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© 2001 American Society for Clinical Oncology Alternating Hepatic Arterial Infusion and Systemic Chemotherapy for Liver Metastases From Colorectal Cancer: A Phase II Trial Using Intermittent Percutaneous Hepatic Arterial AccessFrom the University of Nebraska Medical Center, Omaha, and Saint Francis Cancer Center, Grand Island, NE. Address reprint requests to Margaret Tempero, MD, University of California San Francisco Cancer Center, 2356 Sutter, Ste 708, San Francisco, CA 94115.
PURPOSE: To evaluate the objective response to a short course of hepatic arterial infusion (HAI) using temporary, percutaneously placed catheters alternating with systemic prolonged continuous infusion fluorouracil (ci 5-FU) and daily oral leucovorin (L). PATIENTS AND METHODS: Eligible patients were previously untreated (except for adjuvant therapy) adults with liver-predominant metastases, with Eastern Cooperative Oncology Group performance status of 0 to 2. Treatment regimen included HAI with fluorodeoxyuridine (FUDR) 60 mg/m2/d and L 15 mg/m2/d continuously infused daily for 4 days. After a 1-week rest, ci 5-FU was administered through a central venous access device using a dose of 180 mg/m2/d with a fixed dose of oral L at 5 mg/m2/d for 21 out of 28 days. Cycles were repeated every 6 weeks. After four cycles of therapy, patients were maintained on ci 5-FU and daily oral L until evidence of progression. RESULTS: Forty-three patients were enrolled onto this trial. One patient was ineligible. The objective response rate for all patients (17 partial, zero complete) was 41% (95% confidence interval [CI], 26% to 56%). Five patients were not able to receive at least one complete cycle of HAI. Among patients who received at least one complete cycle of HAI, the response rate was 46% (95% CI, 30% to 62%). Five patients underwent a liver resection after enrolling onto the protocol. At the time of analysis, estimated median time to progression was 6 months, and estimated median overall survival was 13 months. CONCLUSION: The objective response rate was comparable to that achieved with more prolonged and more frequent HAI using FUDR. This approach should be studied as an acceptable alternative to surgically placed hepatic arterial catheters/pumps and may have a role as neoadjuvant therapy for liver metastases that are unresectable, as well as an adjuvant role for patients with resected hepatic metastatic colorectal cancer.
COLORECTAL CANCER is the third most common malignancy in the United States, with an estimated 132,200 new cases in 2000.1 At some point in the course of their disease, up to 60% of patients with colorectal carcinoma develop metastases to the liver, making it the most common site for such involvement.2,3 The response rates with hepatic arterial infusion (HAI) of fluorodeoxyuridine (FUDR) in patients with unresectable metastases from colorectal carcinoma vary from 30% to 88%.4-7 A meta-analysis of six randomized trials suggested a survival advantage for HAI chemotherapy.8 A recent prospective, randomized, multicenter study showed a two-fold increase in time to progression, and a survival benefit was observed in favor of HAI, for patients with an intrahepatic tumor burden of less than 25%.9 High intrahepatic clearance of FUDR makes it an effective drug for liver metastases, but lower levels of systemic drug result in a higher rate of extrahepatic metastases. Also, the toxicity, cost, and complications of surgically placed catheters and/or pumps have limited the use of this approach. Systemic therapy with continuous infusion (ci) fluorouracil (5-FU) regimens has produced more objective responses and a slight increase in overall survival compared with bolus administration of 5-FU.10 The addition of systemic infusion 5-FU chemotherapy to HAI of FUDR may improve control of metastatic tumor both within and outside of the liver. Leucovorin (L), a source of intracellular reduced folates, increases binding of 5-fluoro-2'-deoxyuridine-5'-monophosphate to its target enzyme, thymidylate synthetase.11 Nearly all of the clinical trials comparing 5-FU and L to 5-FU alone have documented an improved objective response rate with this combination.12 In our previous experience, we have found the combination of prolonged ci 5-FU and daily oral L to be a well-tolerated and effective regimen.13 Biochemical modulation of FUDR with L also seems to be useful in strategies involving regional therapy. But this approach has been associated with a higher incidence of hepatobiliary toxicity when implanted hepatic arterial infusion pumps are used over 2-week periods to administer FUDR and L.14,15 Therefore, we elected to study the efficacy of a short-course HAI of FUDR and L using temporary, percutaneously placed catheters alternating with systemic continuous infusion 5-FU and daily oral L in patients with liver-predominant colorectal cancer metastases.
Patients All patients had histologic documentation of colorectal adenocarcinoma with liver metastases. Unresectability by the number, size, and location of hepatic tumors in each individual patient was determined by imaging evidence. In our institution, patients with four or more hepatic lesions, any lesion greater than 8 cm in diameter, or presence of extrahepatic metastatic disease are not considered resectable for cure. Extrahepatic metastases were permitted at the investigators’ discretion, provided that liver metastases were the dominant site of disease. The primary colorectal carcinoma was either previously resected or judged to be resectable in patients presenting with synchronous liver metastases. All patients had bidimensional measurable or assessable disease documented by chest x-ray and computed tomographic (CT) scans of the abdomen and pelvis. CT of chest was performed if clinically indicated. Adequate hematologic (WBC count > 3,500; platelet count > 100,000), liver (serum bilirubin < 2 mg/dL; serum AST and alkaline phosphatase < five times upper limits of normal), and coagulation (normal prothrombin time and partial thromboplastin time) profiles were required. Except for adjuvant chemotherapy or chemoradiation at least 6 months before the enrollment onto the study, no patient had any prior treatment. All patients were 19 years or older and had an Eastern Cooperative Oncology Group performance status of 0 to 2. All patients signed an informed consent.
Procedures and Treatment
Patient Follow-Up Patients underwent a history and physical examination before the beginning of each HAI cycle and every 4 weeks during the maintenance. Partial thromboplastin time and electrolytes were monitored daily and complete blood cell counts and chemistry profiles were performed every other day during HAI therapy. Prothrombin time and partial thromboplastin time were repeated during the first week of each prolonged ci 5-FU cycle. Complete blood cell counts and chemistry profiles were repeated every 2 weeks. Proper placement of the hepatic artery catheter was verified by abdominal x-ray daily during the hospitalization for HAI. The puncture site was monitored for signs of bleeding, hematoma, and infection throughout the procedure and after removal of the hepatic artery catheter. The National Cancer Institute common toxicity criteria were used to determine dose modification or treatment discontinuation. For grade 1 mucositis occurring during the HAI of FUDR, immediate discontinuation of therapy with removal of hepatic artery catheter was planned. If grade 3 or greater stomatitis occurred after the HAI of FUDR, the dose was decreased by 25% in subsequent cycles. Patients proceeded with 5-FU/L after HAI after recovery if mucositis was observed. For grade 1 mucositis, or grade 2 gastrointestinal toxicity (ie, diarrhea), or any grade 3 or 4 toxicity, systemic 5-FU was stopped until full recovery. If the time to toxicity was less than 21 days, the 5-FU dose was resumed with a 20% dose reduction. If the subsequent time to toxicity was still less than 21 days, an additional 10% dose reduction was made at the time of the next resumption of therapy. Response evaluation took place after the first full cycle of therapy and before every other cycle thereafter by chest x-rays and CT scans of the abdomen and pelvis. CT of the chest was performed when clinically indicated.
Treatment Evaluation
Statistical Considerations
Patient Characteristics A total of 43 patients were enrolled onto the protocol. One patient was found to have an ineligible diagnosis (cholangiocarcinoma), making 42 eligible patients the basis of this report. The clinical characteristics of all eligible patients are listed in Table 1. During a total of 97 HAI treatments, the entire liver could be perfused in 78 attempts, whereas only the right lobe was perfused for dominant site of disease in the remaining 19 attempts ( Fig 2). Extrahepatic perfusion occurred in seven attempts but all corrected with either further embolization or catheter repositioning ( Fig 3). The median age was 57.5 years (range, 33 to 76 years), with a male to female ratio of 16:26. The primary site of cancer was the colon in 34 patients and the rectum in eight patients. Eight patients presented with metachronous liver metastases and only five of them had received prior adjuvant chemotherapy. The remaining 34 patients had synchronous liver disease at the time of their colon cancer diagnosis. Extrahepatic metastases were present in 14 (33%) of 42 patients, but the liver was the predominant site of metastatic disease in this group. The Eastern Cooperative Oncology Group performance status was 0 in 30 patients (71%), 1 in 11 patients (26%), and 2 in one patient (2%).
Tumor Response and Patient Survival Intent-to-Treat Analysis Seventeen of 42 eligible patients achieved an objective response for a response rate of 41% (95% confidence interval [CI], 26% to 56%). All responses were partial responses. All responders had a decrease in tumor size in both extrahepatic (if present) and hepatic tumor sites. A decrease in tumor measurements in the liver was observed on initial evaluation after one cycle in all responders. Median duration of response in responders was 6 months (95% CI, 3 to 13 months). Five patients who were initially considered unresectable for cure later underwent resection after treatment. In two of these five patients, the total number of hepatic lesions decreased from four to three and the overall tumor size reduced 92% in one and 76% in the other patient. The other two patients had a total of three hepatic lesions each, with the largest lesion 10 x 7 cm in one and 10 x 10 cm in the other. The number of liver lesions in these two patients remained the same after treatment, but the overall size of the tumor was reduced 84% in both patients. In the remaining one patient, there were two hepatic lesions and one (< a 1 cm) lung lesion. After treatment, the lung lesion disappeared and the patient underwent resection of her two liver lesions at another institution. At the time of analysis, the median follow-up of surviving patients was 19 months (range, 7 to 45 months). The estimated time to progression and overall survival experiences are listed in Figs 4 and 5, respectively. The estimated median time to progression was 6 months and estimated median overall survival was 13 months. The median overall survival among patients who did not have resection of liver metastases was 12 months (95% CI, 8 to 18 months).
As-Treated Analysis Five patients did not receive at least one complete HAI cycle: three patients due to inability to perfuse liver for technical and/or anatomic reasons and two patients withdrew from the study before completing the first cycle. Among patients who received at least one complete cycle, the response rate was 46% (95% CI, 30% to 62%), and the estimated time to progression and overall survival experiences are listed in Figs 6, 7, and 8, respectively. There was no significant association of longer patient survival with age, sex, presence of extrahepatic disease, or completeness of hepatic perfusion.
Toxicity and Technical Considerations Complications related to the catheter and the procedure in a total of 97 hepatic arterial perfusions are listed in Table 2. Three patients did not receive at least one complete HAI treatment due to failure to adequately perfuse the liver. In one patient, HAI was discontinued after the third cycle, due to a stroke at the time of catheter removal using the brachial artery approach. In one patient, the third cycle of HAI could not be given due to inability to perfuse the liver. Intrahepatic FUDR chemotherapy was generally well tolerated with no cases of biliary strictures or gastrointestinal ulcers. Toxicities related to HAI of FUDR are illustrated in Table 3. Toxicities from systemic ci 5-FU were minor and consisted primarily of grade 1 stomatitis and hand-foot syndrome and grade 2 nausea, vomiting, and diarrhea. Toxicity incidence for the total number of prolonged ci 5-FU cycles administered is listed in Table 4. Actual doses of 5-FU administered as a function of the target dose are listed in Table 5.
Although the role of hepatic-directed chemotherapy in the management of unresectable colorectal liver metastases remains controversial,19-22 interest in this approach has been renewed, through two widely publicized meta-analyses8,23 and a recent randomized multicenter trial.24 Furthermore, data suggest a survival benefit for HAI therapy plus systemic chemotherapy in patients who have undergone liver resection for metastatic colorectal cancer.25 In many of the early trials, surgical complications or catheter misplacement caused a significant number of patients to not receive adequate hepatic-directed treatment, which led to a potential underestimate of the benefits of hepatic infusion therapy. In this study, we tried to determine the efficacy of a short course of HAI of FUDR and L using temporary percutaneously placed catheters alternating with systemic prolonged ci 5-FU and daily oral L. The results of our study confirm the efficacy of HAI using temporary percutaneously placed hepatic arterial catheters in terms of shrinking liver metastases. Among patients who received at least one complete cycle, the response rate of 46% was obtained. All responders demonstrated a decrease in tumor measurements on initial evaluation after one cycle. Early evaluation for progressive disease after one cycle of treatment prevented unnecessary exposure to continued HAI treatment. The objective response rate, time to progression, and survival with our approach are comparable to those achieved with more prolonged and more frequent HAI using FUDR.26-28 O’Connell et al,29 in a study similar to ours but using surgically placed catheters for HAI alternating with systemic chemotherapy of bolus 5-FU, reported a median time to progression of 9 months and median survival of 18 months in 40 eligible patients out of 57 enrolled patients. We used an intent-to-treat analysis and included all patients enrolled onto the study except one patient with an ineligible diagnosis. This may explain any apparent differences in median time to progression and median survival. Our alternating intrahepatic/systemic chemotherapy regimen was well tolerated and avoided the possible complications related to surgical placement of infusion devices. Cost analysis of both approaches has been previously assessed by Patt,30 suggesting that initiation of hepatic arterial treatment using percutaneous catheters for two to three cycles followed by placement of hepatic arterial pumps in responding patients might accomplish long-term therapy at a reduced cost. Our study design has a shorter treatment plan of HAI (four cycles, 4 days each) and nonresponders after one cycle were not exposed to unnecessary HAI treatments, which reduced the toxicity and cost. We believe that our approach could be studied as an acceptable alternative to surgically placed hepatic arterial catheters or pumps. Our results also compare favorably to recently published trials evaluating the addition of irinotecan to 5-FU based regimens. Saltz et al31 compared weekly irinotecan, 5-FU, and L to 5-FU and L alone and reported a significantly superior response rate (39% v 21%) and longer median survival (14.8 v 12.6 months) with the addition of irinotecan in patients with previously untreated metastatic colorectal cancer. Also, Douillard et al32 demonstrated a median survival advantage (17.4 v 14.1 mos) as well as a superior response rate (35% v 22%) for the combined irinotecan, 5-FU, and L group, compared with 5-FU and L alone as first-line treatment for metastatic colorectal cancer. Our results of response rate and median time to progression compare favorably with the results of combined irinotecan, 5-FU, and L regimens in these two studies. Five patients in this study who were initially considered unresectable for cure later underwent resection after treatment, suggesting a possible role for this approach. Median number of HAI cycles before resection and median time to resection were four cycles (range, three to four cycles) and 12 months (range, 3 to 15 months), respectively. The median follow-up after resection for surviving patients was 31 months (range, 11 to 45 months), and median survival in this small group has not yet been reached. Kemeny et al25 has demonstrated that HAI therapy with systemic chemotherapy can improve survival after resection of hepatic metastases. Based on this, and on our observation of posttreatment resection, it seems reasonable to pursue the role of neoadjuvant HAI therapy. In addition, our approach offers a potential option for adjuvant therapy in patients with synchronous metastases who did not have a pump implanted at the time of resection. In the future, molecular determinants of response, such as thymidylate synthase expression,33-34 may be used to select patients who are most likely to benefit from fluoropyrimidine-based treatment. In this study, all responders showed some regression after one cycle. Until molecular analyses are validated and standardized, another option might involve a single cycle of HAI, using a percutaneously placed catheter to screen for chemosensitivity in patients eligible for HAI therapy with the use of an implanted pump. Based on these considerations, we are planning to study this alternating chemotherapy regimen in the neoadjuvant setting for patients who are candidates for liver resection.
1. Greenlee RT, Taylor M, Bolden S, et al: Cancer statistics 2000. CA Cancer J Clin 50: 7-33, 2000[Abstract] 2. Weiss L, Grundmann E, Torhorst J, et al: Haematogenous metastatic patterns in colonic carcinoma: An analysis of 1541 necropsies. J Pathol 150: 195-203, 1986[Medline] 3. Taylor I, Mullee MA, Campbell MJ: Prognostic index for the development of liver metastases in patients with colorectal cancer. Br J Surg 77: 499-501, 1990[Medline] 4. Schwartz SI, Jones LS, McLune CS: Assessment of treatment of intrahepatic malignancies using chemotherapy via an implantable pump. Ann Surg 201: 560-567, 1985[Medline] 5. Daly JM, Kemeny N, Oderman P, et al: Long-term hepatic arterial infusion chemotherapy: Anatomic considerations, operative techniques, and treatment morbidity. Arch Surg 119: 936-941, 1984[Abstract] 6. Niederhuber JE, Ensminger W, Gyves J, et al: Regional chemotherapy of colorectal cancer metastases to the liver. Cancer 53: 1336-1343, 1984[Medline] 7. Balch CM, Urist MM, McGregor ML: Continuous regional chemotherapy for metastatic colorectal cancer using a totally implantable infusion pump: A feasibility study in 50 patients. Am J Surg 145: 285-290, 1983[Medline] 8. Harmantas A, Rotstein LE, Langer B: Regional versus systemic chemotherapy in the treatment of colorectal carcinoma metastatic to the liver: Is there a survival difference? Meta-analysis of the published literature. Cancer 78: 1639-1645, 1996[Medline]
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Lorenz M, Muller HH: Randomized multicenter trial of fluorouracil plus leucovorin administered either via hepatic arterial or intravenous infusion versus fluorodeoxy-uridine administered via hepatic arterial infusion in patients with nonresectable liver metastases from colorectal carcinoma. J Clin Oncol 18: 243-254, 2000 10. Meta-Analysis Group in Cancer: Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Onc 16: 306-308, 1998
11.
Houghton JA, Maroda SJ, Philips JO, et al: Biochemical determinants of responsiveness to 5-fluorouracil and its derivatives in xenografts of human colon adenocarcinomas in mice. Cancer Res 41: 144-149, 1981 12. Arbuck SG: Overview of clinical trials using 5-FU and leucovorin for the treatment of colorectal cancer. Cancer 63: S1036-S1044, 1989 (suppl 16) 13. Tempero M, Berg A, Block M, et al: A phase II trial of protracted therapy with 5-fluorouracil and daily oral leucovorin in metastatic colorectal carcinoma. J Infusional Chemotherapy 4: 112-115, 1994 14. Lorenz M, Hottenrott C, Maier P, et al: Continuous regional treatment with fluorophyrimidines for metastases from colorectal carcinomas: Influence of modulation with leucovorin. Semin Oncol 19: S163-S170, 1992 (suppl 13) 15. Kemeny N, Seiter K, Conti JA, et al: Hepatic arterial floxuridine and leucovorin for unresectable liver metastases from colorectal carcinoma. Cancer 73: 1134-1142, 1994[Medline] 16. Simon R: Optimal two-stage designs for phase II clinical trials. Controlled Clin Trials 10: 1-10, 1989[Medline] 17. Kaplan E, Meier P: Nonparametric estimation from incomplete observation. J Am Stat Assoc 53: 457-481, 1958 18. Kalbfleisch JD, Prentice RL: The statistical analysis of failure time data. New York NY, John Wiley and Sons, 1980, pp 168-171 19. O’Connell MJ: Is hepatic infusion of chemotherapy effective treatment for liver metastases? No!, in De Vita VT Jr, Hellman S, Rosenberg SA (eds): Important Advances in Oncology 1992. Philadelphia PA, Lippincott, 1992, pp 229-234 20. Kemeny NE: Is hepatic infusion of chemotherapy effective treatment for liver metastases? Yes!, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Important Advances in Oncology 1992. Philadelphia PA, Lippincott, 1992, pp 207-220 21. Cohen AM, Kemeny NE, Kohne C-H, et al: Is intra-arterial chemotherapy worthwhile in the treatment of patients with unresectable hepatic colorectal cancer metastases? Eur J Cancer 32A: 2195-2205, 1996
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Haller DG: Waiting for the definitive trial of hepatic arterial chemotherapy for colorectal cancer. J Clin Oncol 18: 239-242, 2000
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The Meta-Analysis Group in Cancer: Reappraisal of hepatic arterial infusion in the treatment of non-resectable liver metastases from colorectal cancer. J Natl Cancer Inst 88: 252-258, 1996 24. Lorenz M, Muller H-H: Randomized, multicenter trial of fluorouracil plus leucovorin administered either via hepatic arterial or intravenous infusion versus fluorodeoxyuridine administered via hepatic arterial infusion in patients with non-resectable liver metastases from colorectal carcinoma. J Clin Oncol 18: 243-254, 2000
25.
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, 2000 26. Lorenz M, Hottenrott C, Maier P, et al: Continuous regional treatment with fluoropyrimidines for metastases from colorectal carcinomas: Influence of modulation with leucovorin. Semin Oncol 19: S163-S170, 1992 (suppl 3) 27. Kemeny N, Seiter K, Conti JA, et al: Hepatic arterial floxuridine and leucovorin for unresectable liver metastases from colorectal carcinoma. Cancer 73: 1134-1142, 1994 28. Kemeny N, Conti JA, Sigardson E, et al: A pilot study of hepatic artery floxuridine combined with systemic 5-fluorouracil and leucovorin. Cancer 71: 1964-1971, 1993[Medline] 29. O’Connell MJ, Nagorney DM, Bernath AM, et al: Sequential intrahepatic fluorodeoxyuridine and systemic fluorouracil plus leucovorin for the treatment of metastatic colorectal cancer confined to the liver. J Clin Oncol 16: 2528-2533, 1998[Abstract]
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Patt YZ: Regional hepatic arterial chemotherapy for colorectal cancer metastatic to the liver: The controversy continues. J Clin Oncol 11: 815-818, 1993
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Cascinu S, Aschele C, Barni S, et al: Thymidylate synthase protein expression in advanced colon cancer: Correlation with the site of metastasis and clinical response to leucovorin modulated bolus 5-fluorouracil. Clin Cancer Res 5: 1996-1999, 1999 Submitted July 25, 2000; accepted February 6, 2001. This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
