Colorectal cancer is the second most common cause of cancer-related death in industrialized populations. Despite intensive investigation, the prognosis of patients with metastatic disease has not improved over the past 30 years. Estimated 5-year survival is 5%, and systemic therapy affords only a modest survival advantage over supportive care alone. Systemic therapy is therefore given with palliative intent. Disease-related symptoms and quality of life (QOL) are the most relevant end points of palliation and are of major concern to patients with advanced disease.[3,4]
For the first time in many years, a number of new agents are now available for the treatment of advanced colorectal cancer. Assessment of drug efficacy is usually based on the standard criteria of radiologic response, time to progression, and overall survival. These end points do not always correspond to palliation. The assessment of these new agents, therefore, should include a measure of the impact of therapy on disease-related symptoms and quality of life. In this article, we will discuss the basis of this approach and its use in the design of a phase II trial to assess the palliative benefit of irinotecan(Drug information on irinotecan) (CPT-11 [Camptosar]) in patients with colorectal cancer refractory to fluorouracil(Drug information on fluorouracil) (5-FU).
The antimetabolite 5-FU is the most widely used cytotoxic agent in advanced colorectal cancer. It acts through the binding of its metabolite, 5-fluorodeoxyuridylate monophosphate (FdUMP), to thymidylate synthase, which results in the depletion of substrates for DNA synthesis. Response rates of between 15% and 20% have been reported for 5-FU as initial monotherapy.
Over the last decade, biochemical modulators, including leucovorin, have been used to enhance the therapeutic efficacy of 5-FU. A published meta-analysis of nine trials randomizing 1,381 patients to 5-FU and leucovorin vs 5-FU alone confirmed overall response rates of 23% and 11%, respectively. There was no survival advantage reported for either regimen. Improved tumor response rates have also been achieved by varying the administration regimen of 5-FU, especially by using a continuous infusion.[7,8]
In all patients with advanced colorectal cancer, disease eventually progresses on 5-FU therapy, with worsening of disease-related symptoms and QOL. The role of systemic therapy in this patient population is poorly defined, given the poor activity of currently available standard cytotoxic agents. Of the newer agents currently under evaluation, the camptothecin derivatives have generated considerable clinical attention, especially in this population with refractory/resistant disease.
Camptothecin and Its Analogs
The camptothecins act by inhibiting topoisomerase I, an enzyme that forms a covalently linked cleavable complex with DNA, resulting in a single-strand break. Then, the enzyme-DNA complex allows for swiveling of the single strand, followed by replication and subsequent repair. The camptothecin derivatives stabilize this complex, maintaining the single-strand break. With prolonged exposure to the camptothecins, the replication fork collides with the drug-stabilized cleavable complex, inducing a lethal double-strand DNA break.
Irinotecan is a semisynthetic analog of camptothecin that has better water solubility, an improved toxicity profile, and greater activity. In vivo, irinotecan is converted by hepatic carboxylesterase to its active metabolite, 7-ethyl 10-hydroxy-campothecin (SN-38), [14,15] which has demonstrated a greater than 250-fold antitumor activity than the prodrug in vitro. Phase I studies of irinotecan have been carried out in Japan, the United States, and France using various administration schedules. Activity has been observed in non-small-cell lung, breast, colon, and cervical cancers, with minor activity in other malignancies.
The toxicities reported include delayed-onset diarrhea, neutropenia, nausea, vomiting, an acute cholinergic syndrome, fatigue, and alopecia; these have been discussed in detail in a recent review. The principal toxicity in the pivotal US phase II trials in colorectal cancer was delayed diarrhea, which has the potential to diminish QOL. It has a median onset of 11 days from the commencement of therapy, with 31% of patients suffering National Cancer Institute (NCI) grade 3 or 4 toxicity.
The severity of delayed diarrhea has been reduced by the use of intensive, high-dose antidiarrheal medications. In the aforementioned phase II trials, the incidence of severe diarrhea was reduced from 17.5% to 9.8% of courses when this regimen was begun at the onset of diarrhea.
Phase II Trials
Phase II trials of irinotecan in patients with previously treated colorectal cancer have been completed in Japan, France, and multiple centers within the United States. A Japanese phase II study evaluated irinotecan at a dose of 100 mg/m² weekly or 150 mg/m² every 2 weeks in 67 colorectal cancer patients, including 51 who had previously received chemotherapy (oral fluoropyrimidines, intravenous 5-FU, or 5-FU and leucovorin). Irinotecan produced an overall partial response rate of 27%, with a median duration of response of 50 days (range, 9 to 120 days). The response rate in patients previously treated with chemotherapy or radiotherapy was 25%.
Pooled data have been analyzed from US multicenter single-agent trials involving 304 patients with cancers that were refractory or resistant to 5-FU (ie, those who progressed during or relapsed following initial chemotherapy). Irinotecan was administered in a 6-week regimen (weekly treatment for 4 weeks, followed by 2 weeks rest) at a starting dose of 100, 125, or 150 mg/m². Of the 304 patients, 193 commenced treatment at a dose of 125 mg/m². On an intent-to-treat analysis, response rates based on starting dose were as follows: 22% for the 150-mg/m² dose, 15% for 125 mg/m², and 8% for 100 mg/m². Overall, 49% of patients had stable disease for at least 2 months. The median duration of response was 6.0 months.
The European experience with a 3-week regimen in previously treated patients has also been reported. Of 130 pretreated patients enrolled in the trial, 62 patients had progressed while receiving prior 5-FU-based chemotherapy and were defined as 5-FU-resistant. Similar to the US trials, the European investigators observed a response rate to irinotecan of 17.7% in pretreated patients, including a response rate of 16.1% in the 5-FU-resistant subset. The median time to response was 9.3 weeks, and median survival duration was 10 months.
Phase III Trial of Irinotecan as Second-Line Therapy
As reported by Cunningham et al, an inter-European phase III randomized trial comparing irinotecan to best supportive care and to best second-line 5-FU-based therapy in patients with 5-FU-refractory disease has been completed. This trial is described in detail in another article in this supplement ; this article will focus on the trials results with respect to QOL and disease-related symptoms.
Both studies prospectively assessed, as secondary end points, the effect of irinotecan on patients QOL and disease-related symptoms using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30 version 2.0 instrument. In the comparison of irinotecan to best second-line therapy, the irinotecan arm demonstrated an improvement in pain-free survival of 10.3 vs 8.5 months (P = .06), with a reduction in analgesic requirements and an improvement in performance status.
In the comparison of second-line irinotecan vs best supportive care, there was a significant improvement in the global QOL score in favor of irinotecan. In addition, the irinotecan-treated patients demonstrated a significant improvement in pain intensity, as measured by the EORTC QLQ-C30 instrument (P = .002), which was associated with a decrease in analgesic requirements.