Second-Line Therapy in Colorectal Cancer

Second-Line Therapy in Colorectal Cancer

ABSTRACT: Second-line therapy is a relatively new concept for gastrointestinal oncologists. Although retreatment with fluorouracil (5-FU) is common, offering colorectal cancer patients a different chemotherapeutic agent as second-line therapy is a fairly recent strategy. The focus of this article is on the use and efficacy of oxaliplatin (Eloxatin) as second-line therapy for colorectal cancer. As such, this article will present very limited data on the toxicity of oxaliplatin regimens. [ONCOLOGY 14(Suppl 11):21-26, 2000]


With the exception of surgically
resectable liver or lung metastases, the majority of patients with metastatic
colorectal cancer are treated primarily with systemic chemotherapy. It is now
common for many of these patients to not only receive one, but two or more
chemotherapy regimens during the course of their illness.

In a recently reported randomized trial, 45% of patients
receiving first-line fluorouracil (5-FU) and leucovorin received second-line
irinotecan (CPT- 11, Camptosar).[1] Most of the current available data for
second-line therapy of colorectal cancer comes from phase II trials. These
trials have all the limitations of other phase II trials. In addition, there is
significant heterogeneity in the colorectal cancer population considered for
"second-line" therapy. This group may include patients who first
presented with metastatic disease, patients who have progressed rapidly after
adjuvant therapy, patients who have had more than one resection for disease, and
patients who may have had liver-directed therapy. In addition, as more knowledge
develops on the molecular basis of disease, properties of the cancers themselves
have been identified that may predict chemotherapy effects.

The data regarding the use of oxaliplatin as second-line (or
later-line) chemotherapy will be highlighted herein. The article will
demonstrate that phase II data in this setting are mature and that the time has
come for randomized trials to establish the true role of oxaliplatin in
second-line chemotherapy.

Combinations as
First-Line Therapy

An important variable in future results of second-line therapy
may be the shifting paradigm for first-line therapy. (Use of oxaliplatin
(Eloxatin) as first-line therapy is discussed elsewhere.) Recently, two clinical
trials compared fluorouracil (5-FU) and leucovorin with 5-FU, leucovorin, and
irinotecan combination therapy. Both trials showed that the addition of
irinotecan increased the response rate, time to progression, and overall
survival compared to 5-FU and leucovorin alone, at the expense of potential
added toxicity.[1-3] Thus, at least in the United States, many patients are now
receiving a combination regimen as first-line therapy.

However, investigators initially assessed irinotecan as
second-line therapy for metastatic colorectal cancer. In that respect, data from
those trials remain the best framework in which to evaluate second-line
oxaliplatin. Single-agent irinotecan as second-line therapy has yielded response
rates of 10% to 22% and median survivals of 8 to 10 months.[4] In two randomized
trials, irinotecan also established a survival benefit over both best supportive
care and second-line infusional 5-FU.[5,6] The trials had different eligibility
criteria and, therefore, patient populations.[7-12]

Single-Agent Oxaliplatin

The activity of single-agent oxaliplatin as second-line therapy
was established in three trials reported in two articles.[7,13] In the trials by
Machover et al, patients received intravenous infusions of oxaliplatin over 2
hours. Doses were repeated every 3 weeks.[7] The study by Levi et al used a
chronomodulated infusion, with the peak dose administered at 4 PM,
over 5 days, also repeated every 3 weeks.[7]

Response rates were 10% to 11%, with stable disease seen in 24%
to 42% of patients. Median time to progression was 4.5 to 6 months and median
survival was 8 to 9 months. These results are comparable to the results achieved
with irinotecan as second-line therapy.[4-6]

Combination Regimens

The Folfox Regimens

De Gramont and colleagues have pioneered several regimens
combining 5-FU and leucovorin with oxaliplatin.[7-11] The majority of these
regimens are administered every 2 weeks, and contain infusions of leucovorin and
5-FU. Most also contain one or two bolus doses of 5-FU. For example, folfox4
(oxaliplatin, leucovorin, and fluorouracil) administers oxaliplatin at 85 mg/m2
over 2 hours on day 1. Patients then receive leucovorin at 200 mg/m2
over 2 hours on days 1 and 2 followed each day by bolus 5-FU at 400 mg/m2
on days 1 and 2 and 22 hours of infusional 5-FU 600 mg/m2
on days 1 and 2. These cycles are repeated once every 2 weeks, for up to 12
doses of oxaliplatin (Table 1).[7-12]

When combined, the response rate plus stable disease rate is
generally greater than 50% for the folfox regimens. Of particular note, most of
the patients in these trials had progressed while on the same 5-FU and
leucovorin regimen that they later received on trial with the addition of
oxaliplatin, suggesting that the addition of oxaliplatin resulted in the
antitumor effect. Although these data are from phase II trials, response rates
for the folfox regimens were higher than for single-agent oxaliplatin,
suggesting a possible additive effect when combining 5-FU and oxaliplatin.

Differences in the incidence of toxicity were seen among the
folfox regimens with grade 3/4 neutropenia occurring in 20% to 39% of patients
receving folfox2, 3, 4, or 6, and grade 2/3 neuropathy in 16% to 29% of those
receiving folfox2, 3, 4, or 6.[11]


Chronomodulated 5-FU has also been combined with oxaliplatin in
several phase II trials listed in Table 2.[14-18]
Although two trials involved both previously untreated and previously treated
patients, the data are separated when possible for patients with refractory
disease. As with the folfox trials, response rates were high, ranging from 15%
to 58%. In addition, a progression-free survival ranging from 5 to 10 months and
an overall survival as high as 17 months was observed.

Recently, Giacchetti et al reported results that combined
patients from some of the trials listed in Table
with other patients being considered for resection of hepatic
metastases.[19] In total, 196 patients had been treated with chronomodulated
5-FU and oxaliplatin. Of these, 60% had received only one previous chemotherapy
regimen and 40% had received greater than or equal to two regimens. Median
progression-free survival was 9 months and overall survival was 17 months.
However, hepatic metastases were resected in 18% of patients.

With chronomodulation, grade 3/4 neutropenia occurred in less
than 5% of patients, while grade 2 or higher neuropathy occurred in up to 32% of
pretreated patients and grade 3/4 mucositis in up to 28% of patients.[14,15]

Other 5-FU Regimens

Several schedules and doses for 5-FU, leucovorin, and
oxaliplatin have been investigated; many of these are listed in Table
.[20-24] Although some of the bolus schedules for 5-FU appeared to yield
lower response rates, overall survival was similar to that achieved with the
folfox and chronomodulated schedules shown in Table
and Table 2. Table
is not a comprehensive list of all the trials performed, and more
treatment schedules are likely to be tried. In fact, the Extended Access French
Program (EAFP) allowed the use of over 25 different regimens of oxaliplatin in
combination with 5-FU.[25] This data set incorporated 490 patients from 147
centers, only 18 of whom received single-agent oxaliplatin.

Antitumor effects were reviewed for 370 patients, and 14.6%
responded to therapy with a 9.7-month overall median survival. Response rates
were higher for the biweekly oxaliplatin regimens (36.1%) than for the triweekly
regimens (13.3%) but survivals were similar at 11.1 and 10.0 months,
respectively. The current "compassionate-use trial" in the United
States will accumulate progression and survival data that may help guide a
decision on whether it is worthwhile to explore different regimens in a
randomized fashion.

A single randomized phase II/III trial has been reported that
compared oxaliplatin plus 5-FU vs one of two other second-line regimens, 5-FU or
irinotecan.[26] The trial was divided into two treatment arms with 49 patients
assigned to the oxaliplatin plus 5-FU arm vs 36 patients in the control arm. The
response rate was 37% for the oxalipatin plus 5-FU arm vs 11% for the control
arm, and progression-free survival was 5.1 months vs 2.2 months for the
oxaliplatin plus 5-FU and control arm, respectively.

The final data from this trial may help to clarify the role of
oxaliplatin plus 5-FU in second-line therapy of colorectal cancer. However,
interpretation may be limited by the inclusion of two different single-arm
regimens in the "control" arm.

Overall, it appears that 5-FU plus oxaliplatin is active in the
second-line therapy of colorectal cancer. A number of regimens have been tested
as listed in Tables 1 to 3. While response rates for combination therapy often
seem higher than response rates for single-agent oxaliplatin, survival does not
appear to differ significantly.


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