Japanese Journal of Clinical Oncology 33:580-583 (2003)
© 2003 Foundation for Promotion of Cancer Research
Biweekly Irinotecan Plus Bolus 5-Fluorouracil and Folinic Acid in Patients with Advanced Stage Colorectal Cancer
Department of Medical Oncology, Institute of Oncology, Hacettepe University, Ankara, Turkey
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: In this study, we evaluated the efficacy and tolerability of biweekly irinotecan (CPT-11) plus 5-fluorouracil (5-FU) and folinic acid (FA) regimen (IFL) in patients with advanced stage colorectal cancer.
Methods: A total of 28 patients were examined. The median age was 51 years (range, 30–74 years). One treatment cycle consisted of CPT-11 180 mg/m2 on days 1 and 15; 5-FU 425 mg/m2 on days 1, 2, 15 and 16; and FA 20 mg/m2 on days 1, 2, 15 and 16, every 4 weeks. A total of 119 cycles (median, 4.0 cycles) were administered. Of the 28 patients, 18 received the chemotherapy as first line treatment, seven received it as second line and three received it as third line.
Results: An overall objective response rate of 21.5% was achieved in the patient group. However, the overall response rate for the 18 patients receiving first line treatment was 27.7%. The median response duration was 10.5 months (range, 3–19 months). An additional 28.6% of the patients had stable disease for a median duration of 6.5 months (range, 3–8 months). Median time to disease progression was 4.5 months (range, 1–22+ months) and median overall survival time was 11+ months (95% confidence interval, 9–15 months). Toxicities were mild and manageable.
Conclusions: We conclude that biweekly IFL is a practical and tolerable treatment option with a disease control rate of 50.1% in patients with advanced stage colorectal cancer.
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INTRODUCTION |
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Colorectal carcinoma (CRC) is one of the most common cancers that accounts for approximately 10 to 12% of all cases in Western countries, ranking second only to lung cancer as a cause of cancer-related mortality (1). Surgery for CRC at an early stage can be curative. However, approximately 50% of the patients have advanced stage disease at the time of diagnosis, and 50% of the patients have a relapse after potentially curative surgery (1–3). For a long time, 5-fluorouracil (5-FU) based regimens have been the first line chemotherapy for patients with advanced stage disease. Recently, irinotecan (CPT-11) has been reported to have significant activity against CRC (4,5). The aim of this study was to evaluate the efficacy and tolerability of biweekly irinotecan plus 5-FU and folinic acid (FA) (IFL) combination chemotherapy regimen in patients with advanced stage CRC.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this study, we examined 28 patients with histologically proven advanced stage, inoperable adenocarcinoma of the colon or rectum. The eligibility criteria also included the following: Eastern Cooperative Oncology Group (ECOG) performance status (PS)
2; age between 18 to 75 years; life expectancy greater than 12 weeks; adequate hepatic and renal functions (serum creatinin 1.5 x upper limit normal (ULN), total bilirubin level 1.25 x ULN and aspartate transaminase, alanine transaminase and alkaline phosphatase <2.5 x ULN, or if hepatic metastases were present, alkaline phosphatase <5 x ULN); adequate hematopoiesis (white blood cell count 
4 x 109/l, neutrophil count 1.5 x 109/l, platelet count 100 x 109/l, hemoglobin 10 g/dl); no chemotherapy within the last 4 weeks; no active or uncontrolled infection; absence of pregnancy or lactation; no known central nervous system metastases or carcinomatous meningitis; no concurrent uncontrolled non-malignant diseases (uncontrolled high blood pressure, unstable angina, myocardial infarction within the last 6 months or serious uncontrolled cardiac arrhythmia) or psychiatric conditions that might place patients at a risk during participation in an investigational treatment. Pre-treatment evaluation included a complete medical history, physical examination, electrocardiography, chest x-ray, ultrasound of the abdomen and computed tomography of the abdomen and/or thorax in cases based on assessable target lesions. Complete blood cell counts, blood chemistry, serum tumor markers, carcino-embryogenic antigen and cancer antigen 19–9 levels were obtained at baseline and subsequently after every two cycles.
A treatment cycle consisted of CPT-11 180 mg/m2 on days 1 and 15; 5-FU 425 mg/m2 on days 1, 2, 15 and 16; and FA 20 mg/m2 on days 1, 2, 15 and 16, every four weeks. CPT-11 was administered as a 90-minute intravenous infusion in 250 ml saline solution with appropriate premedication. 5-Hidroxytriptamine-3 antagonists ondansetron, granisetron or tropisetron were administered intravenously, 30 minutes before the infusion of CPT-11 for prophylaxis and treatment of nausea and vomiting. Loperamide was administered to patients at the earliest signs of diarrhea that occurred more than 12 hours after CPT-11 infusion. Initially the drug was prescribed at a dose of 4 mg after the first loose bowel movement and subsequently at 2 mg every 2 hours until the diarrhea was resolved for at least 12 hours.
A complete response (CR) was defined as the total disappearance of all evidence of tumor for at least 4 weeks (6). A partial response (PR) was defined as a greater-than-50% reduction in the products of the bidimensional indicator lesion(s) that lasted for at least 4 weeks. Progressive disease (PD) was defined as the appearance of a new lesion(s) and/or increase in tumor size by at least 25% of the pre-treatment measurements or significant clinical deterioration that could not be attributed to adverse drug effects or other medical conditions besides colorectal cancer. Stable disease (SD) was defined as the failure to meet CR, PR or progression criteria (6). Patients were evaluated for toxicity and were graded according to the National Cancer Institute (NCI) Common Toxicity Criteria (7). The duration of response was defined as the interval between the time of the best response and the time of documented disease progression.
Statistical Methods
Time to disease progression (TTP) was measured from the date of the first chemotherapy to the time of progression. Overall survival (OS) was calculated from the date of first chemotherapy to the death of patient irrespective of the cause. TTP and OS curves were constructed by the Kaplan–Meier method (8,9). Statistical Package for Social Sciences (SPSS) v.6.0 for Windows was used to analyze the data (10).
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this study, 28 consecutive patients with advanced stage CRC were examined from April 2000 to March 2002. Of these, 17 (60.7%) were male and 11 (39.3%) were female. The median age of the patients was 51 years (range, 30–74 years). The patients’ characteristics are listed in Table 1. Thirteen patients had colon adenocarcinoma while 15 patients had rectal adenocarcinoma. Six patients (21.4%) had mucinous and two (7.4%) patients had signet ring cell histology. Six (21.4%) patients had well-differentiated adenocarcinoma, 13 (46.4%) had intermediately-differentiated adenocarcinoma and four (14.3%) had poorly differentiated adenocarcinoma. The differentiation could not be assessed in five (17.9%) patients. Eleven patients (34.4%) were initially detected with advanced disease (stage IV, Dukes’ stage D). Of the remaining patients (65.6%), 25% had localized disease (stage II, Dukes’ stage B) and 25% had locally advanced disease (stage III, Dukes’ stage C), at the time of first diagnosis. Fourteen patients (50%) received prior 5-FU based adjuvant treatment. Eighteen patients (64.3%) received the treatment as first line, while seven (25%) received it as second line and three (10.7%) as third line.
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An overall objective response rate of 21.5% (1 CR and 5 PR) was achieved in the patient group. The overall response rate in 18 patients with measurable disease, receiving the treatment as first line was 27.7%. The median response duration was 10.5 months (range, 3–19 months). An additional 28.6% of the patients had stable disease for a median duration of 6.5 months (range, 3–8 months). Median TTP was 4.5 months (range 1–22+ months) (Fig. 1).
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A total of 119 cycles with a median of 4.0 cycles (range 1–8) were administered to the patients. The toxicities recorded represent the maximum grade seen for a given patient in all cycles of chemotherapy. Except for a single patient who died with grade 4 neutropenic fever, the principle toxicity was gastrointestinal. Grade 3–4 diarrhea was observed in 3.5 % of the patients. The adverse events are listed in Table 2.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The topoisomerase-1 inhibitors represent a promising new family of anti-neoplastic compounds (11,12). CPT-11 is a semisynthetic water-soluble derivative of camptothecin that rapidly esterifies in vivo to SN-38, an active metabolite that contributes significantly to the anti-tumor activity of the drug. The levels of topoisomerase-1 are detected 14- to 16-fold higher in colon cancer cells than in normal tissue, suggesting that this enzyme may be an important target in the treatment of colorectal cancer (11–13). Based on the phase I studies, a dosage schedule of 350 mg/m2 once every 3 weeks was selected in Europe, while a dosage of 125–150 mg/m2 every 4 weeks followed by a 2-week rest period was selected in USA for phase II studies (14–17). The Japanese researchers used CPT-11 at a dose of 100 mg/m2 weekly or 150 mg/m2 biweekly. We selected a biweekly schedule with CPT-11 at a dose of 180 mg/m2 plus bolus 5-FU and FA due to the ease of application and cost of administration (14–20).
In a previous study we observed a 14% response rate in patients with CRC treated with weekly CPT-11 as second line (21). In the present trial, we observed a 28% objective response rate in patients receiving the treatment as first line. At a 95% confidence interval this corresponds to a response rate of 18–47%. Although the range is too broad it is close to the response rates reported with classical bolus IFL regimen (Saltz regimen) and infusional regimens such as infusional 5-FU plus FA and CPT-11 (FOLFIRI) (22). Hematological and non-hematological toxicities were acceptable with appropriate management (23,24). Interestingly, the gastrointestinal toxicity did not increase by the combination regimen when compared to CPT-11 as a single agent (19–22). Responses to the treatment were moderately durable, with a median duration of 10.5 months and longest response duration was 19 months. We concluded that considering the ease of bolus application every 2 weeks instead of a weekly schedule and reduction in the cost by avoiding ports and pumps, coupled with reduced hospital visits, this regimen seems to be a viable alternative for the patients with advanced stage CRC without increasing the toxicity.
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FOOTNOTES |
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+ For all reprints and correspondence: Suayib Yalcin, Department of Medical Oncology, Institute of Oncology, Hacettepe University, Sihhiye 06100, Ankara, Turkey. E-mail: syalcin{at}hacettepe.edu.tr
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Received April 3, 2003; accepted October 6, 2003
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