Irinotecan Drug Information
Generic name: IRINOTECAN HYDROCHLORIDE
Uses of Irinotecan
- Irinotecan hydrochloride injection is a topoisomerase inhibitor indicated for:
- Patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy. ( 1 )
- Irinotecan hydrochloride injection is indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.
Dosage & Administration of Irinotecan
| a Subsequent doses may be adjusted as high as 150 mg/m 2 or to as low as 50 mg/m 2 in 25 to 50 mg/m 2 decrements depending upon individual patient tolerance. | |
|---|---|
| b Subsequent doses may be adjusted as low as 200 mg/m2 in 50 mg/m2 decrements depending upon individual patient tolerance. | |
| c Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit. | |
| 125 mg/m2 intravenous infusion over 90 minutes, days 1,8,15,22 then 2-week rest | |
| Starting Dose | Dose Level -1 |
| 125 | 100 |
| 350 mg/m2 intravenous infusion over 90 minutes, once every 3 weeks | |
| Starting Dose | Dose Level -1 |
| 350 | 300 |
Side Effects of Irinotecan
Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Common adverse reactions ( > 30%) observed in single agent therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia, fever, body weight decreasing, and alopecia. Serious opportunistic infections have not been observed, and no complications have specifically been attributed to lymphocytopenia.
Second-Line Single-Agent Therapy Weekly Dosage Schedule In three clinical studies evaluating the weekly dosage schedule, 304 patients with metastatic carcinoma of the colon or rectum that had recurred or progressed following 5-FU-based therapy were treated with Irinotecan hydrochloride. Seventeen of the patients died within 30 days of the administration of Irinotecan hydrochloride; in five cases (1.6%, 5/304), the deaths were potentially drug-related. One of the patients died of neutropenic sepsis without fever.
Neutropenic fever occurred in nine (3.0%) other patients; these patients recovered with supportive care. One hundred nineteen (39.1%) of the 304 patients were hospitalized because of adverse events; 81 (26.6%) patients were hospitalized for events judged to be related to administration of Irinotecan hydrochloride. The primary reasons for drug-related hospitalization were diarrhea, with or without nausea and/or vomiting (18.4%); neutropenia/leukopenia, with or without diarrhea and/or fever (8.2%); and nausea and/or vomiting (4.9%). The first dose of at least one cycle of Irinotecan hydrochloride was reduced for 67% of patients who began the studies at the 125-mg/m 2 starting dose.
Within-cycle dose reductions were required for 32% of the cycles initiated at the 125-mg/m 2 dose level. The most common reasons for dose reduction were late diarrhea, neutropenia, and leukopenia. Thirteen (4.3%) patients discontinued treatment with Irinotecan hydrochloride because of adverse events.
The adverse events in Table 7 are based on the experience of the 304 patients enrolled in the three studies described in Clinical Studies . Table 7. Adverse Events Occurring in >10% of 304 Previously Treated Patients with Metastatic Carcinoma of the Colon or Rectum a a Severity of adverse events based on NCI CTC (version 1.0) b Occurring >24 hours after administration of Irinotecan hydrochloride c Occurring ≤24 hours after administration of Irinotecan hydrochloride d Primarily upper respiratory infections e Not applicable; complete hair loss = NCI grade 2 Body System & Event % of Patients Reporting NCI Grades 1-4 NCI Grades 3 & 4 GASTROINTESTINAL Diarrhea (late) b 88 31 7–9 stools/day (grade 3) — ≥10 stools/day (grade 4) — Nausea 86 17 Vomiting 67 12 Anorexia 55 6 Diarrhea (early) c 51 8 Constipation 30 2 Flatulence 12 0 Stomatitis 12 1 Dyspepsia 10 0 HEMATOLOGIC Leukopenia 63 28 Anemia 60 7 Neutropenia 54 26 500 to <1000/mm 3 (grade 3) — <500/mm 3 (grade 4) — BODY AS A WHOLE Asthenia 76 12 Abdominal cramping/pain 57 16 Fever 45 1 Pain 24 2 Headache 17 1 Back pain 14 2 Chills 14 0 Minor infection d 14 0 Edema 10 1 Abdominal enlargement 10 0 METABOLIC AND NUTRITIONAL ↓ Body weight 30 1 Dehydration 15 4 ↑ Alkaline phosphatase 13 4 ↑ SGOT 10 1 DERMATOLOGIC Alopecia 60 NA e Sweating 16 0 Rash 13 1 RESPIRATORY Dyspnea 22 4 ↑ Coughing 17 0 Rhinitis 16 0 NEUROLOGIC Insomnia 19 0 Dizziness 15 0 CARDIOVASCULAR Vasodilation (flushing) 11 0 Once-Every-3-Week Dosage Schedule A total of 535 patients with metastatic colorectal cancer whose disease had recurred or progressed following prior 5-FU therapy participated in the two phase 3 studies: 316 received irinotecan, 129 received 5-FU, and 90 received best supportive care. Eleven (3.5%) patients treated with irinotecan died within 30 days of treatment. In three cases (1%, 3/316), the deaths were potentially related to irinotecan treatment and were attributed to neutropenic infection, grade 4 diarrhea, and asthenia, respectively.
One (0.8%, 1/129) patient treated with 5-FU died within 30 days of treatment; this death was attributed to grade 4 diarrhea. Hospitalizations due to serious adverse events occurred at least once in 60% (188/316) of patients who received irinotecan, 63% (57/90) who received best supportive care, and 39% (50/129) who received 5-FU-based therapy. Eight percent of patients treated with irinotecan and 7% treated with 5-FU-based therapy discontinued treatment due to adverse events.
Of the 316 patients treated with irinotecan, the most clinically significant adverse events (all grades, 1-4) were diarrhea (84%), alopecia (72%), nausea (70%), vomiting (62%), cholinergic symptoms (47%), and neutropenia (30%). Table 8 lists the grade 3 and 4 adverse events reported in the patients enrolled to all treatment arms of the two studies described in Clinical Studies . Table 8: Percent of Patients Experiencing Grade 3 & 4 Adverse Events in Comparative Studies of Once-Every-3-Week Irinotecan Therapy a a Severity of adverse events based on NCI CTC (version 1.0) b BSC = best supportive care c Hepatic includes events such as ascites and jaundice d Cutaneous signs include events such as rash e Respiratory includes events such as dyspnea and cough f Neurologic includes events such as somnolence g Cardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction h Other includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss Adverse Event Study 1 Study 2 Irinotecan N=189 BSC b N=90 Irinotecan N=127 5-FU N=129 TOTAL Grade 3/4 Adverse Events 79 67 69 54 GASTROINTESTINAL Diarrhea 22 6 22 11 Vomiting 14 8 14 5 Nausea 14 3 11 4 Abdominal pain 14 16 9 8 Constipation 10 8 8 6 Anorexia 5 7 6 4 Mucositis 2 1 2 5 HEMATOLOGIC Leukopenia/Neutropenia 22 0 14 2 Anemia 7 6 6 3 Hemorrhage 5 3 1 3 Thrombocytopenia 1 0 4 2 Infection without grade 3/4 neutropenia 8 3 1 4 with grade 3/4 neutropenia 1 0 2 0 Fever without grade 3/4 neutropenia 2 1 2 0 with grade 3/4 neutropenia 2 0 4 2 BODY AS A WHOLE Pain 19 22 17 13 Asthenia 15 19 13 12 METABOLIC AND NUTRITIONAL Hepatic c 9 7 9 6 DERMATOLOGIC Hand and foot syndrome 0 0 0 5 Cutaneous signs d 2 0 1 3 RESPIRATORY e 10 8 5 7 NEUROLOGIC f 12 13 9 4 CARDIOVASCULAR g 9 3 4 2 OTHER h 32 28 12 14 The incidence of akathisia in clinical trials of the weekly dosage schedule was greater (8.5%, 4/47 patients) when prochlorperazine was administered on the same day as Irinotecan hydrochloride than when these drugs were given on separate days (1.3%, 1/80 patients). The 8.5% incidence of akathisia, however, is within the range reported for use of prochlorperazine when given as a premedication for other chemotherapies.
Postmarketing Experience
The following adverse reactions have been identified during post approval use of Irinotecan hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Myocardial ischemic events have been observed following Irinotecan hydrochloride therapy.
Thromboembolic events have been observed in patients receiving Irinotecan hydrochloride. Symptomatic pancreatitis, asymptomatic pancreatic enzyme elevation have been reported. Increases in serum levels of transaminases (i.e., AST and ALT) in the absence of progressive liver metastasis have been observed.
Hyponatremia, mostly with diarrhea and vomiting, has been reported. Transient dysarthria has been reported in patients treated with Irinotecan hydrochloride; in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of irinotecan. Interaction between Irinotecan hydrochloride and neuromuscular blocking agents cannot be ruled out.
Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarizing drugs may be antagonized.
Warnings & Cautions for Irinotecan
Diarrhea and Cholinergic Reactions Early diarrhea (occurring during or shortly after infusion
of Irinotecan hydrochloride) is usually transient and infrequently severe. It may be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping. Bradycardia may also occur.
Early diarrhea and other cholinergic symptoms may be prevented or treated. Consider prophylactic or therapeutic administration of 0.25 mg to 1 mg of intravenous or subcutaneous atropine (unless clinically contraindicated). These symptoms are expected to occur more frequently with higher irinotecan doses. Late diarrhea (generally occurring more than 24 hours after administration of irinotecan hydrochloride) can be life threatening since it may be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis.
Grade 3-4 late diarrhea occurred in 23-31% of patients receiving weekly dosing. In the clinical studies, the median time to the onset of late diarrhea was 5 days with 3-week dosing and 11 days with weekly dosing. Late diarrhea can be complicated by colitis, ulceration, bleeding, ileus, obstruction, and infection.
Cases of megacolon and intestinal perforation have been reported. Patients should have loperamide readily available to begin treatment for late diarrhea. Begin loperamide at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normal.
One dosage regimen for loperamide is 4 mg at the first onset of late diarrhea and then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus. During the night, the patient may take 4 mg of loperamide every 4 hours.
Monitor and replace fluid and electrolytes. Use antibiotic support for ileus, fever, or severe neutropenia. Subsequent weekly chemotherapy treatments should be delayed in patients until return of pretreatment bowel function for at least 24 hours without anti-diarrhea medication.
Patients must not be treated with Irinotecan hydrochloride until resolution of the bowel obstruction. If grade 2, 3, or 4 late diarrhea recurs, subsequent doses of Irinotecan hydrochloride should be decreased . Avoid diuretics or laxatives in patients with diarrhea.
Myelosuppression Deaths due to sepsis following severe neutropenia have been reported in
patients treated with Irinotecan hydrochloride. In the clinical studies evaluating the weekly dosage schedule, neutropenic fever (concurrent NCI grade 4 neutropenia and fever of grade 2 or greater) occurred in 3% of the patients; 6% of patients received G-CSF for the treatment of neutropenia. Manage febrile neutropenia promptly with antibiotic support . Hold Irinotecan hydrochloride if neutropenic fever occurs or if the absolute neutrophil count drops <1000/mm 3. After recovery to an absolute neutrophil count ≥1000/mm 3, subsequent doses of irinotecan hydrochloride should be reduced . When evaluated in the trials of weekly administration, the frequency of grade 3 and 4 neutropenia was higher in patients who received previous pelvic/abdominal irradiation than in those who had not received such irradiation (48% versus 24% ; p=0.04). Patients who have previously received pelvic/abdominal irradiation are at increased risk of severe myelosuppression following the administration of Irinotecan hydrochloride.
Based on sparse available data, the concurrent administration of Irinotecan hydrochloride with irradiation is not recommended. Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more also had a greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% versus 18% ; p<0.001). Patients with deficient glucuronidation of bilirubin, such as those with Gilbert's syndrome, may be at greater risk of myelosuppression when receiving therapy with Irinotecan hydrochloride.
Patients With Reduced
UGT1A1 Activity Individuals who are homozygous for the UGT1A1 * 28 allele (UGT1A1 7/7 genotype) are at increased risk for neutropenia following initiation of Irinotecan hydrochloride treatment. In a study of 66 patients who received single-agent Irinotecan hydrochloride (350 mg/m 2 once-every-3-weeks), the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1 * 28 allele was 50%, and in patients heterozygous for this allele (UGT1A1 6/7 genotype) the incidence was 12.5%. No grade 4 neutropenia was observed in patients homozygous for the wild-type allele (UGT1A1 6/6 genotype). When administered as a single-agent, a reduction in the starting dose by at least one level of Irinotecan hydrochloride should be considered for patients known to be homozygous for the UGT1A1 * 28 allele. However, the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment . UGT1A1 Testing A laboratory test is available to determine the UGT1A1 status of patients.
Testing can detect the UGT1A1 6/6, 6/7 and 7/7 genotypes.
Hypersensitivity Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed.
Discontinue Irinotecan hydrochloride if anaphylactic reaction occurs.
Renal Impairment/Renal Failure Renal impairment and acute renal failure have been identified
usually in patients who became volume depleted from severe vomiting and/or diarrhea.
Pulmonary Toxicity Interstitial Pulmonary Disease (IPD)-like events, including fatalities, have occurred in
patients receiving irinotecan (in combination and as monotherapy). Risk factors include pre-existing lung disease, use of pneumotoxic drugs, radiation therapy, and colony stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during Irinotecan hydrochloride therapy. In Japanese studies, a reticulonodular pattern on chest x-ray was observed in a small percentage of patients.
New or progressive, dyspnea, cough, and fever should prompt interruption of chemotherapy, pending diagnostic evaluation. If IPD is diagnosed, Irinotecan hydrochloride and other chemotherapy should be discontinued and appropriate treatment instituted as needed .
Toxicity of the 5 Day Regimen Outside of a well-designed clinical study
irinotecan hydrochloride injection should not be used in combination with a regimen of 5-FU/LV administered for 4-5 consecutive days every 4 weeks because of reports of increased toxicity, including toxic deaths. Irinotecan hydrochloride should be used as recommended in Table 2 .
Increased Toxicity in Patients with Performance Status 2
In the clinical trials, higher rates of hospitalization, neutropenic fever, thromboembolism, first-cycle treatment discontinuation, and early deaths were observed in patients with a baseline performance status of 2 than in patients with a baseline performance status of 0 or 1.
Embryofetal Toxicity Irinotecan hydrochloride can cause fetal harm when administered to a
pregnant woman. Irinotecan was embryotoxic in rats and rabbits at doses significantly lower than those administered to humans on a mg/m 2 basis. In rats, at exposures approximately 0.2 times those achieved in humans at the 125 mg/m 2 dose, irinotecan was embryotoxic and resulted in decreased learning ability and female fetal body weight in surviving pups; the drug was teratogenic at lower exposures (approximately 0.025 times the AUC in humans at the 125 mg/m 2 dose).There are no adequate and well-controlled studies of irinotecan in pregnant women.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Irinotecan hydrochloride. 5.10 Patients with Hepatic Impairment The use of Irinotecan hydrochloride in patients with significant hepatic impairment has not been established. In clinical trials of either dosing schedule, irinotecan was not administered to patients with serum bilirubin >2.0 mg/dL, or transaminase >3 times the upper limit of normal if no liver metastasis, or transaminase >5 times the upper limit of normal with liver metastasis.
In clinical trials of the weekly dosage schedule, patients with modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) had a significantly greater likelihood of experiencing first-cycle, grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% versus 18% ; p<0.001) .
Drug Interactions with Irinotecan
Strong
CYP3A4 Inducers Exposure to irinotecan or its active metabolite SN-38 is substantially reduced in adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital, carbamazepine, or St. John's wort. The appropriate starting dose for patients taking these or other strong inducers such as rifampin and rifabutin has not been defined.
Consider substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of irinotecan hydrochloride injection therapy. Do not administer strong CYP3A4 inducers with irinotecan hydrochloride injection unless there are no therapeutic alternatives.
Strong
CYP3A4 or UGT1A1 Inhibitors Irinotecan and its active metabolite, SN-38, are metabolized via the human cytochrome P450 3A4 isoenzyme (CYP3A4) and uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), respectively,. Patients receiving concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, have increased exposure to irinotecan and its active metabolite SN-38. Coadministration of irinotecan hydrochloride with other inhibitors of CYP3A4 (e.g., clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) or UGT1A1 (e.g., atazanavir, gemfibrozil, indinavir) may increase systemic exposure to irinotecan or SN-38. Discontinue strong CYP3A4 inhibitors at least 1 week prior to starting irinotecan hydrochloride injection therapy. Do not administer strong CYP3A4 or UGT1A1 inhibitors with irinotecan hydrochloride injection unless there are no therapeutic alternatives.
Pediatric Use of Irinotecan
L/h/m 2 for the 50mg/m 2 dose and 16.2 + 4.6 L/h/m
2 for the 125 mg/m 2 dose, which is comparable to that in adults. Dose-normalized SN-38 AUC values were comparable between adults and children. Minimal accumulation of irinotecan and SN-38 was observed in children on daily dosing regimens.
Contraindications for Irinotecan
Hypersensitivity to Irinotecan hydrochloride injection or its excipients Irinotecan hydrochloride injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients.
Overdosage Information for Irinotecan
In U.S. phase 1 trials, single doses of up to 345 mg/m 2 of irinotecan were administered to patients with various cancers. Single doses of up to 750 mg/m 2 of irinotecan have been given in non-U.S. trials. The adverse events in these patients were similar to those reported with the recommended dosage and regimen.
There have been reports of overdosage at doses up to approximately twice the recommended therapeutic dose, which may be fatal. The most significant adverse reactions reported were severe neutropenia and severe diarrhea. There is no known antidote for overdosage of irinotecan hydrochloride.
Maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications.
Clinical Studies of Irinotecan
Metastatic Colorectal Cancer 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 irinotecan hydrochloride 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, irinotecan hydrochloride 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 irinotecan hydrochloride in these trials were 100, 125, or 150 mg/m 2, but the 150-mg/m 2 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/m 2. Study 5 was a multicenter study that enrolled 166 patients from 30 institutions.
The initial dose in Study 5 was 125 mg/m 2 but was reduced to 100 mg/m 2 because the toxicity seen at the 125-mg/m 2 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 a Nine patients received 150 mg/m 2 as a starting dose; two (22.2%) responded to irinotecan hydrochloride. b Relative dose intensity for irinotecan hydrochloride.
Based on planned dose intensity of 100, 83.3, and 66.7 mg/m 2 /wk corresponding with 150, 125, and 100 mg/m 2 starting doses, respectively. c Confirmed ≥ 4 to 6 weeks after first evidence of objective response. Study 3 4 5 Number of Patients 48 90 64 102 Starting Dose (mg/m 2 /week × 4) 125 a 125 125 100 Demographics and Treatment Administration Female/Male (%) 46/54 36/64 50/50 51/49 Median Age in years (range) 63 (29–78) 63 (32–81) 61 (42–84) 64 (25–84) Ethnic Origin (%) White 79 96 81 91 African American 12 4 11 5 Hispanic 8 0 8 2 Oriental/Asian 0 0 0 2 Performance Status (%) 0 60 38 59 44 1 38 48 33 51 2 2 14 8 5 Primary Tumor (%) Colon 100 71 89 87 Rectum 0 29 11 8 Unknown 0 0 0 5 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 Classification Unknown 2 12 0 3 Prior Pelvic/Abdominal Irradiation (%) Yes 3 29 0 0 Other 0 9 2 4 None 97 62 98 96 Duration of Treatment with Irinotecan hydrochloride injection (median, months) 5 4 4 3 Relative Dose Intensity b (median %) 74 67 73 81 Efficacy 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) 2.6 1.5 2.8
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 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/m 2. Among these 193 patients, 2 complete and 27 partial responses were observed, for an overall response rate of 15.0% (95% Confidence Interval, 10.0% to 20.1%) at this starting dose. A considerably lower response rate was seen with a starting dose of 100 mg/m 2. 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/m 2 was 5.8 months (range, 2.6 to 15.1 months). Of the 304 patients treated in the three studies, response rates to irinotecan hydrochloride 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 irinotecan hydrochloride had not responded to prior 5-FU. Patients who had received previous irradiation to the pelvis responded to irinotecan hydrochloride 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/m 2 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/m 2 over 90 minutes once every 3 weeks. The starting dose was 300 mg/m 2 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: LV, 200 mg/m 2 IV over 2 hours; followed by 5-FU, 400 mg/m 2 IV bolus; followed by 5-FU, 600 mg/m 2 continuous IV infusion over 22 hours on days 1 and 2 every 2 weeks; 5-FU, 250 to 300 mg/m 2 /day protracted continuous IV infusion until toxicity; 5-FU, 2.6 to 3 g/m 2 IV over 24 hours every week for 6 weeks with or without LV, 20 to 500 mg/m 2 /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.
Table 12. Once-Every-3-Week Dosage Schedule: Study Results a BSC = best supportive care b Relative dose intensity for irinotecan based on planned dose intensity of 116.7 and 100 mg/m 2 /wk corresponding with 350 and 300 mg/m 2 starting doses, respectively. Study 7 Study 8 Irinotecan BSC a Irinotecan 5-FU Number of patients 189 90 127 129 Demographics and treatment administration Female/Male (%) 32/68 42/58 43/57 35/65 Median age in years (range) 59 (22–75) 62 (34–75) 58 (30–75) 58 (25–75) Performance status (%) 0 47 31 58 54 1 39 46 35 43 2 14 23 8 3 Primary tumor (%) Colon 55 52 57 62 Rectum 45 48 43 38 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)
Relative dose intensity (median %) b 94 -- 95 81–99 Survival Survival
(median, months) (Log-rank test) 9.2 (p=0.0001) 6.5 10.8 (p=0.035) 8.5 image description image description 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 Score a a For 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. QLD-C30 Subscale Study 7 Study 8 Irinotecan BSC p-value Irinotecan 5-FU p-value Global health status 47 37 0.03 53 52
Functional scales Cognitive 77 68 0.07 79 83 0.9 Emotional 68 64
0.4 64 68
Social 58 47 0.06 65 67 0.9 Physical 60 40 0.0003 66
66
Role 53 35 0.02 54 57 0.9 Symptom Scales Fatigue 51 63
0.03 47 46
Appetite loss 37 57 0.0007 35 38 0.9 Pain assessment 41 56
0.009 38 34
Insomnia 39 47 0.3 39 33 0.9 Constipation 28 41 0.03 25
19
Dyspnea 31 40 0.2 25 24 0.9 Nausea/Vomiting 27 29 0.5 25
16 0.09 Financial impact 22 26 0.5 24 15
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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