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© 2001 American Society for Clinical Oncology Phase I Study of Hepatic Arterial Infusion of Floxuridine and Dexamethasone With Systemic Irinotecan for Unresectable Hepatic Metastases From Colorectal CancerFrom the Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Nancy E. Kemeny, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.
PURPOSE: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities of concurrent systemic irinotecan and hepatic arterial infusion (HAI) of floxuridine (FUDR) and dexamethasone in patients with unresectable hepatic metastases from colorectal cancer, to determine the safety of this combination in patients who have undergone cryosurgery, and to evaluate the pharmacokinetic effects of HAI FUDR on the metabolism of irinotecan. PATIENTS AND METHODS: Forty-six previously treated patients with unresectable liver metastases and no known extrahepatic disease were treated concurrently with intravenous irinotecan weekly for 3 weeks and with HAI of FUDR and dexamethasone for 14 days (both were recycled in 28 days). Parallel cohorts of patients treated with or without cryosurgery were entered at escalating dose levels. RESULTS: The MTD for patients who did not undergo cryosurgery was 100 mg/m2 of irinotecan weekly for 3 weeks every 4 weeks with concurrent HAI FUDR (0.16 mg/kg/d x pump volume/flow rate) plus dexamethasone for 14 days of a 28-day cycle. The dose-limiting toxicities were diarrhea and neutropenia. The response rate (complete and partial) among all patients who did not undergo cryosurgery was 74%. All patients in the cryosurgery group responded, and seven of the eight cryosurgery patients developed normal positron emission tomography scans after chemotherapy. HAI FUDR had no effect on the metabolism of irinotecan. CONCLUSION: Combination therapy with HAI FUDR and dexamethasone plus systemic irinotecan may be safely administered to patients with unresectable hepatic metastases from colorectal cancer. The MTD has been reached for patients with unresectable disease, and we continue to investigate the MTD for patients who have undergone cryosurgery. Although the main objective of this study was to evaluate the toxicity of the combined regimen, a high response rate (74%) was observed.
SIXTY PERCENT of patients with colorectal carcinoma develop liver metastases during the treatment of their disease; the median survival for untreated patients is 6 to 12 months. The outlook has been poor for patients with this diagnosis, and treatment options have been limited. Over the last few years, however, significant progress has been made. New chemotherapeutic agents have been developed, and improved resection techniques have increased the number of patients who are considered suitable surgical candidates. In addition, advances in ablative procedures and the delivery of regional chemotherapy have further expanded the options available for the treatment of hepatic metastases. Traditional systemic chemotherapy regimens (ie, fluorouracil [FU] either alone or in combination with leucovorin [LV]) have yielded response rates of approximately 20% and 1-year and 2-year survival rates of 50% and 20%, respectively.1 With the development of new agents such as irinotecan and oxaliplatin, response rates and progression-free survival rates have improved modestly, but 2-year survival is still only 25% in previously untreated patients.2,3 For patients whose metastases are confined to the liver, surgical resection significantly increases survival, with 30% alive at 5 years.4 Resection is considered the optimal treatment approach and is being performed more often as surgical techniques are improved. When resection is not possible, either because of the number or the location of the lesions, cryosurgery (a freeze/thaw process designed to destroy tumor cells) has been suggested as a useful alternative.5 Another option for patients with unresectable disease is the administration of hepatic arterial infusion (HAI) therapy with floxuridine (FUDR) combined with LV, dexamethasone, or both.6-8 Many studies have shown the usefulness of each of these therapies for the treatment of metastatic colorectal cancer. However, each has its own set of drawbacks. Cryosurgery can be used only in limited situations and may not provide complete eradication of tumor cells. HAI therapy may cause biliary toxicity and cannot protect the body against recurrences outside the liver.6-8 Systemic therapy has only modest response rates and effect on survival. We reasoned that a more effective approach may be a combination of two or more of these treatments. Therefore, with the aim of further improving outcomes for patients with unresectable hepatic metastases, we designed a study built on the most promising aspects of each of the three modalities. This phase I study added HAI therapy with FUDR and dexamethasone to systemic therapy with irinotecan to treat metastatic disease confined to the liver both in patients who were candidates for cryosurgery and in those who were not. (The two groups were treated concurrently with equivalent dose-escalation schedules but in independent cohorts so that we could discern potential differences in the toxicity profiles attributable to the cryosurgery.) Pharmacokinetic assessments were performed to determine the effect, if any, of HAI FUDR on the metabolism of irinotecan, including its conversion to its active metabolite, SN-38. In addition, positron emission tomography (PET) scans were performed in selected patients after cryosurgery to evaluate the role of this diagnostic modality in detecting residual tumor activity. Our goal was to assess the tolerability and effectiveness of these combined regimens and ensure that there were no contraindications to their joint administration.
Patients All patients had histologically confirmed colorectal carcinoma with unresectable liver metastases comprising less than 70% of the liver parenchyma and no evidence of extrahepatic disease. To be eligible, patients were required to have disease measurable by computed tomography (CT) and meet the following laboratory conditions: leukocyte count greater than 3,500 cells per cubic millimeter, platelet count greater than 150,000 cells per cubic millimeter, albumin greater than 2.0 g/dL, and total bilirubin less than 2.0 mg/dL. Prior radiation to the liver was not permitted. Other criteria included performance status 60% or greater and the absence of infection or ascites. Prior treatment with systemic chemotherapy was required. The protocol for this study was approved by our institutional review board. Each patient submitted written informed consent before surgery (for pump placement and cryosurgery, if possible). All patients had a preoperative chest radiograph (posteroanterior and lateral views), CT of the abdomen and pelvis, baseline complete blood cell count, carcinoembryonic antigen (CEA), lactate dehydrogenase (LDH), alkaline phosphatase, AST, total bilirubin, albumin, and creatinine. CT was used to determine the percentage of liver involvement by tumor and to assess response. Cryosurgery candidates underwent preoperative PET scans. Eligibility for cryosurgery, determined before registration onto the study, was based on the following criteria: fewer than eight hepatic metastases visualized on CT and no single metastasis greater than 5 cm. Patients were placed into one of two cohorts, depending on whether or not they were able to undergo cryosurgery. Patients who were preoperatively candidates for cryosurgery, but were not able to undergo this procedure, were allowed to remain on the study and were added to the noncryosurgery group of patients. As a result, each dose level contains a minimum of three patients, with a varying maximum number. All patients underwent hepatic arteriography that included the celiac trunk and superior mesenteric artery to evaluate hepatic blood supply and identify branches to the stomach and duodenum. Patients with significant arterial anomalies that would preclude complete liver perfusion were excluded. All patients underwent laparotomy for the placement of an internal pump (manufactured by Arrow International, Walpole, MA), whose mechanism and preparation have been previously described.9 At laparotomy, patients’ para-aortic and portal lymph nodes were explored, biopsies of suspicious areas were obtained, and cryosurgery was performed, if applicable. All patients underwent cholecystectomy if this had not been performed previously. The pump was placed in a subcutaneous abdominal wall pocket. In patients with normal arterial anatomy, the pump’s catheter was inserted into the gastroduodenal artery and positioned at the junction of the proper and the common hepatic arteries. The distal gastroduodenal artery, the right gastric artery, small branches supplying the stomach or duodenum, and all accessory hepatic arteries were ligated. In patients with two dominant arterial supplies to the liver, one artery was ligated to facilitate cross-filling. After surgery, a perfusion study with technetium-99–macroaggregated albumin via the pump’s sideport was compared with a standard sulfur-colloid liver/spleen scan to confirm that the distribution of the pump effluent was confined to the liver.
Toxicity and Response Assessment
Responses in those patients who did not undergo cryosurgery were assessed with CT of the abdomen obtained at 2-month intervals. All responses were confirmed by a reference radiologist (L.S.). A complete response required the complete disappearance of all disease on CT and normalization of CEA levels. A partial response (PR) denoted a reduction of
Chemotherapy Administration
Dose Modifications
Cryosurgery Guidelines Cryosurgery was guided by intraoperative ultrasound; probes were inserted into the center of the tumors and the lesions frozen to 1 cm beyond the tumor edge. Adjacent organs—including the stomach, colon, and diaphragm—were protected from the freezing probe by warm packs. Each lesion was treated with a total of two or three freeze/thaw cycles that lasted approximately 10 to 15 minutes apiece.
Pharmacokinetic Assessment
Statistical Methods Dose escalation of FUDR was planned to take place only after the MTD or the intended maximum dose level of irinotecan had been reached. A cohort of at least three patients was planned at each dose level in each of the two treatment groups (those who did or did not undergo cryosurgery). Survival analysis was performed with Kaplan-Meier methods, whereas comparisons of toxicity and pharmacokinetic parameters were made by rank correlation and Wilcoxon tests.11,12 All P values were computed with the exact permutation distributions. The analyses were performed by pooling the data over the different dose groups.
Patient Characteristics Forty-six patients with unresectable liver metastases from colorectal cancer were entered. All of the 38 patients who did not undergo cryosurgery had received prior FU-based chemotherapy; 16 patients had two prior regimens, and 16 had previously received irinotecan. Median liver involvement was 35% (range, 10% to 60%), median CEA was 101 ng/dL (range, 2.5 to 25,233 ng/dL), and median LDH was 234 mg/dL (range, 114 to 729 mg/dL). Of the eight patients who underwent cryosurgery, all but one patient had prior chemotherapy, and two had received prior irinotecan. Median liver involvement was 30% (range, 10% to 40%), median CEA was 5.2 ng/dL (range, 2.5 to 418.6 ng/dL), and median LDH was 191 mg/dL (range, 126 to 298 mg/dL). Other patient characteristics are listed in Table 2.
Toxicity and Complications Systemic toxicities were analyzed by dose level and are listed in Table 3. Grade 3 or 4 systemic toxicities are presented during the first two treatment cycles and then any toxicities thereafter. The MTD of this combination was irinotecan at 100 mg/m2 for 3 weeks and FUDR at 0.16 mg/kg/d, because at a higher dose of irinotecan (125 mg/m2), two patients had grade 3 or 4 diarrhea, one patient had grade 2 diarrhea and malaise, and another patient developed a peptic ulcer.
The most frequent HAI therapy-related toxicity to occur during the first 2 months of treatment was an increase in hepatic enzymes (Table 4). No patient had a bilirubin level greater than 3.0 mg/dL during the first 2 months of treatment. Two patients developed bilirubin elevation: one 4 months and the other 15 months after the initiation of treatment. The bilirubin elevation initially resolved in these two patients, but the bilirubin again increased and required stent placement 20 months after the initiation of treatment in one patient. The hepatic toxicity for patients who underwent cryosurgery is also listed in Table 4.
Three patients experienced pump complications. Early in the study, there was a mechanical malfunction of the pump that necessitated pump removal and replacement in two patients. We later modified our technique for priming the pump, and no further pump malfunctions occurred. In a third patient, unrecognized extrahepatic perfusion led to the development of a gastric ulcer.
Response
Eight patients underwent cryosurgery, and all underwent preoperative PET. Four patients had PET scans within 4 weeks after surgery and in two, the scans were still positive. PET scans were available on all patients after two cycles of HAI. In seven of eight patients, the PET scans became negative. In the remaining patient with multiple PET-positive lesions after cryosurgery, the scan revealed only one remaining PET-positive lesion after two cycles of HAI and systemic treatment. The CT scans of all the patients after cryosurgery showed multiple low-attenuation lesions, so it was difficult to say whether the lesions were defects from cryosurgery or residual disease. CEA, which was elevated in all eight patients before surgery, decreased but remained increased in four patients after cryosurgery. After HAI and systemic chemotherapy, CEA decreased further in all but two patients.
Progression and Survival
In the group that underwent HAI plus systemic therapy and cryosurgery, median time to progression in any site was 17.3 months (lower confidence limit, 8.2 months). It is important to note that one patient had positive lymph nodes identified and resected at surgery. Three patients (38%) showed disease progression in the liver. Extrahepatic progression was observed in five patients. Sites of progression were lung (n = 5) and the adrenal gland (n = 1). Median time to hepatic progression was 17.3 months (upper confidence limit not yet reached). The median survival for these patients has not yet been reached; there has been only one death. The median follow-up time was 26.4 months (range, 15.2 to 35.5 months); all of these patients were alive at 1 year.
Pharmacokinetics
Rank correlations were computed between diarrhea and the AUCs of irinotecan, SN-38, and SN-38G. This was repeated for liver toxicity as well. The highest absolute value of the correlations was 0.14, which implies no association between AUC and toxicity. Wilcoxon tests were used to test differences in mean AUC (irinotecan, SN-38, and SN-38G) between those who experienced toxicity and those who did not. None of the pairs showed a significant difference (lowest P = 0.4672), nor was there evidence of any association between response and AUCs of irinotecan, SN-38, and SN-38G (highest correlation, 0.19; lowest P = 0.39). No difference in AUC was detected between the two groups of patients (with and without cryosurgery) at the dose levels tested.
Liver metastases cause significant morbidity and mortality for patients with colorectal carcinoma. The average median survival is 6 to 12 months, with fewer than 1% of patients alive at 5 years. With recent advances in surgical techniques, liver resection is now performed much more often and produces a 5-year survival as great as 30%.4 Unfortunately, resection is possible only in patients who have a limited number of lesions in locations amenable to surgery. This excludes most patients with hepatic metastases. Some of these patients are able to undergo ablative techniques, such as cryosurgery or radiofrequency ablation. However, because of the technical limitations of the currently available cryosurgical instruments, most surgeons today will freeze no single lesion greater than 5 centimeters in diameter and no more than four lesions.5 Traditionally, the survival benefit for colorectal cancer patients with unresectable liver metastases treated with intravenous FU-based chemotherapy alone has not been impressive. Median survival for patients is 12 months, with 50% of patients alive at 1 year and 20% alive at 2 years.2 Adding irinotecan to the FU regimen has modestly improved the median survival to approximately 15 months and 1- and 2-year survivals to 60% and 25%, respectively, in previously untreated patients. Less benefit is observed when irinotecan is administered as second-line therapy. Median survival for these patients was 9.2 months, and 1-year survival was only 36%.13 By taking advantage of the liver’s dual blood supply and evidence that metastatic deposits are fed by the hepatic artery, whereas normal liver tissue is supplied by the portal vein,14 HAI therapy has been shown to produce high response rates. Unfortunately, some randomized studies have not demonstrated a significant survival benefit, possibly because of the cross-over option permitted in some studies or to small sample sizes in others. Nevertheless, a meta-analysis did suggest an increase in median survival of 16 v 12 months in favor of HAI.15 This finding was sufficient to encourage us to continue addressing the two issues that have detracted from the more obvious benefits of HAI therapy, ie, hepatic toxicity and systemic recurrences. The addition of dexamethasone to FUDR significantly improved tolerance and a showed trend toward improved survival. Also, careful monitoring of fluctuations in hepatic enzymes has decreased the hepatic toxicity associated with HAI.16 In this study, toxicity attributable to HAI therapy was mild. In particular, an increase in total bilirubin, indicative of potentially severe hepatic damage, was not observed in any patient at any dose level during the first two cycles. Two patients did eventually show an increase, but one had progressive liver disease at the time, and it would be difficult to establish whether the increase was caused by toxicity or by the underlying metastatic disease. The other patient developed jaundice 15 months after the initiation of HAI therapy. In all patients, liver enzyme elevations were minimal and were reversed with dose modification. In response to the second factor mitigating the success of HAI therapy—lack of control over recurrences outside the liver—for the past several years we have been investigating the concomitant administration of systemic therapy. In a recently reported randomized study comparing HAI plus systemic therapy with systemic therapy alone after liver resection, although hepatic recurrence was significantly reduced with HAI, the development of lung metastases remained similar in both study arms.17 In the above study, which opened in 1991, the systemic therapy used was FU and LV. Since then, studies have shown that tumors with high thymidylate synthase (TS) levels preclude a response to FU.18 This was an important finding with regard to the treatment of lung metastases, which we now know often produce increased levels of TS.19 Therefore, to minimize recurrences in the lung—a common site for colorectal metastases—a systemic agent with an alternative mechanism would be required. We believed that the topoisomerase inhibitor irinotecan, an agent whose activity is not precluded by elevated TS, might provide better control over extrahepatic recurrences.20 In this study, the rate of systemic disease progression was still high in both the cryosurgery and noncryosurgery groups. However, 13% of the patients had extrahepatic disease at the time of pump implant. Our ongoing phase II study will further explore the efficacy of systemic irinotecan to control extrahepatic recurrences when it is given in conjunction with HAI. For patients who have had previous chemotherapy, response rates to subsequent systemic therapy regimens have generally been low; with irinotecan alone, the response rate is 15% to 20%.21,22 However, HAI therapy with FUDR, LV, and dexamethasone has produced a 52% response rate and a median survival of 13.5 months in previously treated patients.23 The current regimen also used on previously treated patients (42% of whom had received > one prior regimen) yielded a response rate of 74% and a median survival of 17.2 months. Sixty-five percent of patients were alive at 1 year, and responses were seen at all dose levels. Although we should not compare groups retrospectively, it is interesting to note that the patient populations in this study and the prior HAI study had similar mean percentages of liver involvement (35% and 37.5%, respectively) and that all patients were previously treated. Although cryosurgery is an effective palliation, it is unlikely to be curative while used on its own. In one study, 75% of 67 patients treated solely by this method showed increases in their postoperative CEA level within 6 months.24 Clearly, subsequent treatment with therapy targeting residual hepatic disease is warranted. In our study, remaining malignant cells in the liver after cryosurgery were evident by abnormal postoperative PET scans in some patients and by a continued increased CEA in half of the patients. Subsequent normalization of PET images and of CEA in most patients after treatment with both HAI and systemic therapy suggests that the combination of HAI FUDR and systemic irinotecan may allow the removal of some remaining tumor cells. One of our goals was to establish the feasibility of administering systemic irinotecan in tandem with HAI FUDR. It was demonstrated that the toxicity pattern and metabolic pathways of irinotecan and FUDR are sufficiently distinct to allow nearly full doses of these drugs to be given concurrently. In the group that did not undergo cryosurgery, the MTD of irinotecan was 100 mg/m2 given weekly for 3 weeks with 1 week off. This, cumulatively, is nearly equivalent to the standard dose of 125 mg/m2 given weekly for 4 weeks with 2 weeks off (there is a difference of only 10% over a 3-month period). The MTD of FUDR was 0.16 mg/kg/d (see Chemotherapy Administration), which is comparable to the 0.30-mg/kg/d dose reported in older studies before adjustments for pump volume and flow rate were factored into the dose calculation. Dose escalation still continues for the cryosurgery group. Further confirmation of discrete metabolic pathways is provided by the pharmacokinetic analysis. A previously reported study had suggested that FU reduced the degree of catabolism of irinotecan to SN-38, presumably by interfering with the function of the carboxylesterase that catalyzes this conversion.25 However, these data were based on a relatively small number of patients and were derived by comparing data from patients receiving irinotecan and FU to historical data from other patients who had received irinotecan alone. Additionally, the results reported by Saltz et al26 did not demonstrate that FU reduced the catabolism of SN-38. We were concerned that exposure to FUDR in the liver (where most of the carboxylesterase is) might have some effect on the conversion of irinotecan to SN-38. Therefore, we obtained baseline pharmacokinetic data for irinotecan before HAI and then repeated the studies after 2 weeks of HAI FUDR therapy. In this study, there was no meaningful difference in the Cmax or AUCs of irinotecan between the first and second set of samples in each treatment group. For SN-38, there was a slight, though not significant, decrease in levels. We observed an increase in the mean AUCs of irinotecan with increasing doses, but the mean AUCs of SN-38 flattened after the 80-mg/m2 dose of irinotecan (Fig 2). This suggests that the converting enzyme (carboxylesterase) may reach saturation. However, these numbers are too small for a meaningful comparison. Our results do indicate that there is no significant deleterious pharmacokinetic effect of FUDR on irinotecan or its metabolic pathway. The optimal strategy for patients with only liver metastases from colorectal cancer remains the complete resection of hepatic disease. For those patients unable to undergo resection, the best outcome may be achieved with a combination of therapeutic modalities. Although cryosurgery seems to be a treatment modality for those patients in whom resection is not feasible, it is often not curative, and adjuvant chemotherapy after cryosurgery, especially therapy targeting the liver, may be useful. Those patients who cannot undergo cryosurgery because of the size, number, or location of their liver lesions may also benefit from a combination of regional and systemic therapies. Because the usefulness of HAI FUDR therapy in controlling liver metastases in resectable and unresectable disease has previously been determined, the search for the optimal companion systemic agent to use in combination with HAI FUDR is the primary focus of current studies. This phase I study of sequentially escalated HAI FUDR and systemic irinotecan has demonstrated that the combination of HAI FUDR and dexamethasone plus systemic irinotecan in patients with unresectable disease is well tolerated. For each drug, the MTD was similar to the dose conventionally given when the drug is administered as a single agent. We are still escalating doses in the cryosurgery group. So far, the combined regimen of irinotecan 80 mg/m2 and FUDR 0.12 mg/kg/d has been well tolerated and has eradicated residual malignant cells from the liver in some of the patients. For patients ineligible for cryosurgery, the combined regional and systemic approach may also be beneficial. Although this trial was not designed to establish efficacy, it seems that both the response rate and survival may be enhanced by the combination of HAI FUDR and dexamethasone plus irinotecan. We are strongly encouraged by the 74% response rate seen in this phase I study. Our ongoing phase II study will more fully characterize the effectiveness of this regimen in both previously treated and untreated populations. Additional studies should explore combinations of other systemic agents or combinations of new agents in conjunction with HAI therapy.
Supported by grant no. 5R01CA61524 from the National Cancer Institute.
1. Advanced Colorectal Cancer Meta-Analysis Project: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: Evidence in terms of response rate. J Clin Oncol 10:896-903, 1992
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Saltz LB, Cox JV, Blank C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343: 905-914, 2000
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De Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line as first treatment in advanced colorectal cancer. J Clin Oncol 18: 2938-2947, 2000
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Fong Y, Cohen AM, Fortner JG, et al: Liver resection for colorectal metastases. J Clin Oncol 15: 938-946, 1997 5. Ravikumar TS, Kane R, Cady B, et al: A 5-year study of cryosurgery in the treatment of liver tumors. Arch Surg 126: 1520-1523, 1991[Abstract] 6. Kemeny N, Cohen A, Bertino JR, et al: Continuous intrahepatic infusion of floxuridine and leucovorin through an implantable pump for the treatment of hepatic metastases from colorectal carcinoma. Cancer 65: 2446-2450, 1990[Medline] 7. 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[Medline]
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Kemeny N, Conti JA, Cohen A, et al: Phase II study of hepatic arterial floxuridine, leucovorin, and dexamethasone for unresectable liver metastases from colorectal carcinoma. J Clin Oncol 12: 2288-2295, 1994
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Coombs D, Fine N: Spinal anesthesia using subcutaneously implanted pumps for intrathecal drug infusion. Anesth Analg 73: 226-231, 1991 10. Akhurst T, Larson S: Positron emission tomography imaging of colorectal cancer. Semin Oncol 26: 577-583, 1999[Medline] 11. Kaplan EP, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 12. Wilcoxon F: Individual comparisons by ranking methods. Biometrics 1: 80-83, 1945 13. Rougier P, Van-Cutbem E, Bujetta E, et al: Randomized trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil in patients with metastatic colorectal cancer. Lancet 352: 1407-1412, 1998[Medline] 14. Bierman HR, Byron RL, Kelley KH, et al: Studies on the blood supply of tumor in man: III. Vascular patterns of the liver by hepatic arteriography in vivo. J Natl Cancer Inst 12: 107, 1951 15. Meta-Analysis Group in Cancer: Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer. J Natl Cancer Inst 88:252-258, 1996 16. Kemeny N, Atig OT: Non-surgical treatment for liver metastases. Baillieres Best Pract Res Clin Gastroenterol 13: 593-610, 1999[Medline]
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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 18. Leichman L, Lenz J, Leichman CG, et al: Quantitation of intratumoral thymidylate synthase expression predicts for resistance to protracted infusion of 5-fluorouracil and weekly leucovorin in disseminated colorectal cancers: Preliminary report from an ongoing trial. Eur J Cancer 31A: 1306-1310, 1995
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Gorlick R, Metzger R, Danenberg KD, et al: Higher levels of thymidylate synthase gene expression are observed in pulmonary as compared with hepatic metastases of colorectal adenocarcinoma. J Clin Oncol 16: 1465-1469, 1998 20. Saltz L, Danenberg P, Paty P, et al: High thymidylate synthase (TS) expression does not preclude activity of CPT-11 in colorectal cancer (CRC). Proc Am Soc Clin Oncol 17: 281a, 1998 (abstr 1080)
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Rougier P, Bugat R, Douillard J, et al: Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naïve patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 15: 251-260, 1997 23. Kemeny N, Conti JA, Cohen A, et al: Phase II study of hepatic arterial floxuridine, leucovorin, and dexamethasone for unresectable liver metastases from colorectal carcinoma. J Clin Oncol 12: 2288-2295, 1994 24. Morris D, Ross W: Australian experience of cryoablation of liver tumors: Metastases. Surg Oncol Clin North Am 5: 391-397, 1996[Medline]
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Sasaki Y, Ohtsu A, Shimada Y, et al: Simultaneous administration CPT-11 and fluorouracil: Alteration of the pharmacokinetics of CPT-11 and SN-38 in patients with advanced colorectal cancer. J Natl Cancer Inst 86: 1096-1098, 1994 (letter) 26. Saltz LB, Kanowitz J, Kemeny N, et al: Phase I clinical and pharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patients with advanced solid tumors. J Clin Oncol 14: 2959-2967, 1996[Abstract] Submitted October 18, 2000; accepted February 20, 2001. This article has been cited by other articles:
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TOP
ABSTRACT
INTRODUCTION
50% in the sum of the products of the greatest perpendicular diameters of tumor nodules measured on any follow-up CT compared with baseline. A reduction of less than 50% was considered stable disease. Because patients who underwent cryosurgery were potentially free of discernible disease at the initiation of chemotherapy, these patients were evaluated for evidence of recurrence of disease by using both PET and CT.
300 mg/dL had a 1-year survival rate of 85% (median survival not reached), whereas those with a baseline LDH of more than 300 mg/dL had a 1-year survival rate of 60% (median survival, 15.9 months). 
