Phase I trials of irinotecan (CPT-11 [Camptosar]), conducted at Johns Hopkins and the University of Texas, San Antonio, demonstrated some activity in patients with refractory advanced cancer. Three pivotal phase II studies of
ABSTRACT: Phase I trials of irinotecan (CPT-11 [Camptosar]), conducted at Johns Hopkins and the University of Texas, San Antonio, demonstrated some activity in patients with refractory advanced cancer. Three pivotal phase II studies of irinotecan in advanced colorectal carcinoma were conducted at The University of Texas, San Antonio, Mayo/North Central Cancer Treatment Group (NCCTG), and the CPT-11 Study Group in a total of 304 patients. All patients had received prior fluorouracil (5-FU) chemotherapy, and over 90% had progressed while on treatment within the last 6 months. The initial starting dose of irinotecan ranged from 100 to 150 mg/m². The overall response rate was 12.8% (95% confidence interval, 9.1% to 16.6%) with a 15% response rate at a recommended starting dose of 125 mg/m². The response durations and overall median survivals were similar in the three studies. The principal toxicities included diarrhea, nausea, vomiting, and neutropenia. Severe diarrhea was limited by use of an intensive loperamide regimen and appropriate dose modification. The three pivotal studies of irinotecan in advanced colorectal carcinoma demonstrate consistent response rates and duration, with manageable toxicity.Future studies will focus on the use of irinotecan in chemotherapeutically naive colorectal carcinoma, the adjuvant treatment of colon carcinoma, combination chemotherapeutic regimens, and treatment of other malignant diseases. [ONCOLOGY 12(Suppl 6):48-53, 1998]
Carcinoma of the colon and rectum remains one of the most common malignant diseases afflicting people living in industrialized countries. The estimated number of new cases of colorectal cancer in the United States in 1998 will exceed 131,000. During the same year, colorectal carcinoma will result in an estimated 55,000 deaths, remaining the second most common cause of cancer-related deaths in the United States. The US populations lifetime risk of ever developing invasive colorectal cancer is approximately 1 in 17.
Five-year relative survival rates for colorectal cancer have improved modestly over the last 2 decades, and death rates for men with this disease have decreased about 1.9% per year from 1990 to 1994. Despite these results, 19% to 25% of patients will be diagnosed with advanced colorectal cancer, for which systemic chemotherapy is the mainstay of treatment.
Fluorouracil (5-FU) has been used in the treatment of cancer for nearly 40 years. The rates of regression in advanced colorectal cancer patients treated with the same dose and schedule of 5-FU have ranged from 8% to 85%. A recent meta-analysis reported an 11% overall response rate to single-agent 5-FU among patients with previously untreated metastatic disease.
Modulation of 5-FU has been pursued using several agents, including leucovorin, methotrexate, interferon-alfa (Intron A, Roferon-A), and N-(phosphonacetyl)-L-aspartate (PALA), as a means to increase antitumor activity. In the meta-analysis, the combination of 5-FU and leucovorin showed an increase in response rate (23%) but not an improvement in overall survival. Randomized trials of 5-FU vs 5-FU and leucovorin have demonstrated prolongation of median survival with the biochemically modulated regimens.[5,6]
A phase II study by the Southwest Oncology Group (SWOG) assessed the efficacy and toxicity of seven different regimens of 5-FU in patients with untreated advanced colorectal carcinoma. The median survival for the entire patient cohort was 14 months, and no regimen was superior relative to single-agent 5-FU (bolus or continuous infusion) therapy in terms of response or survival. For patients treated with bolus 5-FU or continuous-infusion 5-FU, the overall objective response rate (confirmed and unconfirmed) was 29%, although the continuous infusion produced a more favorable toxicity profile.
A recent meta-analysis demonstrated a higher tumor response rate in patients treated with continuous-infusion 5-FU than in those given bolus 5-FU (23% vs 14%), as well as a slight increase in overall survival. With the limited advantages of prolonged infusion of 5-FU or modulation of 5-FU, development of alternative agents for treatment of patients with metastatic colorectal carcinoma remains of great interest.
Camptothecin is a natural alkaloid product first extracted from the stem wood of the Chinese tree Camptotheca acuminata. Preclinical studies of the purified drug demonstrated activity in mouse L1210 leukemia and rat Walker carcinosarcoma.[9,10] The original preparation (camptothecin sodium) was evaluated in clinical trials in the late 1960s and early 1970s. A preliminary trial by Gottlieb and colleagues was encouraging, with 11 of 18 patients showing evidence of response or improvement (> 50% decrease in tumor mass in 5 patients).
Subsequent phase II trials in advanced gastrointestinal cancer and malignant melanoma failed to demonstrate significant clinical activity of camptothecin sodium.[12,13] The toxic effects encountered in both studies included gastrointestinal and hematologic effects and hemorrhagic cystitis. Based on these data, Moertel et al concluded in 1972 that "camptothecin is a drug of protean and unpredictable toxicity that has no clinical value in the management of gastrointestinal cancer."
Clinical drug development from 1970 to 1985 yielded few agents of merit for patients with advanced colorectal cancer. Marsoni et al reviewed 42 investigational agents evaluated during this period and determined 41 to be inactive against colon cancer. The only drug with potential activity, tegafur, did not demonstrate significant activity in a confirmatory trial when compared to 5-FU.
Investigators began to search for analogs of camptothecin with an improved toxicity profile, better water solubility, and enhanced therapeutic efficacy. Work by Kunimoto and colleagues led to the synthesis of a more water-soluble, semisynthetic derivative of camptothecin. Irinotecan hydrochloride (CPT-11 [Camptosar]) was found to have greater in vitro and in vivo activity than its parent compound while demonstrating less severe, more predictable toxicity. Interest in the camptothecins increased with the discovery of the novel mechanism of action of this class of chemotherapeutic agents in preclinical studies.
Many anticancer agents are known to act as topoisomerase inhibitors. Hsiang et al, while evaluating compounds for topoisomerase II inhibitory activity, demonstrated that camptothecins blocked the enzymatic action of topoisomerase I. Several authors have reviewed the action of camptothecins on topoisomerase I activity.[19,20] The topoisomerase I enzyme transiently cleaves and reseals one DNA strand through a transesterification reaction. This allows the other DNA strand to pass through the transient break and changes the DNA topology. The resulting topoisomerase I/DNA complex, also known as the cleavable complex, is the target for camptothecin and its derivatives. Irinotecan binds to the cleavable complex and inhibits resealing of the parent DNA, thereby halting nucleic acid synthesis. Collision between the replication fork and the stable cleavable complex results in double-strand DNA breaks and ultimately cellular death through apoptosis.
Irinotecan is rapidly converted in vivo by cellular carboxylesterases to its active metabolite, SN-38, which is 250 to 1,000 times more potent an inhibitor of topoisomerase I than the parent compound. It has also been shown that the antitumor effectiveness of irinotecan can be accounted for by the intracellular concentrations of SN-38.
Topoisomerase I activity is present in all cells, but Giovanella and colleagues have shown that levels of the enzyme in colon cancers are 30-fold higher than in normal colonic mucosa. Several colon cancer xenografts that have been studied also expressed significantly higher levels of topoisomerase I. In these experiments, the xenografts were highly resistant to multiple chemotherapeutic agents; however, several camptothecin analogs demonstrated significant activity. Giovanella et al found 9-amino-camptothecin to be highly effective in this xenograft model, inducing disease-free remissions in several established tumors.
Houghton et al have also studied camptothecin analogs in chemotherapy-resistant colon cancer xenografts. These analogs demonstrated impressive in vivo activity, which was strongly schedule dependent. The optimal schedule was equivalent to a low-dose continuous administration of the camptothecin analog. As a result of these preclinical findings and the development of more soluble analogs, camptothecin derivatives once again moved into the clinical arena.
Multiple phase I studies of irinotecan have been performed using many different schedules. Initial phase I studies of irinotecan began in Japan in 1986. The common dose-limiting toxicities (DLTs) encountered in these studies were hematologic (primarily leukopenia/neutropenia) and gastrointestinal (primarily diarrhea). The schedules currently used in Japan include 100 mg/m² of irinotecan weekly or 150 mg/m² every 2 weeks.[24,25]
European phase I studies have concentrated on three different schedules; the most widely used of these involves a single irinotecan infusion every 3 weeks. Abigerges and colleagues encountered a DLT of delayed diarrhea with a dosage of 350 mg/m² every 3 weeks. Subsequent incorporation of high-dose loperamide allowed for further dose escalation. At the highest dose of 750 mg/m², grade 4 granulocytopenia was the DLT.
Initial phase I trials in the United States used two different dose schedules. Rowinsky and colleagues evaluated a single 90-minute infusion of irinotecan every 3 weeks, with doses ranging from 100 to 345 mg/m². At the highest dose levels of 290 and 345 mg/m², the investigators encountered a spectrum of gastrointestinal side effects, including diarrhea, nausea, vomiting, abdominal cramps, and anorexia. They suggested a phase II starting dose of 240 mg/m².
Rothenberg et al at the University of Texas Health Science Center in San Antonio developed another schedule consisting of weekly treatments for 4 weeks, followed by 2 weeks rest, with courses repeated every 6 weeks. With this regimen, the DLT was diarrhea at the 180 mg/m² dose level, and the recommended starting dose for phase II trials was 150 mg/m². The definition of maximum tolerated dose (MTD) differed between these two US phase I trials, as did the supportive measures, which likely accounts for the differences in recommended phase II starting doses.
Other investigators have used granulocyte colony-stimulating factor (G-CSF [Neupogen]) support in an attempt to escalate the irinotecan dose on the weekly × 4 schedule while minimally increasing the MTD. The MTD for an every-other-week schedule also is under investigation.
Based on the phase I schedule developed in San Antonio and initial encouraging results from Japan, further phase II trials were developed to assess the efficacy and toxicity of CPT-11 in patients with advanced colorectal carcinoma.
The initial phase II study of irinotecan was reported by Shimada and colleagues in Japan. A total of 67 patients were treated with irinotecan weekly or every other week; 52 (81%) of these patients had received prior radiotherapy or 5-FU chemotherapy. The overall response rate was 27% (25% in previously treated patients). The duration of response was 7.2 months, as measured from the initial time of treatment until tumor progression. Investigators reported no difference in response or toxicity between the weekly vs every-other-week schedule.
The first two pivotal phase II studies of irinotecan were conducted at The University of Texas, San Antonio (San Antonio Regional) and Mayo/North Central Cancer Treatment Group (NCCTG) in 1993; the final pivotal study was performed by the CPT-11 Study Group.[32, 33, Rothenberg ML et al, unpublished data] Each protocol involved multiple sites (ranging from 4 at San Antonio to 30 in the CPT-11 Study Group trial), including academic centers and private practice oncology clinics. Chemotherapeutically naive patients with advanced colorectal cancer were treated in two separate studies.[33,34]
All three pivotal trials enrolled patients with measurable metastatic colorectal carcinoma who had progressed after 5-FU-based chemotherapy regimens. All patients were required to have a baseline performance status (ECOG and SWOG scales) of 0 to 2 and adequate hematologic function (absolute neutrophil count > 1,500/mm³, platelet count > 100,000/mm³), hepatic function (serum glutamic-oxaloacetic acid [SGOT] £ 3 to 5 times upper limit of normal, bilirubin < 2 mg/dL), and renal function (serum creatinine < 2 mg/dL).
Irinotecan was administered as a 90-minute intravenous infusion weekly for 4 weeks followed by a 2-week rest. Courses were repeated approximately every 42 days. Dose modifications were incorporated into the schedule according to individual patient tolerance at the four weekly intervals, as well as with each course evaluation. The criteria for response were based on standard cooperative group criteria, and in all three studies there was independent peer review confirmation of all responses.
Use of antidiarrheal supportive measures changed during the accrual phase of the first two studies to incorporate an intensive loperamide regimen after reports by Abigerges et al indicated improved control of diarrhea. The recommended regimen consisted of 4 mg of loperamide orally at the first sign of a change in bowel habits, then 2 mg every 2 hours during the day (4 mg every 4 hours at night) until the patient was diarrhea-free for at least 12 hours. The intensive loperamide regimen was written into the protocol at the start of the CPT-11 Study Group trial.
The recommended phase II starting dose was 150 mg/m². Investigators at San Antonio Regional treated the first nine patients at this dose level and observed four episodes of grade 4 diarrhea and dehydration during cycle 1 of treatment. Because of this toxicity, the protocol was amended to start at 125 mg/m² (Table 1). The CPT-11 Study Group initially treated 64 patients with 125 mg/m² of irinotecan, while the last
102 patients were started at a 100-mg/m² dose level to evaluate whether a lower starting dose would result in less severe toxicity without altering efficacy.
Patient characteristics for the three pivotal studies are summarized in Table 2. Of note, 52% of the patients had symptoms related to their disease (as judged by a performance status of 1 or 2), and 84% of patients had never responded to prior 5-FU chemotherapy for their metastatic disease. The principal sites of metastatic disease were the liver and lungs (70% and 38% of patients, respectively).
The majority of patients (70%) had received prior chemotherapy for metastatic disease, and the time interval for disease progression relative to prior 5-FU chemotherapy was 6 months for over 90% of the patients. Pelvic radiotherapy was allowed for study entry on the NCCTG protocol, whereas patients with prior pelvic irradiation were disqualified in the CPT-11 study group. The San Antonio protocol was amended to exclude prior pelvic radiotherapy after one such patient had been enrolled.
Response Rates and Survival
The overall response rates in the pivotal trials are outlined in Table 3. Two complete responses were seen at the 125-mg/m² starting dose level, one in the San Antonio protocol, and one in the CPT-11 Study Group trial. The combined response rate among all 304 patients was 12.8% (95% confidence interval [CI], 9.1% to 16.6%). For the 193 patients receiving a starting dose of 125 mg/m², the response rate was 15% (95% CI, 10.1% to 20.1%). Another 44% of patients had stable disease as their best response.
Median duration of response for all three studies was approximately 6 months (range, 2.6 to 15.1 months) and was very similar for all three protocols (Table 4). Several of the responses were quite durable, lasting more than 12 months, with the progression dates confirmed by peer review committees. Onset of response to irinotecan was rapid; 90% of patients responded by the end of cycle 2 in the first two studies, and 10 of 18 responses were seen by 12 weeks in the CPT-11 Study Group protocol. Median survival for this refractory group was similar in the three trials, ranging from 8.3 months in the NCCTG study to 10.6 months for patients receiving 125 mg/m² in the CPT-11 Study Group protocol.
Serial carcinoembryonic antigen (CEA) measurements were obtained in a subset of patients (n = 160). Responding patients (n = 20) exhibited a mean decrease in CEA of 82%, while patients with progressive disease (n = 61) had an 18% mean increase in their serial CEA measurements. In patients whose disease remained stable (n = 79), CEA decreased by a mean of 28%.
Symptoms that improved during therapy for responding patients (n = 12) included tumor pain as well as ascites. Significant predictors of response in this cohort of patients included a performance status of 0, previous 5-FU therapy given for metastatic disease vs adjuvant therapy, and diarrhea during the first course of therapy.
The principal toxicities of irinotecan in the pivotal trials included diarrhea, nausea, vomiting, and neutropenia (Table 5).
Diarrhea--Overall, grade 3 or 4 diarrhea occurred in 31% of patients (11.5% of all courses). The median time to onset of diarrhea was day 11, and median duration was 2 days.
The San Antonio group reported a decrease in the incidence of grade 4 diarrhea from 17% to 5% of courses after routine use of loperamide. The NCCTG trial investigators also reported a decline in the overall incidence of grade 3 or 4 diarrhea from 50% to 32% following a protocol amendment encouraging the use of intensive loperamide support.
In the CPT-11 Study Group trial, the frequency of grade 3 or 4 diarrhea was somewhat higher in patients treated at the 125-mg/m² dose level than in those starting at the 100-mg/m² dose (32.8% and 23.5%, respectively).[Rothenberg ML et al, unpublished data] When baseline characteristics were analyzed to look for predictors of grade 3 or 4 diarrhea, the only significant factor was age ³ 65 years. A prospective study has been performed to evaluate age as a risk factor for developing irinotecan toxicity. This trial failed to identify a statistically significant difference in toxicity based on age, and thus a reduced starting dose for the older population was not recommended.
Use of routine intensive loperamide support and appropriate dose reductions are the standard recommendations for prevention of grade 3 or 4 diarrhea.
Nausea and Vomiting--Other severe gastrointestinal toxicities included nausea and vomiting. Grade 3 or 4 vomiting occurred in 12.8% of patients overall, and this was possibly dose related in the CPT-11 Study Group. As noted in Table 5, 21.9% of patients given the 125-mg/m² dose had grade 3/4 vomiting, while only 2% of patients at the 100-mg/m² dose level experienced severe vomiting.
Use of an aggressive antiemetic regimen, including intravenous dexamethasone and a serotonin antagonist, is recommended before irinotecan chemotherapy. Additional oral antiemetic agents should be provided to prevent any delayed emesis.
Neutropenia--Severe hematologic toxicity with irinotecan is limited primarily to white blood cells. The incidence of grade 3 or 4 neutropenia ranged from 20.4% in the CPT-11 Study Group at the 100-mg/m2 dose level to 32% in the 48 patients treated on the San Antonio protocol. The NCCTG trial reported a higher incidence of grade 4 leukopenia in patients who had received prior pelvic radiotherapy, and caution was recommended when treating this patient cohort.
Despite the myelosuppression observed in these trials, only 3% of patients developed neutropenic fever, and only one patient died due to drug-related neutropenic sepsis. Severe anemia or thrombocytopenia were uncommon events with irinotecan treatment.
Uncommon Toxicities--Other toxicities not commonly seen with irinotecan therapy are listed in Table 6.
Results of the three pivotal trials of irinotecan were presented to the Food and Drug Administrations Oncologic Drugs Advisory Committee in June 1996. Based on these results, the Food and Drug Administration approved irinotecan for the treatment of patients with advanced colorectal carcinoma whose disease has progressed or recurred after 5-FU chemotherapy.
Ongoing studies are investigating irinotecan in combination with 5-FU and leucovorin using several different schedules. A phase I trial has been completed that combined the weekly × 4 schedule of irinotecan with weekly 5-FU and low-dose leucovorin.
An ongoing phase III trial is assessing the use of irinotecan in patients who have not received prior chemotherapy for their advanced colorectal carcinoma. Patients will be randomized to treatment with irinotecan alone, 5-FU and leucovorin (Mayo regimen), or irinotecan in combination with 5-FU and leucovorin. Results of this trial are expected within the next 2 years.
Trials of single agent irinotecan are ongoing to assess this drug in the treatment of many solid tumor malignancies including refractory gliomas, lung carcinoma, ovarian carcinoma, and other gastrointestinal cancers. Investigations with the combination of irinotecan and different chemotherapeutic agents including cisplatin, carboplatin, and docetaxel may result in future combination trials for patients with advanced solid tumor malignancies.
1. Landis SH, Murray T, Bolden S et al: Cancer statistics, 1998. CA Cancer J Clin 48:6-29, 1998.
2. Curreri AR, Ansfield FJ, McIver FA, et al: Clinical studies with 5-fluorouracil. Cancer Res 18:748-784, 1958.
3. Moertel CG: Chemotherapy for colorectal cancer. N Engl J Med 330:1136-1142, 1994.
4. Advanced Colorectal Cancer 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.
5. Poon MA, OConnell MJ, Wieand HS, et al: Biochemical modulation of fluorouracil with leucovorin: Confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol 9:1967-1972, 1991.
6. Erlichman C, Fine S, Wong A, et al: A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol 6:469-475, 1988.
7. Leichman CG, Fleming TR, Muggia FM, et al: Phase II study of fluorouracil and its modulation in advanced colorectal cancer: A Southwest Oncology Group Study. J Clin Oncol 13:1303-1311, 1995.
8. 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.
9. Wall ME, Wani MC, Gook CE, et al: Plant antitumor agents: 1. The isolation and structure of camptothecin, a novel alkaloid leukemia and tumor inhibitor from Camptotheca acuminata. J Am Chem Soc 88:3888-3890, 1966.
10. DeWys WD, Humphreys SR, Goldin A: Studies on therapeutic effectiveness of drugs with tumor weight and survival time indices of Walker 256 carcinosarcoma. Cancer Chemother Rep 52:229-242, 1968.
11. Gottlieb JA, Guarino AM, Call JB, et al: Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC-100880). Cancer Chemother Rep 54:461-470, 1970.
12. Moertel CG, Schutt AJ, Reitemeier RJ, et al: Phase II study of camptothecin (NSC-100880) in the treatment of advanced gastrointestinal cancer. Cancer Chemother Rep 56:95-101, 1972.
13. Gottlieb J, Luce JK: Treatment of malignant melanoma with camptothecin (NSC-100880). Cancer Chemother Rep 56:103-105, 1972.
14. Marsoni S, Hoth D, Simon R, et al: Clinical drug development: An analysis of phase II trials, 1970-1985. Cancer Treat Rep 71:71-80, 1987.
15. Bedikian AY, Stroehlein J, Korinek J et al: A comparative study of oral tegafur and intravenous 5-fluorouracil in patients with metastatic colorectal cancer. Am J Clin Oncol 6:181-186, 1983.
16. Kunimoto T, Nitta K, Tanaka T, et al: Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Res 47:5944-5947, 1987.
17. Hsiang YH, Liu LF: Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 48:1722-1726, 1988.
18. Hsiang YH, Hertzberg R, Hecht S, et al: Camptothecin induces protein-linked DNA brakes via mammalian DNA topoisomerase-I. J Biol Chem 260:14873-14878, 1985.
19. Slichenmeyer WJ, Rowinsky EK, Donehower RC, et al: The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst 85:271-291, 1993.
20. Pommier Y: Eukaryotic DNA topoisomerase-I: Genome gatekeeper and its intruders, camptothecins. Semin Oncol 23(suppl 3):3-10, 1996.
21. Kawato Y, Aonuma M, Hirota Y, et al: Intracellular roles of SN-38, a metabolite of camptothecin derivative CPT-11, in the antitumor effect of CPT-11. Cancer Res 51:4187-4191, 1991.
22. Giovanella BC, Stehlin JS, Wall ME, et al: DNA topoisomerase I-targeted chemotherapy of human colon cancer in xenografts. Science 246:1046-1048, 1989.
23. Houghton PJ, Cheshire PJ, Hallman JC, et al: Efficacy of topoisomerase-I inhibitors, topotecan, and irinotecan administered at low-dose levels in protracted schedules in mice bearing xenografts of human tumors. Cancer Chemother Pharmacol 36:393-403, 1995.
24. Negoro S, Fukuoka M, Masuda N, et al: Phase I study of weekly intravenous infusion of CPT-11, a derivative of camptothecin, in the treatment of advanced non-small-cell lung cancer. J Natl Cancer Inst 83:1164-1168, 1991.
25. Armand JP: CPT-11: Clinical experience in phase I studies. Semin Oncol 23(suppl 3):27-33, 1996.
26. Abigerges D, Chabot GG, Armand JP, et al: Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients. J Clin Oncol 13:210-221, 1995.
27. Rowinsky EK, Grochow LB, Ettinger DS, et al: Phase I and pharmacological study of the novel topoisomerase I inhibitor 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11) administered as a ninety-minute infusion every three weeks. Cancer Res 54:427-436, 1994.
28. Rothenberg ML, Kuhn JG, Burris III HA, et al: Phase I and pharmacokinetic trial of weekly CPT-11. J Clin Oncol 11:2194-2204, 1993.
29. Lestingi TM, Vokes EE, Gray W, et al: A phase I trial of CPT-11 in solid tumors with G-CSF and antidiarrheal support. Proc Am Soc Clin Oncol 14:480, 1995.
30. Rothenberg ML, Rinaldi DA, Smith LS, et al: Every-other-week irinotecan (CPT-11): Results of a phase I and pharmacokinetic study. Proc Am Soc Clin Oncol 15:489, 1996.
31. Shimada Y, Yoshino M, Wakui A, et al: Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. J Clin Oncol 10:909-913, 1993
32. Rothenberg ML, Eckardt JR, Kuhn JG, et al: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14:1128-1135, 1996.
33. Pitot HC, Wender DB, OConnell MJ, et al: A phase II trial if irinotecan (CPT-11) in patients with metastatic colorectal carcinoma. J Clin Oncol 15:2910-2919, 1997.
34. Conti JA, Kemeny NE, Saltz LB, et al: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 14:709-715, 1996.
35. Abigerges D, Armand JP, Chabot GG et al: Irinotecan (CPT-11) high-dose escalation using intensive high-dose loperamide to control diarrhea. J Natl Cancer Inst 86:46-49, 1994.
36. Von Hoff DD, Rothenberg ML, Pitot HC, et al: Irinotecan (CPT-11) therapy for patients with previously treated metastatic colorectal cancer (CRC): Overall results of FDA-reviewed pivotal US clinical trials. Proc Am Soc Clin Oncol 16:228a, 1997.
37. Pazdur R, Zinner R, Rothenberg ML et al: Age as a risk factor in irinotecan (CPT-11) treatment of 5-FU refractory colorectal cancer. Proc Am Soc Clin Oncol 16:200a, 1997.
38. Saltz LB, Kanowitz J, Kemeny NE et al: Phase I clinical and pharmacokinetic study of irinotecan, fluorouracil and leucovorin in patients with advanced solid tumors. J Clin Oncol 14:2959-2967, 1996.