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Mechanism of Action
Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with the enzyme topoisomerase I, which relieves torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase IDNA complex and prevent religation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan is due to double-strand DNA damage produced during DNA synthesis when replication enzymes interact with the ternary complex formed by topoisomerase I, DNA, and either irinotecan or SN-38. Mammalian cells cannot efficiently repair these double-strand breaks.
Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38. SN-38 is formed from irinotecan by carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain. SN-38 is approximately 1000 times as potent as irinotecan as an inhibitor of topoisomerase I purified from human and rodent tumor cell lines. In vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies from 2- to 2000-fold; however, the plasma area under the concentration versus time curve (AUC) values for SN-38 are 2% to 8% of irinotecan and SN38 is 95% bound to plasma proteins compared to approximately 50% bound to plasma proteins for irinotecan. The precise contribution of SN38 to the activity of CAMPTOSAR is thus unknown. Both irinotecan and SN-38 exist in an active lactone form and an inactive hydroxy acid anion form. A pH-dependent equilibrium exists between the two forms such that an acid pH promotes the formation of the lactone, while a more basic pH favors the hydroxy acid anion form.
Administration of irinotecan has resulted in antitumor activity in mice bearing cancers of rodent origin and in human carcinoma xenografts of various histological types.
After intravenous infusion of irinotecan in humans, irinotecan plasma concentrations decline in a multiexponential manner, with a mean terminal elimination half-life of about 6 to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 10 to 20 hours. The half-lives of the lactone (active) forms of irinotecan and SN-38 are similar to those of total irinotecan and SN-38, as the lactone and hydroxy acid forms are in equilibrium.
Over the recommended dose range of 50 to 350 mg/m², the AUC of irinotecan increases linearly with dose; the AUC of SN-38 increases less than proportionally with dose. Maximum concentrations of the active metabolite SN-38 are generally seen within 1 hour following the end of a 90-minute infusion of irinotecan. Pharmacokinetic parameters for irinotecan and SN-38 following a 90-minute infusion of irinotecan at dose levels of 125 and 340 mg/m² determined in two clinical studies in patients with solid tumors are summarized in Table 9:
Table 9: Summary of Mean (±Standard Deviation) Irinotecan
and SN-38 Pharmacokinetic Parameters in Patients with Solid Tumors
|Cmax (ng/mL)||AUC0-24 (ng•h/mL)||t½ (h)||Vz (L/m²)||CL (L/h/m²)||Cmax (ng/mL)||AUC0-24 (ng•h/mL)||t½ (h)|
|125 (N=64)||1,660 ±797||10,200 ±3,270||5.8a ±0.7||110 ±48.5||13.3 ±6.01||26.3 ±11.9||229 ±108||10.4a ±3.1|
|340 (N=6)||3,392 ±874||20,604 ±6,027||11.7b ±1.0||234 ±69.6||13.9 ±4.0||56.0 ±28.2||474 ±245||21.0b ±4.3|
|Cmax -Maximum plasma concentration
AUC0-24 -Area under the plasma concentration-time curve from time 0 to 24 hours after the end of the 90-minute infusion
t½ - Terminal elimination half-life Vz - Volume of distribution of terminal elimination phase CL - Total systemic clearance
aPlasma specimens collected for 24 hours following the end of the 90-minute infusion.
bPlasma specimens collected for 48 hours following the end of the 90-minute infusion. Because of the longer collection period, these values provide a more accurate reflection of the terminal elimination half-lives of irinotecan and SN-38.
Irinotecan exhibits moderate plasma protein binding (30% to 68% bound). SN-38 is highly bound to human plasma proteins (approximately 95% bound). The plasma protein to which irinotecan and SN-38 predominantly binds is albumin.
The metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by carboxylesterase enzymes and primarily occurs in the liver. In vitro studies indicate that irinotecan, SN-38 and another metabolite aminopentane carboxylic acid (APC), do not inhibit cytochrome P-450 isozymes. SN-38 is subsequently conjugated predominantly by the enzyme UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite. UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity such as the UGT1A1*28 polymorphism. Approximately 10% of the North American population is homozygous for the UGT1A1*28 allele (also referred to as UGT1A1 7/7 genotype). In a prospective study, in which irinotecan was administered as a single-agent (350 mg/m²) on a once-every-3-week schedule, patients with the UGT1A1 7/7 genotype had a higher exposure to SN-38 than patients with the wild-type UGT1A1 allele (UGT1A1 6/6 genotype) [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION]. SN-38 glucuronide had 1/50 to 1/100 the activity of SN-38 in cytotoxicity assays using two cell lines in vitro.
The disposition of irinotecan has not been fully elucidated in humans. The urinary excretion of irinotecan is 11% to 20%; SN-38, < 1%; and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) over a period of 48 hours following administration of irinotecan in two patients ranged from approximately 25% (100 mg/m²) to 50% (300 mg/m²).
Effect of Age
The pharmacokinetics of irinotecan administered using the weekly schedule was evaluated in a study of 183 patients that was prospectively designed to investigate the effect of age on irinotecan toxicity. Results from this trial indicate that there are no differences in the pharmacokinetics of irinotecan, SN-38, and SN-38 glucuronide in patients < 65 years of age compared with patients ≥ 65 years of age. In a study of 162 patients that was not prospectively designed to investigate the effect of age, small (less than 18%) but statistically significant differences in dose-normalized irinotecan pharmacokinetic parameters in patients < 65 years of age compared to patients ≥ 65 years of age were observed. Although dose-normalized AUC0-24 for SN-38 in patients ≥ 65 years of age was 11% higher than in patients < 65 years of age, this difference was not statistically significant. No change in the starting dose is recommended for geriatric patients receiving the weekly dosage schedule of irinotecan [see DOSAGE AND ADMINISTRATION].
Effect of Gender
The pharmacokinetics of irinotecan do not appear to be influenced by gender.
Effect of Race
The influence of race on the pharmacokinetics of irinotecan has not been evaluated.
Effect of Hepatic Impairment
Irinotecan clearance is diminished in patients with hepatic impairment while exposure to the active metabolite SN-38 is increased relative to that in patients with normal hepatic function. The magnitude of these effects is proportional to the degree of liver impairment as measured by elevations in total bilirubin and transaminase concentrations. However, the tolerability of irinotecan in patients with hepatic dysfunction (bilirubin greater than 2 mg/dl) has not been assessed sufficiently, and no recommendations for dosing can be made [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and Use in Specific Populations].
Effect of Renal Impairment
The influence of renal impairment on the pharmacokinetics of irinotecan has not been evaluated. Therefore, caution should be undertaken in patients with impaired renal function. Irinotecan is not recommended for use in patients on dialysis [see Use In Specific Populations].
Irinotecan has been studied in clinical trials in combination with 5-fluorouracil (5-FU) and leucovorin (LV) and as a single agent [see DOSAGE AND ADMINISTRATION]. When given as a component of combination-agent treatment, irinotecan was either given with a weekly schedule of bolus 5-FU/LV or with an every-2-week schedule of infusional 5-FU/LV. Weekly and once-every-3-week dosage schedules were used for the single-agent irinotecan studies. Clinical studies of combination and single-agent use are described below.
Metastatic Colorectal Cancer
First Line Therapy in Combination with 5-FU/LV: Studies 1 and 2
Two phase 3, randomized, controlled, multinational clinical trials support the use of CAMPTOSAR Injection as first-line treatment of patients with metastatic carcinoma of the colon or rectum. In each study, combinations of irinotecan with 5-FU and LV were compared with 5FU and LV alone. Study 1 compared combination irinotecan/bolus 5-FU/LV therapy given weekly with a standard bolus regimen of 5-FU/LV alone given daily for 5 days every 4 weeks; an irinotecan-alone treatment arm given on a weekly schedule was also included. Study 2 evaluated two different methods of administering infusional 5-FU/LV, with or without irinotecan. In both studies, concomitant medications such as antiemetics, atropine, and loperamide were given to patients for prophylaxis and/or management of symptoms from treatment. In Study 2, a 7-day course of fluoroquinolone antibiotic prophylaxis was given in patients whose diarrhea persisted for greater than 24 hours despite loperamide or if they developed a fever in addition to diarrhea. Treatment with oral fluoroquinolone was also initiated in patients who developed an absolute neutrophil count (ANC) < 500/mm³, even in the absence of fever or diarrhea. Patients in both studies also received treatment with intravenous antibiotics if they had persistent diarrhea or fever or if ileus developed.
In both studies, the combination of irinotecan/5-FU/LV therapy resulted in significant improvements in objective tumor response rates, time to tumor progression, and survival when compared with 5-FU/LV alone. These differences in survival were observed in spite of second-line therapy in a majority of patients on both arms, including crossover to irinotecan-containing regimens in the control arm. Patient characteristics and major efficacy results are shown in Table 10.
Table 10: Combination Dosage Schedule: Study Results
|Study 1||Study 2|
|Irinotecan + Bolus 5-FU/LV weekly x 4 every 6 weeks||Bolus 5-FU/LV daily x 5 every 4 weeks||Irinotecan weekly x 4 every 6 weeks||rinotecan + Infusional 5-FU/LV||Infusional 5-FU/LV|
|Number of patients||231||226||226||198||187|
|Demographics and treatment administration|
|Median age in years (range)||62 (25-85)||61 (19-85)||61 (30-87)||62 (27-75)||59 (24-75)|
|Performance status (%)|
|Primary tumor (%)|
|Median time from diagnosis to randomization (months, range)||1.9(0-161)||1.7(0-203)||1.8(0.1-185)||4.5 (0-88)||2.7 (0-104)|
|Prior adjuvant 5-FU therapy (%)||89||92||90||74||76|
|Median duration of study treatmenta (months)||5.5||4.1||3.9||5.6||4.5|
|Median Relative Dose Intensity (%)a||72||—||75||87||—|
|Confirmed objective tumor||39||21||18||35||22|
|response rateb (%)||(p < 0.0001)c||(p < 0.005)c|
|Median time to tumor progressiond (months)||7.0||4.3||4.2||6.7||4.4|
|(p=0.004)d||(p < 0.001)d|
|Median survival (months)||14.8||12.6||12.0||17.4||14.1|
|(p < 0.05)d||(p < 0.05)d|
|aStudy 1: N=225 (irinotecan/5-FU/LV),N=219
(5-FU/LV),N=223 (irinotecan) Study 2: N=199 (irinotecan/5-FU/LV),N=186
bConfirmed ≥ 4 to 6 weeks after first evidence of objective response
Improvement was noted with irinotecan-based combination therapy relative to 5-FU/LV when response rates and time to tumor progression were examined across the following demographic and disease-related subgroups (age, gender, ethnic origin, performance status, extent of organ involvement with cancer, time from diagnosis of cancer, prior adjuvant therapy, and baseline laboratory abnormalities). Figures 1 and 2 illustrate the Kaplan-Meier survival curves for the comparison of irinotecan/5-FU/LV versus 5-FU/LV in Studies 1 and 2, respectively.
Figure 1: Survival
First-Line Irinotecan/5-FU/LV vs 5-FU/LV
Figure 2: Survival
First-Line Irinotecan/5-FU/LV vs 5-FU/LV
Second-Line Therapy After 5-FU-Based Treatment
4 Weekly Doses on a 6-Week Cycle: Studies 3, 4, and 5
Data from three open-label, single-agent, clinical studies, involving a total of 304 patients in 59 centers, support the use of CAMPTOSAR in the treatment of patients with metastatic cancer of the colon or rectum that has recurred or progressed following treatment with 5-FU-based therapy. These studies were designed to evaluate tumor response rate and do not provide information on effects on survival and disease-related symptoms. In each study, CAMPTOSAR was administered in repeated 6-week cycles consisting of a 90-minute intravenous infusion once weekly for 4 weeks, followed by a 2-week rest period. Starting doses of CAMPTOSAR in these trials were 100, 125, or 150 mg/m², but the 150-mg/m² dose was poorly tolerated (due to high rates of grade 4 late diarrhea and febrile neutropenia). Study 3 enrolled 48 patients and was conducted by a single investigator at several regional hospitals. Study 4 was a multicenter study conducted by the North Central Cancer Treatment Group. All 90 patients enrolled in Study 4 received a starting dose of 125 mg/m². Study 5 was a multicenter study that enrolled 166 patients from 30 institutions. The initial dose in Study 5 was 125 mg/m² but was reduced to 100 mg/m² because the toxicity seen at the 125-mg/m² dose was perceived to be greater than that seen in previous studies. All patients in these studies had metastatic colorectal cancer, and the majority had disease that recurred or progressed following a 5-FU-based regimen administered for metastatic disease. The results of the individual studies are shown in Table 11.
Table 11: Weekly Dosage
Schedule: Study Results
|Number of Patients||48||90||64||102|
|Starting Dose (mg/m²/week x 4)||125a||125||125||100|
|Demographics and Treatment Administration|
|Median Age in years (range)||63 (29-78)||63 (32-81)||61 (42-84)||64 (25-84)|
|Ethnic Origin (%)|
|Performance Status (%)|
|Primary Tumor (%)|
|Prior 5-FU Therapy (%)|
|For Metastatic Disease||81||66||73||68|
|≤ 6 months after Adjuvant||15||7||27||28|
|> 6 months after Adjuvant||2||16||0||2|
|Prior Pelvic/Abdominal Irradiation (%)|
|Duration of Treatment with CAMPTOSAR (median, months)||5||4||4||3|
|Relative Dose Intensityb (median %)||74||67||73||81|
|Confirmed Objective Response Rate (%)c (95% CI)||21 (9.3 - 32.3)||13 (6.3 - 20.4)||14 (5.5 - 22.6)||9 (3.3 - 14.3)|
Time to Response (median, months)
|Response Duration (median, months)||6.4||5.9||5.6||6.4|
|Survival (median, months)||10.4||8.1||10.7||9.3|
|1-Year Survival (%)||46||31||45||43|
|a Nine patients received 150 mg/m² as a starting dose; two (22.2%) responded to CAMPTOSAR.
bRelative dose intensity for CAMPTOSAR based on planned dose intensity of 100, 83.3, and 66.7 mg/m²/wk corresponding with 150, 125, and 100 mg/m² starting doses, respectively.
cConfirmed ≥ 4 to 6 weeks after first evidence of objective response.
In the intent-to-treat analysis of the pooled data across all three studies, 193 of the 304 patients began therapy at the recommended starting dose of 125 mg/m². Among these 193 patients, 2 complete and 27 partial responses were observed, for an overall response rate of 15.0% (95% Confidence Interval [CI], 10.0% to 20.1%) at this starting dose. A considerably lower response rate was seen with a starting dose of 100 mg/m². The majority of responses were observed within the first two cycles of therapy, but responses did occur in later cycles of treatment (one response was observed after the eighth cycle). The median response duration for patients beginning therapy at 125 mg/m² was 5.8 months (range, 2.6 to 15.1 months). Of the 304 patients treated in the three studies, response rates to CAMPTOSAR were similar in males and females and among patients older and younger than 65 years. Rates were also similar in patients with cancer of the colon or cancer of the rectum and in patients with single and multiple metastatic sites. The response rate was 18.5% in patients with a performance status of 0 and 8.2% in patients with a performance status of 1 or 2. Patients with a performance status of 3 or 4 have not been studied. Over half of the patients responding to CAMPTOSAR had not responded to prior 5-FU. Patients who had received previous irradiation to the pelvis responded to CAMPTOSAR at approximately the same rate as those who had not previously received irradiation.
Once-Every-3-Week Dosage Schedule
Single Arm Study: Study 6
Data from an open-label, single-agent, single-arm, multicenter, clinical study involving a total of 132 patients support a once every-3-week dosage schedule of irinotecan in the treatment of patients with metastatic cancer of the colon or rectum that recurred or progressed following treatment with 5-FU. Patients received a starting dose of 350 mg/m² given by 30-minute intravenous infusion once every 3 weeks. Among the 132 previously treated patients in this trial, the intent-to-treat response rate was 12.1% (95% CI, 7.0% to 18.1%).
Randomized Studies: Studies 7 and 8
Two multicenter, randomized, clinical studies further support the use of irinotecan given by the once-every-3-week dosage schedule in patients with metastatic colorectal cancer whose disease has recurred or progressed following prior 5-FU therapy. In Study 7, second-line irinotecan therapy plus best supportive care was compared with best supportive care alone. In Study 8, second-line irinotecan therapy was compared with infusional 5-FU-based therapy. In both studies, irinotecan was administered intravenously at a starting dose of 350 mg/m² over 90 minutes once every 3 weeks. The starting dose was 300 mg/m² for patients who were 70 years and older or who had a performance status of 2. The highest total dose permitted was 700 mg. Dose reductions and/or administration delays were permitted in the event of severe hematologic and/or nonhematologic toxicities while on treatment. Best supportive care was provided to patients in both arms of Study 7 and included antibiotics, analgesics, corticosteroids, transfusions, psychotherapy, or any other symptomatic therapy as clinically indicated. In both studies, concomitant medications such as antiemetics, atropine, and loperamide were given to patients for prophylaxis and/or management of symptoms from treatment. If late diarrhea persisted for greater than 24 hours despite loperamide, a 7-day course of fluoroquinolone antibiotic prophylaxis was given. Patients in the control arm of the Study 8 received one of the following 5-FU regimens: (1) LV, 200 mg/m² IV over 2 hours; followed by 5-FU, 400 mg/m² IV bolus; followed by 5-FU, 600 mg/m² continuous IV infusion over 22 hours on days 1 and 2 every 2 weeks; (2) 5-FU, 250 to 300 mg/m²/day protracted continuous IV infusion until toxicity; (3) 5FU, 2.6 to 3 g/m² IV over 24 hours every week for 6 weeks with or without LV, 20 to 500 mg/m²/day every week IV for 6 weeks with 2-week rest between cycles. Patients were to be followed every 3 to 6 weeks for 1 year.
A total of 535 patients were randomized in the two studies at 94 centers. The primary endpoint in both studies was survival. The studies demonstrated a significant overall survival advantage for irinotecan compared with best supportive care (p=0.0001) and infusional 5-FU-based therapy (p=0.035) as shown in Figures 3 and 4. In Study 7, median survival for patients treated with irinotecan was 9.2 months compared with 6.5 months for patients receiving best supportive care. In Study 8, median survival for patients treated with irinotecan was 10.8 months compared with 8.5 months for patients receiving infusional 5-FU-based therapy. Multiple regression analyses determined that patients' baseline characteristics also had a significant effect on survival. When adjusted for performance status and other baseline prognostic factors, survival among patients treated with irinotecan remained significantly longer than in the control populations (p=0.001 for Study 7 and p=0.017 for Study 8). Measurements of pain, performance status, and weight loss were collected prospectively in the two studies; however, the plan for the analysis of these data was defined retrospectively. When comparing irinotecan with best supportive care in Study 7, this analysis showed a statistically significant advantage for irinotecan, with longer time to development of pain (6.9 months versus 2.0 months), time to performance status deterioration (5.7 months versus 3.3 months), and time to > 5% weight loss (6.4 months versus 4.2 months). Additionally, 33.3% (33/99) of patients with a baseline performance status of 1 or 2 showed an improvement in performance status when treated with irinotecan versus 11.3% (7/62) of patients receiving best supportive care (p=0.002). Because of the inclusion of patients with non-measurable disease, intent-to-treat response rates could not be assessed.
Figure 3: Survival
Second-Line Irinotecan vs Best Supportive Care (BSC)
Figure 4: Survival
Second-Line Irinotecan vs Infusional 5-FU
Table 12: Once-Every-3-Week Dosage Schedule: Study
|Study 7||Study 8|
|Number of patients||189||90||127||129|
|Demographics and treatment administration|
|Median age in years (range)||59 (22-75)||62 (34-75)||58 (30-75)||58 (2575)|
|Performance status (%)|
|Primary tumor (%)|
|Prior 5-FU therapy (%)|
|For metastatic disease||70||63||58||68|
|As adjuvant treatment||30||37||42||32|
|Prior irradiation (%)||26||27||18||20|
|Duration of study treatment (median, months) (Log-rank test)||4.1||--||4.2 (p=0.02)||2.8|
|Relative dose intensity (median %)b||94||--||95||81-99|
|Survival (median, months) (Log-rank test)||9.2(p=0.0001)||6.5||10.8 (p=0.035)||8.5|
|aBSC = best supportive care
bRelative dose intensity for irinotecan based on planned dose intensity of 116.7 and 100 mg/m²/wk corresponding with 350 and 300 mg/m² starting doses, respectively.
In the two randomized studies, the EORTC QLQ-C30 instrument was utilized. At the start of each cycle of therapy, patients completed a questionnaire consisting of 30 questions, such as “Did pain interfere with daily activities?” (1 = Not at All, to 4 = Very Much) and “Do you have any trouble taking a long walk?” (Yes or No). The answers from the 30 questions were converted into 15 subscales, that were scored from 0 to 100, and the global health status subscale that was derived from two questions about the patient's sense of general well being in the past week. The results as summarized in Table 13 are based on patients' worst post-baseline scores. In Study 7, a multivariate analysis and univariate analyses of the individual subscales were performed and corrected for multivariate testing. Patients receiving irinotecan reported significantly better results for the global health status, on two of five functional subscales, and on four of nine symptom subscales. As expected, patients receiving irinotecan noted significantly more diarrhea than those receiving best supportive care. In Study 8, the multivariate analysis on all 15 subscales did not indicate a statistically significant difference between irinotecan and infusional 5-FU.
Table 13: EORTC QLQ-C30: Mean Worst Post-Baseline Scorea
|QLQ-C30 Subscale||Study 7||Study 8|
|Global health status||47||37||0.03||53||52||0.9|
|aFor the five functional subscales and global health status subscale, higher scores imply better functioning, whereas, on the nine symptom subscales, higher scores imply more severe symptoms. The subscale scores of each patient were collected at each visit until the patient dropped out of the study.|
NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193.
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Last reviewed on RxList: 8/9/2012
This monograph has been modified to include the generic and brand name in many instances.
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