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© 2003 American Society for Clinical Oncology 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 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: Patients who undergo resection of liver metastases from colorectal cancer have an average 2-year survival of 65%. With hepatic arterial infusion (HAI) plus systemic fluorouracil and leucovorin, 2-year survival increased to 86%. For further improvement in both local and systemic control, combinations of new systemic drugs with HAI are being explored. The purpose of this study was to determine the maximum-tolerated dose (MTD) of systemic irinotecan (CPT-11) and HAI floxuridine (FUDR) plus dexamethasone (DEX) as combination adjuvant therapy after liver resection. Patients and Methods: Ninety-six patients who underwent complete resection of liver metastases from colorectal cancer were treated with six monthly cycles of HAI FUDR plus DEX for 14 days of each 4-week cycle plus escalating doses of systemic CPT-11. The primary end points of the phase I/II study were the MTD and efficacy of this regimen. Results: The MTD for combined systemic CPT-11 and HAI FUDR was CPT-11 at 200 mg/m2 every other week and FUDR at 0.12 mg/kg x pump volume ÷ pump flow rate. The dose-limiting toxicities were diarrhea and neutropenia. With a median follow-up time of 26 months, the 2-year survival rate is 89%. All of the 27 patients who were treated at the MTD are alive. Conclusion: In patients who undergo resection of liver metastases from colorectal cancer, adding systemic CPT-11 to HAI therapy in an adjuvant regimen is feasible. This regimen seems to have comparable activity to fluorouracil and leucovorin, but further studies are needed to assess whether it improves local control or decreases extrahepatic recurrences.
NEARLY 129,000 new cases of colorectal cancer are diagnosed each year in the United States.1 Fifteen percent to 25% of patients have metastatic liver disease when the primary tumor is diagnosed, and an additional 35% to 45% of patients will develop hepatic metastases during the course of their disease.2 Complete resection of hepatic metastases yields 2- and 5-year survival rates of 65% and 30%, respectively.3 Approximately 14,300 patients undergo liver resection each year. Seventy-five percent of these patients will have a recurrence, 50% in the liver and 50% in extrahepatic sites. Approximately 65% to 80% of all recurrences appear within the first 2 years.4 In an effort to decrease recurrence rates, a number of randomized studies have explored the use of combined regional and systemic chemotherapy. The use of hepatic arterial infusion (HAI) exploits the liver’s dual blood supply. Established hepatic metastases greater than 3 cm are supplied almost entirely by the hepatic arterial system, whereas normal liver cells derive most of their blood supply from the portal vein.5 Thus, HAI offers the possibility of delivering high-dose regional chemotherapy without systemic toxicity. Two large American trials demonstrated a clear reduction in hepatic recurrence with the use of HAI and systemic therapy after liver resection.6,7 In both trials, floxuridine (FUDR) was used as the regional agent, and fluorouracil (FU) plus or minus leucovorin (LV) was used as the systemic therapy. More recent studies have investigated using newer drugs, such as irinotecan (CPT-11) and oxaliplatin, as the systemic agents.8,9 A phase I/II trial of patients with unresectable disease demonstrated that the combination of CPT-11 and HAI FUDR produced a 74% response rate.10 The current study was designed to test this combination in the adjuvant setting.
Eligibility Criteria and Pretreatment Evaluation All patients had histologically confirmed colorectal adenocarcinoma with completely resectable hepatic metastases. Patients were excluded from the study for any of the following reasons: extrahepatic disease, prior hepatic radiation, infection, Karnofsky performance status less than 60, previous or concurrent malignancy (unless patient had been free of disease for at least 5 years), WBC count less than 3,000 cells/ìL, platelet count less than 100,000 cells/µL, or total bilirubin  1.5 mg/dL. Prior chemotherapy was permitted if the last dose was given 1 month before the date of hepatic resection. Computed tomography scans of the abdomen and pelvis and a chest radiograph had to be performed within 6 weeks before surgery. All patients signed informed consent forms. The protocol and informed consent were approved by the Memorial Sloan-Kettering Cancer Center institutional review board. Pretreatment evaluation included a complete history, physical examination, and laboratory studies, including complete blood count, total bilirubin, alkaline phosphatase, AST, carcinoembryonic antigen (CEA), and lactose dehydrogenase, obtained within 1 week before commencement of chemotherapy. All patients underwent preoperative hepatic computed tomography angiogram, including visualization of the celiac and superior mesenteric arteries, to evaluate hepatic arterial blood supply. Surgical guidelines for pump placement have been previously reported.11 Suspicious nodes, masses, or both were biopsied, and cholecystectomy was performed if it had not been performed previously. The pump catheter was positioned at the junction of the proper and common hepatic arteries via the gastroduodenal, splenic, or celiac artery. The distal gastroduodenal, the right gastric artery, and small branches supplying the stomach or duodenum were ligated, as were all accessory hepatic arteries. The catheter was secured in the artery with at least two nonabsorbable ties. An intraoperative injection of fluorescein was used to check the flow immediately after placement. Postoperatively, technetium-99m macroaggregated human serum albumin was infused via the sideport of the pump to assess adequacy of perfusion.
Chemotherapy Administration and Toxicity Evaluation
All toxicities were graded according to the National Cancer Institute common toxicity criteria. FUDR dose modifications for hepatic toxicity are outlined in Table 2  . As stated in Table 2, in the case of elevated transaminases, total bilirubin, or both, FUDR administration was held until laboratory values improved as indicated. Epigastric pain prompted an evaluation with an upper gastrointestinal endoscopy. If an ulcer or gastroduodenitis was documented, HAI therapy was held for 1 month to allow healing. Severe abdominal pain or diarrhea during HAI treatment resulted in immediate emptying of drug from the pump and instillation of heparinized saline or glycerol (50%) until further evaluation was completed (including a repeat flow scan to rule out extrahepatic perfusion) and the symptoms resolved.
For the purposes of dose escalation, dose-limiting toxicity (DLT) was defined as any of the following occurring during the first two cycles of treatment: grade 4 neutropenia or thrombocytopenia; neutropenic fever, defined as grade 3 or 4 neutropenia plus fever higher than 38.3°C; grade 3 or 4 diarrhea despite aggressive use of loperamide; or total bilirubin 3.0 mg/dL not caused by disease progression (ie, biliary obstruction as a result of tumor was ruled out). DLTs occurring in later cycles will also be reported.
Study Design and Statistical Analysis In the phase I portion, a cohort of at least three patients was entered at each dose level. If none of the patients experienced a DLT, the next cohort was opened for enrollment. If two of the three patients experienced a DLT, then it was concluded that the previous level was the MTD. If one of the three patients experienced a DLT, then at least three more patients were enrolled at the same dose. If none of the additional three patients experienced a DLT, then the next cohort was opened for enrollment. If there were any DLTs in the additional patients, then it was concluded that the previous level was the MTD. This design had a high probability of allowing dose escalation if the current dose level was not toxic and a low probability of escalation if the current dose level was too toxic. For example, if the chance of experiencing a DLT at a given dose level was 10%, then the probability of advancing to the next dose level would be 91%. This probability decreases to 49% if the chance of experiencing a DLT was 30% and to only 17% if the chance of experiencing a DLT was 50%. The primary objective of the phase II portion of this study was to estimate the preliminary treatment efficacy at the MTD level established in the phase I trial by estimating the 2-year overall survival and recurrence rates. A total of 26 patients were accrued for this phase II trial, including the patients treated at the MTD level in the phase I trial. This sample size allows an estimation of survival and recurrence rates to within ± 19.2% using the Kaplan-Meier method. The prevalence of baseline characteristics between the current study and the previous study were compared using the Fisher’s exact test for dichotomous variables and the Wilcoxon rank sum test for continuous variables.12 Survival was reported at 2 years because the follow-up for survivors is more than 2 years. However, hepatic and extrahepatic progression was reported at 18 months because the median follow-up for patients who have not yet progressed was only 19 months.
Patient Characteristics Ninety-six patients who underwent liver resection were entered onto the study. All patients had liver resections, and none had radiofrequency ablation or cryosurgery of their liver lesions. Patient characteristics are listed in Table 3 . There were 44 women and 52 men. Sixty-four percent of patients were staged as having Dukes’ C cancer. Sixty percent of patients had two or more hepatic metastases. Seventy-five percent of patients had prior FU therapy, and 23% had prior CPT-11 therapy. The interval between diagnosis of the primary tumor and discovery of hepatic metastases was less than 12 months in 74% of patients. Preoperative CEA was elevated in 76% of patients and greater than 30 mg/dL in 42% of patients. Postoperative CEA (1 month after liver resection) remained elevated (greater than 5 mg/dL) in 33% of patients. Surgical resection of margins less than 1 cm were reported in 29% of patients.
Dose Escalation and Toxicity Initially, the HAI FUDR dose was fixed at 0.12 mg/kg x pump volume ÷ pump flow rate, whereas the CPT-11 dose was escalated. The first CPT-11 dose was 60 mg/m2, administered once weekly for 3 weeks of a 4-week cycle. No DLTs were observed at this dose level, and the CPT-11 was escalated to 80 mg/m2 and 100 mg/m2 in subsequent cohorts. At the 100-mg/m2 level, there was one incidence of grade 3 diarrhea among an expanded cohort of six patients. In the next cohort, the FUDR dose was increased to 0.14 mg/kg, while the CPT-11 dose continued at 100 mg/m2. Because of toxicities experienced at this level, the next lower dose (100 mg/m2 of CPT-11 and 0.12 mg/kg of FUDR) was identified as the MTD. In the phase II portion of the study, additional patients were entered at the MTD level. Unfortunately, of the 18 patients, seven experienced DLTs (two patients experienced grade 4 diarrhea [one of these patients also had grade 4 neutropenia] and five patients experienced grade 3 diarrhea [one of these patients also had grade 4 bilirubin elevation]). On further follow-up, two patients from the group who were receiving CPT-11 100 mg/m2 weekly for 3 weeks had a bilirubin elevation. One developed a stricture that required stent placement. Another patient developed bilirubin elevation 15 months after initiation of treatment; it was not clear if this was a result of progression of disease, but the bilirubin returned to normal after stent placement. Because an unanticipated number of patients were experiencing severe toxicity in the expanded cohort, we amended the protocol to test an every-other-week schedule of CPT-11. The FUDR dose remained at 0.12 mg/kg. The first dose level of CPT-11 under the revised schedule was 150 mg/m2 every other week. Of the eight patients entered at this dose level, only one DLT was observed (grade 4 diarrhea). We were able to continue escalation of the CPT-11 dose to 200 mg/m2 and 225 mg/m2 with no further serious toxicity. At 250 mg/m2, two patients experienced DLT, both diarrhea. Therefore, we identified the new MTD as 225 mg/m2 of CPT-11 given biweekly in combination with 0.12 mg/kg of FUDR via HAI. To verify the MTD, additional patients were treated at this dose level. Three of 11 patients experienced DLT (diarrhea and neutropenia) during the first two cycles. The neutropenic patient was a 76-year-old woman who recovered from neutropenic fever after antibiotic therapy, but she later developed an ileus complicated by aspiration and died. A fourth patient had a DLT in cycle 5 (6 months after resection) after experiencing no toxicity in the first four cycles. He developed diarrhea and then a small bowel obstruction, which led to a laparotomy to lyse adhesions. Afterwards, he had progressive deterioration, including development of a lung abscess, pulmonary decompensation, and death. After these DLTs, we concluded that the MTD was CPT-11 200 mg/m2. Twenty-four additional patients were treated at this dose level with no DLTs occurring during the first two cycles. Three of these patients developed bilirubin elevations during subsequent cycles 5, 6, and 7 months after initiation of chemotherapy. In all these patients, the bilirubin returned to normal. Toxicities encountered during the first two cycles of therapy are presented in Tables 4 and 5. Toxicities encountered during all cycles of therapy are listed in Tables 6 and 7. Pump complications included two catheter thromboses, two flipped pumps, one extrahepatic perfusion, and two instances of pump catheter dislodgement (occurring 30 and 31 months after pump placement).
To address whether toxicity is related to the type of resection, we analyzed patients who had wedge resections versus lobectomies. Seven (37%) of 19 patients who had wedge resections went on to develop toxicity, whereas 22 (29%) of 77 patients with more extensive resection experienced toxicity (Fisher’s exact test, P = .57). Because CPT-11 is glucuronidated by liver enzymes, patients were examined to see whether the elevations in alkaline phosphatase, bilirubin, and/or transaminase at the time of chemotherapy would increase toxicity such as diarrhea or neutropenia. Of the 68 patients who had increased liver function tests, 17 (25%) experienced diarrhea or neutropenia; whereas out of the 28 patients who did not have increased liver function tests, 12 (43%) experienced diarrhea or neutropenia (Fisher’s exact test, P = .09). To see whether patients who had received previous CPT-11 therapy would experience less toxicity on this regimen than patients who were CPT-11–naïve, we compared the 22 patients who had received prior CPT-11 to the 74 CPT-11–naïve patients, and four (18%) of 22 and 25 (34%) of 74 had toxicity, respectively (Fisher’s exact test, P = .20).
Overall, Hepatic Disease-Free, and Disease-Free Survival The 1-year and 1.5-year hepatic disease-free survival rates were 92% and 88%, respectively, for the entire cohort (median follow-up, 19 months). In the MTD cohort, only one patient experienced a recurrence in the liver at 16 months; the other patients were disease-free in the liver at the time of analysis. The disease-free survival rate for the entire cohort was 69% at 1-year and 47% at 1.5 years. Extrahepatic progression occurred in 47 patients, with the most common recurrences seen in the lung (36 patients) and in lymph nodes (eight patients). Sixteen of the 47 patients with extrahepatic progression also recurred in the liver. In the MTD cohort, four patients have recurred, with a 1-year progression-free survival rate of 91%. Patients who had progression were treated with resections, if possible, or further chemotherapy. There were 17 patients who went on to further surgical resections of recurrence (12 patients for lung metastases, two for lymph nodes, and the others for intra-abdominal recurrence). If patients progressed, they received systemic chemotherapy; 28 patients received CPT-11 again, 15 received oxaliplatin, and 36 received capecitabine.
Fortunately for patients with colorectal cancer, new systemic chemotherapy agents have improved both response and survival. Nevertheless, for patients who receive systemic chemotherapy alone for metastatic disease, 5-year survival remains dismal. For patients who are able to undergo liver resection, the 5-year survival rate is approximately 30%, with a 2-year disease-free survival rate of 20%.3 Two studies adding HAI and systemic therapy after hepatic resection demonstrated 5-year survival rates of approximately 50% to 60%.6,7 In the Memorial Sloan-Kettering Cancer Center study of HAI plus systemic FU and LV, the 2-year disease-free survival rate was 56%. This study is a phase I/II trial testing an alternative systemic chemotherapy, CPT-11, with HAI after liver resection. In our first study6 comparing HAI therapy plus systemic FU and LV to systemic FU and LV alone, the development of lung metastases was similar in both study arms. Because lung metastases express a higher level of thymidylate synthetase (TS) than other sites,13 FU (an inhibitor of TS) may not be the most appropriate drug to use to control the development of disease in the lung. A drug such as CPT-11 (an inhibitor of topoisomerase I), the effect of which is not influenced by TS, would arguably be a more appropriate systemic agent.14 In a previous study of patients with unresectable disease, the addition of CPT-11 to HAI therapy produced a 74% response rate even in patients who had previously received CPT-11.10 Because the addition of CPT-11 actually improved hepatic control in this group, we were hopeful that the combination of systemic CPT-11 and HAI FUDR would help decrease local recurrence as well as control extrahepatic disease in the adjuvant setting. When using the combination of systemic CPT-11 and HAI FUDR + DEX for patients who did not have a liver resection (unresectable disease), our MTD for systemic CPT-11 was higher (100 mg/m2 weekly x 3 in a 4-week cycle). After resection, this dose seems to be more difficult to administer, with a number of patients developing grade 3 or 4 diarrhea. A biweekly schedule was much more tolerable, and at the MTD, no patients (zero of 27 patients) had grade 3 or 4 diarrhea. Hepatic toxicity was decreased in this study, possibly because of a lower FUDR dose. The FUDR dose calculation used in the previous adjuvant study6 was 0.25 mg/kg per day x 14 days, and this dose was not adjusted for flow rate. Using a new method of dose calculation, this dose was equivalent to a dose of 0.14 mg/kg x pump volume ÷ pump flow rate. In the present study, the majority of patients received 0.12 mg/kg x pump volume ÷ pump flow rate (a lower dose). In the original adjuvant study,6 18 patients (24%) developed total bilirubin elevations (> 3 mg/dL), and four patients required biliary stents. In the present study, this was reduced to seven patients (7%), with only two requiring stents. Overall survival in this study is again excellent, with a 2-year survival rate of 89%. The hepatic disease-free survival seemed to be similar to that seen in our previous study, but because this is a phase I/II study, most of the patients received subtherapeutic systemic doses. For the 17 patients who did have liver recurrence, several had extensive disease or difficult surgical procedures. However, at the MTD dose, the cohort seems to be doing better, with only one patient with liver recurrence, but the follow-up is insufficient to be conclusive. The recurrence-free survival rate for patient at the MTD is presently 57% at 18 months (95% confidence interval, 39% to 57%). The wide confidence interval reflects the small sample size as well as the relatively immature follow-up. For these reasons, we feel it is premature to make conclusions about the efficacy of this regimen.
To gain further insight on the issue of recurrence, we compared the baseline characteristics of the patients who received FU/LV in our earlier study and the patients who received CPT-11 in this study (Table 3 In conclusion, our MTD for combined systemic CPT-11 and HAI FUDR after resection of hepatic metastases from colorectal cancer is CPT-11 200 mg/m2 every other week and FUDR 0.12 mg/kg x pump volume ÷ pump flow rate administered with DEX and heparin plus saline for 14 days of a 28-day cycle. The 2-year survival is presently 89%. Further randomized phase III trials are needed to clearly determine the usefulness of this regimen.
We thank Maria-Leticia Bravo for manuscript preparation.
1. Jemal A, Murray T, Samuels A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5–26, 2003 2. August DA, Sugarbaker PH, Ottow RT, et al: Hepatic resection of colorectal metastases: Influence of clinical factors and adjuvant intraperitoneal 5-fluorouracil via Tenckhoff catheter on survival. Ann Surg 201:210–218, 1985[Medline] 3. Hughes K, Scheele J, Sugarbaker P: Surgery for colorectal cancer metastatic to the liver: Optimizing the results of treatment. Surg Clin North Am 69:339–359, 1989[Medline]
4. Fong Y, Cohen AM, Fortner JG, et al: Liver resection for colorectal metastases. J Clin Oncol 15:938–946, 1997 5. Ackerman NB: The blood supply of experimental liver metastases: IV. Changes in vascularity with increasing tumor growth. Surgery 75:589–596, 1974[Medline]
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7. 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
8. Saltz LB, Cox JV, Blanke 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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10. Kemeny N, Gonen M, Sullivan D, et al: Phase I study of hepatic arterial infusion of floxuridine and dexamethasone with systemic irinotecan for unresectable hepatic metastases from colorectal cancer. J Clin Oncol 19:2687–2695, 2001 11. Minsky BD, Cohen AM, Kemeny N, et al: Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy. J Clin Oncol 10:79–84, 1992[Abstract]
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13. 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 14. 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) 15. Fong Y, Fortner J, Sun RL, et al: Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: Analysis of 1001 consecutive cases. Ann Surg 230:309–318, 1999[CrossRef][Medline] 16. Jarnigin W, Gonen M, Fong Y, et al: Improvement in perioperative outcome after hepatic resection: Analysis of 1,803 consecutive cases over the past decade. Ann Surg 236:397–406, 2002[CrossRef][Medline] Submitted March 24, 2003; accepted June 13, 2003. Related Correspondence
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
