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Oxaliplatin in Colorectal Cancer: Current Studies

Oxaliplatin in Colorectal Cancer: Current Studies

ABSTRACT: One of the more promising chemotherapeutic agents for patients with metastatic colorectal cancer is oxaliplatin (Eloxatin), a third-generation platinum derivative with a unique mechanism of action. Preclinical studies corroborated by results from early trials suggested that oxaliplatin could be particularly advantageous when used in combination with fluorouracil (5-FU)/leucovorin. In addition, early studies of oxaliplatin as monotherapy showed clear activity similar in magnitude to that observed with other active agents. When administered as neoadjuvant therapy in patients with unresectable liver metastases, the responses were substantial enough for some patients to undergo potentially curative hepatic resection. These trials also demonstrated a reasonable safety profile for oxaliplatin. In light of the accumulating data on the use of oxaliplatin in advanced colorectal cancer, the North Central Cancer Treatment Group (NCCTG) and other cooperative groups developed trials to further define the specific therapeutic roles and optimal regimens of oxaliplatin combined with 5-FU and leucovorin, as well as other agents. A number of studies are underway in the United States, including the three-arm NCCTG N9741 trial in patients with previously untreated metastatic colorectal cancer, the NCCTG N9841 trial in patients who progressed on 5-FU/leucovorin, and the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 adjuvant trial for stage II and III colorectal cancer. [ONCOLOGY 14(Suppl 11):42-47, 2000]


The treatment of colorectal carcinoma
presents many challenges to the clinician. Among those are the presence of
intrinsic or the development of acquired drug resistance, the aggressive nature
of the disease, and (most notably) the limited number of treatment options.[1-3]
Although fluorouracil (5-FU) has been the mainstay of treatment for colorectal
cancer for 4 decades, as a single agent it is associated with only a 10% to 15%
objective response rate. Patients treated with
5-FU can expect to achieve a median survival of about 10 months.[4-6]

The addition of folinic acid, also known as leucovorin,
increases the response rate, but does not improve the overall median survival
regardless of delivery as bolus 5-FU/leucovorin or as a continuous or short-term
(24- to 48-hour) infusion.[7-11] While regimens consisting of short-term
infusions of
5-FU with high-dose leucovorin have acceptable tolerability and are widely used
for the treatment of colorectal cancer, especially in Europe, the fact that the
median survival reported in most trials using these regimens is in the range of
9 to 14 months has prompted the search for alternative approaches to

One of the more promising new treatment options for patients
with metastatic colorectal cancer is oxaliplatin (Eloxatin), a third-generation
platinum derivative with a unique mechanism of action.[3,12,13] Oxaliplatin is
among the few drugs that have activity against human colorectal cancers. In
vitro, human tumor xenograft, and clinical studies indicate that it is
synergistic with 5-FU and leucovorin.[3,12,13]

Phase II and III clinical trials conducted in Europe show that
the combination of oxaliplatin with 5-FU/leucovorin is effective as first- or second-line treatment for patients with
metastatic colorectal cancer. Objective response rates as first-line treatment
were > 50% and as second-line treatment, ranged between 20% and 45%. However,
the trials comparing triple- drug therapy to 5-FU/leucovorin did not show a
significant advantage in terms of mean duration of survival compared to
5-FU/leucovorin alone. These trials did, however, meet their original goals of
demonstrating a significant improvement in response rate and progression-free
survival. Thus, a number of studies are currently underway in North America that
are exploring various oxaliplatin combination regimens to help determine the
optimal dosage and administration schedule of combination therapy (Table

NCCTG Trial N9741: A Randomized, Phase III Intergroup Trial

Rationale and Design

Because of the discovery and development of a number of active
new agents, the treatment of colon and rectal cancer is at a crossroads.
5-FU/leucovorin regimens have been the standard treatment for decades, and a
multitude of regimens using differing doses, sequences, and lengths of drug
delivery (ranging from bolus to continuous administration) have been studied. In
addition, several combination regimens of 5-FU/leucovorin plus irinotecan
(CPT-11, Camptosar) have shown promise, including the weekly schedule of
administration widely known as the Saltz regimen (named after the physician who
developed and initially tested this regimen).[14]

Based on a randomized study comparing 5-FU/leucovorin with
irinotecan plus 5-FU/leucovorin and irinotecan alone, the Oncologic Drugs
Advisory Committee (ODAC) of the US Food and Drug Administration (FDA) approved
the three-drug regimen as first-line therapy of advanced colorectal cancer in
March 2000. The approval was based on an improvement in response rate (from 21%
to 39%) in the two- vs three-drug regimen, and a commensurate improvement in
median survival of 2.2 months (from 12.6 to 14.8 months). When asked if the
Saltz regimen should henceforth be considered the new regimen to which other
agents or multidrug regimens should be compared, ODAC answered in the
affirmative. This had major consequences for ongoing and future trial designs.

The Redesign Process

The North Central Cancer Treatment Group (NCCTG) N9741 study has
undergone several metamorphoses since it first opened in November 1998. It was
originally designed as a four-arm trial comparing three regimens of
5-FU/leucovorin plus irinotecan vs the Mayo/NCCTG regimen control arm:
5-FU at 425 mg/m2 plus leucovorin at 20 mg/m2.

The rationale for using the 5-FU at 425 mg/m2 plus leucovorin at
20 mg/m2 regimen as the control arm was based on a meta-analysis published in
1992 that showed a 23% response rate and a 12-month median survival for the
regimen.[9] This was still the expectation for the overall success rate in the
control group when trial NCCTG N9741 began.

However, one 5-FU/leucovorin regimen—a 2-g/24-hour infusion of
5-FU—was dropped because of toxicity issues. Shortly after the study opened,
and oxaliplatin became available for US trials, the study was amended (June
1999) to include three oxaliplatin arms. Thus, the NCCTG N9741 trial temporarily
became a six-arm study in which patients were randomized to one of six treatment
regimens: (1) 5-FU/leucovorin (Mayo/NCCTG), (2) 5-FU/leucovorin plus irinotecan
(Saltz simultaneous), (3) 5-FU/leucovorin plus irinotecan (Mayo sequential), (4)
irinotecan plus oxaliplatin (combination), (5) 5-FU/leucovorin plus oxaliplatin (bolus), or (6)
5-FU/leucovorin plus oxaliplatin (infusion).

In June 2000, the study was finally amended because of two
issues. First, the ODAC’s suggestion that the Saltz regimen should be the new
comparator arm in future trials made it necessary to delete the old comparator
arm of 5-FU/leucovorin (Mayo/NCCTG regimen—arm 1) from the study. Second, the
third and fifth arms of the study were noted to be associated with excessive
toxicity, including several treatment-related patient deaths. In addition, the
investigators participating in the trial and the leaders of the gastrointestinal
committees from the cooperative groups participating in the trial now felt that
a simpler three-arm trial was a better design. By comparing arms 2, 4, and 6,
the most important variations of these three active agents could be examined
side by side, and results would be available much sooner than would have been
possible with the six-arm trial (Figure 1).

Mayo Sequential Regimen: Mullany and coworkers[18] first
described sequence-dependent synergy in colon cancer xenografts when they noted
that the optimal interval between administration of irinotecan and 5-FU was
about 24 hours. Consequently, a three-drug regimen was developed on the basis of
laboratory studies performed by Fonseca et al at the Mayo Clinic.[19]

This phase I study in 56 patients began initially with the
administration of a very low dose of irinotecan plus
5-FU due to concerns about synergistic diarrhea.[20] Although most of the
patients were refractory to previous therapy, there were 10 partial or minor
responses. Toxicity consisted of the usual diarrhea, neutropenia, and vomiting.
Doses recommended for further testing were irinotecan at 275 mg/m2 administered
on day 1, and 5-FU at 400 mg/m2 plus leucovorin at 20
mg/m2 administered on days
2 to 5.

Because this regimen is repeated every 3 weeks, the dose
intensity of 5-FU and leucovorin is similar to that of the standard Mayo regimen
described by Poon and coworkers,[21] which is given every 4 or 5 weeks. However,
5 of the first 60 patients accrued to this arm died, possibly of
treatment-related causes. Therefore, it appeared unlikely that this regimen
would prove to be superior to the one developed by Saltz and colleagues, and it
was certainly more toxic. Thus, rather than reduce the doses prescribed by this
regimen, the arm was dropped from the trial.

Oxaliplatin Bolus Regimen: In the United States, many
members of the Gastrointestinal (GI) Intergroup and others regarded bolus 5-FU
dosing as the most familiar method by which to administer 5-FU and leucovorin.
Therefore, an oxaliplatin regimen given in concert with bolus 5-FU was included
in this trial. This regimen was based on a European trial in 115 patients who
progressed after being treated with a regimen of 5-FU plus leucovorin
(unpublished data on file, Sanofi-Synthelabo). Oxaliplatin at 130 mg/m2 was
administered on day 1, followed by
5-FU at 320 mg/m2 plus leucovorin at 20 mg/m2 on days 1 to 5. (This regimen was
repeated every 3 weeks.)

Although the response rate in the original report was 13%, this
was a second-line regimen and therefore, was felt to have demonstrated
sufficient activity to merit further testing. Both the median time to
progression (4.3 months) and median survival (10.1 months) were similar to the
rates reported with other second-line regimens. The main toxicities included
nausea, neutropenia, and neuropathy.

Early in the NCCTG N9741 trial, after about 25 patients had
received this regimen, three deaths occurred due to toxicity. All the patients
developed fatigue, neutropenia, and dehydration, and died within 1 or 2 weeks
following treatment. Representatives of the National Cancer Institute (NCI), the
cooperative groups participating in the trial, and patient representatives held
a meeting to discuss these reports. As a result, the doses of both oxaliplatin
and 5-FU were reduced.

Patients in the oxaliplatin bolus regimen arm of the N9741 trial
then began to receive oxaliplatin at 100 mg/m2 on day 1, followed by 5-FU at 280
mg/m2 plus leucovorin at 20 mg/m2 on days 1 to 5. When two additional
treatment-related deaths were observed at the reduced dose level, this arm of
the trial was dropped.


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