Intrahepatic Therapy for Resected Hepatic Metastases From Colorectal Carcinoma

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

Introduction

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

The liver represents one of the most common sites of diseaserecurrence in patients with colorectal carcinoma, and is a major cause ofmorbidity and mortality in this patient population. In an autopsy series ofpatients 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 to12 months.[5-7]

Surgical Resection

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

In a multi-institutional review, Hughes noted 5-year actuarialsurvivals of 37% for patients with solitary lesions, 34% for patients with twometastatic lesions (most of which were unilobar), 8% for those with threemetastatic lesions, and 18% for those with four or more lesions.[9]Corresponding 5-year actuarial disease-free survivals were 36%, 32%, 0%, and14%, respectively.

When patients with three metastatic lesions were groupedtogether with patients who had four or more metastatic lesions, the actuarial5-year survival was 14%, and disease-free survival was 7%, respectively. Thiscompares to the 35% actuarial and disease-free survival for patients with one ortwo metastatic lesions.

Regional Therapy

Patients who have undergone resection of colorectal metastasesto the liver may be candidates for regional infusion therapy.[10-12] The patternof recurrence after the first liver resection shows that 41% of subsequentrecurrences involve only the liver.[13] Recent studies of patients undergoinghepatic artery infusion after resection report an improved survival as well as adecrease in hepatic recurrence compared with those receiving systemic therapy.These studies were built upon the prior observation of benefit from regionaltherapy in patients with unresectable liver metastases from colorectalcarcinoma.[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 trialconfirmed significantly higher tumor response rates for intrahepatic FUDR (55%)compared to systemic 5-FU (17%; P < .01), and significantly longer time tohepatic progression with intrahepatic FUDR compared to systemic5-FU. Despite the higher response rate with FUDR, no improvement in survival wasseen due to the higher incidence of extrahepatic tumor progression in theFUDR-treated group.

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

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

A prospective Mayo Clinic/NCCTG trial of systemic 5-FU andleucovorin combined with hepatic artery infusion FUDR following hepaticresection has now reached its targeted accrual of 96 patients (unpublisheddata).

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

The median survival in the combined-therapy group was 72.2months, compared with 59.3 months for those receiving systemic therapy alone. At2 years, the rate of survival (free of hepatic recurrence) was 90% in thecombined-therapy group compared with 60% in the systemic therapy-only group (P< .001). However, recurrence rates outside the liver appeared similar in bothgroups (Table 1).

In another study, patients with two to four resected hepaticmetastases were randomized to resection alone vs hepatic artery infusion FUDRcombined with systemic continuous-infusion 5-FU.[23] As in the MemorialSloan-Kettering trial, this study showed a marked decrease in hepatic recurrencewith hepatic artery infusion and a significant improvement in recurrence-freesurvival.

Role for Oxaliplatin

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

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

Clinical Trials

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

Grade 3 neurosensory toxicity occurred in 18.2% of patientsreceiving oxaliplatin, grade 3/4 diarrhea in 11.9%, and grade 3/3 vomiting andmucositis in 5.8%. Grade 3/4 neutropenia occurred in 41.7% of patients receivingoxaliplatin and 5.3% of patients receiving 5-FU and leucovorin alone. These didnot significantly impair quality-of-life parameters, and indeed, de Gramont andcolleagues noted a reversal of grade 3 neurosensory toxicity in 74% (25/34) ofpatients.

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

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

Conclusions

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

Other groups are performing additional studies exploring therole of hepatic artery infusion using oxaliplatin.[30] These studies offer hopeof increased survival for patients with resected hepatic metastases fromcolorectal carcinoma (Table 2).[22,31-33] The use of oxaliplatin-based systemictherapy also offers the potential for a greater reduction in the incidence ofextrahepatic 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 oncolorectal cancer. Cancer 74:1979-1989, 1994.

3. Moertel CG, Fleming TR, MacDonald JS, et al: Levamisole andfluorouracil for adjuvant therapy of resected colon cancer. N Engl J Med322:352-358, 1990.

4. Weiss L, Grundmann E, Torhorst J, et al: Haematogenousmetastatic patterns in colonic carcinoma: An analysis of 1541 necropsies. JPathol 150:195-203, 1986.

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

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

7. Bengtsson G, Carlsson G, Hafstrom L, et al: Natural historyof patients with untreated liver metastases from colorectal cancer. Am J Surg141:586-589, 1981.

8. Fong Y, Fortner J, Sun RL, et al: Clinical score forpredicting 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 colorectalcancer metastatic to the liver. Optimizing the results of treatment. Surg ClinNorth Am 69:339-359, 1989.

10. Ambiru S, Miyazaki M, Ito H, et al: Adjuvant regionalchemotherapy after hepatic resection for colorectal metastases. Br J Surg86:1025-1031, 1999.

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

12. Lorenz M, Muller HH, Schramm H, et al: Randomized trial ofsurgery vs surgery followed by adjuvant hepatic arterial infusion with5-fluorouracil and folinic acid for liver metastases of colorectal cancer.German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen). Ann Surg228:756-762, 1998.

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

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

15. Kemeny N, Daly J, Reichman B, et al: Intrahepatic orsystemic infusion of fluorodeoxyuridine in patients with liver metastases fromcolorectal carcinoma. A randomized trial. Ann Intern Med 107:459-465, 1987.

16. Chang AE, Schneider PD, Sugarbaker PH, et al: A prospectiverandomized trial of regional vs systemic continuous 5-fluorodeoxyuridinechemotherapy in the treatment of colorectal liver metastases. Ann Surg206:685-693, 1987.

17. Erlichman C, Fine S, Wong A, et al: A randomized trial offluorouracil 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 prospectiverandomized trial of 5-fluorouracil vs 5-fluorouracil and high-dose leucovorin vs5-fluorouracil and methotrexate in previously untreated patients with advancedcolorectal carcinoma. J Clin Oncol 5:1559-1565, 1987.

19. Poon MA, O’Connell MJ, Wieand HS, et al: Biochemicalmodulation of fluorouracil with leucovorin: Confirmatory evidence of improvedtherapeutic 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/FUin 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: Sequentialintrahepatic fluorodeoxyuridine and systemic fluorouracil plus leucovorin forthe treatment of metastatic colorectal cancer confined to the liver. J ClinOncol 16:2528-2533, 1998.

22. Kemeny N, Huang Y, Cohen AM, et al: Hepatic arterialinfusion of chemotherapy after resection of hepatic metastases from colorectalcancer. N Engl J Med 341:2039-2048, 1999.

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

24. Mathe G, Kidani Y, Segiguchi M, et al: Oxalato-platinum or1-Ohp, a third-generation platinum complex: An experimental and clinicalappraisal and preliminary comparison with cisplatinum and carboplatinum. BiomedPharmacother 43:237-250, 1989.

25. Tashiro T, Kawada Y, Sakurai Y, et al: Antitumor activity ofa 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 linesof the National Cancer Institute’s Anticancer Drug Screen panel. BiochemPharmacol 52:1855-1865, 1996.

27. Pendyala L, Creaven PJ: In vitro cytotoxicity, proteinbinding, 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 andfluorouracil with or without oxaliplatin as first-line treatment in advancedcolorectal cancer. J Clin Oncol 18:2938-2947, 2000.

29. Bismuth H, Adam R, Levi F, et al: Resection of nonresectableliver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg224:509-520, 1996.

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

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

32. Wood CB, Gillis CR, Blumgart LH: A retrospective study ofthe 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.