Improved Hepatic Toxicity Profile of Portal Vein Adjuvant Hepatic Infusional Chemotherapy
http://www.100md.com
《临床肿瘤学》
the Divisions of Surgery, Medical Oncology, and Bioinformatics, City of Hope National Medical Center, Duarte, CA
ABSTRACT
PURPOSE: To determine whether floxuridine (FUDR) can be delivered with low hepatic toxicity through the portal vein (PV) as an adjuvant to surgically treated colorectal metastases.
PATIENTS AND METHODS: Fifty-one patients undergoing complete resection and/or ablation for colorectal hepatic metastases were prospectively enrolled at a National Cancer Institute–designated comprehensive cancer center. Two sequential phase II trials were performed. Each trial included complete surgical treatment followed by sequential, alternating (22 patients) or concurrent (29 patients) regional PV FUDR and systemic fluorouracil (FU) with leucovorin chemotherapy.
RESULTS: Fifty percent of patients were male. The mean age at diagnosis was 57 years. The mean number of lesions resected was three (range, one to 11 lesions). The stage at diagnosis was II, III, and IV in 16.9%, 52.8%, and 28.3% of patients, respectively. One- and 3-year overall survival rates were 92.7% and 41.8%, respectively. The 1- and 3-year disease-free survival rates were 64.5% and 19%, respectively. The site of first recurrence was hepatic in 35.9% of patients. Treatment was terminated early in 24 patients (17 patients progressed, two refused treatment, and five had nonhepatic toxicities). Fifty-five percent of patients received 75% to 100% of the planned FUDR courses, and 72% received greater than 50% of the planned FUDR dose. Only four patients required dose reductions of FUDR because of grade 3 hepatic toxicity. No patient required biliary stenting or had discontinuation of PV infusion because of hepatic toxicity.
CONCLUSION: The delivery of PV FUDR and FU with leucovorin can be performed with a high percentage of expected drug delivery and a low drug-induced hepatic toxicity rate, while achieving acceptable overall and disease-free survival.
INTRODUCTION
Despite improvements in surgical and ablative techniques for metastatic colorectal carcinoma to the liver, hepatic recurrence remains a major problem. The role of systemic therapy after surgical resection of hepatic disease has not yet demonstrated a clear advantage.1 Because the liver is the most common site of recurrence after resection of hepatic metastases, regional chemotherapy represents an attractive approach.2 In experimental and clinical models, macroscopic hepatic tumors greater than 0.5 to 1.0 cm derive their blood supply preferentially from the hepatic artery compared with normal hepatocytes.3 This differential blood supply may be exploited to achieve differential exposure of hepatic macrometastases to higher concentrations of chemotherapy by infusing cytotoxic agents via the hepatic artery. A 95% first-pass drug extraction with low systemic toxicity is achieved.4,5 We hypothesized that the portal vein (PV) infusion would provide perfusion of micrometastases not identifiable during pre- or intraoperative evaluation and high first-pass extraction.
5-Fluoro-2'-deoxyuridine (floxuridine [FUDR]) is an antimetabolite that is converted to fluorouracil (FU), thereby blocking thymidylate synthase, which interferes with DNA synthesis. Randomized, prospective trials comparing response rates in patients with unresected hepatic metastases treated with either systemic or hepatic arterial infusion (HAI) of FUDR have demonstrated a 30% to 45% advantage when treatment is delivered through the hepatic artery.6-8
Two randomized, controlled studies have concluded that HAI FUDR administered after resection of hepatic metastases prolongs the disease-free and liver-specific disease-free survival compared with systemic adjuvant therapy alone.9,10 Data from the Memorial Sloan-Kettering Cancer Center report 2-year survival rates free of hepatic recurrence of 90% for combined therapy and 60% for systemic therapy alone.9 This benefit was noted for patients having the poor prognostic features of more than three lesions, lesions greater than 5 cm, and a short interval to hepatic recurrence. Therefore, the PV is not useful in the treatment of macrometastatic disease because of the preferential arterial blood supply. In contrast, micrometastases receive their blood from the portal system.
In 1983, the first case of biliary sclerosis in a patient receiving FUDR by HAI was published.11 Since this initial observation, it has become clear that transaminitis, cholestasis, and biliary sclerosis occur with a regular frequency after HAI FUDR; however, the mechanism by which these changes occur is not yet clear. Histologic studies have implicated both direct hepatocyte toxicity as well as ischemic cholangiopathy as possible mechanisms for the observed biliary sclerosis.12,13 In addition, gastric and duodenal erosions, as well as pancreatitis, may occur if arterial perfusion to the liver is not isolated by devascularization of arterial tributaries arising from the common hepatic artery. These complications often lead to delays or termination of regional therapy.
The dual blood supply of the liver has allowed the investigation of the alternate delivery of FUDR by the PV route. In 1986, we initiated a feasibility study to evaluate PV delivery of FUDR after curative hepatic resection.14 The results of this initial pilot study proved that PV FUDR is well tolerated with few observed hepatic toxicities. In an effort to reduce the rate of hepatic and systemic recurrences, a subsequent protocol was initiated that doubled the chemotherapy dose-intensity by delivering regional and systemic therapies concomitantly. The end points of the follow-up trial included overall and disease-free survival and the incidence of hepatic toxicity requiring dose modification. Here, we present the combined data from these studies examining the safety, tolerance, and efficacy associated with PV FUDR. This is the largest series of patients treated with PV FUDR as definitive therapy after liver resection and/or ablation for colorectal cancer metastases.
PATIENTS AND METHODS
Fifty-one patients with histologically confirmed primary colorectal carcinoma with either synchronous or metachronous hepatic metastases were enrolled onto two sequential, phase II, nonrandomized, prospective trials. The goal of these trials was to evaluate the efficacy of continuous PV infusion of FUDR and systemic FU and leucovorin administered in a sequential schedule, either alternating or concurrent (overlapping) every month for 1 year. Patients had undergone prior surgical resection and/or ablation of hepatic colorectal metastases. The experimental protocols were approved by the City of Hope National Medical Center Institutional Review Board. Witnessed informed consent was obtained from all patients before surgery. A Karnofsky performance status greater than 60% was required. Total bilirubin greater than 2.0 mg/dL, prior liver radiation, and a history of prior noncolorectal malignancy within 5 years were considered exclusion criteria. Prior chemotherapy was allowed with no restriction on the type or number of regimens.
Planned Interventions
Surgical treatment. Patients between the ages of 18 and 70 years were determined to be surgical candidates based on preoperative abdominal/pelvic computed tomography, chest radiograph, physical examination, colonoscopy/barium enema, and liver function studies. Patients were excluded if evidence of extrahepatic disease was identified before or at the time of surgery, with the exception of local bowel recurrence and mesenteric adenopathy. A maximum of 15 hepatic lesions were allowed. The estimated residual hepatic parenchyma remaining after resection/ablation had to be 40%. Resection consisted of any combination of formal segmentectomy, lobectomy, or nonanatomic resection. The initial protocol, which accrued 22 patients, required resection. The subsequent protocol allowed hepatic disease to be managed with any combination of radiofrequency ablation, cryoablation, and/or surgical resection at the discretion of the surgeon. Cholecystectomy was routinely performed. Intraoperative ultrasound was used routinely after 1998.
An implanted drug delivery system (Infusaid 4000 pump; Infusaid Corp, Norwood, MA) was implanted in the subcutaneous tissues of the left hemi-abdomen or the left lower thorax. Catheters were inserted via the superior mesenteric vein and passed just proximal to the confluence of the right and left PVs or remnant lobar branch. The adequacy of hepatic perfusion was confirmed at the time of placement by infusion of fluorescein dye and Wood’s lamp visualization and before initiating PV FUDR by technetium-99 macroaggregated albumin scintigraphy.
Regional and systemic chemotherapy. The initial 22 patients (group A) were scheduled to undergo 12 monthly infusions consisting of one treatment of systemic FU/leucovorin alternating with one treatment of PV FUDR. Thus, group A was scheduled to receive six courses of systemic FU/leucovorin alternating monthly with six courses of PV FUDR.
Because the initial experience with this regimen demonstrated excellent tolerance with low hepatic toxicity, a follow-up protocol was developed to administer concurrent regional and systemic treatment doses. Hence, 29 patients were scheduled for a doubling of the dose density. This planned treatment consisted of 12 monthly cycles of PV FUDR administered concurrently with 12 monthly cycles of systemic FU/leucovorin, instead of alternating treatments for a total of six courses each.
FUDR was initiated at a dose of 0.2 mg/kg/d and escalated to 0.3 mg/kg/d on subsequent cycles if no grade 2 or greater toxicities were noted. The toxicities triggering FUDR dose reduction included nonliver toxicities such as mucositis or diarrhea. FUDR dose adjustments thereafter were based only on hepatic toxicities.
Systemic FU was administered at a dose of 300 mg/m2/d for 5 consecutive days. Patients received a continuous infusion of leucovorin at a dose of 500 mg/m2/d over 7 days beginning 1 day before the start of FU and ending 1 day after the completion of FU. Dose reduction of FU was based on associated toxicities. No dose reductions of leucovorin were made. Treatment was initiated when AST, ALT, alkaline phosphatase, and total bilirubin were less than three times the normal values after surgery.
Outcome Measurements
Biweekly CBC counts, liver function studies, and serum chemistry panels were monitored. Physical examination and carcinoembryonic antigen levels were performed on a monthly basis. Abdominal computed tomography scans were obtained every 3 months. Toxicities were defined and graded using the National Cancer Institute Common Toxicity Criteria version 2.0. Grade 2 hepatic toxicity was considered to be less than 1.5x normal serum bilirubin or 2.5 to 5.0x normal serum transaminase or alkaline phosphatase levels. Grade 3 toxicity was categorized as 1.5 to 3.0x normal serum bilirubin or 5.1 to 20.0x normal serum transaminase or alkaline phosphatase levels. Measured outcomes included overall and disease-free survival, sites of recurrence, number of completed PV infusions (either six or 12), incidence of transaminitis requiring dose reduction, and incidence of all toxicities.
Statistical Methods
Data for each protocol were pooled for this analysis. The mean and standard deviations of disease-free and overall survival were calculated to describe continuous variables from data collected prospectively. Plots were derived for actual disease-free and overall survival with 95% CIs to account for patient attrition.
RESULTS
Fifty percent of patients were male. Mean age at diagnosis was 57 years (range, 29 to 77 years). There were 42 colon and nine rectal primary tumors. Patients entered the protocol a median of 6 months after the time of diagnosis of their colorectal primary cancer. The median number of lesions resected was three (range, one to 11 lesions). The stages at diagnosis were II, III, and IV in 16.9%, 52.8%, and 28.3%, respectively. The 1- and 3-year overall survival rates were 92.7% and 41.8%, respectively. The median overall survival time was 30.4 months. One- and 3-year disease-free survival rates were 64.5% and 19%, respectively. Median progression-free survival time was 14.5 months.
The site of first recurrence was hepatic in 35.9% of patients. Treatment was terminated early in 24 patients (17 patients progressed, two refused further treatment, and five had nonhepatic toxicities). Twenty-three patients completed treatment with 12 courses of FUDR. Fifty-seven percent of patients received 75% to 100% of the planned FUDR courses, and 75% of patients received 50% or more of planned FUDR courses. Only four patients required dose reduction of FUDR because of grade 3 hepatic toxicity. A total of 10 grade 4 toxicities were identified, of which six were neutropenia and four were diarrhea. No episodes of pancreatitis were recorded. One case of grade 2 abdominal pain was caused by gastritis after the sixth course of concomitant therapy. The abdominal pain responded to oral proton pump inhibitor therapy and did not recur on subsequent treatment cycles. No episodes of gastrointestinal bleeding were recorded, and no patients required biliary stenting or were taken off PV infusion because of hepatic toxicity. Two patients (4%) developed PV thrombosis requiring 6 months of anticoagulation with no long-term sequelae. FUDR dose reduction was not required in either patient.
DISCUSSION
A prospective, randomized trial at the City of Hope using resection and intra-arterial FUDR demonstrated the efficacy of adjuvant regional therapy in preventing hepatic recurrence after curative resection.15 However, the survival benefit was limited by the development of sclerosing cholangitis. In 1985, a City of Hope experience with HAI FUDR for colorectal metastases was published, reporting a 16% incidence of sclerosing cholangitis and a 50% incidence of transaminitis requiring treatment delays or termination.16 Three patients went on to develop fatal hepatic failure, and three patients required drainage procedures (one patient died of this complication while remaining free of any cancer recurrence).
Hohn et al17 treated 35 patients with HAI FUDR, and all of the patients required dose reduction. Early termination of therapy secondary to hepatic toxicity was required in 15% of patients. In five patients with persistently elevated alkaline phosphatase, cholangiograms demonstrated varying degrees of biliary sclerosis involving the common hepatic duct. Two patients underwent cholecystectomy for presumed drug-induced cholecystitis. Intraoperative cholangiograms in these patients demonstrated focal narrowing of the proper hepatic ducts despite the absence of preoperative evidence of cholestasis. In addition, liver biopsies were obtained in three patients showing focal pericholangitis, whereas hepatocytes were noted to be relatively normal. Histologic examination of the cystic duct of a patient treated with HAI FUDR demonstrated an obliterative endarteritis and mural fibrosis.12 These findings suggest that the etiology for the extrahepatic biliary damage is associated with hepatic artery delivery and that pathologic biliary changes may manifest themselves despite normal liver function studies. This raises the question of whether the incidence of biliary sclerosis is underappreciated in patients receiving HAI.
Our previous experience and the experiences of others support the view that HAI FUDR carries a significant risk of biliary toxicity. In many cases, this toxicity limits the application of this valuable modality and, therefore, impacts on therapeutic efficacy. Strategies incorporating alternating courses of continuous infusions of FUDR with FU or saline have lowered the risk of biliary toxicity; however, it remains a significant morbidity.18
Animal studies comparing cholangiograms performed before and after PV infusion of FUDR failed to demonstrate changes consistent with biliary sclerosis despite ALT and alkaline phosphatase elevations similar to those achieved in HAI controls.19 Histologic examination revealed that the hepatic parenchyma infused by the PV lacked the bile duct fibrosis observed in specimens from animals infused via the hepatic artery.
Although randomized studies of unresected metastases that compare tumor response rates show HAI to be superior to PV FUDR, caution must be taken in extrapolating these results to patients who have undergone resection of gross metastatic disease.20 These studies have examined the effects of FUDR infusion on tumor size in unresected patients with measurable tumor metastases. Sufficient evidence exists to suggest that metastatic tumors are supplied by the arterial blood supply. However, the goal of PV infusion in the postresectional setting is to treat microscopic disease, which travels through the portal system and lodges in the portal venules. The advantage of arterial infusion may not be relevant in this scenario.
Our results show PV FUDR to be well tolerated with less hepatic toxicity than that observed with HAI FUDR. The low incidence of treatment delays and dose reductions may translate to a therapeutic advantage over HAI. This becomes of greater interest when considering patients with pre-existing hepatic insufficiency or small residual liver volumes, which may place them at greater risk of hepatic complications related to regional therapy. In addition, patients who may have experienced treatment-limiting toxicities related to previous HAI may be candidates for PV FUDR. The current intergroup North Central Cancer Treatment Group study has been written to limit the number of cycles of HAI FUDR to four in an effort to limit the incidence of hepatic toxicities.
It is important to point out that PV catheter placement is technically easier than arterial placement. The catheter used is the same as that used in the hepatic artery and is placed through an easily accessible jejunal branch feeding to the PV. The PV anatomy is far more constant than that of the hepatic arterial tree, which is subject to considerable variation. In addition, there is no need for ligation of feeding branches because there is no concern of drug delivery to adjacent organs, such as the pancreas and stomach, through collateral or redundant vessels. Isolated hepatic perfusion is confirmed intraoperatively by fluorescein infusion through the pump as well as with a microaggregated albumin scan before FUDR infusion.
More than half our patients received at least 75% of the planned courses of FUDR through the PV. This translates to at least 4.5 courses in the first trial and nine courses in the follow-up trial. This illustrates that PV FUDR is a well-tolerated route for therapy. The low incidence of toxicity with regard to pancreatitis and gastritis also supports this approach. In contrast, only 4% of patients received more than 75% of the projected dose delivered via HAI in the prospective randomized trial reported from Memorial Sloan-Kettering Cancer Center.9
Although the 3-year disease-free survival rate is only 19%, it is important to note that 80% of our patients presented with stage III and IV disease and nearly one third of our patients presented with stage IV disease. This patient population has been demonstrated to have a poor prognosis. Furthermore, the short interval between primary diagnosis and identification of hepatic disease also places this patient population in a higher risk stratum for recurrence and must be considered when evaluating the survival and recurrence outcomes presented.
A phase I/II study reporting combining HAI FUDR with systemic irinotecan achieved an 89% 2-year survival.21 The use of newer regimens for adjuvant systemic therapy after resection and/or ablation of liver metastases should be expected to be more effective than FU/leucovorin, particularly in patients previously treated with a fluoropyridine.
The PV as a route of administration for regional FUDR should be considered for those patients who may otherwise be at too high a risk for HAI as a result of pre-existing hepatic insufficiency or unfavorable arterial anatomy or who have demonstrated poor tolerance to previous HAI therapy. Phase I and II studies of newer chemotherapy agents delivered through the PV after liver resection may provide improved outcome survival data in patients with hepatic colorectal disease.
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by grant No. CA 33572.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Fong Y, Kemeny N, Paty P, et al: Treatment of colorectal cancer: Hepatic metastases. Semin Surg Oncol 12: 219-252, 1996
Fortner JG: Recurrence of colorectal cancer after hepatic resection. Am J Surg 155: 378-382, 1988
Breedis C, Young G: The blood supply of neoplasms in the liver. Am J Pathol 30: 969-977, 1954
Ensminger WD, Gyves JW: Clinical pharmacology of hepatic arterial chemotherapy. Semin Oncol 10: 176-182, 1983
Sigurdson ER, Ridge JA, Kemeny N, et al: Tumor and liver drug uptake following hepatic artery and portal vein infusion. J Clin Oncol 5: 1836-1840, 1987
Hohn DC, Stagg RJ, Friedman MA, et al: A randomized trial of continuous intravenous versus hepatic intraarterial floxuridine in patients with colorectal cancer metastatic to the liver: The Northern California Oncology Group trial. J Clin Oncol 7: 1646-1654, 1989
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: 685-693, 1987
Kemeny N, Daly J, Reichman B, et al: Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma: A randomized trial. Ann Intern Med 107: 459-465, 1987
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
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
Hohn D, Melnick J, Stagg R, et al: Biliary sclerosis in patients receiving hepatic arterial infusions of floxuridine. J Clin Oncol 3: 98-102, 1985
Haq MM, Valdes LG, Peterson DF, et al: Fibrosis of extrahepatic biliary system after continuous hepatic artery infusion of floxuridine through an implantable pump (Infusaid pump). Cancer 57: 1281-1283, 1986
Ludwig J, Kim CH, Wiesner RH, et al: Floxuridine-induced sclerosing cholangitis: An ischemic cholangiopathy? Hepatology 9: 215-218, 1989
Leong LA: Hepatic resection of colorectal cancer followed by portal vein infusion of fluorodeoxyuridine and systemic 5-fluorouracil and folinic acid. Proc Am Soc Clin Oncol 9: 107, 1990 (abstr 414)
Wagman LD, Kemeny MM, Leong L, et al: A prospective, randomized evaluation of the treatment of colorectal cancer metastatic to the liver. J Clin Oncol 8: 1885-1893, 1990
Kemeny MM, Battifora H, Blayney DW, et al: Sclerosing cholangitis after continuous hepatic artery infusion of FUDR. Ann Surg 202: 176-181, 1985
Hohn D, Melnick J, Stagg R, et al: Biliary sclerosis in patients receiving hepatic arterial infusions of floxuridine. J Clin Oncol 3: 98-102, 1985
Davidson BS, Izzo F, Chase JL, et al: Alternating floxuridine and 5-fluorouracil hepatic arterial chemotherapy for colorectal liver metastases minimizes biliary toxicity. Am J Surg 172: 244-247, 1996
Andrews JC, Kuntsen C, Terio P, et al: Hepatobiliary toxicity of 5-fluoro-2'-deoxyuridine: Intra-arterial versus portal venous routes of infusion. Invest Radiol 26: 461-464, 1991
Daly JM, Kemeny N, Sigurdson E, et al: Regional infusion for colorectal hepatic metastases: A randomized trial comparing the hepatic artery with the portal vein. Arch Surg 122: 1273-1277, 1987
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(Moshe Faynsod, Lawrence D)
ABSTRACT
PURPOSE: To determine whether floxuridine (FUDR) can be delivered with low hepatic toxicity through the portal vein (PV) as an adjuvant to surgically treated colorectal metastases.
PATIENTS AND METHODS: Fifty-one patients undergoing complete resection and/or ablation for colorectal hepatic metastases were prospectively enrolled at a National Cancer Institute–designated comprehensive cancer center. Two sequential phase II trials were performed. Each trial included complete surgical treatment followed by sequential, alternating (22 patients) or concurrent (29 patients) regional PV FUDR and systemic fluorouracil (FU) with leucovorin chemotherapy.
RESULTS: Fifty percent of patients were male. The mean age at diagnosis was 57 years. The mean number of lesions resected was three (range, one to 11 lesions). The stage at diagnosis was II, III, and IV in 16.9%, 52.8%, and 28.3% of patients, respectively. One- and 3-year overall survival rates were 92.7% and 41.8%, respectively. The 1- and 3-year disease-free survival rates were 64.5% and 19%, respectively. The site of first recurrence was hepatic in 35.9% of patients. Treatment was terminated early in 24 patients (17 patients progressed, two refused treatment, and five had nonhepatic toxicities). Fifty-five percent of patients received 75% to 100% of the planned FUDR courses, and 72% received greater than 50% of the planned FUDR dose. Only four patients required dose reductions of FUDR because of grade 3 hepatic toxicity. No patient required biliary stenting or had discontinuation of PV infusion because of hepatic toxicity.
CONCLUSION: The delivery of PV FUDR and FU with leucovorin can be performed with a high percentage of expected drug delivery and a low drug-induced hepatic toxicity rate, while achieving acceptable overall and disease-free survival.
INTRODUCTION
Despite improvements in surgical and ablative techniques for metastatic colorectal carcinoma to the liver, hepatic recurrence remains a major problem. The role of systemic therapy after surgical resection of hepatic disease has not yet demonstrated a clear advantage.1 Because the liver is the most common site of recurrence after resection of hepatic metastases, regional chemotherapy represents an attractive approach.2 In experimental and clinical models, macroscopic hepatic tumors greater than 0.5 to 1.0 cm derive their blood supply preferentially from the hepatic artery compared with normal hepatocytes.3 This differential blood supply may be exploited to achieve differential exposure of hepatic macrometastases to higher concentrations of chemotherapy by infusing cytotoxic agents via the hepatic artery. A 95% first-pass drug extraction with low systemic toxicity is achieved.4,5 We hypothesized that the portal vein (PV) infusion would provide perfusion of micrometastases not identifiable during pre- or intraoperative evaluation and high first-pass extraction.
5-Fluoro-2'-deoxyuridine (floxuridine [FUDR]) is an antimetabolite that is converted to fluorouracil (FU), thereby blocking thymidylate synthase, which interferes with DNA synthesis. Randomized, prospective trials comparing response rates in patients with unresected hepatic metastases treated with either systemic or hepatic arterial infusion (HAI) of FUDR have demonstrated a 30% to 45% advantage when treatment is delivered through the hepatic artery.6-8
Two randomized, controlled studies have concluded that HAI FUDR administered after resection of hepatic metastases prolongs the disease-free and liver-specific disease-free survival compared with systemic adjuvant therapy alone.9,10 Data from the Memorial Sloan-Kettering Cancer Center report 2-year survival rates free of hepatic recurrence of 90% for combined therapy and 60% for systemic therapy alone.9 This benefit was noted for patients having the poor prognostic features of more than three lesions, lesions greater than 5 cm, and a short interval to hepatic recurrence. Therefore, the PV is not useful in the treatment of macrometastatic disease because of the preferential arterial blood supply. In contrast, micrometastases receive their blood from the portal system.
In 1983, the first case of biliary sclerosis in a patient receiving FUDR by HAI was published.11 Since this initial observation, it has become clear that transaminitis, cholestasis, and biliary sclerosis occur with a regular frequency after HAI FUDR; however, the mechanism by which these changes occur is not yet clear. Histologic studies have implicated both direct hepatocyte toxicity as well as ischemic cholangiopathy as possible mechanisms for the observed biliary sclerosis.12,13 In addition, gastric and duodenal erosions, as well as pancreatitis, may occur if arterial perfusion to the liver is not isolated by devascularization of arterial tributaries arising from the common hepatic artery. These complications often lead to delays or termination of regional therapy.
The dual blood supply of the liver has allowed the investigation of the alternate delivery of FUDR by the PV route. In 1986, we initiated a feasibility study to evaluate PV delivery of FUDR after curative hepatic resection.14 The results of this initial pilot study proved that PV FUDR is well tolerated with few observed hepatic toxicities. In an effort to reduce the rate of hepatic and systemic recurrences, a subsequent protocol was initiated that doubled the chemotherapy dose-intensity by delivering regional and systemic therapies concomitantly. The end points of the follow-up trial included overall and disease-free survival and the incidence of hepatic toxicity requiring dose modification. Here, we present the combined data from these studies examining the safety, tolerance, and efficacy associated with PV FUDR. This is the largest series of patients treated with PV FUDR as definitive therapy after liver resection and/or ablation for colorectal cancer metastases.
PATIENTS AND METHODS
Fifty-one patients with histologically confirmed primary colorectal carcinoma with either synchronous or metachronous hepatic metastases were enrolled onto two sequential, phase II, nonrandomized, prospective trials. The goal of these trials was to evaluate the efficacy of continuous PV infusion of FUDR and systemic FU and leucovorin administered in a sequential schedule, either alternating or concurrent (overlapping) every month for 1 year. Patients had undergone prior surgical resection and/or ablation of hepatic colorectal metastases. The experimental protocols were approved by the City of Hope National Medical Center Institutional Review Board. Witnessed informed consent was obtained from all patients before surgery. A Karnofsky performance status greater than 60% was required. Total bilirubin greater than 2.0 mg/dL, prior liver radiation, and a history of prior noncolorectal malignancy within 5 years were considered exclusion criteria. Prior chemotherapy was allowed with no restriction on the type or number of regimens.
Planned Interventions
Surgical treatment. Patients between the ages of 18 and 70 years were determined to be surgical candidates based on preoperative abdominal/pelvic computed tomography, chest radiograph, physical examination, colonoscopy/barium enema, and liver function studies. Patients were excluded if evidence of extrahepatic disease was identified before or at the time of surgery, with the exception of local bowel recurrence and mesenteric adenopathy. A maximum of 15 hepatic lesions were allowed. The estimated residual hepatic parenchyma remaining after resection/ablation had to be 40%. Resection consisted of any combination of formal segmentectomy, lobectomy, or nonanatomic resection. The initial protocol, which accrued 22 patients, required resection. The subsequent protocol allowed hepatic disease to be managed with any combination of radiofrequency ablation, cryoablation, and/or surgical resection at the discretion of the surgeon. Cholecystectomy was routinely performed. Intraoperative ultrasound was used routinely after 1998.
An implanted drug delivery system (Infusaid 4000 pump; Infusaid Corp, Norwood, MA) was implanted in the subcutaneous tissues of the left hemi-abdomen or the left lower thorax. Catheters were inserted via the superior mesenteric vein and passed just proximal to the confluence of the right and left PVs or remnant lobar branch. The adequacy of hepatic perfusion was confirmed at the time of placement by infusion of fluorescein dye and Wood’s lamp visualization and before initiating PV FUDR by technetium-99 macroaggregated albumin scintigraphy.
Regional and systemic chemotherapy. The initial 22 patients (group A) were scheduled to undergo 12 monthly infusions consisting of one treatment of systemic FU/leucovorin alternating with one treatment of PV FUDR. Thus, group A was scheduled to receive six courses of systemic FU/leucovorin alternating monthly with six courses of PV FUDR.
Because the initial experience with this regimen demonstrated excellent tolerance with low hepatic toxicity, a follow-up protocol was developed to administer concurrent regional and systemic treatment doses. Hence, 29 patients were scheduled for a doubling of the dose density. This planned treatment consisted of 12 monthly cycles of PV FUDR administered concurrently with 12 monthly cycles of systemic FU/leucovorin, instead of alternating treatments for a total of six courses each.
FUDR was initiated at a dose of 0.2 mg/kg/d and escalated to 0.3 mg/kg/d on subsequent cycles if no grade 2 or greater toxicities were noted. The toxicities triggering FUDR dose reduction included nonliver toxicities such as mucositis or diarrhea. FUDR dose adjustments thereafter were based only on hepatic toxicities.
Systemic FU was administered at a dose of 300 mg/m2/d for 5 consecutive days. Patients received a continuous infusion of leucovorin at a dose of 500 mg/m2/d over 7 days beginning 1 day before the start of FU and ending 1 day after the completion of FU. Dose reduction of FU was based on associated toxicities. No dose reductions of leucovorin were made. Treatment was initiated when AST, ALT, alkaline phosphatase, and total bilirubin were less than three times the normal values after surgery.
Outcome Measurements
Biweekly CBC counts, liver function studies, and serum chemistry panels were monitored. Physical examination and carcinoembryonic antigen levels were performed on a monthly basis. Abdominal computed tomography scans were obtained every 3 months. Toxicities were defined and graded using the National Cancer Institute Common Toxicity Criteria version 2.0. Grade 2 hepatic toxicity was considered to be less than 1.5x normal serum bilirubin or 2.5 to 5.0x normal serum transaminase or alkaline phosphatase levels. Grade 3 toxicity was categorized as 1.5 to 3.0x normal serum bilirubin or 5.1 to 20.0x normal serum transaminase or alkaline phosphatase levels. Measured outcomes included overall and disease-free survival, sites of recurrence, number of completed PV infusions (either six or 12), incidence of transaminitis requiring dose reduction, and incidence of all toxicities.
Statistical Methods
Data for each protocol were pooled for this analysis. The mean and standard deviations of disease-free and overall survival were calculated to describe continuous variables from data collected prospectively. Plots were derived for actual disease-free and overall survival with 95% CIs to account for patient attrition.
RESULTS
Fifty percent of patients were male. Mean age at diagnosis was 57 years (range, 29 to 77 years). There were 42 colon and nine rectal primary tumors. Patients entered the protocol a median of 6 months after the time of diagnosis of their colorectal primary cancer. The median number of lesions resected was three (range, one to 11 lesions). The stages at diagnosis were II, III, and IV in 16.9%, 52.8%, and 28.3%, respectively. The 1- and 3-year overall survival rates were 92.7% and 41.8%, respectively. The median overall survival time was 30.4 months. One- and 3-year disease-free survival rates were 64.5% and 19%, respectively. Median progression-free survival time was 14.5 months.
The site of first recurrence was hepatic in 35.9% of patients. Treatment was terminated early in 24 patients (17 patients progressed, two refused further treatment, and five had nonhepatic toxicities). Twenty-three patients completed treatment with 12 courses of FUDR. Fifty-seven percent of patients received 75% to 100% of the planned FUDR courses, and 75% of patients received 50% or more of planned FUDR courses. Only four patients required dose reduction of FUDR because of grade 3 hepatic toxicity. A total of 10 grade 4 toxicities were identified, of which six were neutropenia and four were diarrhea. No episodes of pancreatitis were recorded. One case of grade 2 abdominal pain was caused by gastritis after the sixth course of concomitant therapy. The abdominal pain responded to oral proton pump inhibitor therapy and did not recur on subsequent treatment cycles. No episodes of gastrointestinal bleeding were recorded, and no patients required biliary stenting or were taken off PV infusion because of hepatic toxicity. Two patients (4%) developed PV thrombosis requiring 6 months of anticoagulation with no long-term sequelae. FUDR dose reduction was not required in either patient.
DISCUSSION
A prospective, randomized trial at the City of Hope using resection and intra-arterial FUDR demonstrated the efficacy of adjuvant regional therapy in preventing hepatic recurrence after curative resection.15 However, the survival benefit was limited by the development of sclerosing cholangitis. In 1985, a City of Hope experience with HAI FUDR for colorectal metastases was published, reporting a 16% incidence of sclerosing cholangitis and a 50% incidence of transaminitis requiring treatment delays or termination.16 Three patients went on to develop fatal hepatic failure, and three patients required drainage procedures (one patient died of this complication while remaining free of any cancer recurrence).
Hohn et al17 treated 35 patients with HAI FUDR, and all of the patients required dose reduction. Early termination of therapy secondary to hepatic toxicity was required in 15% of patients. In five patients with persistently elevated alkaline phosphatase, cholangiograms demonstrated varying degrees of biliary sclerosis involving the common hepatic duct. Two patients underwent cholecystectomy for presumed drug-induced cholecystitis. Intraoperative cholangiograms in these patients demonstrated focal narrowing of the proper hepatic ducts despite the absence of preoperative evidence of cholestasis. In addition, liver biopsies were obtained in three patients showing focal pericholangitis, whereas hepatocytes were noted to be relatively normal. Histologic examination of the cystic duct of a patient treated with HAI FUDR demonstrated an obliterative endarteritis and mural fibrosis.12 These findings suggest that the etiology for the extrahepatic biliary damage is associated with hepatic artery delivery and that pathologic biliary changes may manifest themselves despite normal liver function studies. This raises the question of whether the incidence of biliary sclerosis is underappreciated in patients receiving HAI.
Our previous experience and the experiences of others support the view that HAI FUDR carries a significant risk of biliary toxicity. In many cases, this toxicity limits the application of this valuable modality and, therefore, impacts on therapeutic efficacy. Strategies incorporating alternating courses of continuous infusions of FUDR with FU or saline have lowered the risk of biliary toxicity; however, it remains a significant morbidity.18
Animal studies comparing cholangiograms performed before and after PV infusion of FUDR failed to demonstrate changes consistent with biliary sclerosis despite ALT and alkaline phosphatase elevations similar to those achieved in HAI controls.19 Histologic examination revealed that the hepatic parenchyma infused by the PV lacked the bile duct fibrosis observed in specimens from animals infused via the hepatic artery.
Although randomized studies of unresected metastases that compare tumor response rates show HAI to be superior to PV FUDR, caution must be taken in extrapolating these results to patients who have undergone resection of gross metastatic disease.20 These studies have examined the effects of FUDR infusion on tumor size in unresected patients with measurable tumor metastases. Sufficient evidence exists to suggest that metastatic tumors are supplied by the arterial blood supply. However, the goal of PV infusion in the postresectional setting is to treat microscopic disease, which travels through the portal system and lodges in the portal venules. The advantage of arterial infusion may not be relevant in this scenario.
Our results show PV FUDR to be well tolerated with less hepatic toxicity than that observed with HAI FUDR. The low incidence of treatment delays and dose reductions may translate to a therapeutic advantage over HAI. This becomes of greater interest when considering patients with pre-existing hepatic insufficiency or small residual liver volumes, which may place them at greater risk of hepatic complications related to regional therapy. In addition, patients who may have experienced treatment-limiting toxicities related to previous HAI may be candidates for PV FUDR. The current intergroup North Central Cancer Treatment Group study has been written to limit the number of cycles of HAI FUDR to four in an effort to limit the incidence of hepatic toxicities.
It is important to point out that PV catheter placement is technically easier than arterial placement. The catheter used is the same as that used in the hepatic artery and is placed through an easily accessible jejunal branch feeding to the PV. The PV anatomy is far more constant than that of the hepatic arterial tree, which is subject to considerable variation. In addition, there is no need for ligation of feeding branches because there is no concern of drug delivery to adjacent organs, such as the pancreas and stomach, through collateral or redundant vessels. Isolated hepatic perfusion is confirmed intraoperatively by fluorescein infusion through the pump as well as with a microaggregated albumin scan before FUDR infusion.
More than half our patients received at least 75% of the planned courses of FUDR through the PV. This translates to at least 4.5 courses in the first trial and nine courses in the follow-up trial. This illustrates that PV FUDR is a well-tolerated route for therapy. The low incidence of toxicity with regard to pancreatitis and gastritis also supports this approach. In contrast, only 4% of patients received more than 75% of the projected dose delivered via HAI in the prospective randomized trial reported from Memorial Sloan-Kettering Cancer Center.9
Although the 3-year disease-free survival rate is only 19%, it is important to note that 80% of our patients presented with stage III and IV disease and nearly one third of our patients presented with stage IV disease. This patient population has been demonstrated to have a poor prognosis. Furthermore, the short interval between primary diagnosis and identification of hepatic disease also places this patient population in a higher risk stratum for recurrence and must be considered when evaluating the survival and recurrence outcomes presented.
A phase I/II study reporting combining HAI FUDR with systemic irinotecan achieved an 89% 2-year survival.21 The use of newer regimens for adjuvant systemic therapy after resection and/or ablation of liver metastases should be expected to be more effective than FU/leucovorin, particularly in patients previously treated with a fluoropyridine.
The PV as a route of administration for regional FUDR should be considered for those patients who may otherwise be at too high a risk for HAI as a result of pre-existing hepatic insufficiency or unfavorable arterial anatomy or who have demonstrated poor tolerance to previous HAI therapy. Phase I and II studies of newer chemotherapy agents delivered through the PV after liver resection may provide improved outcome survival data in patients with hepatic colorectal disease.
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by grant No. CA 33572.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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