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The Role of Irinotecan and Oxaliplatin in the Treatment of Advanced Colorectal Cancer

The Role of Irinotecan and Oxaliplatin in the Treatment of Advanced Colorectal Cancer

ABSTRACT: Colorectal carcinoma is one of the most common malignancies in the western world, and although fluorouracil (5-FU) has been used in its treatment for almost 40 years, new agents with significant activity have been introduced recently. Irinotecan (CPT-11, Camptosar), a topoisomerase I inhibitor, administered at 300 to 350 mg/m2 every 3 weeks is significantly more active than continuous-infusion 5-FU in patients who have experienced disease progression after conventional therapy with 5-FU. In comparison to best supportive care, irinotecan improves survival and preserves quality of life despite treatment-related toxicity. Moreover, the combination of irinotecan and 5-FU has been explored in a number of different schedules. In previously untreated patients, overall response rates are high. Irinotecan can also be combined with mitomycin (mitomycin-C [Mutamycin]), oxaliplatin, or raltitrexed (Tomudex). Oxaliplatin is a new-generation platinum compound that has demonstrated activity against colorectal carcinoma in preclinical trials. It has been evaluated as a single agent against advanced colorectal carcinoma in the salvage setting and also in combination with 5-FU as initial therapy for metastatic disease (where it shows significant activity). The toxicity profile of oxaliplatin (chiefly characterized by neurotoxicity) differs from that of irinotecan (primarily producing diarrhea) and the potential, therefore, exists for combining these agents or for exploiting their possible synergy with 5-FU. The introduction of these two new active agents of different pharmacologic classes promises to enable significant improvements in the treatment of patients with colorectal carcinoma. [ONCOLOGY 15(4):415-434, 2001]

Introduction

Colorectal cancer is one of the
most common malignancies in
the western world, with over 300,000 new cases diagnosed in Europe and the
United States each year. Surgery is the principal treatment for operable
patients, but for patients who have relapsed following surgery or who present
with metastatic disease, the prognosis is poor. Although systemic treatment is
possible, the effect is mainly palliative. For almost 40 years, fluorouracil
(5-FU) has been the mainstay of the treatment of patients with advanced
colorectal cancer.

Over the past 15 years, several attempts have been made to
increase the efficacy of 5-FU, either through modulation of its activity with
compounds such as leucovorin, methotrexate, or interferon-alpha, or through
techniques that increase tumor exposure to the drug by means of protracted
continuous infusion. Although these methods have increased the efficacy of 5-FU
by a factor of two to three in terms of response rate, survival of patients with
advanced colorectal cancer remains relatively disappointing, rarely exceeding a
median of 12 months.

Treatment options for these patients remained limited until
recently, when the topoisomerase I inhibitor irinotecan (CPT-11, Camptosar) and
the diaminocyclohexane (DACH) platinum compound oxaliplatin (EDITOR'S
NOTE:
roxaliplatin is
investigational in the United States and available as Eloxatin in France
) were developed and
approved for use in advanced colorectal carcinoma.

Irinotecan

Irinotecan is a water-soluble semisynthetic compound derived
from the antineoplastic agent camptothecin, a natural alkaloid of the Chinese
tree Camptotheca acuminata. It is a selective inhibitor of the DNA enzyme
topoisomerase I. In preclinical studies, irinotecan and its active metabolite
SN38 demonstrated significant antitumor activity against a variety of tumor cell
lines in vitro and also showed activity in in vivo models, including tumors
(such as colorectal cancer) that express the p-glycoprotein-mediated,
multidrug-resistant phenotype.[1]

Single-Agent Trials

Irinotecan has demonstrated activity as a single agent in
several phase I and phase II trials conducted in Europe, Japan, and the United
States. Initial phase I studies of irinotecan began in Japan in 1986, and the
most common dose-limiting toxicities were found to be hematologic (neutropenia)
and gastrointestinal (delayed diarrhea).[2] Early in its development, irinotecan
was tested as a short infusion (30 to 90 min) using three different schedules:
(1) 100 mg/m2/d over 3 days, repeated every week; (2) 100 to
125 mg/m2/d every week; and (3) 350 mg/m2 every 3 weeks.

The most widely used schedule of irinotecan in European phase I
studies was a single dose administered every 3 weeks. These studies led to
the recommendation that a dose of 350 mg/m2 every 3 weeks be evaluated in
clinical phase II trials. Delayed diarrhea was countered by subsequent
incorporation of high-dose loperamide.

In a multicenter phase II trial in 166 patients with previously
treated colorectal cancer, Rothenberg et al administered irinotecan at 125
mg/m2/wk to the first 64 patients and at 100 mg/m2 to the subsequent 102
patients.[3] Irinotecan was administered as a 90-minute infusion for
4 consecutive weeks followed by 2 weeks’ rest. There were no significant
differences in grade 3/4 toxicities between those receiving 125 mg/m2 and
those receiving 100 mg/m2, except for grade 3/4 emesis (22% vs 2%;

P
 < .001.[3] Compared with younger patients, elderly patients (>
65 years old) were twice as likely (38.6% vs 18.8%, P < .008) to develop
grade 3/4 diarrhea.

Objective responses to irinotecan were observed in 18 patients
(1 complete response and 17 partial responses) for an overall response rate of
10.8% (95% confidence interval (CI) = 6.1%-15.6%). In addition, 67 patients
(40.4%) had stable disease. The treatment response rates were 14.1% (9/64) for
the 125-mg/m2 arm and 8.8% (9/102) for the 100-mg/m2 arm. This trial suggested
a trend toward a higher response rate without substantially greater toxicity for
the 125-mg/m2 dose, while the overall median survival was 9.9 months
(range: 0.3 to 38.8 months, Table 1).[3]

Multicenter Phase III Trials: Two important randomized
multicenter phase III studies of irinotecan as a single agent were performed
during its development in Europe. The first, conducted by Rougier et al,
compared irinotecan with continuous-infusion
5-FU[4] in 267 advanced colorectal cancer patients who either did not respond or
whose disease had progressed after first-line treatment with 5-FU. Patients were
randomly assigned to receive a 90-minute infusion of irinotecan at 300 to 350
mg/m2 every 3 weeks or a continuous infusion of 5-FU according to three
different schedules (Table 2).[4] Both treatments were given until the
development of disease progression or unacceptable toxicity.

As second-line therapy, irinotecan improved survival and median
time to disease progression compared to continuous-infusion 5-FU, with relative
outcomes of 10.8 vs 8.5 months (P = .035) and 4.2 vs 2.9 months (P = .035),
respectively (Figure 1 and Figure
2
).[4] Both treatments were well tolerated except
for vomiting and diarrhea, and patients were able to maintain good quality of
life (Figure 3) and tumor control.[4] Because irinotecan has proven to
significantly improve progression-free and overall survival compared to
continuous-infusion 5-FU after failure of therapy with standard 5-FU, it should
be considered one of the reference drugs for second-line treatment of advanced
colorectal cancer.

The second trial, conducted by Cunningham et al in 279 advanced
colorectal cancer patients, compared irinotecan plus best supportive care vs
best supportive care alone after 5-FU failure.[5] A 90-minute infusion of
irinotecan at 300 to 350 mg/m2 every 3 weeks plus best supportive care was
administered to 189 patients, while another 90 patients received best supportive
care alone (Figure 4).[5] At a median follow-up of 13 months, overall survival
was significantly better in the irinotecan arm (P = .0001) (Figure
5
).[5]
The 1-year survival reported for the irinotecan arm was 36.2%, compared to 13.8%
for the best supportive
care arm, thus showing a clear advantage for salvage chemotherapy with
irinotecan.

A multivariate analysis adjusted to prognostic factors
significantly favored irinotecan when assessed in terms of survival (P = .001),
survival without performance status deterioration (P = .0001), survival without
a weight loss of more than 5% (P = .018), and pain-free survival (P = .003)
(Figure 6).[5] Despite the presence of treatment-induced diarrhea,
significant differences in the quality-of-life analysis were also found to favor
irinotecan. This study showed that despite the side effects, patients with
metastatic colorectal cancer in whom 5-FU therapy has failed have a longer
survival with fewer tumor-related symptoms and better quality of life when they
are treated with irinotecan, as compared to best supportive care alone.

Four Different Schedules: A recent randomized phase II
multicenter trial compared four different schedules of irinotecan as second-line
therapy in advanced colorectal cancer patients.[6] Patients were randomized to
arm A (350 mg/m2 every 3 weeks), arm B (125 mg/m2, weekly, for 4 weeks, in
6-week cycles), arm C (250 mg/m2 every 2 weeks), or arm D (10 mg/m2/d by
continuous infusion for 14 days every 3 weeks).

All four regimens were well tolerated and demonstrated efficacy.
Arm C (every 2 weeks) and arm A (every 3 weeks) showed similar results for
survival and tumor control while showing better efficacy compared to the weekly
schedule (arm B). Continuous-infusion irinotecan (arm D) did not show the
expected efficacy or safety (producing diarrhea, nausea, and vomiting), although
it was associated with a low incidence of grade 3/4 neutropenia.[6] Therefore,
the new standard schedule to be adopted for further development will consist of
irinotecan administered every 2 or 3 weeks.

Combination Regimens

Several combination regimens containing irinotecan have been
tested in Europe and the United States in recent years. The superiority of
irinotecan over best supportive care and other second-line chemotherapy in
colorectal cancer patients suggested that it would be of interest to combine
irinotecan with other active agents such as 5-FU, oxaliplatin, or mitomycin
(mitomycin-C [Mutamycin]).

Irinotecan and 5-FU or 5-FU/Leucovorin: A phase I trial and
pharmacokinetic analysis performed between 1995 and 1997 at the
Pitié-Salpêtrière Hospital in 41 patients with solid tumors (29 advanced
colorectal cancer patients), demonstrated the feasibility and safety of
irinotecan in combination with 5-FU (Table 3).[7,8] Irinotecan was administered
on day 0 followed by 5-FU on days 1 to 5 in cycle 1 and on day 6 after 5-FU in
cycle 2. The aim of the trial was to determine the relationship between the
sequence of irinotecan administration and toxicity when combined with 5-FU.

The maximum tolerated dose of irinotecan was established at 350
mg/m2. For further phase II trials, the investigators recommended that
irinotecan be given at 200 mg/m2 in combination with 5-FU at 375 mg/m2
and leucovorin at 20 mg/m2 on days 1 and 5 (Mayo Clinic regimen). No
difference in the clearance of irinotecan or its active metabolite SN38 was
observed, but a reduction in the catabolism of 5-FU was demonstrated, suggesting
a potential benefit if irinotecan is administered before 5-FU.[7,8]

In a phase I study conducted in Spain by Aranda et al,
irinotecan was administered on day 1 at 150 to 250 mg/m2 followed by a 14-day
continuous-infusion of 5-FU at 250 mg/m2/d and 1 week of rest in a variety
of solid tumors. Three partial responses (gastric, colon, and rectum) and two
minor responses (colon) were observed.[9,10]

Barone et al conducted a multicenter study in Italy in 33
advanced colorectal cancer patients who were treated with irinotecan at 350 mg/m2, over a 90-minute infusion on day 1 every 3 weeks, plus 5-FU and
leucovorin for 5 consecutive days according to the Mayo Clinic schedule as
first-line treatment.[11] This combination was well tolerated despite moderate
neutropenia and diarrhea and achieved an overall response rate of 31% with a
median progression-free survival of 7.2 months and an overall survival of 16
months.

Rothenberg et al conducted another multicenter phase II trial in
which 71 previously untreated patients received weekly irinotecan at 100 mg/m2
for 4 weeks every 6 weeks and 5-FU/leucovorin over 5 days (according
to the Mayo Clinic schedule) every 4 weeks.[12] The main toxicities were
diarrhea and neutropenia (without severe consequences). The overall response
rate with this regimen was 32% (95% CI: 21.5%-43.3%), and the median survival
was 17.8 months.[12]

Rougier et al recently published the results of a phase I/II
trial in which irinotecan was administered in combination with FUFOL (5-FU and
leucovorin [folinic acid]) according to the de Gramont schedule in 55 advanced
colorectal cancer patients who had previously been treated with 5-FU (Table 4).[13] This combination was tolerated well, with no cumulative
toxicity and produced a response rate of 22%. The maximum tolerated dose of
irinotecan was 300 mg/m2 dose level; thus, the recommended dose for phase
II trials was a 90-minute infusion of irinotecan at 180 mg/m2 on day 1,
and biweekly leucovorin/5-FU on days 1 and 2 every 2 weeks. A
pharmacokinetic analysis performed in 21 patients showed that the maximum
concentration of SN38 appeared 30 to 60 minutes after the administration of
irinotecan (Table 4).[13]

These results have been confirmed at our institution in 39
patients with advanced colorectal cancer, using the recommended dose of
irinotecan (180 mg/m2 on day 1) and biweekly leucovorin/5-FU on days 1 and
2. Eight patients achieved an objective response (overall response rate =
20.5%), and 12 demonstrated disease stabilization or minor responses (tumor
control = 49%).[14,15] Of eight patients who underwent hepatic resection, seven
achieved a complete response. The median duration of response and the median
survival were 14 and 11 months, respectively. Neutropenia was the most
serious side effect (affecting 29% of patients in 2% of cycles), with four
patients developing febrile neutropenia and grade 3 diarrhea.[14,15]

De Gramont and colleagues performed a phase II study to evaluate
the FOLFIRI combination (irinotecan, 180 mg/m2 on day 1, plus a simplified
biweekly leucovorin/5-FU regimen, with the daily 5-FU bolus omitted) in heavily
pretreated colorectal cancer patients (Figure 7).[16] The treatment was well
tolerated, and the main toxicities were nausea and vomiting. Of 34 evaluable
patients, 2 achieved a partial response (overall response rate: 6%), and disease
stabilization was observed in 20, for a tumor control rate of 65% (Table 5).[16]

Irinotecan and Mitomycin: A phase I/II study was performed
at our institution to assess the feasibility of irinotecan in combination with
mitomycin, another active compound in the treatment of gastrointestinal tract
tumors, including advanced colorectal cancer.[17] Between January 1996 and June
1997, the study accrued 26 heavily pretreated patients with advanced
gastrointestinal cancer (22 with colorectal cancer). Mitomycin was administered
as an IV bolus, and irinotecan as a 30-minute infusion. Four dose levels of
irinotecan/mitomycin were evaluated: 300/8 mg/m2, 325/8 mg/m2, 350/8
mg/m2, and
325/10 mg/m2 administered on day 1 every 21 days (Table
6
).[17]

The dose-limiting toxicity was neutropenia, but it was of short
duration and associated with rapid recovery. Cumulative thrombocytopenia
occurred at the highest dose level as did one case of delayed hemolytic-uremic
syndrome (both of which were due to mitomycin). Other toxicities included
diarrhea and four cases of febrile neutropenia but no toxic deaths (Table
6).[17]

Objective responses were reported at all dose levels, for an
overall response rate of 28% (which is higher than expected for this heavily
pretreated population and suggests a possible synergism between the two drugs) (Table 6).[17] The recommended doses for further studies were
325 mg/m2 of irinotecan and 8 mg/m2 of mitomycin.[18]

Irinotecan and Oxaliplatin: Irinotecan in combination with
oxaliplatin has also shown activity in 5-FU-refractory patients. Cvitkovic et
al recently performed three phase I/II studies in which the combination was
administered following two different schedules[19]:

  1. Groups A and B received irinotecan, 150 to 250 mg/m2, plus
    oxaliplatin, 85 to 110 mg/m2, every 3 weeks.

  2. Group C received irinotecan, 100 to 200 mg/m2, plus
    oxaliplatin, 85 mg/m2, every 2 weeks.

Of 34 patients, 15 responded (for an overall response rate of
44%), and toxicity was acceptable (Table 7). The recommended doses were
irinotecan, 200 mg/m2, and oxaliplatin, 85 mg/m2, every 3 weeks (group A)
or irinotecan, 175 mg/m2, and oxaliplatin, 85 mg/m2, every 2 weeks (group
C).[19]

Wasserman et al published a pharmacokinetic analysis of two
independent phase I studies of the combination of irinotecan and oxaliplatin in
patients with gastrointestinal tumors.[20] Oxaliplatin was first administered as
a 120-minute infusion followed by irinotecan as a 30-minute infusion, every
3 weeks. Pharmacokinetic analyses were performed during the first and
second cycle. The maximum tolerated dose was reached at level 3, but two
patients with Gilbert’s syndrome developed severe neutropenia,
thrombocytopenia, and diarrhea.

Of 24 evaluable patients, 7 achieved a partial response (overall
response rate: 29%), and 9 (38%) experienced disease stabilization. The
pharmacokinetic parameters of the combined regimen were similar to those of the
single agents.[20]

Based on previous data, a phase I/II study and pharmacokinetic
analysis of four drugs in combination (irinotecan, oxaliplatin, and biweekly
5-FU/leucovorin) is ongoing at our center in patients with advanced colorectal
cancer. To date, 34 patients have been enrolled to receive oxaliplatin on day 1
(in a 2- to 4-hour infusion), irinotecan on day 2 (30-minute infusion), and
leucovorin/5-FU (de Gramont schedule) in a fixed dose on days 2 and 3, every 2
weeks. Pharmacokinetic samples are drawn during cycles 1 and 2. In the second
cycle, irinotecan is given on day 1 and oxaliplatin on day 2 (Table
8
).[21]

Five dose-levels are being evaluated: level 1 = oxaliplatin, 65
mg/m2, and irinotecan, 150 mg/m2; level 2 = oxaliplatin, 75
mg/m2, and
irinotecan, 165 mg/m2; level 3 = oxaliplatin, 85 mg/m2, and
irinotecan, 165 mg/m2; level 4 = oxaliplatin, 85 mg/m2, and
irinotecan, 180 mg/m2. Dose level 5 is ongoing: oxaliplatin, 100 mg/m2, and
irinotecan, 180 mg/m2. To date, the maximum tolerated dose has not
been reached but preliminary results show high antitumor activity with
acceptable toxicity at all dose levels (Table 8).[21]

Of 24 evaluable patients in this study, 2 achieved complete
responses and 8 achieved partial responses, for an overall response rate of 41%;
6 of these patients underwent subsequent partial hepatectomy and have achieved a
complete response (Table 8).[21] Preliminary pharmacokinetic results have
revealed that oxaliplatin clearance is significantly lower (27.87 vs
23.24 L/h, P = .0047) when irinotecan is administered on day 1 before
oxaliplatin, as compared to the reverse schedule.[21]

Irinotecan and Raltitrexed: In a recent phase II study
conducted by Nobile et al, the combination of irinotecan and raltitrexed was
evaluated in 14 patients with advanced colorectal cancer.[22] Irinotecan was
given at 300 to 350 mg/m2 on day 1, and raltitrexed at 3 mg/m2 on day 2, with
the cycle repeated every 3 weeks. The main toxicities were grade 3/4 diarrhea in
14% of patients, grade 3/4 nausea/vomiting in 42% of patients, and asthenia in
35.7% of patients; the incidence of febrile neutropenia was rare (7%). Of 10
evaluable patients, 3 achieved a partial response, 1 a minor response, and 4
disease stabilization (overall response rate: 30%). This represents an
encouraging level of tumor control for this combination (Table
9
).[22]

Phase III Trials of Irinotecan/FUFOL Combinations: Two
important randomized trials of irinotecan and FUFOL in combination have been
conducted in the United States and Europe. The first trial, performed by Saltz
et al, compared weekly irinotecan plus FUFOL to FUFOL (Mayo Clinic regimen) or
weekly irinotecan alone in patients with previously untreated metastatic
colorectal cancer.[23] This trial demonstrated that the combination achieves
better results than either single-agent therapy. The overall response rates were
49%, 27%, and 29% for the combination, irinotecan, and FUFOL, respectively.
Although more grade 3/4 diarrhea and vomiting were observed with the
combination, more grade 4 neutropenia and mucositis were seen with
5-FU/leucovorin alone.[23]

The second randomized phase III trial, conducted by Douillard et
al, compared FUFOL (at high doses, either according to the AIO [Arbeitsgruppe
Internistische Onkologie, of the German Cancer Society] or de Gramont regimen)
with or without irinotecan.[24] Included in the trial were 385 previously
untreated metastatic colorectal cancer patients: 145 received irinotecan plus
biweekly leucovorin/5-FU and 143 received FUFOL alone, while 54 and 43 patients received FUFOL
according to the AIO regimen, in combination with irinotecan or FUFOL/AIO alone,
respectively.

More toxicity was observed with the combination than with FUFOL
alone, resulting in higher rates of grade 3/4 neutropenia (42% vs 11% of
patients) and febrile neutropenia (5% vs 1% of patients), as shown in Table
10
.[24] In terms of nonhematologic grade 3/4 toxicities, patients who received
the combination experienced more diarrhea than those who received FUFOL alone
(22% vs 10% of patients). Of 169 patients evaluable for response in both arms,
4% achieved a complete response, and 37% a partial response, for an overall
response rate of 41% for irinotecan plus 5-FU/leucovorin and a 23% overall
response rate for the 5-FU/leucovorin combination (P < .001).

A substantial number of patients experienced disease
stabilization in both groups (38% and 50%, respectively) (Table
10
)[24];
however, the disease-free survival and median overall survival (Figure
8
) was
also significantly superior (16.8 vs 14 months,
P
= .031) in favor of the irinotecan/FUFOL combination, with good
quality-of-life results (Figure 9).[24]

A pooled analysis of these two phase III randomized trials,
comparing irinotecan plus FUFOL vs FUFOL alone in advanced colorectal cancer
patients who received no prior chemotherapy showed that the time to progression
and overall survival were significantly higher for the irinotecan plus FUFOL
combination in both studies, as well as in the combined analysis (time to
progression: P < .001; overall survival: P < .009). In conclusion,
the combination of irinotecan and FUFOL as first-line treatment significantly
improved tumor control and overall survival compared to FUFOL alone. This
combination may, therefore, be considered the new standard for first-line
treatment of advanced colorectal cancer.[25]

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