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Intrahepatic Therapy for Resected Hepatic Metastases From Colorectal Carcinoma

Intrahepatic Therapy for Resected Hepatic Metastases From Colorectal Carcinoma

ABSTRACT: A significant number of patients with colorectal cancer will present with hepatic metastases as their only site of metastatic disease. Surgical resection in patients with a limited number of metastases will lead to long-term survival in up to one-third. However, following surgery, many of these patients will relapse within the liver, and many will develop extrahepatic metastases. The use of hepatic artery infusion alternating with systemic therapy has proven to reduce the risk of recurrent disease and improve survival. Impressive response rates have been achieved with the combination of oxaliplatin and fluorouracil (5-FU) in patients with metastatic colorectal carcinoma. In one trial, this combination resulted in significant tumor shrinkage allowing resection of previously unresectable hepatic metastases. Given the promising activity of oxaliplatin (Eloxatin), 5-FU, and leucovorin, a trial is now in development to assess the efficacy of this combination when used together with hepatic artery infusion. [ONCOLOGY 14(Suppl 11):48-51, 2000]

Introduction

An estimated 130,200 people in the United States will develop colorectal cancer in the year 2000,[1] and approximately 15% to 17% of these will initially present with stage IV disease.[2] In addition, approximately 40% of patients undergoing potentially curative resection for stage II and III disease will subsequently recur.[3]

The liver represents one of the most common sites of disease recurrence in patients with colorectal carcinoma, and is a major cause of morbidity and mortality in this patient population. In an autopsy series of patients who died of colorectal carcinoma, 44% had liver metastases.[4] In 46% of those cases (20% overall), the liver was the only site of metastatic disease. Without treatment, patients with liver metastases have a median survival of 5 to 12 months.[5-7]

Surgical Resection

In a review of 1,001 patients undergoing resection of hepatic metastases at the Memorial Sloan-Kettering Cancer Center, Fong et al found that resection of a solitary metastasis was associated with the best prognosis.[8] The 5-year survival for this group of patients was 44%. Patients with more extensive disease had a shorter survival.

In a multi-institutional review, Hughes noted 5-year actuarial survivals of 37% for patients with solitary lesions, 34% for patients with two metastatic lesions (most of which were unilobar), 8% for those with three metastatic lesions, and 18% for those with four or more lesions.[9] Corresponding 5-year actuarial disease-free survivals were 36%, 32%, 0%, and 14%, respectively.

When patients with three metastatic lesions were grouped together with patients who had four or more metastatic lesions, the actuarial 5-year survival was 14%, and disease-free survival was 7%, respectively. This compares to the 35% actuarial and disease-free survival for patients with one or two metastatic lesions.

Regional Therapy

Patients who have undergone resection of colorectal metastases to the liver may be candidates for regional infusion therapy.[10-12] The pattern of recurrence after the first liver resection shows that 41% of subsequent recurrences involve only the liver.[13] Recent studies of patients undergoing hepatic artery infusion after resection report an improved survival as well as a decrease in hepatic recurrence compared with those receiving systemic therapy. These studies were built upon the prior observation of benefit from regional therapy in patients with unresectable liver metastases from colorectal carcinoma.[14]

The Mayo Clinic and North Central Cancer Treatment Group (NCCTG) conducted a trial of intrahepatic floxuridine (FUDR) vs systemic fluorouracil (5-FU) in patients with unresectable colorectal liver metastases.[14] This trial confirmed significantly higher tumor response rates for intrahepatic FUDR (55%) compared to systemic 5-FU (17%; P < .01), and significantly longer time to hepatic progression with intrahepatic FUDR compared to systemic 5-FU. Despite the higher response rate with FUDR, no improvement in survival was seen due to the higher incidence of extrahepatic tumor progression in the FUDR-treated group.

Two additional phase III trials comparing intrahepatic vs systemic FUDR for the treatment of colorectal liver metastases yielded similar results.[15,16] However, systemic chemotherapy has improved with the advent of combination chemotherapy, and several controlled clinical trials have demonstrated a significant increase in objective tumor response rates when 5-FU is combined with leucovorin vs single-agent 5-FU[17-19] and when used in the three-drug regimen of irinotecan (CPT-11, Camptosar)/5-FU/leucovorin.[20]

A pilot Mayo Clinic/NCCTG study of systemic 5-FU/leucovorin combined with hepatic artery infusion FUDR demonstrated that this regimen is tolerable.[21] Among 40 eligible patients who received therapy, 62% had regression of their liver metastases. Median time to tumor progression was 9 months, and median survival was 18 months. The toxicity was tolerable, and there were no cases of biliary sclerosis.

A prospective Mayo Clinic/NCCTG trial of systemic 5-FU and leucovorin combined with hepatic artery infusion FUDR following hepatic resection has now reached its targeted accrual of 96 patients (unpublished data).

Two randomized trials of hepatic artery infusion following surgical resection of hepatic metastases from colorectal carcinoma have been reported recently. In a study from Memorial Sloan-Kettering Cancer Center, 82 patients were randomized to systemic chemotherapy alone, with either bolus 5-FU and leucovorin or continuous-infusion 5-FU, vs 74 patients randomized to systemic chemotherapy combined with hepatic artery infusion FUDR.[22] A significant benefit was seen in patients receiving the combined therapy.

The median survival in the combined-therapy group was 72.2 months, compared with 59.3 months for those receiving systemic therapy alone. At 2 years, the rate of survival (free of hepatic recurrence) was 90% in the combined-therapy group compared with 60% in the systemic therapy-only group (P < .001). However, recurrence rates outside the liver appeared similar in both groups (Table 1).

In another study, patients with two to four resected hepatic metastases were randomized to resection alone vs hepatic artery infusion FUDR combined with systemic continuous-infusion 5-FU.[23] As in the Memorial Sloan-Kettering trial, this study showed a marked decrease in hepatic recurrence with hepatic artery infusion and a significant improvement in recurrence-free survival.

Role for Oxaliplatin

Recent experience with hepatic artery infusion combined with systemic chemotherapy suggests that, despite improved disease-free survival, both intrahepatic and extrahepatic recurrence of colorectal carcinoma continues to be a problem for patients undergoing resection of hepatic metastases. As such, better systemic regimens are needed.

Oxaliplatin (Eloxatin) is a platinum complex that has shown activity against a number of human and murine tumors in vitro and in vivo, including colorectal carcinoma-derived cell lines.[24,25] It possesses a higher cytotoxic potency on a molar basis than either cisplatin (Platinol) or carboplatin (Paraplatin), and is also active against various cell lines that have been selected on the basis of their resistance to cisplatin.[26,27]

Clinical Trials

In an ongoing randomized phase III trial, the combination of oxaliplatin, 5-FU, and leucovorin is being compared to 5-FU and leucovorin in a group of 420 previously untreated patients with advanced colorectal carcinoma. An interim analysis showed a significantly higher response rate in patients (n = 210) receiving oxaliplatin (50.7% vs 22.3%; P < .001).[28] However, the addition of oxaliplatin also increased toxicity.[28]

Grade 3 neurosensory toxicity occurred in 18.2% of patients receiving oxaliplatin, grade 3/4 diarrhea in 11.9%, and grade 3/3 vomiting and mucositis in 5.8%. Grade 3/4 neutropenia occurred in 41.7% of patients receiving oxaliplatin and 5.3% of patients receiving 5-FU and leucovorin alone. These did not significantly impair quality-of-life parameters, and indeed, de Gramont and colleagues noted a reversal of grade 3 neurosensory toxicity in 74% (25/34) of patients.

Bismuth et al reported on the potential surgical resection of initially unresectable liver metastases from colorectal carcinoma in a group of patients receiving neoadjuvant chemotherapy with oxaliplatin, 5-FU, and leucovorin.[29] A total of 330 patients with advanced disease that was determined to be unresectable by surgical evaluation were enrolled in the trial. All patients were initially treated with chemotherapy, and responses were assessed every three courses; a surgical resection was considered after each assessment.

A total of 53 patients demonstrated sufficient response to chemotherapy to allow for surgical exploration. This included a group of 13 patients who were known to have associated extrahepatic disease. The surgical complication rate was 26%, with no operative mortality. The cumulative 3-year and 5-year survival rates were 54% and 40%, respectively, including patients with known extrahepatic disease. Despite the fact that this was a selected group of patients, these findings were quite provocative given the overall dismal prognosis for this group of patients.

Conclusions

The above studies showed (1) improved survival following resection of hepatic metastases from colorectal carcinoma, (2) improved survival with the combination of hepatic artery infusion FUDR and systemic chemotherapy, and (3) the significant activity of oxaliplatin, 5-FU, and leucovorin in metastatic colorectal carcinoma. Based on these findings, the NCCTG is conducting a study of hepatic artery infusion FUDR alternating with systemic oxaliplatin, 5-FU, and leucovorin in patients undergoing resection of hepatic metastases.

Other groups are performing additional studies exploring the role of hepatic artery infusion using oxaliplatin.[30] These studies offer hope of increased survival for patients with resected hepatic metastases from colorectal carcinoma (Table 2).[22,31-33] The use of oxaliplatin-based systemic therapy also offers the potential for a greater reduction in the incidence of extrahepatic metastases following resection of hepatic metastases.

References

1. Greenlee RT, Murray T, Bolden S, et al: Cancer statistics, 2000. CA Cancer J Clin 50:7-33, 2000.

2. Steele GD, Jr: The National Cancer Database report on colorectal cancer. Cancer 74:1979-1989, 1994.

3. Moertel CG, Fleming TR, MacDonald JS, et al: Levamisole and fluorouracil for adjuvant therapy of resected colon cancer. N Engl J Med 322:352-358, 1990.

4. 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.

5. Finan PJ, Marshall RJ, Cooper EH, et al: Factors affecting survival in patients presenting with synchronous hepatic metastases from colorectal cancer: A clinical and computer analysis. Br J Surg 72:373-377, 1985.

6. Goslin R, Steele G, Jr, Zamcheck N, et al: Factors influencing survival in patients with hepatic metastases from adenocarcinoma of the colon or rectum. Dis Colon Rectum 25:749-754, 1982.

7. Bengtsson G, Carlsson G, Hafstrom L, et al: Natural history of patients with untreated liver metastases from colorectal cancer. Am J Surg 141:586-589, 1981.

8. 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.

9. Hughes K, Scheele J, Sugarbaker PH: Surgery for colorectal cancer metastatic to the liver. Optimizing the results of treatment. Surg Clin North Am 69:339-359, 1989.

10. Ambiru S, Miyazaki M, Ito H, et al: Adjuvant regional chemotherapy after hepatic resection for colorectal metastases. Br J Surg 86:1025-1031, 1999.

11. Berlin J, Merrick HW, Smith TJ, et al: Phase II evaluation of treatment of complete resection of hepatic metastases from colorectal cancer and adjuvant hepatic arterial infusion of floxuridine: An Eastern Cooperative Oncology Group Study (PB083). Am J Clin Oncol 22:291-293, 1999.

12. Lorenz M, Muller HH, Schramm H, et al: Randomized trial of surgery vs surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen). Ann Surg 228:756-762, 1998.

13. Fong Y, Cohen AM, Fortner JG, et al: Liver resection for colorectal metastases. J Clin Oncol 15:938-946, 1997.

14. Martin JK, O’Connell MJ, Wieand HS, et al: Intra-arterial floxuridine vs systemic fluorouracil for hepatic metastases from colorectal cancer. A randomized trial. Arch Surg 125:1022-1027, 1990.

15. 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.

16. Chang AE, Schneider PD, Sugarbaker PH, et al: A prospective randomized trial of regional vs systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases. Ann Surg 206:685-693, 1987.

17. Erlichman C, Fine S, Wong A, et al: A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol 6:469-475, 1988.

18. Petrelli N, Herrera L, Rustum Y, et al: A prospective randomized trial of 5-fluorouracil vs 5-fluorouracil and high-dose leucovorin vs 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol 5:1559-1565, 1987.

19. Poon MA, O’Connell MJ, Wieand HS, et al: Biochemical modulation of fluorouracil with leucovorin: Confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol 9:1967-1972, 1991.

20. Saltz LB, Locker PK, Pirotta N, et al: Weekly irinotecan (CPT-11), leucovorin (LV), and fluorouracil (FU) is superior to daily ´ 5 LV/FU in patients (PTS) with previously untreated metastatic colorectal cancer (CRC) (abstract 898). Proc Am Soc Clin Oncol 18:233a, 1999.

21. 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.

22. 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.

23. Kemeny MM, Adak S, Lipsitz S, et al: Results of the intergroup [Eastern Cooperative Oncology Group (ECOG) and Southwestern Oncology Group (SWOG)] prospective randomized study of surgery alone vs continuous hepatic artery infusion of FUDR and continuous systemic infusion of 5-FU after hepatic resection for colorectal liver metastases (abstract 1012). Proc Am Soc Clin Oncol 18:264a, 1999.

24. Mathe G, Kidani Y, Segiguchi M, et al: Oxalato-platinum or 1-Ohp, a third-generation platinum complex: An experimental and clinical appraisal and preliminary comparison with cisplatinum and carboplatinum. Biomed Pharmacother 43:237-250, 1989.

25. Tashiro T, Kawada Y, Sakurai Y, et al: Antitumor activity of a new platinum complex, oxalato (trans-L-1,2-diaminocyclohexane) platinum(II): New experimental data. Biomed Pharmacother 43:251-260, 1989.

26. Rixe O, Ortuzar W, Alvarez M, et al: Oxaliplatin, tetraplatin, cisplatin, and carboplatin: Spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institute’s Anticancer Drug Screen panel. Biochem Pharmacol 52:1855-1865, 1996.

27. Pendyala L, Creaven PJ: In vitro cytotoxicity, protein binding, red blood cell partitioning, and biotransformation of oxaliplatin. Cancer Res 53:5970-5976, 1993.

28. De Gramont A, Figer A, Seymor M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000.

29. Bismuth H, Adam R, Levi F, et al: Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 224:509-520, 1996.

30. Kern W, Beckert B, Lang N, et al: Phase I and pharmacokinetic study of hepatic arterial infusion with oxaliplatin, folinic acid, and 5-fluorouracil in patients with hepatic metastases from colorectal cancer (abstract 1132). Proc Am Soc Clin Oncol 19:289a, 2000.

31. Wagner JS, Adson MA, Van Heerden JA, et al: The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Ann Surg 199:502-508, 1984.

32. Wood CB, Gillis CR, Blumgart LH: A retrospective study of the natural history of patients with liver metastases from colorectal cancer. Clin Oncol 2:285-288, 1976.

33. Fong Y: Surgical therapy of hepatic colorectal metastasis. CA Cancer J Clin 49:231-255, 1999.

 
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