Irinotecan: Toward Clinical End Points in Drug Development

Introduction

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(Drug information on 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 1).

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.

Results

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 3 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.