VA Class:AN900
Irinotecan, a type I DNA topoisomerase inhibitor, is an antineoplastic agent.1, 2, 3, 6, 7, 9, 13
Irinotecan is commercially available in 2 types of formulations: conventional (nonencapsulated) and liposomal irinotecan hydrochloride.1, 65 The efficacy and safety of irinotecan for each indication is based on research and clinical experience using a specific formulation.1, 65
Combination Therapy for Colorectal Cancer
Conventional irinotecan hydrochloride is used as a component of first-line therapy in combination with fluorouracil and leucovorin for the treatment of metastatic carcinoma of the colon or rectum.1, 27, 36, 37
The current indication for use of conventional irinotecan in combination therapy for advanced colorectal cancer is based principally on data from 2 phase 3, multinational, randomized, controlled trials evaluating the combination of conventional irinotecan with fluorouracil and leucovorin compared with fluorouracil and leucovorin alone.1, 53, 54 In both studies, the addition of irinotecan to fluorouracil and leucovorin prolonged survival and increased objective response rate and time to tumor progression.1, 53, 54
In a randomized trial involving 3 treatment arms, combination therapy with conventional irinotecan and rapid IV (“bolus”) fluorouracil/leucovorin weekly for 4 weeks every 6 weeks was compared with a standard regimen of rapid IV (“bolus”) fluorouracil/leucovorin daily for 5 consecutive days every 4 weeks and with conventional irinotecan alone weekly for 4 weeks every 6 weeks.1, 54 Higher confirmed objective response rate (39 vs 21%), longer median time to disease progression (7 vs 4.3 months), and prolonged median survival (14.8 vs 12.6 months) were observed in patients receiving combination therapy with irinotecan and fluorouracil/leucovorin compared with fluorouracil/leucovorin alone.1, 54 This difference in survival with the triple-drug regimen was noted even though 56% of the patients receiving fluorouracil/leucovorin received an irinotecan-based regimen after the conclusion of the study.54 Outcome was similar for patients receiving irinotecan alone compared with fluorouracil/leucovorin.1, 54 Grade 3 diarrhea and grade 3 or 4 vomiting occurred more frequently in patients receiving the irinotecan-containing combination regimen, whereas grade 3 or 4 mucositis, grade 4 neutropenia, and neutropenic fever were more common in patients receiving fluorouracil/leucovorin.54 No difference between the irinotecan-combination and fluorouracil/leucovorin treatment groups was observed in a quality-of-life analysis, and the incidence of treatment-related mortality was approximately 1% in each of the 3 groups.54
In another randomized trial, the addition of conventional irinotecan to infusional fluorouracil/leucovorin increased objective response rate (35 vs 22%), median time to disease progression (6.7 vs 4.4 months) and median survival (17.4 vs 14.1 months).1, 53 Diarrhea, neutropenia, leukopenia, and asthenia occurred with greater frequency and severity in patients receiving irinotecan-based combination chemotherapy compared with those receiving fluorouracil/leucovorin alone.53
Higher rates of hospitalization, neutropenic fever, thromboembolism, treatment discontinuance during the first cycle, and early deaths were associated with a baseline performance status of 2 (vs 0 or 1) regardless of treatment regimen.1 Diarrhea and neutropenia occurred frequently and were often severe in patients receiving irinotecan-based combination therapy or fluorouracil/leucovorin alone;1, 53, 54 comparison of data from the randomized trial including a group of patients receiving irinotecan alone reveals that nausea, vomiting, and alopecia each occurs at a higher incidence or with greater severity in patients receiving irinotecan, whereas neutropenic fever and mucositis are more commonly associated with fluorouracil/leucovorin.1, 54
The optimal dosage regimen for conventional irinotecan-based combination therapy has not been established.55, 56 An unexpectedly high rate of death associated with use of the conventional irinotecan and rapid IV (“bolus”) fluorouracil/leucovorin regimen (3 times the rate of death in the comparative regimens) resulted in the suspension of enrollment in 2 randomized trials (one for metastatic colon cancer and one for adjuvant treatment of resectable colon cancer).55, 56 Most of the deaths occurred during or immediately after the first 6-week cycle of treatment, particularly during the first 3-4 weeks, and were attributed to the combined effect of several moderate or severe toxicities described either as a GI syndrome or as a vascular syndrome.55, 56 (See GI Toxicity and Cardiovascular Toxicity under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration.) A direct comparison of the safety and efficacy of the 2 regimens has not been performed; however, lower rates of treatment-related mortality have been reported when fluorouracil was administered by IV infusion.55, 56, 58
Monotherapy for Colorectal Cancer
Conventional irinotecan hydrochloride is used as a single agent for the treatment of metastatic carcinoma of the colon or rectum in patients whose disease has recurred or progressed following initial therapy with fluorouracil-based antineoplastic regimens.1, 2, 3, 8, 11, 17, 18, 19, 28, 32, 33, 36, 37 The drug originally became commercially available in the US under the principles and procedures of the FDA's accelerated review policy that allows approval based on effects on a clinical endpoint (e.g., tumor shrinkage) other than survival, irreversible morbidity, or quality of life pending completion of studies to establish and define the degree of clinical benefit.22, 23, 24, 25, 26 Conventional irinotecan received full approval following the completion of randomized trials demonstrating prolonged survival in patients receiving the drug for this use.35
Evidence of clinical benefit of conventional irinotecan is based principally on data from 2 randomized trials in which conventional irinotecan 300-350 mg/m2 was administered once every 3 weeks1, 32, 33 and in 3 phase 2 trials in which conventional irinotecan 125 mg/m2 was administered once weekly for 4 weeks followed by a 2-week rest period.1, 3, 17, 18, 19 In 2 randomized trials involving a total of 535 patients with metastatic carcinoma of the colon or rectum that recurred or progressed following fluorouracil-containing chemotherapy, survival was prolonged in those receiving conventional irinotecan compared with those receiving fluorouracil or supportive care.1, 32, 33
In a randomized trial of patients with metastatic colorectal cancer that progressed within 6 months following treatment with fluorouracil, patients receiving conventional irinotecan 300-350 mg/m2 as a single 90-minute infusion once every 3 weeks and supportive care had longer median survival (9.2 vs 6.5 months) than those receiving supportive care alone.1, 33 Patients receiving irinotecan had longer time to development of pain (6.9 vs 2 months), longer time to deterioration of performance status (5.7 vs 3.3 months), and longer time to weight loss of 5% or greater (6.4 vs 4.2 months) compared with those receiving supportive care alone; although patients receiving irinotecan had a higher rate of diarrhea than those receiving supportive care alone, other quality-of-life measures were comparable or better for patients receiving the drug.1, 33 In addition, patients with a baseline performance status of 1 or 2 receiving irinotecan and supportive care or supportive care alone showed an improvement in performance status of 33.3 or 11.3%, respectively.1 Supportive care included the use of anti-infectives, analgesics, corticosteroids, transfusions, psychotherapy, or any other symptomatic therapy as clinically indicated, including palliative radiation therapy.1, 33 Approximately 21% of patients treated with irinotecan and supportive care also received other chemotherapy regimens, and 31% of patients treated with supportive care also received various chemotherapy regimens.1, 33, 34
In another randomized trial, patients with recurrent or refractory metastatic colorectal cancer receiving conventional irinotecan 300-350 mg/m2 as a single 90-minute IV infusion once every 3 weeks had longer median survival (10.8 vs 8.5 months) than those receiving fluorouracil by continuous IV infusion.1, 32 The rate of survival at 1 year was higher in patients receiving irinotecan compared with those receiving fluorouracil (45 vs 32%); the quality of life as assessed by the European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) was similar and both treatments were equally well tolerated.1, 32
In an open-label, single-agent, multicenter study involving 132 patients with metastatic cancer of the colon or rectum that recurred or progressed following therapy with fluorouracil-containing regimens, the intent-to-treat response rate was 12% in patients receiving conventional irinotecan at a starting dose of 350 mg/m2 administered by 30-minute IV infusion once every 3 weeks.1 In 3 phase 2 clinical trials, 304 patients with metastatic colorectal cancer who previously had been treated with a fluorouracil-containing antineoplastic regimen received conventional irinotecan 125 mg/m2 once weekly.1, 2, 3, 7, 8, 17, 18, 19, 28 These open-label, single-agent trials evaluated the surrogate endpoint of tumor response rate and did not provide information on actual clinical benefit (e.g., decrease in disease-related symptoms, increase in survival) of irinotecan therapy.1, 2, 8, 17, 18, 19 Patients received irinotecan in repeated 6-week cycles, each cycle consisting of once-weekly, 90-minute IV infusions of irinotecan for 4 weeks followed by a 2-week drug-free period.1, 2, 3, 7, 8, 16, 17, 18, 19 In one trial, an initial weekly irinotecan hydrochloride dose of 150 mg/m2 was administered to a few patients; however, these patients developed unacceptably high rates of severe diarrhea, dehydration, and febrile neutropenia, and subsequent patients in the trial received an initial dose of 125 mg/m2.1, 2, 3, 17, 22 In another trial, the initial dose of irinotecan hydrochloride was reduced from 125 to 100 mg/m2 to evaluate the therapeutic ratio of this initial dose.18, 22 In these trials, 34, 63, or 3% of patients received initial irinotecan hydrochloride doses of 100, 125, or 150 mg/m2, respectively.7
Intent-to-treat analysis of the pooled data from the 3 trials revealed an overall response rate of 15% (2 complete and 27 partial responses) among patients who received the recommended initial conventional irinotecan hydrochloride dose of 125 mg/m2;1, 7, 17, 18, 19 however, the response rate was only 7.8% among patients who received an initial dose of 100 mg/m2.1, 2, 18 More than 50% of patients responding to irinotecan in these trials had failed to respond to previous fluorouracil-based regimens administered for colorectal cancer with metastases.1, 17, 18, 19 The median response duration for patients receiving an initial irinotecan hydrochloride dose of 125 mg/m2 was 5.8 months (range: 2.6-15.1 months).1, 2, 17, 18, 19, 28 Among patients with disease responding to irinotecan, all but 2 patients achieved responses by the second 6-week cycle of irinotecan therapy; one response was observed by the fourth and one after the eighth cycle of therapy.1, 2
Among patients receiving irinotecan on a weekly dosage schedule in phase 2 trials, response rates were similar regardless of gender, age (greater than or less than 65 years), primary cancer site (colon or rectum), history of previous pelvic radiation therapy, or number of metastatic lesions (single or multiple).1, 17, 18, 19 The response rate among patients with a performance status of zero (i.e., fully active; able to perform all predisease activities without restriction) was 18.5%, while the response rate among those with a performance status of 1 (i.e., restricted in physically strenuous activity but ambulatory and able to perform work of a light or sedentary nature [e.g., light housework, office work]) or 2 (i.e., ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours) was 8.2%.1, 17, 18, 19 Patients with a performance status of 3 or 4 have not been studied.1
Liposomal irinotecan hydrochloride is used in combination with fluorouracil and leucovorin for the treatment of metastatic adenocarcinoma of the pancreas in patients whose disease has progressed following gemcitabine-based chemotherapy;65, 68 liposomal irinotecan is designated an orphan drug by FDA for the treatment of this cancer.67
The current indication for use of liposomal irinotecan in combination therapy with fluorouracil and leucovorin for the treatment of metastatic adenocarcinoma of the pancreas in patients whose disease has progressed following gemcitabine-based chemotherapy is based principally on data from a randomized, controlled, open-label phase 3 study (NAPOLI-1).65, 68 In patients with previously treated metastatic adenocarcinoma of the pancreas, liposomal irinotecan has been shown to prolong overall survival compared with fluorouracil and leucovorin alone.65
In this study, 417 patients were randomized in a 1:1:1 ratio to receive liposomal irinotecan (70 mg/m2 by IV infusion over 90 minutes) in combination with fluorouracil and leucovorin (leucovorin 400 mg/m2 by IV infusion over 30 minutes followed by fluorouracil 2.4 g/m2 by IV infusion over 46 hours) administered every 2 weeks, liposomal irinotecan (100 mg/m2 by IV infusion over 90 minutes) administered every 3 weeks, or fluorouracil and leucovorin (leucovorin 200 mg/m2 by IV infusion over 30 minutes followed by fluorouracil 2 g/m2 by IV infusion over 24 hours) administered on days 1, 8, 15, and 22 of each 6-week cycle.65, 68 The initial dosage of liposomal irinotecan was reduced by 20 mg/m2 in patients who were homozygous for the UGT1A1*28 allele; however, the dose was increased to the full dosage following the first cycle if adverse events did not occur.68 Treatment was continued until disease progression or unacceptable toxicity occurred.65, 68 The primary measure of efficacy was overall survival.65, 68 The median age of patients was 63 years; 53% had a baseline Karnofsky performance status of 90-100, 67% had liver metastasis, and 31% had lung metastasis.65, 68 All patients enrolled in the study had received prior therapy with gemcitabine; 54% had received prior therapy with gemcitabine in combination with another agent, and 13% had received prior therapy with gemcitabine in combination with albumin-bound paclitaxel.65
In this study, patients randomized to receive liposomal irinotecan in combination with fluorouracil and leucovorin had longer median overall survival (6.1 versus 4.2 months) and progression-free survival (3.1 versus 1.5 months) compared with patients receiving fluorouracil and leucovorin alone; however, improvement in overall survival was not demonstrated in patients receiving liposomal irinotecan alone compared with those receiving fluorouracil and leucovorin (4.9 versus 4.2 months, respectively).65, 68 In addition, patients receiving liposomal irinotecan in combination with fluorouracil and leucovorin had a higher overall response rate compared with those receiving fluorouracil and leucovorin alone (7.7 versus 0.8%, respectively).65 Results of a subgroup analysis (based on age, disease stage, Karnofsky performance status, baseline albumin concentration, previous lines of therapy for metastatic disease, prior exposure to radiation therapy or surgery, prior exposure to fluorouracil-, irinotecan-, or platinum-based chemotherapy) suggested that the drug's effect on overall survival was consistent across most subgroups.68
Conventional irinotecan is used in combination with cisplatin for the initial treatment of extensive small cell lung cancer†.27, 46
A phase 3, randomized trial was terminated early when interim analysis of the data showed that median overall survival was prolonged (12.8 versus 9.4 months) and the rate of survival at 2 years was higher (19.5 versus 5.2%) in patients receiving irinotecan and cisplatin versus etoposide and cisplatin for extensive small cell lung cancer.61 Patients received a regimen of conventional irinotecan 60 mg/m2 on days 1, 8, and 15 and cisplatin 60 mg/m2 on day 1 during a 4-week cycle for 4 cycles; or a regimen of etoposide 100 mg/m2 on days 1, 2, and 3 and cisplatin 80 mg/m2 on day 1 during a 3-week cycle for 4 cycles.61 Severe or life-threatening diarrhea occurred more frequently in patients receiving irinotecan and cisplatin, whereas severe or life-threatening myelosuppression occurred more frequently in those receiving etoposide and cisplatin.61 Interim analysis of another randomized trial using a modified irinotecan-containing regimen suggests that overall survival is similar in patients receiving a regimen of either irinotecan and cisplatin or etoposide and cisplatin.62
In phase 2 studies, objective response rates of 16-47% have been observed in patients receiving conventional irinotecan alone, typically at initial doses of 100-125 mg/m2 infused IV over a period of 90 minutes once weekly, for refractory or relapsed small cell lung cancer.40, 41, 42 Higher doses of irinotecan are associated with increased frequency and severity of adverse effects, particularly neutropenia.41
Because the current prognosis for small cell lung cancer is unsatisfactory regardless of stage and despite considerable diagnostic and therapeutic advances, all patients with this cancer are candidates for inclusion in clinical trials at the time of diagnosis.46
Conventional irinotecan is being investigated as an active agent in the treatment of metastatic or recurrent cervical cancer†.27, 47, 48, 49, 50, 51 Objective response rates of 13-21% have been reported with use of irinotecan as a single agent for advanced squamous cell carcinoma of the cervix.48, 49 Although no responses to irinotecan were observed in one small uncontrolled phase 2 study of patients with platinum-resistant advanced squamous cell carcinoma of the cervix,50 responses to the drug have been reported in similar patients in another phase 2 study.49, 52 The benefit of combination chemotherapy regimens vs single-agent therapy (e.g., cisplatin alone) has not been fully established, and further study is needed to determine the role of irinotecan in the treatment of advanced cervical cancer.48, 49, 50, 51, 52 (See Uses: Cervical Cancer in Cisplatin 10:00 for an overview of therapy for cervical cancer.)
Irinotecan is commercially available in 2 types of formulations: conventional (nonencapsulated) and liposomal irinotecan hydrochloride.1, 65 The properties of irinotecan may differ according to formulation, and the dosage and reconstitution instructions for irinotecan are specific to formulation.1, 65 Liposomal irinotecan hydrochloride may not be substituted for other formulations of irinotecan hydrochloride.65
Dosage of liposomal irinotecan hydrochloride is expressed in terms of anhydrous irinotecan,65, 69 whereas dosage of conventional irinotecan hydrochloride is expressed in terms of the hydrated salt.1
In addition to GI and hematologic toxicity, other severe adverse effects have occurred in patients receiving conventional or liposomal irinotecan.1, 65 Hypersensitivity reactions, including severe anaphylactic or anaphylactoid reactions, have been reported.1, 65 Renal impairment and acute renal failure have occurred, usually in patients who became volume-depleted from severe vomiting and/or diarrhea.1, 65 Cardiovascular and thromboembolic events also have been reported in patients receiving conventional irinotecan.1, 56 (See Cardiovascular Toxicity under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration.)
The manufacturer of conventional irinotecan recommends close monitoring in patients older than 65 years of age because of increased risk of treatment-related toxicity, such as early and late diarrhea, during therapy with conventional irinotecan.1, 56 Patients receiving conventional irinotecan/fluorouracil/leucovorin therapy should be monitored closely (e.g., weekly assessment), particularly during the first cycle of treatment, since most of the treatment-related toxicities leading to early death occurred within the first 3-4 weeks.56 Changes in serum electrolytes and/or acid-base balance, including hyponatremia or hypernatremia, hypokalemia, and/or metabolic acidosis, may be an early indication of treatment-related toxicity; patients with abnormalities in serum sodium, potassium, and/or bicarbonate concentrations, with or without concomitant elevations in BUN or serum creatinine concentrations, should be evaluated carefully for dehydration and receive aggressive medical management, including fluid and electrolyte replacement.56
Liposomal irinotecan hydrochloride can only be obtained through select specialty distributors.66 Clinicians may consult the Onivyde® website for specific availability information ([Web]).66
Conventional or liposomal irinotecan hydrochloride is administered by IV infusion.1, 65 Care should be taken to avoid extravasation of conventional irinotecan, and the infusion site should be monitored for signs of inflammation.1, 22 Should manifestations of extravasation appear, the infusion should immediately be stopped and restarted in another vein.22 The manufacturer of conventional irinotecan recommends that extravasation of the drug be treated by flushing the infusion site promptly with sterile water and applying an ice pack.1
Procedures for proper handling and disposal of antineoplastic drugs (e.g., use of protective clothing and gloves) should be used to avoid exposure to conventional or liposomal irinotecan during preparation of IV solutions.1, 65 If conventional irinotecan hydrochloride for injection concentrate or a solution of the drug comes in contact with the skin or mucous membranes, the skin should be washed immediately and thoroughly with soap and water or the mucosa should be flushed with copious amounts of water.1
Conventional Irinotecan Hydrochloride
Commercially available conventional irinotecan hydrochloride for injection concentrate must be diluted prior to IV administration. 1, 22 For IV infusion, the manufacturer recommends diluting the drug in 5% dextrose injection to a final irinotecan hydrochloride concentration of 0.12-2.8 mg/mL.1 In most clinical trials, the dose of conventional irinotecan hydrochloride was diluted in 250-500 mL of 5% dextrose injection.3, 16, 17, 18, 19 The manufacturer states that although 5% dextrose injection is the preferred diluent, 0.9% sodium chloride injection also may be used for dilution of conventional irinotecan.1 The diluted solution of conventional irinotecan should be infused over a period of 90 minutes;1 more rapid infusion rates may increase the likelihood of cholinergic symptoms (e.g., early diarrhea, diaphoresis, flushing, abdominal cramping, rhinitis, increased salivation, miosis, lacrimation).22
Solutions of conventional irinotecan hydrochloride prepared in 5% dextrose injection are physically and chemically stable for up to 24 hours when stored at room temperature (approximately 25°C) under ambient fluorescent lighting or for up to 48 hours when protected from light and refrigerated at 2-8°C.1 For conventional irinotecan hydrochloride solutions prepared in 5% dextrose injection, the manufacturer recommends administration of such drug solutions within 24 hours if refrigerated or within 4 hours if maintained at room temperature because of the potential for microbial contamination during preparation of the admixtures; however, if dilution is performed under strict aseptic conditions (e.g., under laminar airflow conditions), administration of solutions prepared in 5% dextrose injection and stored at room temperature should be completed within 12 hours.1 Solutions of conventional irinotecan hydrochloride prepared in 0.9% sodium chloride are stable for up to 24 hours when stored at room temperature (approximately 25°C) under ambient fluorescent lighting.1, 2 The manufacturer states that solutions of conventional irinotecan hydrochloride prepared in 0.9% sodium chloride may occasionally develop visible particulates when refrigerated at 2-8°C; therefore, solutions prepared in sodium chloride injection should not be refrigerated but should be stored at room temperature and used within 4 hours.1 However, if dilution is performed under strict aseptic conditions (e.g., under laminar airflow conditions), administration of solutions prepared in 0.9% sodium chloride injection and stored at room temperature should be completed within 12 hours.1 Freezing of commercially available conventional irinotecan hydrochloride for injection concentrate or IV admixtures of the drug may result in formation of a precipitate and should be avoided.1
Conventional irinotecan hydrochloride for injection concentrate should be inspected visually for particulate matter in the vial and again in the syringe when transferring the drug solution to prepare admixtures of the drug.1 The manufacturer states that other drugs should not be added to IV solutions of conventional irinotecan hydrochloride.1
Liposomal Irinotecan Hydrochloride
Liposomal irinotecan hydrochloride for injection concentrate must be diluted prior to IV infusion. 65 The concentrate should be diluted in 500 mL of 5% dextrose injection or 0.9% sodium chloride injection.65 The diluted solution of liposomal irinotecan should be infused over a period of 90 minutes.65 The manufacturer states that in-line filters should not be used during administration of liposomal irinotecan hydrochloride.65 Any unused solution should be discarded.65
Solutions of liposomal irinotecan hydrochloride should be administered within 24 hours of preparation when stored under refrigeration at 2-8°C or within 4 hours when stored at room temperature.65 The diluted drug should be protected from light and should not be frozen.65 Prior to administration, the diluted solution should be allowed to come to room temperature.65
Because irinotecan often causes neutropenia, leukopenia, and anemia, which can be severe, the drug should not be used in patients with severe bone marrow failure.63 In addition, concurrent radiation therapy has not been adequately studied and is not recommended.1 Because conventional irinotecan hydrochloride for injection concentrate contains sorbitol, the drug should not be given to patients with hereditary fructose intolerance.63 Treatment with conventional or liposomal irinotecan should not be initiated until resolution of bowel obstruction.1, 65
Irinotecan is considered an antineoplastic agent of moderate emetic risk (i.e., incidence of emesis without antiemetics exceeds 30% but does not exceed 90%).64 Because nausea and/or vomiting occur frequently in patients receiving irinotecan therapy and may be severe, effective antiemetic therapy (e.g., dexamethasone 8 mg and a 5-HT3 serotonin receptor antagonist such as palonosetron) should be administered orally or IV at least 30 minutes prior to irinotecan therapy.1, 7, 8, 22, 28, 64, 65 Additional oral antiemetic therapy also should be considered for subsequent home use by the patient as needed.1, 22, 64 Unless clinically contraindicated, clinicians should consider prophylactic or therapeutic administration of antimuscarinic therapy (e.g., 0.25-1 mg of atropine sulfate by IV or subcutaneous injection) for patients experiencing rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, bradycardia, abdominal cramping, or early diarrhea (i.e., diarrhea with an onset during or shortly after [within 24 hours of] administration of irinotecan);1, 65 such symptoms are expected to occur more frequently in patients receiving higher doses of irinotecan.1, 8, 22, 28
Dosage adjustment may be required according to the patient's status for activity of UGT1A1, a uridine diphosphate-glucuronosyltransferase (UGT) enzyme involved in the metabolism of SN-38, an active metabolite of irinotecan.1, 65 In patients who are homozygous for the UGT1A1*28 allele, UGT1A1 activity is reduced, and the risk of irinotecan-induced neutropenia is increased; reduction in the initial dosage of conventional irinotecan by at least one dose level should be considered in such patients.1 The optimal dosage reduction for conventional irinotecan has not been established, and subsequent dosage adjustment may be necessary according to patient tolerance.1 The recommended initial dose of liposomal irinotecan in patients with metastatic adenocarcinoma of the pancreas who are homozygous for the UGT1A1*28 allele is 50 mg/m2; the dose may be increased to 70 mg/m2 as tolerated during subsequent cycles.65 In patients who are heterozygous for the UGT1A1*28 allele, UGT1A1 activity is intermediate, and the risk of irinotecan-induced neutropenia may be increased.1 Clinical results have been variable with conventional irinotecan.1
Inadvertent overdosage of conventional irinotecan has occurred in several patients, including at least one fatal case, because the manufacturer's label on the vial was misread.31 Therefore, particular care should be taken to ensure that the correct dose of the drug is administered, including careful attention to the concentration of conventional irinotecan for injection concentrate present in the vial and the appropriate volume needed to provide the prescribed dose.31
Patients should be instructed to contact their clinician if any of the following occur during irinotecan therapy: diarrhea for the first time during treatment; black or bloody stools; symptoms of dehydration, such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth because of nausea or vomiting; inability to control diarrhea within 24 hours; new-onset cough or dyspnea; manifestations of severe hypersensitivity reactions; or fever or evidence of infection.1, 65 Patients should be warned about the potential for dizziness or visual disturbances that may occur within 24 hours following the administration of conventional irinotecan and be advised not to drive or operate machinery if these symptoms occur.1, 63 Patients also should be alerted to the possibility of alopecia during conventional or liposomal irinotecan therapy.1, 65
For use in a combination regimen as first-line therapy for metastatic carcinoma of the colon or rectum, conventional irinotecan is administered with leucovorin and fluorouracil.1 For all regimens, the dose of leucovorin should be administered immediately following conventional irinotecan, and then followed immediately by administration of fluorouracil.1 The optimal dosage regimen for conventional irinotecan-based combination therapy has not been established; an unexpectedly high rate of death has been reported in 2 clinical trials using irinotecan with fluorouracil given by rapid IV injection (“bolus”), and some clinicians prefer administration of fluorouracil by IV infusion in this regimen.55, 56 (See Combination Therapy for Colorectal Cancer in Uses: GI Cancers.)
In regimen 1, the initial dose of conventional irinotecan hydrochloride is 125 mg/m2 infused IV over a period of 90 minutes followed by leucovorin 20 mg/m2 given by rapid IV injection and then fluorouracil 500 mg/m2 given by rapid IV injection (“bolus”).1, 54 Treatment is given weekly for 4 weeks on days 1, 8, 15, and 22 during a 6-week cycle; the next cycle begins on day 43.1
In regimen 2, the initial dose of conventional irinotecan hydrochloride is 180 mg/m2 infused IV over a period of 90 minutes followed by leucovorin 200 mg/m2 infused IV over 2 hours, then fluorouracil 400 mg/m2 by rapid IV injection (“bolus”), and then fluorouracil 600 mg/m2 infused IV over 22 hours.1, 53 Treatment is given during a 6-week cycle with administration of conventional irinotecan on days 1, 15, and 29, and administration of the leucovorin and fluorouracil (rapid IV injection [“bolus”] and infusional) component of the regimen on days 1, 2, 15, 16, 29, and 30, with the next cycle beginning on day 43.1
Patients who have received prior pelvic or abdominal radiation therapy, who have a performance status of 2, or who have modestly elevated baseline total serum bilirubin concentrations (i.e., 1-2 mg/dL) are at increased risk for irinotecan-induced toxicity such as grade 3 or 4 neutropenia; the manufacturer states that reduction of the initial dose of conventional irinotecan hydrochloride by one dose level (e.g., to 100 mg/m2 for regimen 1 or to 150 mg/m2 for regimen 2) should be considered in such patients.1 The manufacturer states that specific dosage recommendations for conventional irinotecan for patients with baseline total serum bilirubin concentrations exceeding 2 mg/dL currently are not available.1
During a cycle of therapy or when initiating a subsequent cycle of therapy, the dose level should be reduced as necessary based on modification for toxicity.1 (See Table 1 and Table 2.) Further reductions in dose level in decrements of 20% may be warranted in patients who continue to experience toxicity.1 Unless intolerable toxicity develops, treatment with additional cycles may be administered every 6 weeks in patients who continue to experience clinical benefit.1
| Initial Dosage and Dosage Modifications for Combination Therapy (mg/m2) |
|
|
|---|---|---|---|
Regimen/Agent | Initial Dosage | Reduced Dosage Level 1 | Reduced Dosage Level 2 |
Regimen 1 a |
|
|
|
Irinotecan hydrochloride | 125 | 100 | 75 |
Leucovorin | 20 | 20 | 20 |
Fluorouracil | 500 | 400 | 300 |
Regimen 2 b |
|
|
|
Irinotecan hydrochloride | 180 | 150 | 120 |
Leucovorin | 200 | 200 | 200 |
Fluorouracil bolus | 400 | 320 | 240 |
Fluorouracil infusion | 600 | 480 | 360 |
aTreatment on days 1, 8, 15, and 22.
bAdministration of irinotecan on days 1, 15, and 29, and administration of leucovorin, bolus fluorouracil, and infusional fluorouracil on days 1, 2, 15, 16, 29, and 30.
Outside of a well-designed clinical trial, irinotecan should not be used in combination with the “Mayo clinic” regimen of rapid IV injection (“bolus”) fluorouracil/leucovorin (i.e., administration for 4-5 consecutive days every 4 weeks) because of increased toxicity, including deaths.1
For the treatment of metastatic carcinoma of the colon or rectum in patients whose disease has recurred or progressed following fluorouracil-based antineoplastic therapy, conventional irinotecan may be administered on a weekly dosage schedule or once every 3 weeks with doses specific to the selected dosage schedule.1
The recommended initial dose of conventional irinotecan hydrochloride as a single agent for the treatment of metastatic carcinoma of the colon or rectum in patients receiving the drug on a weekly dosage schedule is 125 mg/m2 infused IV over a period of 90 minutes.1, 3, 7, 8, 28 The dose of conventional irinotecan is administered once weekly for 4 weeks followed by a 2-week rest period.1, 3, 7, 8, 17, 18, 19, 22 Additional cycles (i.e., weekly doses for 4 weeks followed by a 2-week rest period) may be administered every 6 weeks in patients who attain a response or whose disease remains stable, provided intolerable toxicity does not develop.1, 7, 8
The recommended initial dose of conventional irinotecan hydrochloride for the treatment of metastatic carcinoma of the colon or rectum in patients receiving the drug once every 3 weeks is 350 mg/m2 infused IV over a period of 90 minutes.1 The dose of conventional irinotecan is administered once every 3 weeks for as long as intolerable toxicity does not occur and the patient continues to experience clinical benefit.1
Patients who have received prior pelvic or abdominal radiation therapy, who have a performance status of 2, or who have modestly elevated baseline total serum bilirubin concentrations (i.e., 1-2 mg/dL) are at increased risk for irinotecan-induced toxicity such as grade 3 or 4 neutropenia; the manufacturer states that reduction of the initial dose of conventional irinotecan hydrochloride by one dose level (e.g., to 100 mg/m2 for the weekly dosage schedule or to 300 mg/m2 for the once-every-3-weeks dosage schedule) should be considered in such patients.1 A reduced initial dose of 300 mg/m2 also is recommended for patients 70 years of age or older who are receiving the once-every-3-weeks dosage schedule of conventional irinotecan hydrochloride; however, the manufacturer states that geriatric patients receiving the weekly dosage schedule of conventional irinotecan may receive the usual initial dose of the drug.1 Reduction in the initial dose of conventional irinotecan may be considered in patients with baseline total serum bilirubin concentrations exceeding 2 mg/dL;38 the manufacturer states that specific dosage recommendations for conventional irinotecan for such patients currently are not available.1
For use in a combination regimen for metastatic adenocarcinoma of the pancreas that has progressed following gemcitabine-based therapy, liposomal irinotecan is administered with leucovorin and fluorouracil.65 Liposomal irinotecan is not indicated as a single agent for the treatment of metastatic adenocarcinoma of the pancreas.65
The recommended initial dose of liposomal irinotecan is 70 mg/m2 infused IV over a period of 90 minutes followed by leucovorin 400 mg/m2 infused IV over 30 minutes and then fluorouracil 2.4 g/m2 infused IV over 46 hours.65 Treatment is repeated every 2 weeks.65
The manufacturer makes no specific dosage recommendations for liposomal irinotecan for patients with total serum bilirubin concentrations exceeding the upper limit of normal (ULN).65
Dosage Modification for Toxicity and Contraindications for Continued Therapy
Dosage of conventional or liposomal irinotecan should be modified as necessary based on individual patient tolerance; the patient should be monitored carefully to obtain optimum therapeutic response with minimum adverse effects.1, 7, 8, 17, 18, 19, 22, 65 Among those receiving conventional or liposomal irinotecan-based combination therapy, doses of fluorouracil also should be modified as necessary based on individual patient tolerance.1, 65
The manufacturer states that a new cycle of conventional irinotecan therapy should not be undertaken until the granulocyte count has recovered to at least 1500/mm3, the platelet count has recovered to at least 100,000/mm3, and treatment-related diarrhea has fully resolved.1 If the patient experiences multiple toxicities, adjustment of conventional irinotecan hydrochloride dose within a cycle of therapy and prior to starting a new cycle of therapy should be based on the preceding toxicity requiring the largest dose reduction.1, 17, 18, 19 Treatment should be delayed for 1-2 weeks to allow for recovery from treatment-related toxicities.1 If the patient experiences an irinotecan-induced toxicity that does not resolve after delaying drug administration for 2 weeks, discontinuance of the drug should be considered.1
Among patients receiving conventional irinotecan as a single agent, initial doses of conventional irinotecan hydrochloride are based on body surface area alone, but subsequent doses within a cycle of therapy or for a new cycle of therapy in patients receiving the drug on a weekly dosage schedule should be adjusted in increments of 25-50 mg/m2 to a dose within the range of 50-150 mg/m2 based on the worst toxicity encountered with the previous dose of conventional irinotecan;1, 7, 17, 18, 19, 22 subsequent doses for a new cycle of therapy in patients receiving the drug once every 3 weeks should be decreased in increments of 50 mg/m2 to a dose as low as 200 mg/m2 based on the worst toxicity encountered with the previous dose of conventional irinotecan.1 If the patient experiences no toxicity within a cycle of therapy using the once-every-3-weeks dosage schedule, the current conventional irinotecan hydrochloride dose should be maintained for the subsequent cycle of therapy.1, 15, 18, 19 If the patient experiences no toxicity during an entire 6-week cycle of therapy using the weekly dosage schedule, the dose of conventional irinotecan hydrochloride may be increased by 25 mg/m2 at the start of the next cycle; however, the dose should not exceed 150 mg/m2.1, 17, 18, 19
The Recommended Dosage Modifications tables (Tables 2-4) describe recommended modifications in conventional irinotecan hydrochloride dose based on commonly observed toxicities of the drug for patients receiving combination or single-agent therapy with the drug.1 The dose-limiting toxicities of conventional irinotecan are diarrhea and neutropenia.1, 2, 16, 17, 18, 19, 21, 27, 28
Recommended dosage modifications for liposomal irinotecan based on observed toxicities of the drug are described in the following sections on specific types and severities of toxicity.
For a more complete discussion of dosage modifications, cautions, and precautions associated with conventional or liposomal irinotecan therapy, the respective manufacturer's labeling should be consulted.1, 65
Conventional or liposomal irinotecan may induce both early and late forms of diarrhea, both of which may be severe.1, 2, 16, 17, 18, 19, 27, 28, 65 Early diarrhea (occurring during or within 24 hours of administration of conventional or liposomal irinotecan) is cholinergic in nature and generally is transient; diarrhea may be accompanied by diaphoresis, flushing, rhinitis, increased salivation, miosis, lacrimation, bradycardia, and abdominal cramping and may be prevented or ameliorated by administration of atropine sulfate (e.g., 0.25-1 mg by IV or subcutaneous injection) unless administration of the drug is clinically contraindicated.1, 28, 65 Late diarrhea (occurring more than 24 hours after administration of conventional or liposomal irinotecan) can be life-threatening since it may be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis.1, 65
Patients receiving conventional irinotecan in combination with rapid IV (“bolus”) fluorouracil/leucovorin have experienced early death induced or exacerbated by treatment-related GI toxicity, typically during or immediately following the first cycle of treatment.56 This GI syndrome is manifested by diarrhea, nausea, vomiting, anorexia, and abdominal cramping, and is often associated with severe dehydration, neutropenia, fever, and electrolyte abnormalities.56 Radiographic findings include dilated bowel, air-fluid levels without anatomic obstruction, and thickened bowel wall.56 An independent panel of clinicians that reviewed the causes of these early deaths has recommended close monitoring and prompt, aggressive treatment of toxicity in conjunction with treatment discontinuance in patients experiencing unresolved drug-related toxicity.56
Late diarrhea, as an isolated event or as part of the GI syndrome, should be treated promptly with intensive oral loperamide hydrochloride therapy (e.g., 4 mg at the onset of diarrhea, then 2 mg every 2 hours until the patient is diarrhea-free for 12 hours).1, 2, 16, 17, 18, 19, 21, 22, 28, 56 Use of loperamide at these doses should not exceed 48 consecutive hours because of the risk of paralytic ileus.1, 63 The efficacy of other antiperistaltic agents in the management of irinotecan-induced diarrhea is unclear.22 During the night, the patient may take loperamide hydrochloride 4 mg every 4 hours.1, 56 Baseline bowel patterns should be documented prior to initiation of irinotecan therapy, and any increase in the frequency of bowel movements or change in stool consistency should prompt initiation of loperamide therapy.1, 22 Premedication with loperamide is not recommended.1 If diarrhea persists for more than 24 hours despite loperamide therapy, or if diarrhea occurs with fever, some clinicians recommend a 7-day course of oral fluoroquinolone therapy.1, 56 If diarrhea persists for longer than 48 hours, some clinicians advise discontinuance of loperamide and hospitalization of the patient for parenteral hydration.56 Prophylactic treatment with an oral fluoroquinolone also should be initiated in patients with an absolute neutrophil count below 500/mm3, even in the absence of fever or diarrhea.1, 56
Cases of late diarrhea complicated by colitis, ulceration, bleeding, ileus, and infection have occurred in patients receiving conventional irinotecan; megacolon and intestinal perforation also have been reported.1 Anti-infective therapy should be initiated promptly in patients who develop ileus.1
Patients with bowel obstruction should not receive conventional or liposomal irinotecan.1, 65
Patients with diarrhea should be monitored carefully and given fluid and electrolyte replacement if they become dehydrated or anti-infective therapy if they develop ileus, fever, or severe neutropenia.1, 22 Some clinicians recommend appropriate anti-infective therapy in any patient with prolonged diarrhea, regardless of neutrophil count, with treatment continued until resolution.56 Delayed initiation of anti-infective therapy, premature discontinuance of anti-infective therapy, or selection of inappropriate anti-infectives probably contributed to early deaths among patients receiving conventional irinotecan with rapid IV (“bolus”) fluorouracil/leucovorin.56 Patients experiencing severe diarrhea that does not resolve to baseline bowel function for at least 24 hours without the use of antidiarrheal medications or anti-infectives should not receive further treatment with the conventional irinotecan/fluorouracil/leucovorin regimen.56
Following the first treatment with conventional irinotecan-based 3-drug combination therapy, subsequent weekly chemotherapy treatments should be delayed until pretreatment bowel function has been restored for at least 24 hours without the need for antidiarrhea medication.1 If NCI grade 2, 3, or 4 late diarrhea occurs, administration of conventional irinotecan should be interrupted until the patient recovers, and subsequent doses of the drug should be reduced within the current treatment cycle.1 An independent panel of clinicians that reviewed the causes of early deaths in patients receiving the 3-drug regimen has recommended that the same guidelines for dosage modification be followed for abdominal cramping; if grade 2 or higher abdominal cramping occurs, treatment should be interrupted until the cramping has fully resolved, and subsequent doses of the drug should be reduced within the current treatment cycle.56 Among patients receiving conventional irinotecan as a single agent, subsequent doses within the treatment cycle should be reduced in those experiencing grade 2 diarrhea.1 If severe (NCI grade 3 or 4) diarrhea occurs, administration of conventional irinotecan should be interrupted until the patient recovers, and subsequent doses of the drug should be reduced.1
If grade 2-4 diarrhea occurs in patients receiving liposomal irinotecan, therapy with the drug should be withheld until diarrhea resolves to grade 1 or less.65 Liposomal irinotecan therapy may then be resumed at a reduced dosage (i.e., 70 mg/m2 reduced to 50 mg/m2 or 50 mg/m2 reduced to 43 mg/m2).65 If grade 2-4 diarrhea recurs following dosage reduction, therapy should be withheld again until diarrhea resolves to grade 1 or less; therapy may then be resumed at a further reduced dosage (i.e., 50 mg/m2 reduced to 43 mg/m2 or 43 mg/m2 reduced to 35 mg/m2).65 If grade 2-4 diarrhea recurs at this reduced dosage, treatment with liposomal irinotecan should be discontinued.65
Conventional or liposomal irinotecan can induce severe myelosuppression, particularly neutropenia,1, 16, 17, 18, 19, 27, 65 and deaths caused by sepsis have been reported in patients treated with the drug.1, 18, 19, 28, 65 In studies using the weekly dosage schedule for conventional irinotecan monotherapy, patients with even modestly elevated (i.e., 1-2 mg/dL) total serum bilirubin concentrations and those who had received prior pelvic or abdominal radiation therapy were at increased risk of grade 3 or 4 neutropenia associated with the drug.1 The risk of myelosuppression also may be greater in patients with deficient glucuronidation of bilirubin (e.g., Gilbert's syndrome) who are receiving conventional irinotecan.1 Complications of neutropenia should be managed promptly with anti-infective therapy.1
Therapy with conventional irinotecan should be interrupted during a treatment cycle if neutropenic fever occurs or if the absolute neutrophil count (ANC) drops below 1000/mm3.1, 18, 19 Following recovery to an ANC of at least 1000/mm3, subsequent doses of conventional irinotecan should be reduced according to the level of neutropenia observed (see the Recommended Dosage Modifications tables [Tables 2-4]).1 Blood tests should be obtained no sooner than 48 hours before scheduled treatment and trends in the ANC as well as absolute values should be considered; in patients with a rapidly falling ANC, conventional irinotecan therapy should be interrupted even if the current ANC is considered adequate to permit treatment.56
The manufacturer of liposomal irinotecan recommends that complete blood cell (CBC) counts be obtained on days 1 and 8 of each cycle and more frequently if clinically indicated.65 Therapy with liposomal irinotecan should be interrupted if neutropenic fever occurs or if the ANC drops below 1500/mm3.65 Following recovery to an ANC of at least 1500/mm3, subsequent doses of liposomal irinotecan should be reduced if grade 3 or 4 neutropenia or neutropenic fever was observed.65
Patients receiving conventional irinotecan in combination with rapid IV (“bolus”) fluorouracil/leucovorin have experienced early death induced or exacerbated by treatment-related cardiovascular toxicity, typically during or immediately following the first cycle of treatment.56 This vascular syndrome is characterized by an acute, fatal myocardial infarction, pulmonary embolus, or cerebrovascular accident that occurs during or shortly after receiving chemotherapy.56 An underlying cardiovascular or thromboembolic condition, if present, was considered stable or well-compensated at the time of treatment.56 Vascular syndrome may occur as an isolated event or in association with GI or other toxicities of conventional irinotecan-based therapy.56 Cardiovascular and thromboembolic events also have been reported in patients receiving conventional irinotecan with fluorouracil administered as an IV infusion.60
Interstitial lung disease (ILD), sometimes fatal, has been reported in patients receiving conventional irinotecan-based therapy.1, 65 Patients who have preexisting lung disease or those who have received pneumotoxic drugs, radiation therapy, or hematopoietic agents (i.e., granulocyte or granulocyte-macrophage colony-stimulating factors [G-CSF, GM-CSF]) may be at greater risk for ILD.1 Patients at risk for developing ILD should be closely monitored for respiratory symptoms before and during irinotecan-based therapy.1 If manifestations of ILD (i.e., new or progressive dyspnea, cough, or fever) occur, therapy with conventional or liposomal irinotecan should be withheld pending results of clinical investigation.1, 65 Conventional or liposomal irinotecan should be discontinued in patients who are diagnosed with treatment-related ILD.1, 65
If severe hypersensitivity reactions, including anaphylaxis, occur, therapy with conventional or liposomal irinotecan should be permanently discontinued.1, 65
If grade 3 or 4 adverse events occur in patients receiving liposomal irinotecan, therapy with the drug should be withheld until the toxicity resolves to grade 1 or less.65 Liposomal irinotecan therapy may then be resumed at a reduced dosage (i.e., 70 mg/m2 reduced to 50 mg/m2 or 50 mg/m2 reduced to 43 mg/m2).65 If grade 3 or 4 adverse events recur following dosage reduction, therapy should be withheld again until the toxicity resolves to grade 1 or less; therapy may then be resumed at a further reduced dosage (i.e., 50 mg/m2 reduced to 43 mg/m2 or 43 mg/m2 reduced to 35 mg/m2).65 If grade 3 or 4 adverse events recur at this reduced dosage, treatment with liposomal irinotecan should be discontinued.65
The administration of chemotherapy treatments should be delayed until pretreatment bowel function has been restored for at least 24 hours without the need for antidiarrhea medication.1 A new cycle of conventional irinotecan-based combination therapy should not begin until the granulocyte count has recovered to ≥1500/mm3, the platelet count has recovered to ≥100,000/mm3, and treatment-related diarrhea is fully resolved.1 Treatment should be delayed 1-2 weeks to allow for recovery from treatment-related toxicities.1 If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing conventional irinotecan.1 |
Toxicity - NCI Grade (Value)a | During a Cycle of Therapyb | At the Start of Subsequent Cycles of Therapyb |
|---|---|---|
No toxicity | Maintain dose level | Maintain dose level |
Neutropenia |
|
|
1 (1500 to 1999/mm3) | Maintain dose level | Maintain dose level |
2 (1000 to 1499/mm3) | Decrease by 1 dose level | Maintain dose level |
3 (500 to 999/mm3) | Omit dose until resolved to ≤ grade 2, then decrease by 1 dose level | Decrease by 1 dose level |
4 (<500/mm3) | Omit dose until resolved to ≤ grade 2, then decrease by 2 dose levels | Decrease by 2 dose levels |
Neutropenic fever | Omit dose until resolved, then decrease by 2 dose levels |
|
Other hematologic toxicities | Dose modifications for leukopenia or thrombocytopenia during a cycle of therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above |
|
Diarrhea |
|
|
1 (2-3 stools/day > pretreatment) | Delay dose until resolved to baseline, then resume the same dose | Maintain dose level |
2 (4-6 stools/day > pretreatment) | Omit dose until resolved to baseline, then decrease by 1 dose level | Maintain dose level |
3 (7-9 stools/day > pretreatment) | Omit dose until resolved to baseline, then decrease by 1 dose level | Decrease by 1 dose level |
4 (≥10 stools/day > pretreatment) | Omit dose until resolved to baseline, then decrease by 2 dose levels | Decrease by 2 dose levels |
Other nonhematologic toxicitiesc |
|
|
1 | Maintain dose level | Maintain dose level |
2 | Omit dose until resolved to ≤ grade 1, then decrease by 1 dose level | Maintain dose level |
3 | Omit dose until resolved to ≤ grade 2, then decrease by 1 dose level | Decrease by 1 dose level |
4 | Omit dose until resolved to ≤ grade 2, then decrease by 2 dose levels | Decrease by 2 dose levels |
| Note : For mucositis/stomatitis, decrease only fluorouracil, not conventional irinotecan | Note : For mucositis/stomatitis, decrease only fluorouracil, not conventional irinotecan |
aNational Cancer Institute Common Toxicity Criteria (version 1.0).
bAll dose modifications should be based on the worst preceding toxicity.
A new cycle of conventional irinotecan therapy should not begin until the granulocyte count has recovered to ≥1500/mm3, the platelet count has recovered to ≥100,000/mm3, and treatment-related diarrhea is fully resolved.1 Treatment should be delayed 1-2 weeks to allow for recovery from treatment-related toxicities.1 If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing conventional irinotecan.1 |
Toxicity - NCI Gradeb | During a Cycle of Therapya | At the Start of the Next Cycle of Therapya |
|---|---|---|
No toxicity | Maintain dose level | Increase dose by 25 mg/m2 up to a maximum dose of 150 mg/m2 |
Neutropenia |
|
|
1 (1500 to 1999/mm3) | Maintain dose level | Maintain dose level |
2 (1000 to 1499/mm3) | Decrease dose by 25 mg/m2 | Maintain dose level |
3 (500 to 999/mm3) | Omit dose until resolved to ≤ grade 2, then decrease dose by 25 mg/m2 | Decrease dose by 25 mg/m2 |
4 (<500/mm3) | Omit dose until resolved to ≤ grade 2, then decrease dose by 50 mg/m2 | Decrease dose by 50 mg/m2 |
Neutropenic fever | Omit dose until resolved, then decrease dose by 50 mg/m2 | Decrease dose by 50 mg/m2 |
Other hematologic toxicities | Dose modifications for leukopenia, thrombocytopenia, and anemia during a cycle of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above | Dose modifications for leukopenia, thrombocytopenia, and anemia at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above |
Diarrhea |
|
|
1 (2-3 stools/day > pretreatment) | Maintain dose level | Maintain dose level |
2 (4-6 stools/day > pretreatment) | Decrease dose by 25 mg/m2 | Maintain dose level |
3 (7-9 stools/day > pretreatment) | Omit dose until resolved to ≤ grade 2, then decrease dose by 25 mg/m2 | Decrease dose by 25 mg/m2 |
4 (≥10 stools/day > pretreatment) | Omit dose until resolved to ≤ grade 2, then decrease dose by 50 mg/m2 | Decrease dose by 50 mg/m2 |
Other nonhematologic toxicitiesc |
|
|
1 | Maintain dose level | Maintain dose level |
2 | Decrease dose by 25 mg/m2 | Decrease dose by 25 mg/m2 |
3 | Omit dose until resolved to ≤ grade 2, then decrease dose by 25 mg/m2 | Decrease dose by 25 mg/m2 |
4 | Omit dose until resolved to ≤ grade 2, then decrease dose by 50 mg/m2 | Decrease dose by 50 mg/m2 |
aAll dose modifications should be based on the worst preceding toxicity.
bNational Cancer Institute Common Toxicity Criteria (version 1.0).
A new cycle of conventional irinotecan therapy should not begin until the granulocyte count has recovered to ≥1500/ mm3, the platelet count has recovered to ≥100,000/ mm3, and treatment-related diarrhea is fully resolved. 1 Treatment should be delayed 1-2 weeks to allow for recovery from treatment-related toxicities.1 If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing conventional irinotecan.1 |
Toxicity - NCI Grade b | At the Start of the Next Cycle of Therapy a |
|---|---|
No toxicity | Maintain dose level |
Neutropenia |
|
1 (1500 to 1999/mm3) | Maintain dose level |
2 (1000 to 1499/mm3) | Maintain dose level |
3 (500 to 999/mm3) | Decrease dose by 50 mg/m2 |
4 (<500/mm3) | Decrease dose by 50 mg/m2 |
Neutropenic fever | Decrease dose by 50 mg/m2 |
Other hematologic toxicities | Dose modifications for leukopenia, thrombocytopenia, and anemia at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above |
Diarrhea |
|
1 (2-3 stools/day > pretreatment) | Maintain dose level |
2 (4-6 stools/day > pretreatment) | Maintain dose level |
3 (7-9 stools/day > pretreatment) | Decrease dose by 50 mg/m2 |
4 (≥10 stools/day > pretreatment) | Decrease dose by 50 mg/m2 |
Other nonhematologic toxicities c |
|
1 | Maintain dose level |
2 | Decrease dose by 50 mg/m2 |
3 | Decrease dose by 50 mg/m2 |
4 | Decrease dose by 50 mg/m2 |
aAll dose modifications should be based on the worst preceding toxicity.
bNational Cancer Institute Common Toxicity Criteria (version 1.0).
Dosage in Renal and Hepatic Impairment
Conventional Irinotecan Hydrochloride
Safety and efficacy of conventional irinotecan hydrochloride have not been evaluated systematically in patients with renal impairment.1 The manufacturer makes no specific recommendations regarding dosage adjustment in patients with renal impairment, but states that use of conventional irinotecan in patients requiring dialysis is not recommended.1
In patients with hepatic impairment, clearance of conventional irinotecan is decreased and exposure to the SN-38 active metabolite is increased.1 In clinical trials for GI cancer using either dosage schedule, conventional irinotecan was not administered to patients with serum bilirubin concentrations exceeding 2 mg/dL; specific dosage recommendations are not available for such patients.1, 22 The drug also was not administered to patients who had serum aminotransferase concentrations exceeding 3 times the ULN in the absence of hepatic metastases or to those with hepatic metastases who had serum aminotransferase concentrations exceeding 5 times the ULN.1, 22 The manufacturer states that reduction of the initial dose of conventional irinotecan hydrochloride by one dose level (e.g., to 100 mg/m2 for regimen 1 or to 150 mg/m2 for regimen 2 as first-line combination therapy; to 100 mg/m2 for the weekly dosage schedule or to 300 mg/m2 for the once-every-3-weeks dosage schedule as monotherapy) should be considered for patients with modestly elevated serum bilirubin concentrations (i.e., 1-2 mg/dL).1 (See Colorectal Cancer under Dosage and Administration: Dosage.)
Liposomal Irinotecan Hydrochloride
In a population pharmacokinetic analysis of liposomal irinotecan hydrochloride, systemic exposure to the SN-38 active metabolite in patients with mild (creatinine clearance of 60-89 mL/minute) or moderate (creatinine clearance of 30-59 mL/minute) renal impairment was similar to that in patients with normal renal function.65 Pharmacokinetic data in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) are limited.65 The manufacturer makes no specific dosage recommendations for patients with renal impairment.65
Formal pharmacokinetic studies with liposomal irinotecan hydrochloride have not been conducted in patients with hepatic impairment.65 Data from a population pharmacokinetic analysis indicate that average steady-state concentrations of total SN-38 are increased by 37% in patients with baseline serum bilirubin concentrations of 1-2 mg/dL compared with patients with baseline serum bilirubin concentrations of less than 1 mg/dL; however, elevated concentrations of serum aminotransferases (ALT or AST) did not affect total SN-38 concentrations.65 The drug has not been studied in patients with serum bilirubin concentrations exceeding 2 mg/dL, and patients with bilirubin concentrations exceeding the ULN were not included in the pivotal clinical trial evaluating liposomal irinotecan therapy for metastatic pancreatic cancer.65 The manufacturer makes no specific recommendations regarding dosage adjustment in patients with hepatic impairment.65
Irinotecan (CPT-11), a semisynthetic derivative of camptothecin, is an antineoplastic agent.1, 2, 3, 6, 7, 9, 13 Camptothecins are alkaloids with antitumor activity that are extracted from plants such as Camptotheca acuminata .1, 2, 4, 5, 6, 7, 11, 13 Conventional and liposomal preparations of irinotecan hydrochloride are commercially available as the trihydrate.1, 65 Each mL of conventional irinotecan hydrochloride for injection concentrate contains 20 mg of the drug in terms of the hydrated salt.1 Each mL of liposomal irinotecan hydrochloride for injection concentrate contains 4.3 mg of the drug in terms of the anhydrous base.65, 69
Irinotecan is a type I DNA topoisomerase inhibitor.1, 2, 6, 9, 11, 12, 13, 28 DNA topoisomerases (i.e., types I and II) are enzymes in the cell nucleus that regulate DNA topology (3-dimensional conformation)2 and facilitate nuclear processes such as DNA replication, recombination, and repair.9, 11, 12, 13, 14 During these processes, type I DNA topoisomerase creates transient (reversible) single-stranded breaks in double-stranded DNA, allowing intact single DNA strands to pass through the break and relieve the topologic constraints (e.g., torsional strain) inherent in supercoiled DNA.1, 4, 9, 11, 12, 13, 14 The 3'-DNA terminus of the broken DNA strands bind covalently with the topoisomerase enzyme to form a catalytic intermediate, termed a cleavable complex.4, 9, 11, 12, 13 After the DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the chemically unaltered topoisomers that allow transcription to proceed.9, 11, 12, 13, 14 Irinotecan is a water-soluble precursor to the lipophilic active metabolite SN-38 (7-ethyl-10-hydroxycamptothecin), which is 1000 times as potent as irinotecan in vitro as an inhibitor of type I DNA topoisomerase.1, 2, 4, 7, 8, 9, 10, 11, 13, 14, 16, 18, 19, 28 However, the precise contribution of SN-38 to the pharmacologic activity of administered irinotecan is unknown because of the variable in vitro cytotoxic potency reported for SN-38 relative to the parent drug and differences in the area under the plasma concentration-time curve and plasma protein binding of SN-38 compared with irinotecan.1, 2, 8, 10, 16
Irinotecan, its active metabolite SN-38, and other type I topoisomerase inhibitors are believed to exert their cytotoxic effects during the S-phase of DNA synthesis through an interaction with the DNA-DNA topoisomerase cleavable complex.1, 9, 11, 12, 13, 14 The cleavable complex is bound and stabilized by irinotecan and/or SN-38, preventing the topoisomerase from religating the single-strand breaks.9, 10, 11, 12, 13, 14 The ternary complex of irinotecan/SN-38, DNA, and DNA topoisomerase interferes with the moving replication fork, inducing replication arrest and lethal double-stranded breaks in DNA.1, 2, 4, 9, 10, 11, 12, 13 This DNA damage is not efficiently repaired and apparently leads to apoptosis (programmed cell death).1, 2, 9, 17, 18, 19, 29, 30
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Distribution of liposomal irinotecan hydrochloride is restricted.66 (See Dosage and Administration.)
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Concentrate, for injection, for IV infusion only | 20 mg/mL (40 and 100 mg)* |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Pfizer. Camptosar® (irinotecan hydrochloride) injection prescribing information. New York, NY; 2016 Apr.
2. Pharmacia & Upjohn Inc. Oncologic Drugs Advisory Committee Brochure. Irinotecan hydrochloride (CPT-11, Camptosar®). Kalamazoo, MI: undated.
3. Pitot HC, Wender DB, O'Connell MJ et al. Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol . 1997; 15:2910-9. [PubMed 9256135]
4. Sinha BK. Topoisomerase inhibitors: a review of their therapeutic potential in cancer. Drugs . 1995; 49:11-9. [PubMed 7705211]
5. Giovanella BC. New perspectives in colon cancer chemotherapy. Dis Colon Rectum . 1994; 37(Suppl):S96-9. [PubMed 8313802]
6. Lee R. Irinotecan—a novel drug for treating colorectal cancer. Inpharma . 1995; 973:9-10.
7. Wiseman LR, Markham A. Irinotecan: a review of its pharmacological properties and clinical efficacy in the management of advanced colorectal cancer. Drugs . 1996; 52:606-23. [PubMed 8891470]
8. Conti JA, Kemeny NE, Saltz LB et al. Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol . 1996; 14:709-15. [PubMed 8622015]
9. Pommier Y. Eukaryotic DNA topoisomerase I: genome gatekeeper and its intruders, camptothecins. Semin Oncol . 1996; 23(Suppl 3):3-10. [PubMed 8633251]
10. Tanizawa A, Fujimori A, Fujimori Y et al. Comparison of topoisomerase I inhibition, DNA damage, and cytotoxicity of camptothecin derivatives presently in clinical trials. J Natl Cancer Inst . 1994; 86:836-42. [PubMed 8182764]
11. Slichenmyer WJ, Rowinsky EK, Donehower RC et al. The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst . 1993; 85:271-91. [PubMed 8381186]
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