The article by Drs. Khayat and Gil-Delgado
outlines the exciting new developments in the treatment of advanced colorectal
cancer with irinotecan (CPT-11 [Camptosar]) and oxaliplatin. Although the
development of these drugs provides an alternative to fluorouracil (5-FU) in the
treatment of this common tumor, it is still unclear how to optimally integrate
these promising compounds into therapy for colorectal cancer.
Improving the Efficacy of 5-FU
Fluorouracil has remained the mainstay of the treatment of
advanced colorectal cancer for over 40 years. Unfortunately, only about 20% of
patients who receive 5-FU demonstrate objective responses by standard criteria.
Over the past 25 years, a tremendous effort has been made to improve the
efficacy of 5-FU. One such line of research has shown that, compared with bolus
administration, protracted intravenous infusion produces a marginally higher
rate of response but is also associated with reduced toxicity.[1,2]
Biochemical modulatorseg, methotrexate, interferon-alpha,
and, most extensively, leucovorinhave also been explored to increase the
antitumor activity of 5-FU. In a meta-analysis of nine randomized trials of 5-FU
alone vs 5-FU plus leucovorin for advanced cancer, a significant improvement in
response rate was seen in patients who received 5-FU and leucovorin. However,
this level of improvement in response rate failed to translate into a
significant survival advantage.
In 1996, based on trials reviewed by the US Food and Drug
Administration (FDA), irinotecan was approved as a second-line treatment for
patients with colorectal cancer whose disease had progressed after 5-FU-based
therapy. Initial approval was based on tumor response alone. The survival
benefit of irinotecan as a second-line treatment in colorectal cancer refractory
to bolus 5-FU was clearly shown in two phase III randomized studies conducted in
Europe. The results of those studies led to full approval of this drug in the
The survival benefit of irinotecan administered in combination
with 5-FU and leucovorin as first-line treatment for advanced colorectal cancer
was demonstrated recently in two phase III randomized studies. The first trial
compared weekly irinotecan plus 5-FU/leucovorin to 5-FU/leucovorin (Mayo
regimen) or weekly irinotecan. Objective response rates documented by
investigators were noted in 50% of patients receiving the three-drug combination
vs 28% of patients receiving 5-FU/leucovorin (confirmed response rate: 39% vs
21%, P < .001). Median survival for the irinotecan/5-FU/leucovorin arm
was 14.8 months vs 12.6 months for the 5-FU/leucovorin arm (P = .04).
Grade 3 (severe) diarrhea was more common during treatment with
irinotecan/5-FU/leucovorin, but the incidence of grade 4 (life-threatening)
diarrhea was similar in both groups.
The other trial, conducted in Europe, also found a significant
advantage in favor of the irinotecan/5-FU/leucovorin combination vs infusional
5-FU/leucovorin in terms of median overall survival (17.4 vs 14.1 months, P = .035),
progression-free survival (6.7 vs 4.4 months, P < .001), and confirmed
objective response (35% vs 22%, P < .005). All these end points
demonstrated the modest but definite superiority of the combination of
irinotecan, 5-FU, and leucovorin.
After many years of clinical trials in colorectal cancer,
however, several issues remain unresolved. Data from the European trials suggest
that infusional 5-FU in combination therapy might be a better approach, both in
terms of activity and toxicity. Whether sequential rather than concomitant
administration of these drugs could achieve a similar effect with less toxicity
is still somewhat uncertain. Retrospective data from the combination trials
suggest that a survival benefit is maintained, even when the majority of
patients assigned to single-agent therapy initially received subsequent
second-line chemotherapy or other salvage treatments. Only a well-designed trial
with a fixed crossover design, such as the MRC CR-08 ("FOCUS") trial
in the United Kingdom, may find a definitive answer.
Furthermore, should the combination of irinotecan, 5-FU, and
leucovorin be considered as the first-line treatment in a subgroup of patients
with poor performance status (³ ECOG 2), or with
abnormal organ system function for survival, toxicity, and clinical benefit?
Ultimately, biological markers that may predict response or toxicity from
standard chemotherapy drugs may help determine which patients should receive
irinotecan, 5-FU, and leucovorin as the first-line treatment.
Historical controls, from the era prior to standard adjuvant
chemotherapy, demonstrated cure rates for stage III (lymph node positive) colon
cancer of about 40% to 50%. Adjuvant chemotherapy with 5-FU/leucovorin
increased the 5-year overall survival rate to 60% or 65%.[10,11] Since the
degree of antitumor activity may improve the success of adjuvant treatment,
regimens with higher antitumor response rates could logically be expected to
provide superior results in the adjuvant setting. An ongoing phase III US
intergroup study (Cancer and Leukemia Group B [CALGB]-89803) that is randomizing
patients with stage III colon cancer to either standard weekly 5-FU/leucovorin
or irinotecan, 5-FU, and leucovorin may provide the answer.
There are also several similar trials (eg, ACCORD2, AERO R98) in
Europe evaluating the same issue, with the use of infusional 5-FU methods.
Because all patients with metastatic disease may not benefit equally from
combination chemotherapy, all patients at different risks in the adjuvant
setting may not necessarily require or achieve the same degree of benefit from
more intensive treatment approaches. Trials specifically addressing high-risk
node-positive patients may provide early and more profound evidence of the
benefit achieved with combination chemotherapy.
Role of Oxaliplatin
Oxaliplatin, a diaminocyclohexane (DACH) platin, inhibits DNA
replication and transcription through the formation of intra- and interstrand
DNA adducts. The drug has demonstrated synergistic antitumor activity in
combination with 5-FU and leucovorin both in vitro and in vivo.[12,13] In phase
II trials, the clinical activity of oxaliplatin as first-line monotherapy has
been shown to be similar to that of single-agent irinotecan. Phase II trials
evaluating the combination of oxaliplatin and 5-FU/leucovorin as initial therapy
for patients with metastatic colorectal cancer (using chronomodulated drug
administration schedules) suggested increased cytotoxicity, manifested by
encouraging response rates, as well as improved progression-free and overall
Based on these encouraging data, European investigators
conducted two randomized trials comparing oxaliplatin in combination with 5-FU
and leucovorin vs 5-FU/leucovorin alone as first-line therapy in patients with
metastatic colorectal cancer (EFC 2961 and EFC 2962).[17,18] The results of
these trials showed a statistically significant benefit in objective response
rate favoring oxaliplatin (53% vs 16% in EFC 2961; 50.7% vs 22.3% in EFC 2962),
and progression-free survival (8.7 vs 6.1 months, P = .048, in EFC 2961;
9.0 vs 6.2 months, P = .0003, in EFC 2962). Although a trend toward a
longer median survival was seen in the oxaliplatin-treated groups, the
difference did not achieve statistical significance in either study (16.2 vs
14.7 months, P = .12, in EFC 2962; 19.4 vs 19.9 months in EFC 2961).
Because oxaliplatin did not demonstrate a detectable impact on prolonging
overall survival, it was not approved by the FDA for use in the first-line
treatment of advanced colorectal cancer.
The explanation for this discrepancy is not clear. Subtle, but
clinically important differences in baseline patient characteristics could have
obscured assessment of the impact of oxaliplatin on survival. When these
baseline differences were taken into account by Cox regression analysis, overall
survival was significantly enhanced by the addition of oxaliplatin to first-line
therapy in the EFC 2962 study (P = .0001).
Other possible explanations are that the effects of oxaliplatin
are too transient to have an impact on overall survival, or that the use of
other salvage therapies (eg, surgery or irinotecan) influenced survival results.
It is also possible that the infusional 5-FU/leucovorin control arm in both
trials was more active than the bolus control arms in other studies, manifested
by an unusually good survival among patients in the control arms in both
Of patients in the control arm, 57% received oxaliplatin after
treatment with 5-FU/leucovorin failed in EFC 2961, and 37% of patients in EFC
2962 received poststudy chemotherapy with oxaliplatin and/or irinotecan as well
as salvage surgery. The sample size of both studies was relatively small, which
may explain why significant differences in response rate and progression-free
survival did not translate into a statistically significant survival benefit.
This underscores the need for trials with adequate sample sizes that are able to
properly assess modest yet clinically worthwhile benefits.
Studies of the combination of oxaliplatin and 5-FU/leucovorin in
the second-line setting have shown encouraging results. However, several
important questions still need to be answered, including the impact of
re-treatment with alternative methodologies of 5-FU/leucovorin in the
combination. As a second-line therapy, how much activity is due to oxaliplatin,
and how much is secondary to a change in the dose or schedule of
A pivotal trial currently underway in the United States is
attempting to answer these questions. Patients with advanced colorectal cancer
in whom disease progressed after treatment with irinotecan/5-FU/leucovorin are
being randomized to one of three arms: (1) a control arm of bolus plus
infusional 5-FU and leucovorin (de Gramont regimen), (2) oxaliplatin as a single
agent every 2 weeks, or (3) the combination of 5-FU, leucovorin, and
In summary, the combination of irinotecan, 5-FU, and leucovorin
has been confirmed as a new first-line treatment for advanced colorectal cancer.
Several important clinical trials are in the process of clarifying the role of
oxaliplatin in the treatment of patients with metastatic colorectal cancer.
In addition to developing new agents for this disease, clinical
research should be directed at optimizing and individualizing therapy for
patients to achieve maximal clinical benefit. In this regard, the use of
combination chemotherapy before planned hepatic resection for liver metastases
is among the most exciting possibilities for improvement, and may convert the
therapy of some patients from palliative to curative treatment.
1. Lokich JJ, Ahlgren JD, Gullo JJ, et al: A prospective
randomized comparison of continuous-infusion fluorouracil with a conventional
bolus schedule in metastatic colorectal carcinoma: A Mid-Atlantic Oncology
Program Study. J Clin Oncol 7:425-432, 1989.
2. The Meta-Analysis Group in Cancer: Efficacy of intravenous
continuous infusion of fluorouracil compared with bolus administration in
advanced colorectal cancer. J Clin Oncol 16:301-308, 1998.
3. Advanced Colorectal Meta-Analysis Project: Modulation of
fluorouracil by leucovorin in patients with advanced colorectal cancer: Evidence
in terms of response rate. J Clin Oncol 10:896-903, 1992.
4. Pitot HC: US pivotal studies of irinotecan in colorectal
carcinoma. Oncology 12(suppl 6):48-53, 1998.
5. Cunningham D, Pyrhonen S, James RP, et al: Randomised trial
of irinotecan plus supportive care vs supportive care alone after fluorouracil
failure for patients with metastatic colorectal cancer. Lancet 352:1413-1418,
6. Rougier P, Van Cutsem E, Bajetta E, et al: Randomized trial
of irinotecan vs fluorouracil by continuous infusion after fluorouracil failure
in patients with metastatic colorectal cancer. Lancet 352:1407-1412, 1998.
7. Saltz LB, Cox JV, Blanke CB, et al: Irinotecan plus
fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med
8. Douillard JY, Cunningham D, Roth AD et al: Irinotecan
combined with fluorouracil compared with fluorouracil alone as first-line
treatment for metastatic colorectal cancer: A multicenter randomized trial.
Lancet 355:1041-1047, 2000.
9. Willett CG, Tepper JE, Cohen AM: Failure patterns following
curative resection of colonic carcinoma. Ann Surg 200:685-690, 1984.
10. Moertel CG, Catalano PJ, Macdonald JS: Fluorouracil plus
levamisole as effective adjuvant therapy after resection of stage III colon
carcinoma: A final report. Ann Intern Med 122:321-326, 1995.
11. Haller DG, Catalano PJ, MacDonald JS, et al: Fluorouracil
(FU), leucovorin (LV), and levamisole (LEV) adjuvant therapy for colon cancer:
Five-year final report of INT-0089 (abstract). Proc Am Soc Clin Oncol 17:256a,
12. Raymond E, Chaney SG, Taamma A, et al: Oxaliplatin: A review
of preclinical and clinical studies. Ann Oncol 9(10):1053-1071, 1998.
13. De Braud F, Munzone E, Nole F, et al: Synergistic activity
of oxaliplatin and 5-fluorouracil in patients with metastatic colorectal cancer
with progressive disease while on or after 5-fluorouracil. Am J Clin Oncol
14. Becouarn Y, Rougier P: Clinical efficacy of oxaliplatin
monotherapy: Phase II trials in advanced colorectal cancer. Semin Oncol 25(suppl
15. Levi F, Misset JL, Brienz S, et al: A chronopharmacologic
phase II clinical trial with fluorouracil, folinic acid, and oxaliplatin using
an ambulatory multichannel programmable pump. High antitumor effectiveness
against metastatic colorectal cancer. Cancer 69:893-900, 1992.
16. Levi F, Zidani R, Brienza s, et al: A multicenter evaluation
of intensified, ambulatory, chronomodulated chemotherapy with oxaliplatin,
fluorouracil, and leucovorin as initial treatment of patients with metastatic
colorectal carcinoma. Cancer 85:2532-2540, 1999.
17. De Gramont A, Figer A, Seymour M, et al: Leucovorin and
fluorouracil with or without oxaliplatin as first-line treatment in advanced
colorectal cancer. J Clin Oncol 18:2938-2947, 2000.
18. Giacchetti S, Perpoint B, Zidani R, et al: Phase III
multicenter randomized trials of oxaliplatin added to chronomodulated
fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer.
J Clin Oncol 18:136-147, 2000.
19. Bleiberg H, de Gramont A: Oxaliplatin plus fluorouracil:
Clinical experience in patients with advanced colorectal cancer. Semin Oncol
25(suppl 5):32-39, 1998.