therapy for breast cancer.27,28 Kooby et al23 compared outcomes of hepatectomy in 325 patients with steatosis and 160 patients without steatosis. Sixty-six percent of patients with markedly steatotic livers received preoperative chemotherapy with FU, floxuridine, LV, and/or irinotecan. Although mortality was not significantly higher in patients with steatotic compared with nonsteatotic livers, marked steatosis was an independent predictor of infectious complications. Parikh et al22 recently reported a statistically higher incidence of steatosis (nonrandomized comparison) in patients treated with neoadjuvant FU/LV/irinotecan compared with patients treated with FU/LV alone or no neoadjuvant therapy. Although the data are far from complete, the absence of steatosis in the European studies17,21 suggests that oxaliplatin and irinotecan more likely affect the progression but not the development of steatosis. This would distinguish these two agents from FU, which seems to induce steatosis but not steatohepatitis. This is an important distinction because preoperative steatohepatitis is more important than preoperative steatosis in predicting risk for postoperative complications, particularly hepatic insufficiency. Preliminary toxicity data from the European Organisation for Research and Treatment of Cancer Intergroup phase III study of neoadjuvant FOLFOX were presented at the Annual Meeting of the American Society of Clinical Oncology earlier this year.29 The preliminary data indicate that preoperative administration of FOLFOX did not affect the morbidity or mortality of hepatectomy for resectable colorectal hepatic metastases. This might reflect the technique of chemotherapy infusion (chronomodulation v continuous) but is more likely to be a consequence of the short course of FOLFOX (six cycles) and an experienced multidisciplinary team. Surgery was performed a median of 114 days after chemotherapy and was closely monitored by the study team. The survival data from this study are expected in 2007. Oxaliplatin, irinotecan, cetuximab, and bevacizumab are valuable drugs, the judicious use of which may significantly increase the number of candidates for hepatectomy of previously unresectable metastases. In the United States, there is no clear standard for chemotherapy before hepatic resection. Some patients may receive FOLFOX, and others may receive FU, LV, and irinotecan. Because these regimens are often continued until maximal response or onset of progression, this prolonged exposure may result in hepatotoxicity and the potential for more complications. An additional problem of treating to maximal response is the radiographic and possibly intraoperative ultrasonographic disappearance of some smaller metastases. This increases the difficulty of surgical decision making by the hepatobiliary surgical oncologist who wants to extirpate or destroy all areas harboring metastatic disease. Is it safe or wise not to resect/ablate normal-appearing areas that once contained definite metastases? This is a major dilemma for surgeons who now encounter this problem with increasing frequency. Another concern is that many patients will already have received FOLFOX for postoperative adjuvant therapy of stage II or III colon cancer. Subsequent neoadjuvant use of FOLFOX for newly diagnosed stage IV disease increases a patient's exposure to these agents and the potential for drug-induced hepatotoxicity. At present, we do not have data to guide us on the relative merits of preoperative versus postoperative chemotherapy for resectable liver metastases. A trial to assess this question is in the planning stages by the American College of Surgeons Oncology Group. Pending the availability of definitive data, we offer here a considered opinion regarding management decisions. Such recommendations are necessarily general in nature; the particular details and circumstances of each patient should be carefully considered, and care should be individualized appropriately. The implications of these recently described hepatotoxicities suggest that, in low-risk, clearly resectable patients, the potential operative morbidity secondary to hepatotoxicity may outweigh the potential benefits of preoperative treatment; initial surgery should be considered, followed by a course of postoperative adjuvant chemotherapy, if deemed clinically appropriate. Patients with a poorer prognosis pattern of resectable metastatic disease or patients who have borderline resectable or unresectable disease are more appropriate candidates for neoadjuvant treatment. In these patients, efforts should be made to limit the duration of preoperative therapy. Recognizing that data to guide duration of therapy are lacking and that this or any recommendation is empiric, we favor evaluation at short intervals (approximately every 6 weeks) and resection as soon as the metastases become clearly resectable to avoid prolonged exposure and potential toxicity. In the event that bevacizumab is used, caution is necessary regarding the potential for delayed wound healing and possible delayed hepatic regeneration. No specific data are available to guide timing in this setting; however, a delay in elective surgery of at least 6 weeks after completion of bevacizumab and a similar delay in restarting bevacizumab after liver surgery would seem prudent. Often, bevacizumab may be stopped earlier than the cytotoxic chemotherapy with which it is administered, and some oncologists withhold bevacizumab for the first few weeks of postoperative chemotherapy. This intricate timing underscores the need for close, early coordination between the medical and surgical oncologists involved in multimodality management. On the basis of the tumor's response to a neoadjuvant regimen, further postoperative chemotherapy could be considered to attempt to further prevent recurrence. The precise duration of chemotherapy before and/or after surgery is unclear, with some studies suggesting a duration of 4 to 6 months. A clinically effective neoadjuvant therapy might be continued postoperatively, but agents that are not effective before surgery are unlikely to be successful postoperatively. If the patient has undergone prolonged neoadjuvant chemotherapy, a preoperative liver biopsy should be strongly considered because steatohepatitis and veno-occlusive disease may exist in the presence of normal liver function tests.18 Unfortunately, many potentially resectable patients are only referred for resection at the onset of progression and after they have received numerous different chemotherapy regimens. At this point, curative surgery may no longer be possible because of accumulated hepatic toxicity. The protracted use of cytotoxic drugs can also lead to chronic and possibly progressive liver damage.30 Therefore, a close dialogue is needed between medical oncologists, surgeons, and patients to develop an optimal treatment strategy. In patients with unresectable metastases, downsizing therapy may increase the number of candidates for potentially curative resection, and its results may predict the response to a postoperative drug regimen. The integration of novel effective systemic biochemotherapy and advanced surgical procedures for metastatic colorectal cancer has transformed the approach to this disease. The physician's concern becomes not so much the lack of options but the cautious timing and careful selection of the best option at each point in each patient's care. Indeed, although there remains much hard work to be done, there is a brighter future for many of the patients with this common malignancy, and a wonderful and important opportunity exists for interdisciplinary collaboration to further improve our ability to combat this deadly disease. Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their 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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Wolmark N, Wieand HS, Kuebler JP, et al: A phase III trial comparing FU/LV to FU/LV + oxaliplatin in stage II and III carcinoma of the colon: Results of NSABP Protocol C-07. J Clin Oncol 23:246S, 2005 (suppl 16, abstr 3500)[CrossRef] 7. de Gramont A, Boni C, Navarro M, et al: Oxaliplatin/5FU/LV in the adjuvant treatment of stage II and stage III colon cancer: Efficacy results with a median follow-up of 4 years. J Clin Oncol 23:246S, 2005 (suppl 16, abstr 3501)[CrossRef] 8. Hickish T, Boni C, Navarro M, et al: FOLFOX4 as adjuvant treatment for stage II colon cancer (CC): Subpopulation data from the MOSAIC trial. J Clin Oncol 22:275, 2004 (suppl, abstr 3619) 9. Bismuth H, Adam R: Reduction of non-resectable liver metastasis from colorectal cancer after oxaliplatin chemotherapy. Semin Oncol 25:40-46, 1998 (suppl 5)[Medline] 10. Adam R, Delvart V, Pascal G, et al: Rescue surgery for unresectable colorectal liver metastases down-staged by chemotherapy: A model to predict long-term survival. Ann Surg 240:644-657, 2004[Medline] 11. 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 12. 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 13. Kabbinavar FF, Schulz J, McCleod M, et al: Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: Results of a randomized phase II trial. J Clin Oncol 23:3697-3705, 2005 14. 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:S1S, 2005 (suppl 16, abstr 2) 15. Roman CD, Choy H, Nanney L, et al: Vascular endothelial growth factor-mediated angiogenesis inhibition and postoperative wound healing in rats. J Surg Res 105:43-47, 2002[CrossRef][Medline] 16. Hicklin DJ, Ellis LM: Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011-1027, 2005 17. 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 18. Fernandez FG, Ritter J, Linehan DC, et al: Effect of steatohepatitis associated with irinotecan or oxaliplatin pre-treatment on resectability of hepatic colorectal metastases. J Am Coll Surg 200:845-853, 2005[CrossRef][Medline] 19. DeLeve LD, Shulman HM, McDonald GB: Toxic injury to hepatic sinusoids: Sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis 22:27-42, 2002[CrossRef][Medline] 20. Tisman G, MacDonald D, Shindell N, et al: Oxaliplatin toxicity masquerading as recurrent colon cancer. J Clin Oncol 22:3202-3204, 2004 21. Adam R, Sebagh M, Plasse M, et al: Impact of preoperative systemic chemotherapy on liver histology and outcome of hepatic resection for colorectal cancer liver metastases (CRLM). J Clin Oncol 23:253S, 2005 (suppl 16, abstr 3529) 22. 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] 23. 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] 24. Behrns KE, Tsiotos GG, DeSouza NF, et al: Hepatic steatosis as a potential risk factor for major hepatic resection. J Gastrointest Surg 2:292-298, 1998[CrossRef][Medline] 25. Peppercorn PD, Reznek RH, Wilson P, et al: Demonstration of hepatic steatosis by computerized tomography in patients receiving 5-fluorouracil-based therapy for advanced colorectal cancer. Br J Cancer 77:2008-2011, 1998[Medline] 26. Jacobs JE, Birnbaum BA, Shapiro MA, et al: Diagnostic criteria for fatty infiltration of the liver on contrast-enhanced helical CT. Am J Roentgenol 171:659-664, 1998 27. Murata Y, Ogawa Y, Saibara T, et al: Unrecognized hepatic steatosis and non-alcoholic steatohepatitis in adjuvant tamoxifen for breast cancer patients. Oncol Rep 7:1299-1304, 2000[Medline] 28. Nemoto Y, Saibara T, Ogawa Y, et al: Tamoxifen-induced nonalcoholic steatohepatitis in breast cancer patients treated with adjuvant tamoxifen. Intern Med 41:345-350, 2002[Medline] 29. Nordlinger B, Sorbye H, Debois M, et al: Feasibility and risks of pre-operative chemotherapy (CT) with FolFox 4 and surgery for resectable colorectal cancer liver metastases (LM): Interim results of the EORTC Intergroup randomized phase III study 40983. J Clin Oncol 23:253S, 2005 (suppl 16, abstr 3528) 30. Poston GJ: The use of irinotecan and oxaliplatin in the treatment of advanced colorectal cancer. Eur J Surg Oncol 31:325-330, 2005[CrossRef][Medline] This article has been cited by other articles:
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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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$100,000 (N/R) Not Required
