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Originally published as JCO Early Release 10.1200/JCO.2005.03.902 on July 11 2005 © 2005 American Society of Clinical Oncology.
A Role for Hepatic-Directed Chemotherapy in Colorectal Liver MetastasesDepartments of Internal Medicine and Pharmacology and the Cancer Center, University of Michigan, Ann Arbor, MI Recent advances in the systemic therapy of colorectal cancer seem to have made regional therapy of hepatic metastases passé. Although regional therapy of hepatic metastases from colorectal cancer can produce high response rates with control of liver disease, there seems to be minimal impact on survival because of development of limiting extrahepatic disease. Why bother with the complexities of regional treatment requiring a major surgical procedure and possessing a unique toxicity, biliary sclerosis, when intravenous chemotherapy administration can achieve a high response rate and improved survival by treating extrahepatic as well as hepatic cancer? Perhaps hepatic arterial therapy is best viewed as a potentially useful debulking technique for colorectal liver metastases with negligible effect on occult extrahepatic disease. That consideration is evident in the three studies reported by Kemeny et al,1 Ducreux et al,2 and Faynsod et al3 in this issue of the Journal of Clinical Oncology. All three studies attempt to overcome the shortcomings of regional therapy by addressing the therapy of extrahepatic disease and the biliary toxicity accompanying hepatic arterial infusions (HAI) of floxuridine (FUDR). The results of the phase I trial by Kemeny et al1 from the Memorial Sloan-Kettering Cancer Center reported in this issue concerning the treatment of unresectable colorectal liver metastases are extremely positive. In this trial, all patients had implantation of a hepatic arterial catheter and pump and received either a set fixed dose of HAI FUDR (with dexamethasone to diminish biliary toxicity) plus systemic (intravenous) oxaliplatin plus irinotecan (group A) or oxaliplatin plus fluorouracil with leucovorin (group B). In group A, oxaliplatin and irinotecan were escalated separately to determine the maximum-tolerated dose (MTD) of the combination. In group B, dose levels of a 48-hour infusion of fluorouracil were escalated to the MTD, with oxaliplatin held at a conventional dose level. The study successfully defined the MTD for each group. Systemic chemotherapy doses at MTD were within the usual dose range for group A, but the fluorouracil dose was lower in group B. Toxicities were as expected and primarily related to the systemic treatment, and there were no cases of bilirubin elevation noted at MTD. Although this was a phase I study and involved only 36 patients, the response rates and survivals that were achieved were excellent. The complete plus partial response rate was 90% and 87% for groups A and B, respectively. For groups A and B, the median survival from pump placement was 36 and 22 months, respectively, and the median survival from diagnosis of liver metastases was 47 and 35 months, respectively. The patients included in the study were highly selected and had unresectable hepatic metastases with no extrahepatic disease and, in most instances (89% of patients), had experienced failure with undefined previous systemic chemotherapy. It is of interest to examine these results with those reported for similar systemic regimens in the initial treatment of colorectal cancer metastatic to multiple sites including the liver. The results in group A compare favorably with the previously reported response rate and median survival for combined systemic irinotecan and oxaliplatin of 35% and 17.4 months, respectively.4 The outcome in group B compares well with the response rate of 54% for initial systemic treatment with oxaliplatin plus fluorouracil and leucovorin.5 Overall survival time in the Kemeny et al1 HAI study of 35 to 47 months exceeds the approximately 21-month overall median survival time for sequential oxaliplatin plus fluorouracil and leucovorin and for irinotecan plus fluorouracil and leucovorin in previously untreated patients.5 The response rate for the combination of HAI FUDR and systemic chemotherapy seems higher than what would be anticipated for either type of therapy alone, suggesting that the benefits of HAI FUDR may be additive to systemic therapy. The results of this small, phase I study of HAI FUDR plus systemic therapy require confirmation in larger, multicenter, phase III trials. Even if HAI FUDR is shown to provide additive benefit to systemic therapies, there are limiting factors to its application. Despite having a well-founded rationale,6 25 years of history have taught us three practicalities. First, it takes surgical skills that are refined by experience to successfully implant the usual drug delivery system used in the United States (ie, a hepatic arterial catheter and pump).7 The Memorial Sloan-Kettering group unequivocally possesses those surgical skills and the dedication to apply them well. Second, the toxicities of HAI FUDR are not the toxicities usually associated with standard systemic chemotherapy and, instead, consist of abnormalities in liver function tests, which can progress to jaundice and biliary sclerosis. It can be difficult to distinguish drug toxicity from progressive hepatic cancer. The Memorial Sloan-Kettering group has been able to markedly diminish hepatic toxicity through use of dexamethasone, through a lowering of the FUDR dose and, through close monitoring of patients based on their long experience in toxicity management.8 Third, HAI FUDR is effective only against liver metastases, not extrahepatic metastases, from colorectal cancer. Thus, as more effective systemic therapies have been developed, it has been reasonable to try to combine them with HAI FUDR, as has been done in the Kemeny et al1 study and earlier trials by the Memorial Sloan-Kettering group.9 Another approach aimed at improved control of extrahepatic and hepatic colorectal cancer is represented by another article in this issue by Ducreux et al.2 In this French study, oxaliplatin was administered as a 2-hour infusion into the hepatic artery every 2 weeks using surgically implanted catheters attached to subcutaneous ports.2 Systemic therapy with fluorouracil plus leucovorin using the de Gramont regimen was administered concurrently. It is likely that, in addition to improved hepatic exposure to oxaliplatin, low hepatic extraction allows for significant systemic exposure. There was no biliary toxicity generated, and although there was a high incidence of expected systemic toxicities, most of the toxicities were less than grade 3 to 4. The response rate was 64%, with an overall survival time of 27 months. The authors state that catheter obstruction was the main cause for treatment discontinuation and a major problem with this regimen of HAI chemotherapy. It should be noted that the implanted pump system used for most HAI studies in the United States seems, in large part, to overcome the problem of catheter obstruction by producing a constant low flow of heparin-containing solution through the catheter. Future studies comparing HAI oxaliplatin versus systemic oxaliplatin are necessary to define whether HAI oxaliplatin has an important role to play in the treatment of colorectal liver metastases. If HAI oxaliplatin is superior, combination with HAI FUDR should be considered. A crucial question is whether HAI FUDR adds significant benefit to current systemic therapies. The phase I trial by Kemeny et al1 was not designed to answer this question. However, that trial demonstrates that, in experienced hands, HAI FUDR can be safely combined with several modern systemic chemotherapy regimens for colorectal cancer. Definition of the contribution of HAI FUDR requires the successful conduct of large phase III studies comparing systemic therapy alone with systemic therapy combined with HAI FUDR. Unfortunately, there is no clarity as to which of the potential systemic regimens would be best combined with HAI FUDR, although the Memorial Sloan-Kettering study defines two candidates. In addition, because growth factor receptor inhibitors are likely to add efficacy and considering the time to complete such studies, these factors should be integrated into trials as soon as possible. Trials addressing the contribution of HAI FUDR to modern systemic therapies require the cooperation of centers that have a sufficient pool of patients, such as is created by the coexistence of successful resection and ablative programs for colorectal liver metastases. Examples of such cooperation are the North Central Cancer Treatment Group/National Surgical Adjuvant Breast and Bowel Project intergroup studies CI-66 and C-09. Study C-09 is a comparative trial of capecitabine with oxaliplatin with or without HAI FUDR after resection and ablation of liver-only colorectal metastases. Successful conduct of study C-09 will represent a significant contribution in answering whether HAI FUDR contributes significantly to one modern systemic therapy regimen in an important adjuvant setting. The ultimate aim of therapy for metastatic colorectal cancer is cure. It has been demonstrated that cure is attainable in approximately one third of patients who have complete resection of liver-confined hepatic metastases.10-12 Thus, it is noteworthy that hepatic metastases in seven of 21 patients treated in group A of the Memorial Sloan-Kettering trial regressed sufficiently to become totally resectable.1 Two prior studies have demonstrated a potential role for HAI FUDR combined with systemic therapy in improving the results of hepatic resection of colorectal liver metastases.13,14 These prior studies used fluorouracil with leucovorin as the sole systemic therapy, whereas the intergroup studies noted earlier use a more effective systemic regimen of oxaliplatin and capecitabine. Because HAI FUDR carries the potential for biliary sclerosis, it is reasonable to examine other regional approaches for adjuvant therapy after resection of liver metastases. To that end, this issue contains a report on a study by Faynsod et al3 of another hepatic-directed therapy for potential adjuvant use after resection or ablation of hepatic-confined colorectal liver metastases. Investigators at the City of Hope National Medical Center describe two trials in which continuous-infusion FUDR was delivered into the portal vein (PV) in patients after resection or ablation of liver-only colorectal metastases. The rationale for PV infusion is based on the observation that micrometastases are primarily dependent on the PV for their nutrition and that PV infusion of FUDR achieves a significant regional exposure advantage. In addition, it is thought that the biliary tree is essentially fed totally by the hepatic artery. Hence, given these FUDR exposure considerations, PV infusion of FUDR should be less likely to produce biliary toxicity than HAI FUDR and yet improve treatment of occult micrometastases. In two phase II clinical trials, the City of Hope investigators define an implanted system (with the usual implanted pump) and a treatment regimen allowing for PV infusion of FUDR on a 14 days on followed by 14 days off drug schedule at doses approximately two times higher than used in the Memorial Sloan-Kettering HAI study.1 Systemic fluorouracil plus leucovorin was also administered with PV FUDR. This was primarily a feasibility study that successfully demonstrated that PV FUDR can be delivered safely with a low incidence of hepatic drug-induced toxicity in patients after resection or ablation of liver metastases. Overall survival and disease-free survival seem to be somewhat lower than reported with HAI FUDR and systemic fluorouracil.13,14 On the basis of the experience to date, the role for PV FUDR in adjuvant therapy of hepatic metastases after resection or ablation seems less well defined than the role of HAI FUDR. The three investigations of hepatic-directed therapy described in this issue are provocative and an impetus to further study. All three studies demonstrate that methods exist to prevent or minimize the potential for biliary toxicity associated previously with HAI FUDR. Systemic administration of fluorouracil with leucovorin was part of all three investigations and was well tolerated. The two studies using the implanted pump show, again, the diminished likelihood of drug delivery problems, particularly catheter occlusion, with implanted pumps. The Memorial Sloan-Kettering study, although small, suggests that HAI FUDR may be a successful addition to several modern systemic intravenous chemotherapy regimens in terms of response rate and even survival. It is possible that more potent systemic regimens combined with HAI FUDR, such as are defined in the Memorial Sloan-Kettering study, will lead to further improvements in curative outcome after resection of colorectal liver metastases. Finally, efficient conduct of clinical trials addressing the relevance of hepatic-directed infusions to the treatment of colorectal liver metastases will require appropriately designed multicenter phase III trials. Efficient conduct of these studies will require the cooperation of community-based physicians through the referral of appropriate patients for study. Author's Disclosures of Potential Conflicts of Interest The following author or their immediate family members has 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)
REFERENCES
1. Kemeny NE, Fong Y, Jarnagin W, et al: A phase I trial of systemic oxaliplatin combinations with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer. J Clin Oncol 23: 4888-4896, 2005
2. Ducreux M, Ychou M, Laplanche A, et al: Combination of hepatic arterial oxaliplatin infusion and intravenous chemotherapy with leucovorin and fluorouracil in colorectal cancer patients with isolated inoperable hepatic metastases. J Clin Oncol 23: 4881-4887, 2005
3. Faynsod M, Wagman LD, Longmate J, et al: Improved hepatic toxicity profile of adjuvant hepatic infusional chemotherapy utilizing the portal vein (PV) route. J Clin Oncol 23: 4876-4880, 2005
4. 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
5. Tournigand C, André T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22: 229-237, 2004 6. Ensminger WD: Intrahepatic arterial infusion of chemotherapy: Pharmacologic principles. Semin Oncol 29: 119-125, 2002
7. Campbell KA, Burns RC, Sitzmann JV, et al: Regional chemotherapy devices: Effect of experience and anatomy on complications. J Clin Oncol 11: 822-826, 1993 8. Kemeny N, Seiter K, Niedzwiecki D, et al: A randomized trial of intrahepatic infusion of fluorodeoxyuridine with dexamethasone versus fluorodeoxyuridine alone in the treatment of metastatic colorectal cancer. Cancer 69: 327-334, 1992[CrossRef][Medline]
9. Kemeny N, Jarnagin W, Gonen M, et al: Phase I/II study of hepatic arterial therapy with floxuridine and dexamethasone in combination with intravenous irinotecan as adjuvant treatment after resection of hepatic metastases from colorectal cancer. J Clin Oncol 21: 3303-3309, 2003
10. Fong Y, Cohen AM, Fortner JG, et al: Liver resection for colorectal metastases. J Clin Oncol 15: 938-946, 1997 11. Weber SM, Jarnagin WR, DeMatteo RP, et al: Survival after resection of multiple hepatic colorectal metastases. Ann Surg Oncol 7: 643-650, 2000[Abstract] 12. 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 239: 818-827, 2004[CrossRef][Medline]
13. 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
14. 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 Related 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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