Irinotecan: Toward Clinical End Points in Drug Development

Irinotecan: Toward Clinical End Points in Drug Development

ABSTRACT: The objective response rate is the initial method to assess the activity of a novel anticancer agent. Response rates may not characterize a new agent’s clinical benefit, however, especially if moderate to severe toxicity may be associated with treatment. Clinical end points, such as improvement in survival or relief of disease-related symptoms, provide clinicians with a more rational basis for selecting therapies. Irinotecan (CPT-11 [Camptosar]) was introduced into clinical practice based primarily on its consistent phase II activity (response rates of 13.3% to 21.7% in patients with advanced colorectal cancer refractory to 5-fluorouracil [5-FU]). Two recently presented, randomized, phase III trials have examined irinotecan’s impact on clinical end points of survival, quality of life, tolerability, and control of disease-related symptoms in 5-FU-refractory colorectal cancer patients. The first trial prospectively compared irinotecan and best supportive care (BSC) to BSC alone in patients with 5-FU-resistant metastatic colorectal cancer. Irinotecan-treated patients had significantly prolonged survival, improved quality of life, and better control of disease-related symptoms. The second trial compared irinotecan to infusional 5-FU schedules in colorectal cancer patients whose tumors had progressed within 3 months of prior 5-FU. Patients treated with irinotecan lived significantly longer than those given infusional 5-FU and had a comparable quality of life. These randomized trials demonstrate an evolution in our understanding of the clinical utility of irinotecan. [ONCOLOGY 12(Suppl 6):13-21, 1998]


The most commonly prescribed systemic treatment for advanced
colorectal cancer is 5-fluorouracil (5-FU), usually administered with
leucovorin. A recent meta-analysis of trials conducted in previously
untreated colorectal cancer patients demonstrated an overall response
rate of 23% with 5-FU-plus-leucovorin regimens and 11% with
single-agent 5-FU; the addition of leucovorin to 5-FU also produced
little improvement in survival duration.[1] Although 5-FU has been
prescribed for the palliation of advanced colorectal cancer patients
for almost 4 decades, little prospective information exists regarding
the true palliative benefit of this agent and its amelioration of
disease-related symptoms.

For patients whose disease has progressed during 5-FU therapy, no
standard second-line treatment option existed until the availability
of irinotecan (CPT-11 [Camptosar]) in 1996.[2] Irinotecan occupies a
unique position in oncology therapy, being the only drug approved by
the FDA for the treatment of 5-FU-refractory colorectal cancer patients.

Phase II trials in which patients were treated with irinotecan at a
dose of 125 mg/m²/wk for 4 consecutive weeks every 6 weeks noted
response rates of 20.8% (10/48; 95% confidence interval [CI], 9.3% to
32.3%) and 13.3% (12/90; 95% CI, 6.3% to 20.4%).[3,4] Japanese
investigators administered irinotecan at doses of either 100
mg/m² weekly (without a rest period) or 150 mg/m² every 2
weeks and observed an overall response rate of 21.7% (10/46; 95% CI,
9.8% to 33.7%) in previously treated patients.[5] French
investigators used 350 mg/m² of irinotecan every 3 weeks; their
intent-to-treat analysis indicated a response rate of 15.6% (23/147;
95% CI, 10.1% to 22.5%).[6] Thus, the various schedules of irinotecan
described above show comparable response rates.

In the FDA-reviewed pivotal trials, a 15% (29/193; 95% CI, 10.1% to
20.1%) response rate with a median response duration of 6 months was
noted for patients treated at the recommended irinotecan dose of 125
mg/m²/wk for 4 weeks every 6 weeks.[2] Although the initial
rationale for prescribing irinotecan was based primarily on the
aforementioned phase II response rate data, these clinical trials
also suggested that patients may derive benefit that may not be
apparent when one solely examines response rates. In the FDA-reviewed
trials, 49% of patients had a best response to treatment designated
as "stable disease," often with tumor reductions that did
not achieve the requisite definition of partial response. Decrements
in serial carcinoembryonic antigen (CEA) determinations (mean 28%
decrease in 79 stable disease patients) were observed. Palliative
benefits of a decrease in pain were observed in 12 responding patients.[2]

Nevertheless, 30% of irinotecan-treated patients experienced grade 3
or 4 diarrhea, and 20% were hospitalized for the management of
toxicity. Thus, an accurate depiction of irinotecan’s clinical
benefit may be obscured by a relatively low objective response rate
accompanied by a considerable, yet manageable, toxicity profile.

To more accurately define irinotecan’s clinical benefit in the
treatment of refractory colorectal cancer, two randomized phase III
trials that were presented at the 1998 American Society of Clinical
Oncology (ASCO) meeting will be reviewed herein.[7,8] Rather than
focusing on surrogate end points of response rate or time to
progression, these two trials prospectively examined clinical end
points--irinotecan’s effect on survival, quality of life, and
amelioration of disease-related symptoms.

Irinotecan vs Best Supportive Care

The first trial, conducted by Cunningham et al, was a prospective,
nonblinded, multicenter, randomized phase III trial comparing
irinotecan, 350 mg/m² as a 90-minute infusion every 3 weeks, to
best supportive care (BSC) only.[7] Patients randomized to irinotecan
also received BSC.

The sample size of the clinical trial was determined by a two-tailed
log-rank test with an alpha risk of 0.05 and a power of 80%. Based on
the hypothesis that the expected 1-year survival rate in the
irinotecan arm would be 35% compared to 20% in the BSC arm, the
sample size of the trial was determined to be 254 patients with a 2:1
randomization (176 patients to be treated with irinotecan and 88 with BSC).

To be eligible for the trial, patients were required to have
histologically proven colorectal cancer, evidence of metastatic
disease, and documented progression while receiving 5-FU or within 6
months after the last 5-FU infusion. In addition, patients were
required to have a World Health Organization (WHO) performance status £
2, no more than two prior 5-FU regimens for metastatic disease, and
adequate hematologic, renal, and liver function. This study did not
stratify patients for known prognostic variables (eg, performance status).

Patient Characteristics

A total of 279 patients were enrolled in the trial; 189 in the
irinotecan arm and 90 in the BSC group. The two treatment groups had
similar patient characteristics with regard to median age (59 years
for the irinotecan group vs 62 years for the BSC group) and
proportion of symptomatic patients (75% vs 83%). There was a
statistically significant imbalance between the two groups, however,
with respect to the known prognostic variable of performance status (Table

As shown in Table 2, a similar
percentage of patients was distributed between the irinotecan and BSC
arms with respect to the location of the primary tumor (right/left
colon vs rectum), number of organs involved (1, 2, ³
3), and metastatic disease sites (liver, lung, peritoneum). In
addition, the treatment arms were balanced with respect to prior
surgery, prior radiation therapy, documented progression while on
5-FU therapy, and documented progression within 6 months of 5-FU
therapy. The median time from progression on 5-FU to randomization
was 1.0 months for both treatment groups. The median time from the
last 5-FU infusion to randomization was 1.4 months for the irinotecan
arm vs 1.6 months for the BSC arm.

Table 3 shows patient
characteristics in terms of the number of prior 5-FU regimens, as
well as the last schedule of 5-FU used. A similar number of patients
in both groups (69% of patients treated with irinotecan and 75% of
patients receiving BSC alone) had prior exposure to infusional
schedules of 5-FU.


With a median follow-up of 13 months, the median survival of
irinotecan-treated patients was 9.2 months, as compared with a median
survival of 6.5 months for the patients allocated to BSC alone (P =
.0001, log-rank test; Figure 1).
For the irinotecan arm vs the BSC-alone arm, the survival
probability was 73% vs 54% at 6 months, 53% vs 29% at 9 months, and
36% vs 14% at 12 months (Figure 2).

Because of the imbalance in performance status between the two arms,
a multivariate analysis was performed analyzing treatment effect on
survival adjusted for prognostic factors. After stratification for
performance status, the survival benefit for the irinotecan arm
remained statistically significant (P = .001), with an increased
death risk ratio of 1.71 in the BSC arm (Figure
and Figure 4).

As shown in Figure 5, an
analysis of survival without performance status deterioration showed
a statistically superior median survival without deterioration in
patients allocated to the irinotecan arm compared to those in the BSC
arm (5.7 vs 3.3 months; P < .001); the irinotecan group also fared
better with respect to survival without weight loss > 5% (P =
.018). As illustrated in Figure 6,
median pain-free survival was superior in patients randomized to
irinotecan treatment vs BSC alone (6.9 vs 2.0 months; P = .003).

Rates of grade 3-4 adverse effects were consistent with those
previously published for irinotecan.[2-5] These included neutropenia
(22%), neutropenia associated with fever or infection (3%), infection
without neutropenia (9%), diarrhea (22%), vomiting (14%), asthenia
(15%), mucositis (2%), and drug-related deaths (1%). A higher
percentage of patients in the BSC arm than in the irinotecan arm
experienced grade 3-4 asthenia (19% vs 15%). Rates of other grade 3-4
adverse events experienced in the BSC-alone arm included diarrhea
(6%), vomiting (8%), and nonneutropenic infections (3%).

Quality of life was assessed using the European Organization for
Research and Treatment of Cancer (EORTC) Quality of Life C30
(QLQ-C30) instrument. Compared to patients who received BSC alone,
patients treated with irinotecan had improved scores for physical (P
< .001), role (P = .002), cognitive (P = .006), and social (P =
.006) functioning.

An analysis of the QLQ-C30 compared the worst patient scores during
the study in the two treatment groups. Specific patient scores
examined included asthenia, nausea/vomiting, pain, dyspnea, sleep
disturbance, appetite loss, constipation, diarrhea, and financial
impact. There was no statistical difference between the treatments
with regard to nausea/vomiting and sleep disturbance; diarrhea was
rated higher for the irinotecan-treated arm. All other parameters
(asthenia, pain, dyspnea, appetite loss, constipation, and financial
impact) indicated a favorable effect of irinotecan.

The investigators concluded that irinotecan significantly prolongs
survival, as well as improves quality of life and control of
tumor-related symptoms in patients with 5-FU-refractory colon cancer.
Based on these results, the investigators stated that irinotecan
should be considered the new standard of care for this patient population.


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