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The Oncologist, Vol. 2, No. 6, 402–409, December 1997
© 1997 AlphaMed Press

Clinical Use of Irinotecan:Current Status and Future Considerations

Leonard B. Saltz

Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

Correspondence: Leonard B. Saltz, M.D., Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. Telephone: 212-639-2501; Fax: 212-794-7186; e-mail: saltzl{at}mskcc.org


   ABSTRACT
Top
 Abstract
Historical Background
 Irinotecan in the Treatment...
 Pharmacokinetics
 Toxicity
 Recommendations for Current...
 Future Development
 Conclusion
 References
 
Irinotecan (CPT-11, Camptosar), a semisynthetic, water-soluble derivative of the plant alkaloid camptothecin, is a drug which has undergone extensive clinical investigation worldwide. It is, at this time, commercially available in the United States for the treatment of fluorouracil-refractory colorectal cancer. In this review, I will discuss the current approved clinical use, discuss the issues of toxicity and its management, and consider some of the ongoing clinical investigations which are exploring possible future uses for this agent.

Key Words. Irinotecan • CPT-11 • Topoisomerase I inhibitor • Colorectal cancer


   HISTORICAL BACKGROUND
Top
 Abstract
 Historical Background
Irinotecan in the Treatment...
 Pharmacokinetics
 Toxicity
 Recommendations for Current...
 Future Development
 Conclusion
 References
 
Camptothecin, the material from which irinotecan is derived, is the active agent isolated from the sap of the stem wood of the Asian tree Camptotheca acuminata. Camptothecin was identified in the mid 1960s as having antitumor activity in vitro [1]. Initial clinical trials reported in the early 1970s confirmed this activity, but the toxicities encountered were formidable [2-4]. Myelosuppression and hemorrhagic cystitis were both severe and unpredictable. In retrospect, this unpredictability was probably due to the insolubility of camptothecin. In order to conduct clinical trials, camptothecin was administered as the sodium salt. This disrupted the E-ring lactone portion of the camptothecin molecule, now known to be central to clinical activity, thereby resulting in the need for a tenfold increase in the amount of drug given. The variable dissociation of the sodium salt back into the more active parent compound, especially in the acidic environment of the bladder, most likely accounted for the unpredictable toxicity.

In the mid 1980s, investigators identified the mechanism of action of camptothecin as the inhibition of the nuclear enzyme topoisomerase I [5-9]. The identification of this novel target for therapeutics renewed interest in the camptothecins worldwide, and multiple investigators began working on soluble analogs of camptothecin which could be developed for clinical application [10]. As part of their investigations with soluble camptothecins, scientists at the Yakult Honsha Company in Tokyo, Japan, developed irinotecan, then called CPT-11 (CPT is an abbreviation for camptothecin), and demonstrated that this compound had favorable solubility characteristics and excellent preclinical activity [11-13]. These observations led to extensive phase I and II testing of irinotecan in Japan [14, 15] as well as in the United States and France [16-18]. Activity seen on these phase I trials led to phase II investigations in a number of chemotherapy-refractory solid tumors. Colorectal cancer was among the first tumors demonstrated to be potentially responsive to irinotecan, so development of this drug thus far, at least in North America, has focused on the treatment of colorectal cancer.


   IRINOTECAN IN THE TREATMENT OF COLORECTAL CANCER
Top
 Abstract
 Historical Background
 Irinotecan in the Treatment...
Pharmacokinetics
 Toxicity
 Recommendations for Current...
 Future Development
 Conclusion
 References
 
Antitumor responses in multiple patients with chemotherapy-refractory colorectal cancer were noted in the early phase I trials of irinotecan [14-18]. This finding led Japanes investigators to perform a phase II study of irinotecan in patients with metastatic colorectal cancer, 81% of whom had previously been treated with a fluorouracil-based chemotherapy regimen. Patients were treated with irinotecan at a dose of either 150 mg/m2 given every 14 days, or 100 mg/m2 given weekly. A major objective response rate of 27% was reported for the 63 evaluable patients treated, with a 22% response rate in those patients who had previously been treated with fluorouracil [19]. A subsequent trial conducted at the University of Texas, San Antonio, confirmed this finding, with a major objective response rate of 23% in 43 patients with fluorouracil-refractory colorectal cancer treated with irinotecan by 90-min infusion weekly for four weeks followed by a two-week rest [20]. A small number of patients on this trial received 150 mg/m2 as their starting dose, but toxicities were felt to be unacceptable at this level and the majority of patients were treated at a starting dose, of 125 mg/m2. Twenty-three percent of the patients treated on this trial achieved a major objective response, and an additional 31% of patients demonstrated either stable disease, or a minor clinical regression. Thus, 54% of patients experienced some tangible antitumor activity from receiving irinotecan on this trial.

In order to more fully evaluate the usefulness of irinotecan in fluorouracil-refractory colorectal cancer patients, a large confirmatory effort in the United States was undertaken involving the pooled data from 304 such patients in three essentially identical trials [21]. The initial starting dose of irinotecan in these trials was 125 mg/m2 weekly for four consecutive weeks, followed by a two-week break. Based on concerns of some early toxicity, this starting dose was later reduced to 100 mg/m2. The major objective response rate was 15% for the 125 mg/m2 dose and 8% for the 100 mg/m2 starting dose, with an overall major objective response rate of 13%. An additional 49% of patients experienced either a minor response or a stabilization of disease. It should be noted that this trial represents a sequential, rather than a randomized comparison of the 125mg/m2 and 100 mg/m2 starting dose. As such, one cannot make meaningful comparisons between these doses on the basis of this trial. Overall, the authors concluded that the toxicity at the 125 mg/m2 dose level was acceptable, and this is the recommended starting dose for routine use on this schedule.

Investigators at Memorial Sloan-Kettering Cancer Center evaluated the activity and tolerability of irinotecan in patients with chemotherapy-naive metastatic colorectal cancer. In this trial, forty-one patients received a starting dose of 125 mg/m2 weekly for four weeks, followed by a two-week break. The major objective response rate reported was 32%, with an additional 44% of patients demonstrating some more modest evidence of antitumor activity in the form of either minor response or stable disease [22]. At the same time, a cohort of patients with no prior chemotherapy treated on the same schedule at the Mayo Clinic demonstrated a 26% major objective response [23], confirming the substantial single agent activity of irinotecan in chemotherapy-naive colorectal cancer patients.

Development of irinotecan in Europe has largely utilized a single brief infusion given once every three weeks. A trial reported in final form from Institute Gustave Roussey in France utilizing a 350 mg/m2 starting dose on this every-three-week schedule demonstrated an 18% major objective response rate in 213 enrolled patients [24]. Forty-eight of the patients had had no prior cytotoxic chemotherapy and 165 patients had progressed through one fluorouracil-based chemotherapy regimen. On this trial, the response rate was essentially the same for the chemotherapy-naive and fluorouracil-refractory patients.

A pooling of European trials utilizing a starting dose of 350 mg/m2 given once every three weeks identified a similar activity rate, with 13% of 455 patients with fluorouracil-refractory colorectal cancer experiencing a major objective response (95% C.I. 9.7%-16.8%), with an additional 42% experiencing tumor stabilization, with a median duration of 7.5 months for response and 5 months for stabilization [25].


   PHARMACOKINETICS
Top
 Abstract
 Historical Background
 Irinotecan in the Treatment...
 Pharmacokinetics
Toxicity
 Recommendations for Current...
 Future Development
 Conclusion
 References
 
Irinotecan is metabolized by carboxylesterases in vivo to its active metabolite known as SN-38 [26-28]. SN-38 is several hundred-fold more active than irinotecan, and as such irinotecan serves to some degree as a prodrug. The relationship between irinotecan and SN-38, however, is quite complex. While the activity of SN-38 is several orders of magnitude greater than that of irinotecan, the concentration of irinotecan may be several orders of magnitude higher in the plasma during the time after drug administration. Thus, the view of irinotecan merely as a prodrug for SN-38 may be overly simplistic. As with the parent compound, camptothecin, irinotecan exists in plasma in an equilibrium between the closed-ring lactone form and the open-ring carboxy acid form, as does SN-38. The closed-ring form is substantially more active; however, the dynamic equilibrium, which is pH-dependent, makes accurate measurement of the ring-open form difficult and probably of little clinical importance, since the ratio is likely to be shifted to virtually all ring-closed at intracellular pH.

Correlations of pharmacokinetic parameters of irinotecan and SN-38 with either activity or toxicities have been inconsistent. In a phase I trial, Rothenberg et al. reported a mean terminal half-life for total irinotecan of 7.9 hours (± 2.8) and a mean half-life of 13.0 hours (± 5.8) for SN-38 [16]. The ratio between the area under the concentration versus time curve (AUC) for the lactone and carboxy acid forms of irinotecan and SN-38 remained constant over all dose levels studied. Linear relationships were shown between dose and peak concentration (Cmax), and between dose and AUC of irinotecan, but no such linearity was demonstrable between irinotecan dose and Cmax or AUC of SN-38. Fourteen percent of irinotecan and less than 1% of SN-38 was recovered in the urine, suggesting that renal excretion is not an important mechanism of elimination of this drug. In a phase II trial reported by the same institution, pharmacodynamic relationships between pharmacokinetic parameters and nausea and vomiting, neutropenia, and response were not seen, although some correlation was suggested between SN-38 AUC on week 3 of treatment and diarrhea [20]. Other investigators, however, looking at pharmacokinetics in chemotherapy-naive colorectal cancer patients on a weekly schedule found no correlation between pharmacokinetic values and either toxicity or response [22].

Yet another group explored the pharmacokinetics of irinotecan on a schedule of 30-min infusions daily for three consecutive days every three weeks. They found irinotecan to have a mean terminal half-life of 8.3 hours (half life of SN-38 was not reported), with both irinotecan and SN-38 pharmacokinetics showing high interpatient variability [26]. Irinotecan and SN-38 rebound concentrations were observed in some patients within an hour after infusions, suggesting an enterohepatic recirculation. Total body clearance did not vary with increased dosage on this phase I study, indicating linear pharmacokinetics within the dosage range studied. On this trial, a modest, but statistically significant correlation between irinotecan AUC and SN-38 AUC was observed (r = 0.52, p < 0.05). Hematologic toxicity did not correlate with either irinotecan or SN-38 AUC; however, a correlation between irinotecan (but not SN-38) AUC and grade of diarrhea was reported.

In a pooled analysis of pharmacokinetics from 107 patients in three different phase I trials [27], mean terminal half-lives for irinotecan and SN-38 were 10.7 hours and 10.6 hours, respectively. This larger analysis also demonstrated a positive correlation between irinotecan dose and irinotecan Cmax and AUC (r = 0.78 p < 0.001), and between irinotecan AUC and SN-38 AUC (r = 0.75, p < 0.001). Increasing dose within the dose levels studied did not lead to an increase in the fraction of drug metabolized to SN-38 (metabolic ratio), with a mean value of SN-38 AUC/irinotecan AUC = 3%. There were no significant correlations in this study population between drug clearance or metabolic ratio with age, sex, tumor type, body height or weight, or renal function; however, bilirubin elevations had a negative correlation with drug clearance. However, in this report, AUC of both irinotecan and SN-38 correlated with neutropenia, degree of diarrhea, and intensity of nausea and vomiting. The metabolic ratio did not correlate with any pharmacodynamic parameters.

Some investigators have demonstrated a correlation between glucuronidation of SN-38 and gastrointestinal toxicity [28], and others have suggested that an early rise in the bilirubin after treatment predicts for increased toxicity, presumably because the bilirubin is competing with SN-38 for glucuronidation, and those patients with more limited ability to glucuronidate will show a resultant rise in unconjugated bilirubin in the presence of SN-38. A specific enzyme isoform of uridine diphosphate glucuronosyltransferase, UGT 1.1, has been identified as being responsible for SN-38 glucuronidation [29]. Since this isoform is lacking in patients with Gilbert’s syndrome, it would be anticipated that patients with Gilbert’s syndrome would be highly intolerant of irinotecan. In a sample of 36 evaluable patients that explored the influence of race or gender on the pharmacokinetics and toxicity of irinotecan, no correlatons with these factors were seen [28].

Complicating matters further, other metabolites of irinotecan have been identified. One in particular, known as APC, [30] is a metabolite of irinotecan created by the cytochrome P450-dependent oxidation of irinotecan. While APC cannot be converted into SN-38, it can compete with SN-38 for glucuronidation. As such, the degree to which APC is present may influence the glucuronidation of SN-38, and so potentially influence gastrointestinal toxicity of irinotecan.


   TOXICITY
Top
 Abstract
 Historical Background
 Irinotecan in the Treatment...
 Pharmacokinetics
 Toxicity
Recommendations for Current...
 Future Development
 Conclusion
 References
 
The two major dose-limiting toxicities of irinotecan are neutropenia and diarrhea. In the earlier stages of this drug’s development, diarrhea appeared to be the major dose-limiting toxicity, but greater familiarity with irinotecan and its side-effect profile, and an understanding of procedures for dealing with this toxicity, have lessened the magnitude of this toxicity as an impediment to clinical use (Table 1Go).


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  		Table 1. Factors favorably influencing irinotecan toxicity
 
Diarrhea
Diarrhea secondary to irinotecan can be divided into two distinct syndromes: early-onset diarrhea, which occurs during or shortly after irinotecan administration, and late-onset diarrhea, which is of greater concern, and which develops more than 24 h after drug administration. The early-onset diarrhea is part of a cholinergic syndrome which can be seen with irinotecan administration and which is characterized by rapid-onset diarrhea, and may also include abdominal cramping and diaphoresis [31]. This syndrome is relatively unusual and is easily managed. In the 304 patients with fluorouracil-refractory colorectal cancer included in the three phase II pivotal trials, 24 patients (8%) were reported as having experienced grade III-IV diarrhea within 24 h of irinotecan administration (and were thus adjudicated as having experience early-onset diarrhea) [21]. Twenty-seven (9%) of the 304 patients received atropine 0.25 mg-1.0 mg intravenously as treatment of early-onset diarrhea. While formal data collection on the management of early-onset diarrhea was not done on this study, investigators reported that symptoms rapidly responded to atropine therapy, and only one of the 304 patients discontinued treatment due to early-onset diarrhea. No complications secondary to atropine administration were reported in this population.

Late-onset diarrhea has been a more serious and difficult problem in the management of patients receiving irinotecan, although this toxicity appears to be far more manageable now than it was in the earlier days of irinotecan’s development. Late-onset diarrhea was the major problem encountered in initial phase I trials and early into phase II development, with diarrhea beginning any time after the first 24 h following treatment, bust most commonly occurring approximately 10 days after the initiation of irinotecan therapy.

In 1993, Abigerges et al. reported that intensive administration of loperamide (Table 1Go) was effective in ameliorating much of the late-onset diarrhea caused by irinotecan [32]. For maximum effectiveness, the loperamide must be started at the first signs of diarrhea and taken at a dose of 2 mg every 2 h (or 4 mg every 4 h during the night) until the patient has gone 12 h without diarrhea. Anecdotally, failure to adhere to this rigorous schedule has been associated with less successful treatment of the diarrhea, and the importance of this antidiarrheal regimen must be stressed to each patient prior to the initiation of therapy.

While randomized evaluations of loperamide in the management of late-onset diarrhea have not been done, there are sequential data which give a strong indication of loperamide’s effectiveness. In the trial reported from Memorial Sloan-Kettering cancer center [21] 10 of the first 18 patients treated (56%) required dose attenuations due to the development of grade III-IV diarrhea. The investigators then became aware of the report of Abigerges et al. [32], indicating the usefulness of loperamide, and began strictly adhering to the prescribed loperamide schedule. Of the next 23 patients treated, only two (9%) experienced grade III-IV diarrhea (p = 0.001).

In the three U.S. pivotal phase II studies of fluorouracil-refractory colorectal cancer, 93 of the 304 patients treated (31%) experienced grade III-IV late-onset diarrhea [21]. Of those 193 patients who received the 125 mg/m2 starting dose of irinotecan, 65 (34%) developed grade III-IV diarrhea. It is noteworthy that bowel function is often a problem in patients with advanced colorectal cancer, possibly secondary to such factors as a history of bowel surgery, abdominal carcinomatosis, and/or narcotic analgesic use. These factors make accurate quantitation of gastrointestinal toxicity difficult in this patient population. Of the 304 patients evaluated 96 (32%) were taking laxatives during their irinotecan treatments. To what degree this influenced the incidence of late-onset diarrhea is not known. Overall, 83% of the 304 patients treated on the three phase II pivotal studies took at least one dose of loperamide; however, only four patients (1%) discontinued treatment secondary to late-onset diarrhea [21, 33].

To put the late-onset diarrhea into proper perspective, it is appropriate to compare its incidence with the incidence of severe diarrhea in fluorouracil-based treatments. A phase III trial of the two most widely used schedules of fluorouracil and leucovorin in chemotherapy-naive colorectal cancer patients reported dose-limiting diarrhea in 32% and 18% of patients receiving weekly high-dose leucovorin and daily x 5 low-dose leucovorin, respectively [34]. Especially when considering that this phase III population of patients was receiving initial chemotherapy and was thus earlier into their overall, antineoplastic treatment, the incidence of irinotecan-induced severe diarrhea does not appear to be outside of toxicity parameters seen with more traditional chemotherapy regimens.

Myelosuppression
Myelosuppression is the other major dose-limiting toxicity of irinotecan. Granulocytopenia is the major manifestation, with irinotecan being essentially platelet-sparing. In a trial of 41 chemotherapy-naive colorectal patients, six (15%) experienced grade III granulocytopenia, and three (7%) experienced grade IV [22]. In the pooled analysis of 304 phase II fluorouracil-refractory colorectal cancer patients, grade IV neutropenia was seen in 12% of patients, and 3% developed neutropenic fever [21]. No clinically significant thrombocytopenia was reported. One treatment-related death (0.3%), which was secondary to neutropenic sepsis, was reported in these 304 patients. This death rate compares favorably with the treatment-related mortality seen with other chemotherapy regimens. For example, seven deaths out of 372 patients (1.9%) [34] and eight deaths out of 620 patients (1.3%) [35] were reported in two large multicenter trials of fluorouracil-based chemotherapy in first-line colorectal cancer patients.

Other toxicities include nausea and vomiting, alopecia, and asthenia. Grade III/IV nausea and vomiting were reported in 13% of the 304 patients on the three U.S. pivotal phase II trials [21]. A variety of antinausea regimens have been used. Dexamethasone alone, or dexamethasone plus ondansetron or granisetron, is effective antiemesis for most irinotecan patients. Early reports had suggested that irinotecan might increase the likelihood of akathisias resulting from use of prochlorperazine, but the 8.5% incidence of akathisias reported is comparable to that seen with prochlorperazine alone. Some degree of alopecia was reported by 61% of the 304 patients, with complete hair loss being a relatively uncommon phenomenon. Twelve percent of the 304 patients reported >= grade III asthenia [21, 32].


   RECOMMENDATIONS FOR CURRENT PRACTICE
Top
 Abstract
 Historical Background
 Irinotecan in the Treatment...
 Pharmacokinetics
 Toxicity
 Recommendations for Current...
Future Development
 Conclusion
 References
 
Patient Selection
Irinotecan is a good choice for treatment of some patients with fluorouracil-refractory colorectal cancer and a poor choice for others. A key factor in the safe and effective use of irinotecan is proper patient selection, and the importance of this issue cannot be overemphasized. Patients with a favorable performance status (ECOG 0-1, or at least 2), adequate bowel function and oral intake, and the ability and motivation to follow complex directions are those who are more likely to tolerate irinotecan well (Table 2Go). As is true with virtually all chemotherapies for solid tumors, those patients with severe debilitation and/or inadequate motivation or capacity to follow directions are far more likely to experience severe or even life-threatening toxicity and are far less likely to obtain tangible clinical benefit. A patient who is looking and feeling well after progression through first-line fluorouracil-based therapy may benefit from having irinotecan as a therapeutic option. A patient who is moribund, living a bed-to-chair existence, not maintaining nutritional or fluid intake, or essentially unable to ambulate due to weakness and fatigue is a poor candidate for any cytotoxic chemotherapy, and use of irinotecan in such a patient is likely to have an undesirable result (Table 3Go). Unfortunately, many patients with fluorouracil-refractory colorectal cancer are not in reasonable shape to receive chemotherapy. One must exercise restraint in the management of such patients. The relevant question is not "Is there a drug that can treat this tumor?" but rather, "Is there a drug that can treat this patient?" One must recall that the response and toxicity data for irinotecan are based on the results of treating patients with the performance status, organ function, and motivation to meet the entry criteria of a clinical trial. Extrapolation of those data to patients who do not meet these criteria is neither reliable nor appropriate. Use of irinotecan as a salvage therapy for a severely debilitated patient is likely to result in serious detriment to that patient’s quality of life, and as such, would be inappropriate palliative care.


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  		Table 2. Good candidates for irinotecan treatment
 

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  		Table 3. Characteristics of poor candidates for irinotecan
 
Dose Modifications
On the weekly x 4 schedule, the recommended starting dose is 125 mg/m2. As discussed in the Pharmacokinetics section above, the metabolism of irinotecan to SN-38 and other metabolites varies widely from patient to patient. It is therefore reasonable to expect that a relatively wide range of doses will be required, and thus, that a significant number of dose modifications will be required. At present, there is no direct evidence of a steep dose-response curve with this drug, so that it is not at all clear that a higher dose is going to be more efficacious. For these reasons, it is often necessary and appropriate to modify doses as therapy progresses. For patients experiencing more than mild toxicity (grade 2 or greater) in the first week, a dose reduction of 20% or more may be needed in order to improve tolerability and increase the chance of delivering all planned doses. Patients experiencing a life-threatening (grade 4) toxicity often require larger dose reductions, in the 40% range.

Such dose adjustments are, of course, consistent with standard chemotherapy practices with other chemotherapy treatment regimens. For example, in a large randomized study of different fluorouracil-based regimens for first-line treatment of metastatic colorectal cancer, dose reductions for toxicity were required in 37% of patients receiving daily x 5 fluorouracil with low-dose leucovorin and were required in 41% of patients receiving weekly fluorouracil with high-dose leucovorin [35].

While it is important to adjust doses to individual patient tolerance, it is equally important not to dose-reduce in the absence of toxicity. For this reason, it is extremely important to take a detailed toxicity history, especially with regard to bowel movements. Patients with colorectal cancer rarely have normal bowel function. Some patients may have a large number of bowel movements per day as their normal post-surgical baseline. It is therefore important to inquire about changes in bowel habits rather than simply asking about the number or consistency of bowel movements. For example, a patient with a baseline of four bowel movements per day who reports having five to six bowel movements per day on irinotecan is not necessarily experiencing significant diarrheal toxicity and would not necessarily require dose adjustments on the basis of diarrhea.

A number of patients appear to tolerate their first three weeks of irinotecan therapy reasonably well but then exhibit evidence of toxicity (low blood counts, diarrhea, or fatigue) by the day of the planned fourth treatment. For such patients, it is appropriate to omit the fourth week of therapy and count that week as the first of two rest weeks, thereby reducing the treatment cycle to five weeks (three weeks "on," two weeks "off"). Some patients appear to tolerate this five-week schedule better than the six-week schedule, and the difference in dose intensity is quite minimal (patients treated three out of five weeks receive treatment 60% of the time; patients treated four out of six weeks receive treatment 66% of the time).


   FUTURE DEVELOPMENT
Top
 Abstract
 Historical Background
 Irinotecan in the Treatment...
 Pharmacokinetics
 Toxicity
 Recommendations for Current...
 Future Development
Conclusion
 References
 
With established antitumor activity against fluorouracil-refractory colorectal cancer, irinotecan is currently undergoing further development efforts to determine its usefulness in other aspects of colorectal cancer treatment, in combination regimens, and in earlier stages of the disease. Studies are also under way investigating the use of irinotecan in the management of other malignancies.

Given the activity of irinotecan in fluorouracil-refractory colorectal cancer, a combination regimen of fluorouracil and irinotecan in front-line management of colorectal cancer would appear to be potentially advantageous. Initial reports from investigators in Tokyo, however, indicated that fluorouracil might interefere with the carboxylesterase that converts irinotecan to SN-38, and so might inhibit the activity of irinotecan [36]. This report was based, however, on historical comparisons of the pharmacokinetics from different sets of patients. Investigators at Memorial Hospital in New York designed a phase I trial to explore the clinical possibility of combining irinotecan, leucovorin, and fluorouracil, and to investigate the pharmacokinetic interactions of these agents [37]. A weekly x 4 bolus schedule was chosen for this trial. On day 1, patients received irinotecan only, and a 24-h pharmacokinetic sampling for irinotecan and SN-38 was performed. On day 2, leucovorin and fluorouracil were given. On the following week (day 8), irinotecan was given, with leucovorin and fluorouracil given immediately thereafter, and a second full pharmacokinetic sampling was performed. At the beginning of the second treatment cycle, the leucovorin and fluorouracil were given before the irinotecan, and a third pharmacokinetic sampling was done. Thus, each patient served as his or her own control for irinotecan and SN-38 levels when irinotecan was given alone, given before fluorouracil and leucovorin, or given after fluorouracil and leucovorin. This trial demonstrated no substantial effect of fluorouracil on the conversion of irinotecan to SN-38. The combination regimen was found to be tolerable with full-dose irinotecan given with near full doses of leucovorin and fluorouracil. A phase III trial evaluating the safety and activity of this regimen against irinotecan alone, and against fluorouracil plus leucovorin alone, is currently ongoing. Recently, other treatment schedules of fluorouracil plus irinotecan have also been reported [38-40], and several of these are scheduled to enter phase III trials. A randomized phase II study to compare different irinotecan-plus-fluorouracil schedules with each other is currently planned as well. It should be emphasized that, at the time of this writing, the relative merits of concurrent administration of fluorouracil and irinotecan are as yet unknown, and such combinations are not, at present, recommended for use outside a clinical trial.

Combination trials with a number of schedules of cisplatin plus irinotecan have also been reported [41, 42]. A trial reported from Memorial Sloan-Kettering Cancer Center [41] uses a novel cisplatin schedule, with both cisplatin and irinotecan given weekly in order to maximize the potential for synergistic interaction between these two drugs. Activity on this phase I study was very encouraging. Based on this phase I experience, and on the reported single-agent activity of irinotecan in other malignancies such as non-small cell and small cell lung cancer [43, 44] and cervical cancer [45], investigations of this combination irinotecan/cisplatin regimen in a number of solid tumors, including lung cancer, esophageal cancer, gastric cancer, and ovarian cancer are currently under way. Trials of irinotecan in combination with other agents such as taxotere [46] and oxaliplatin [47] have also been reported, and investigations in combination with gemcitabine and other antitumor agents are currently under way. Phase I investigations of an oral formulation of irinotecan are planned for initiation in early 1998.

Adjuvant Therapy of Colorectal Cancer
Despite the antitumor activity which has been demonstrated to date, no patient is known to be alive and free of disease because of irinotecan. All of the above-mentioned uses of irinotecan, either alone or in combinations, have been targeted at patients with incurable metastatic disease. Irinotecan has therefore contributed thus far to the palliative care of many patients, and in doing so has provided substantial clinical benefit in many cases, but it has yet to save a life.

The potential for cure with currently available chemotherapy for advanced solid tumors lies in the appropriate use of active agents and regimens in the adjuvant setting, in order to eradicate microscopic metastatic disease and thus cure patients who would be otherwise destined to relapse and die after surgery. Based on the demonstrated activity of irinotecan in the metastatic setting, we at Memorial Sloan-Kettering have begun studying the use of irinotecan in the adjuvant setting of colorectal cancer. We are exploring both concurrent and sequential administration schedules of irinotecan plus fluorouracil and leucovorin for resected stage III and high-risk stage II colon cancer patients. Based on our prior phase I study of daily low-dose irinotecan [48], we are also exploring the use of concurrent daily irinotecan plus pelvic radiation in the preoperative treatment of locally advanced rectal cancer. It is hoped that incorporation of irinotecan into adjuvant regimens for colorectal cancer will lead to increased cure rates in these earlier-stage patients. These clinical trials are now under way and are actively accruing patients.


   CONCLUSION
Top
 Abstract
 Historical Background
 Irinotecan in the Treatment...
 Pharmacokinetics
 Toxicity
 Recommendations for Current...
 Future Development
 Conclusion
References
 
Irinotecan is an important new tool in the treatment of cancer. Its current indication is in the second-line therapy of metastatic colorectal cancer, and in this setting it provides the potential for palliation in a patient population with an extremely limited number of viable treatment options. Diarrhea and neutropenia are the major dose-limiting toxicities; however, in appropriately selected patients, these toxicities are usually manageable and are comparable in frequency and severity to other routinely used chemotherapeutic agents. Ongoing studies are exploring the role of this agent in the adjuvant treatment of earlier-stage colorectal cancer, where, it is hoped, the demonstrated antitumor activity of irinotecan can be utilized to improve the cure rate and thus save lives. Other ongoing studies will further clarify the role of this new agent in combination chemotherapy regimens and in the treatment of other malignant tumors. On the basis of preliminary data, there is reason for optimism that irinotecan may become an important weapon in the armamentarium used to combat a number of different human malignancies. Clinical trials investigating and defining the therapeutic potential of irinotecan are currently ongoing on a large scale internationally, and patient participation in these trials is to be strongly encouraged so that we may more accurately define the proper uses for this promising new anticancer agent.


   REFERENCES
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 Abstract
 Historical Background
 Irinotecan in the Treatment...
 Pharmacokinetics
 Toxicity
 Recommendations for Current...
 Future Development
 Conclusion
 References
 

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accepted for publication November 13, 1997.




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