An estimated 130,200 people in the United States will develop
colorectal cancer in the year 2000, and approximately 15% to 17% of these
will initially present with stage IV disease. In addition, approximately 40%
of patients undergoing potentially curative resection for stage II and III
disease will subsequently recur.
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. 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
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.
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.
Corresponding 5-year actuarial disease-free survivals were 36%, 32%, 0%, and
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.
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. 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
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. 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
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.
A pilot Mayo Clinic/NCCTG study of systemic 5-FU/leucovorin
combined with hepatic artery infusion FUDR demonstrated that this regimen is
tolerable. 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
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. 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. 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
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]
In an ongoing randomized phase III trial, the combination of
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). However, the addition
of oxaliplatin also increased toxicity.
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
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. 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
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.
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
Other groups are performing additional studies exploring the
role of hepatic artery infusion using oxaliplatin. 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.
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