Defining the Role of Hepatic Arterial Infusion Chemotherapy in Metastatic Colorectal Cancer
Defining the Role of Hepatic Arterial Infusion Chemotherapy in Metastatic Colorectal Cancer
In their article, Drs. Whisenant and
Venook review data regarding the
value of hepatic arterial infusion
(HAI) chemotherapy for hepatic colorectal
metastases. In fact, their analysis
reveals the absence of any
material progress in HAI therapy since
the first reports of continuous infusion
of chemotherapy through the hepatic
artery. During the same
period, there has been dramatic improvement
in hepatic imaging, outcome
from hepatic resection, systemic
chemotherapy, and survival following
treatment of hepatic colorectal
metastases. Failure of HAI therapy to
advance in parallel with other treatments
for liver metastases-whether
used prior to or after resection, or as
definitive treatment for unresectable
disease apparently confined to the liver-
suggests a limited role for HAI
therapy in this disease. Several points
In the treatment of unresectable
disease, HAI therapy has failed to live
up to its initial promise, and is now
clearly losing ground to constantly
improving systemic chemotherapy.
Irinotecan (Camptosar) and oxaliplatin
(Eloxatin), when used in combination
therapy with fluoropyrimidines,
can yield high response rates (54% to
56%) and a median survival of 22
months with acceptable toxicity.
Recently approved targeted therapies
for colorectal cancer-including bevacizumab
(Avastin), an anti-vascular
endothelial growth factor monoclonal
antibody, and cetuximab (Erbitux), a
monoclonal epithelial growth factor
receptor antibody-have further increased
the prospects for higher tumor
The best reported response rates
using HAI chemotherapy (from the
centers with the greatest experience
with this mode of therapy) are 50% to
62%[3,4] in studies that date from the
late 1980s, and have not consistently
been reproduced (even by the same
authors). The most recent multicenter
study of HAI chemotherapy reported a
response rate of only 48% and a median
survival of 22.7 months, similar
to leucovorin/fluorouracil (5-FU)/
oxaliplatin (FOLFOX) or leucovorin/
5-FU/irinotecan (FOLFIRI). Furthermore,
these response rates are
achieved only in selected patients who
will tolerate laparotomy (systemic
chemotherapy is available to patients
with less favorable performance status),
and only at the expense of an
added layer of complications related
to pump placement and subsequent
Complications and Toxicity
The potential complications and toxicity of HAI chemotherapy cannot be overemphasized, and have not improved significantly over time. In the most recent update of the experience at Memorial Sloan-Kettering Cancer Center, the technical complication rate related to insertion of implantable pumps remains 12%, no different from the 10% rate reported by Kemeny nearly 10 years earlier. Complications of the HAI chemotherapy also remain unacceptably high. Gastritis (25%), ulcer (9%), diarrhea (5%), and the dreaded biliary sclerosis (11%) are consistent and persistent potentially serious complications of therapy that may also prohibit the appropriate subsequent deployment of systemic therapy. In Kemeny's important study in the New England Journal of Medicine, wherein HAI chemotherapy was investigated as an adjuvant to hepatic resection, only 26% of patients received the therapy, 4 of 74 patients developed biliary strictures (5.5%), and two late deaths (2.7%) occurred as a result of hepatic failure. Pump infections, hepatic artery thrombosis, catheter displacement, and intraabdominal hemorrhage complicated treatment in 14 of 74 patients (19%). Similarly, in the series from Duke University, 4 of 21 patients (19%) treated with HAI therapy required chronic indwelling stents for biliary strictures, and one patient died with liver failure (4.8%). In comparison, it should be noted that the mortality for FOLFOX or FOLFIRI is ≤ 1.1%, while two large multicenter trials of irinotecan plus bolus 5-FU/ leucovorin (Saltz regimen) reported treatment-related mortality of 3.1% and 2.5%, respectively. Preoperative Use of HAI Chemotherapy
Similarly, support for use of HAI chemotherapy before surgery is lacking. HAI chemotherapy is not efficient in downstaging unresectable disease to enable resection. In over 300 collected cases from the University of San Francisco reported by Drs. Whisenant and Venook in the accompanying article, < 1% were explored for possible resection and presumably fewer resected as a result of response to HAI chemotherapy. The abovementioned toxicity to the liver and bile ducts may preclude patients from safe resection even when tumor response occurs.[12,13] In contrast, we have shown that perioperative complications are not significantly increased following hepatic resection in patients who have undergone preoperative systemic chemotherapy.[ 14] It is clear that as experience with HAI chemotherapy has evolved, this modality has not enabled subsequent downstaging and hepatic resection at a rate that compares to the initial report by Bismuth (16%) or to the rate of resection following modern chemotherapy in Europe (51% of 151 patients treated with chronomodulated oxaliplatinbased chemotherapy were explored, 38% underwent complete resection)[ 16] or in the United States (33% underwent complete resection following FOLFOX). Postresection Adjuvant Treatment With HAI
The rationale for postresection adjuvant treatment with HAI therapy is flawed for three major reasons. First, with complete resection, hepatic-only recurrence has fallen from about 36% in collected series before 1986 to only 11% in our latest series. Otherwise stated, the majority of patients fail with extrahepatic disease as a component of their recurrence, which reiterates the need for systemic rather than regional treatment after complete resection. Second, the premise that HAI chemotherapy treats tumors preferentially because of their dependence on arterial inflow to the liver applies only to large tumors, not to residual "micrometastatic" disease in the liver left after resection-it has been known since the 1950s that hepatic metastases < 3 millimeters in size derive blood from the portal vein, not the hepatic artery. Third, pump complications, liver failure, and death negate the advances in safety and outcome from complete hepatic resection. Mortality of major hepatic resection is approaching zero and outcome for hepatic resection is improving. Choti et al recently reported that 5-year survival for patients who underwent resection between 1993 and 1999 was 58%. Similarly, the 5-year survival rate for patients at M. D. Anderson Cancer Center who underwent resection of colorectal liver metastases (1992- 2002) was 58%. As a result, the implantation of HAI pumps at M. D. Anderson has fallen dramatically over the past few years (see Figure 1). Conclusions
In summary, in over 40 years, there has been minimal progress in the treatment of colorectal metastases to the liver using HAI chemotherapy, for either unresectable disease, as neoadjuvant therapy before resection, or as adjuvant therapy following resection. There is no improvement in survival as compared to systemic treatment, and the risks for toxicity from HAI therapy-especially biliary sclerosis (5% to 19%) and death from liver failure (3% to 5%), even in centers with the largest experience-are not inconsequential. Furthermore, technical complications of pump placement occur in ≥ 10% of patients, and this rate has remained stable over time. In parallel, during this same interval there have been dramatic advances in outcome from surgery, with a near-zero mortality for extended hepatic resection.[ 21] There have also been marked improvements in systemic and molecularly targeted chemotherapy which better address the systemic disease ultimately seen in the majority of those who initially present with colorectal metastases apparently confined to the liver.
2. Tournigand C, Andre 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(2):229-237, 2004.
3. Kemeny MM, Goldberg D, Beatty JD, et al: Results of a prospective randomized trial of continuous regional chemotherapy and hepatic resection as treatment of hepatic metastases from colorectal primaries. Cancer 57(3):492- 498, 1986.
4. Chang AE, Schneider PD, Sugarbaker PH, et al: A prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases. Ann Surg 206(6):685-693, 1987.
5. Kemeny N, Niedzwieck D, Hollis DR, et al: Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: A CALGB randomized trial for efficacy, quality of life, cost effectiveness and mollecular markers (abstract 1010). Proc Am Soc Clin Oncol 22:252, 2003.
6. Allen PJ, Stojadinovic A, Ben-Porat L, et al: The management of variant arterial anatomy during hepatic arterial infusion pump placement. Ann Surg Oncol 9(9):875-880, 2002.
7. Kemeny N, Seiter K, Conti JA, et al: Hepatic arterial floxuridine and leucovorin for unresectable liver metastases from colorectal carcinoma. New dose schedules and survival update. Cancer 73(4):1134-1142, 1994.
8. Vauthey JN, Marsh RdW, Cendan JC, et al: Arterial therapy of hepatic colorectal metastases. Br J Surg 83(4):447-455, 1996.
9. 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(27):2039- 2048, 1999.
10. Onaitis M, Morse M, Hurwitz H, et al: Adjuvant hepatic arterial chemotherapy following metastasectomy in patients with isolated liver metastases. Ann Surg 237(6):782-789, 2003.
11. Rothenberg ML, Meropol NJ, Poplin EA, et al: Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: Summary findings of an independent panel. J Clin Oncol 19(18):3801-3807, 2001.
12. Meric F, Patt YZ, Curley SA, et al: Surgery after downstaging of unresectable hepatic tumors with intra- arterial chemotherapy. Ann Surg Oncol 7(7):490-495, 2000.
13. Elias D, Lasser P, Rougier P, et al: Frequency, technical aspects, results, and indications of major hepatectomy after prolonged intra-arterial hepatic chemotherapy for initially unresectable hepatic tumors. J Am Coll Surg 180(2):213-219, 1995.
14. 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(8):1082-1088, 2003.
15. Bismuth H, Adam R, Levi F, et al: Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 224(4):509-522, 1996.
16. Giacchetti S, Itzhaki M, Gruia G, et al: Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 10(6):663-669, 1999.
17. Alberts SR, Donohue JH, Mahoney MR, et al: Liver resection after 5-fluorouracil, leucovorin and oxaliplatin for patients with metastatic colorectal cancer (MCRC) limited to the liver: A North Central Cancer Treatment Group (NCCTG) phase II study (abstract 1053). Proc Am Soc Clin Oncol 22:263, 2003.
18. Bozzetti F, Bonfanti G, Morabito A, et al: A multifactorial approach for the prognosis of patients with carcinoma of the stomach after curative resection. Surg Gynecol Obstet 162(3):229-234, 1986.
19. Abdalla EK, Vauthey JN, Ellis LM, et al: Recurrence and outcome following hepatic resection, radiofrequency ablation and combined resection/ablation for colorectal liver metastases. Ann Surg (in press).
20. Breedis C, Young G: The blood supply of neoplasms in the liver. Am J Pathol 30(5):969-977, 1954.
21. Vauthey JN, Pawlik TM, Abdalla EK, et al: Is extended hepatectomy for hepatobiliary malignancy justified? Ann Surg 239(5):722- 732, 2004.
22. Choti MA, Sitzmann JV, Tiburi MF, et al: Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 235(6):759-766, 2002.