Japanese Journal of Clinical Oncology Advance Access originally published online on August 24, 2007
Japanese Journal of Clinical Oncology 2007 37(9):686-691; doi:10.1093/jjco/hym091
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© 2007 Foundation for Promotion of Cancer Research
Efficacy and Safety of an Irinotecan plus Bolus 5-Fluorouracil and L-Leucovorin Regimen for Metastatic Colorectal Cancer in Japanese Patients: Experience in a Single Institution in Japan
Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
For reprints and all correspondence: Takayuki Yoshino, Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan; E-mail: t.yoshino{at}scchr.jp
Received January 4, 2007; accepted May 17, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: Short-term infusion of 5-fluorouracil with leucovorin in combination with irinotecan or oxaliplatin has been considered as standard treatment for metastatic colorectal cancer. However, until infusion of 5-fluorouracil regimens and oxaliplatin was approved for the treatment of metastatic colorectal cancer in Japan early in 2005, combination of irinotecan with bolus 5-fluorouracil/leucovorin had been the standard treatment. This retrospective study evaluates the efficacy and safety of a modified irinotecan with bolus 5-fluorouracil/leucovorin regimen in Japanese colorectal cancer patients.
Methods: Forty-six patients untreated with chemotherapy for metastatic colorectal cancer received a modified form of the irinotecan with bolus 5-fluorouracil/leucovorin regimen, consisting of intravenous irinotecan (100 mg/m2) and L-leucovorin (10 mg/m2), and then 5-fluorouracil 500 mg/m2 as an intravenous bolus infusion, weekly for 4 weeks, repeated every 6 weeks until progression or unacceptable toxicity.
Results: The overall response rate was 48% (95% confidence interval, 34–62%), and 48% of patients had stable disease. Median progression-free survival was 8.3 months and overall survival was 20.3 months. The incidence of grade 3 or 4 toxicity was as follows: neutropenia, 50%; diarrhea, 4%; fatigue, 13%; nausea, 7%; and vomiting, 7%. Neither treatment-related nor all-cause mortality occurred within 60 days of chemotherapy initiation. Despite the limited availability of oxaliplatin, 29 patients received an oxaliplatin-based regimen after progression.
Conclusion: A modified irinotecan plus bolus 5-fluorouracil/L-leucovorin regimen was an active and well-tolerated regimen in Japanese patients with advanced colorectal cancer, showing a different toxicity profile from Western patients.
Key Words: colorectal cancer • 5-fluorouracil • irinotecan • L-leucovorin • IFL regimen
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Approximately 92 000 new cases of colorectal cancer (CRC) are diagnosed each year in Japan, of which 61 000 are colon and the remainder rectal cancers. In 2004, more than 40 000 Japanese died of CRC (1).
Irinotecan, a potent inhibitor of topoisomerase I, extends survival significantly as compared with the best supportive care or 5-fluorouracil (5-FU) infusion as second-line therapy for colorectal cancer. Three pivotal phase III trials demonstrated combined irinotecan plus 5-FU/leucovorin (LV) compared with 5-FU/LV alone in the first-line treatment provided a survival benefit, with a median overall survival time of 12.6–16.9 to 14.8–20.1 months (2–4). At that point, irinotecan in combination with either bolus or infusion of 5-FU/LV had been considered the standard of care as first-line treatment.
Despite favorable initial reports, randomized trials have suggested that the irinotecan plus bolus 5-FU/LV (IFL) regimen may be more toxic than originally suspected. In two United States Cooperative Group trials (one for metastatic CRC, the other in the adjuvant setting), unacceptably high incidences of early treatment-related death were noted, leading to suspension of accrual in both studies (5,6). The patients who died had shown similar clinical course (dehydration, neutropenia, and sepsis), with the majority of the deaths occurring during the first 6 weeks of therapy or shortly thereafter (7). Subsequently, a reduced-dose IFL regimen consisting of irinotecan 100 mg/m2 and bolus 5-FU 400 mg/m2 plus L-leucovorin 20 mg/m2, was developed, showing a lower incidence of severe toxicity as compared with original IFL regimen in treatment-related or 60-day all-cause death. The reduced-dose IFL was associated with a significantly worse response rate, progression-free survival, and overall survival, compared with FOLFOX4 (oxaliplatin plus infusion of 5-FU/LV) (8). Moreover, a recent randomized phase III study has shown that infusion of 5-FU regimens (FOLFIRI) may be a safer option and superior to bolus 5-FU regimens in terms of progression-free and overall survival (9). As a result, either the original IFL or the reduced-dose IFL regimen should no longer be considered as an appropriate choice for irinotecan/5-FU/LV therapy.
Despite publication of these data, neither infusion of 5-FU regimens nor oxaliplatin were approved for metastatic CRC in Japan until early 2005, so the IFL regimen had been considered as the standard treatment for metastatic CRC, instead of FOLFIRI or FOLFOX. A previously reported single phase I and single phase I/II trial of a modified form of the IFL regimen in Japanese patients with metastatic colorectal cancer demonstrated that this modified regimen, whose recommended doses were irinotecan 100 mg/m2, 5-FU 500 mg/m2, and L-LV 10 mg/m2 or 25 mg/body, was highly active, with a response rate of 44–69% and median time to progression of 7.8 months (10,11). However, the efficacy and toxicity profile of this modified IFL regimen in Japanese patients has remained unclear because of the low numbers of patients included in these studies. The aim of the retrospective analysis is to evaluate efficacy and toxicity of the modified IFL regimen as a first-line treatment against metastatic CRC in Japanese patients.
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PATIENTS AND METHODS |
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Patient Selection
The selection criteria for inclusion in this retrospective analysis were: histologically or cytologically proven metastatic and unresectable colorectal adenocarcinoma; no prior chemotherapy or receiving adjuvant chemotherapy completed at least 6 months before; an age of
20 to 
75; an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2; a leukocyte count of 3000–12 000 cells/µl; a hemoglobin level of 8 g/dl; >100 000 platelets/µl; a serum bilirubin level of 1.1 mg/dl; serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) level of 100 U/l; a serum creatinine level of <1.1 mg/dl (for men) or 0.8 mg/dl (for women). Patients who had an active extracolonic malignancy or had received prior radiotherapy were also excluded.
Treatment Plan
The treatment schedule consisted of irinotecan 100 mg/m2 given intravenously as a 90-min infusion, L-leucovorin 10 mg/m2 as an intravenous (i.v.) bolus, and then 5-FU 500 mg/m2 as an i.v. bolus infusion, given once every week for 4 weeks, and repeated every 6 weeks (modified IFL regimen). All patients routinely received 3 mg of granisetron plus 8 mg dexamethasone in a 30 min intravenous infusion before administration of irinotecan. Treatment continued until disease progression, unacceptable toxicity, or patient refusal. Whenever severe adverse events occurred, the doses were adjusted to accommodate individual levels of tolerance based on the physician's assessment. Any grade 3 or 4 adverse events resulted in an approximately 20% dose reduction of irinotecan and bolus 5-FU for subsequent cycles. Persistent grade 2 or worse adverse events delayed therapy until recovery.
The use of colony-stimulating factors was allowed if medically justified. Intensive treatment with loperamide, if needed, was used for diarrhea. Other supportive treatments were given if required.
Evaluation of Patients
We retrospectively reviewed clinical records of patients including characteristics (age, gender, ECOG PS, primary site, number of organs involved, metastatic site, history of primary tumor resection, carcinoembryonic antigen (CEA), and prior adjuvant chemotherapy), dosage, schedule of irinotecan, L-leucovorin and 5-FU, and observed toxicities after the initial treatment. We also evaluated the confirmed response rate, progression-free survival, and overall survival.
All patients underwent physical examination, chest X-ray, and computed tomographic scans of the abdomen, pelvis, and chest before starting treatment at baseline. All patients were included in safety and efficacy analyses. Safety assessment and laboratory tests were performed weekly. The severity of adverse effects was evaluated according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 2.0. Tumors were measured at 6- to 8-week intervals, and response was evaluated according to the response evaluation criteria for solid tumors (RECIST). Relative dose intensities of irinotecan and 5-FU were calculated by dividing the actual delivered dose by the planned dose.
The evaluation of response and progression was based on radiologist-reported measurements. Complete and partial response required subsequent confirmation of response after an interval of at least 4 weeks. All clinical courses including subsequent chemotherapy were surveyed until death or last contact. The Kaplan–Meier method was used to evaluate median duration of treatment, progression-free survival, and overall survival. The median duration of treatment was calculated from the date of starting treatment to the date of disease progression or cessation of treatment for any reason, whichever date occurred first. Progression-free survival was calculated from the date of starting treatment to the earlier date of disease progression or death. Without contradictory dates, patients who were lost to follow-up were assumed to have progressed at the last date of confirmation to be progression free. For patients whose treatments were ceased without progression who had received subsequent surgery or another treatment, progression-free survival was defined as the time from the date of starting treatment to the date of its cessation. Overall survival was calculated from the date of starting treatment to death or last contact. Patients who were lost to follow-up were assumed to have been dead at the last contact. The cutoff dates were October 31, 2006 for progression-free survival and overall survival.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Patient Characteristics
From September 2002 to December 2004, when neither infusion of 5-FU nor oxaliplatin was available in Japan, we administered a modified form an IFL regimen to 57 patients with metastatic CRC in a first-line treatment setting. Eleven patients (19%) were excluded according to the selection criteria. The excluded patients consisted of two patients with neuroendocrine carcinoma, one patient over 75 years old, a patient with an ECOG PS >2, five patients who had inadequate hematological, renal, and liver function, and two patients having extracolonic malignancy.
Characteristics of the 46 selected patients included in this study are shown in Table 1. Their median age was 59 years. Sixty-five percent of the patients had an ECOG PS of 0 at baseline. Seventy-six percent of the patients had at least two organs involved, with the liver being the most common site of metastasis. Because most patients had synchronous metastatic disease at diagnosis, only two of them had received adjuvant therapy.
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Treatment
The median duration of treatment with the modified IFL regimen was 7.9 months. The total number of administrations was 1137 for the 46 patients with a median of 23.5 times per patient (range 4–63).
Dose reduction was required in 11 out of the 46 patients (24%), in three of whom dose reduction was performed at the beginning of the treatment, in four during the first course, in three during the second, and in one during the third. The reasons for dose reduction at initiation were age over 70 years old (two patients out of 11, 18%) and starting treatment immediately after surgery (one of 11, 9%). The main reasons for dose reduction during all treatment periods was toxicity including grade 4 leukopenia (two of 11, 18%), grade 3 fatigue (one of 11, 9%), grade 3 leukopenia (one of 11, 9%), grade 3 diarrhea plus vomiting (one of 11, 9%), grade 2 prolonged nausea (one of 11, 9%), grade 2 weight loss (one of 11, 9%), and grade 4 anemia (one of 11, 9%).
Forty patients (87%) required delayed administration, with the median number being three times, during all treatment periods. The total number of delayed administrations was 162 out of 1299 planned administrations (12%). The reasons for delayed administration were patient preference without toxicity (75 out of 162, 46%), grade 2 leukopenia (37 of 162, 23%), grade 2 nausea (nine of 162, 6%), grade 1 infection without neutropenia (nine of 162, 6%), grade 2 vomiting (five of 162, 3%), grade 3 fatigue (four of 162, 4%), grade 2 diarrhea (two of 162, 1%), grade 2 anemia (two of 162, 1%), grade 2 fatigue (two of 162, 1%), and other reasons (17 of 162, 10%).
Hospitalization due to toxicities was required in six out of the 46 patients (13%). The reasons for hospitalization were grade 3 nausea plus vomiting in two patients (33%), grade 3 diarrhea plus vomiting in one (17%), grade 3 diarrhea in one (17%), grade 4 anemia in one (17%), and grade 3 fatigue in one (17%).
During all treatment periods, the mean doses of irinotecan and 5-FU were 55 mg/m2/week and 290 mg/m2/week, respectively. The mean relative doses of irinotecan and 5-FU were 82 and 87%, respectively.
Efficacy
The confirmed response rate was 48 percent (95% confidence interval, 34–62%) (Table 2). All patients ceased treatment. Forty-two (91%) ceased treatment because of disease progression; the remaining four patients (9%) did so because of complete response in one patient and subsequent rescue surgeries after tumor shrinkage in three patients. Thirty-six patients (78%) were dead. Median progression-free survival was 8.3 months and median overall survival was 20.3 months, with a median follow-up time among survivors of approximately 30 months. Progression-free survival and overall survival curves are shown in Figure 1.
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Adverse Events
The worst grade of toxicity per patient is shown in Table 3. Grade 3 or 4 fatigue occurred in six patients (13%), and grade 3 or 4 nausea and vomiting in three patients (7%), respectively. Two patients (4%) had grade 3 or 4 diarrhea. Moreover, the incidence of grade 4 neutropenia was 22%, while febrile neutropenia did not occur. Neither treatment-related nor 60-day all-cause mortality was seen in this study.
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Second-Line Therapy
Among patients with follow-up data, 39 patients (85%) received subsequent chemotherapy after first-line treatment. Twenty-nine patients (63%) received an oxaliplatin-based regimen, in spite of the limited availability of that agent in Japan until April 2005, because efficacy and safety data of oxaliplatin with bolus 5-FU plus L-leucovorin in Japanese patients had been reported and we treated the patients with this regimen who had failed to the IFL regimen since May 2003, after informed consent from each patient and approval of the compassionate use of oxaliplatin by the clinical practice committee in our institution had been obtained.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Our retrospective study assessed the efficacy and safety of a modified IFL regimen in Japanese patients with previously untreated metastatic colorectal cancer. The patient baseline characteristics in this study were similar compared with Western studies except for the incidence of prior adjuvant chemotherapy. The incidence of adjuvant chemotherapy was lower, not only in this study, but also in another Japanese study (4–5%), as compared with an incidence of 11–28% in Western countries (3,8–13). This difference might influence the clinical outcome, because the overall response rate (48%) was higher than originally reported in the United States (39%), but similar to those reported in Japan (44–69%) (3,10,11).
The toxicity profile for the regimen, especially the lower incidence of diarrhea, might be notable in comparison with either original or reduced-dose IFL regimens. Although there are limitations in comparing the results of different studies and our findings were based on a retrospective analysis in the single institution, one of the potential reasons for the difference in the incidence of diarrhea of this regimen is 5-FU tolerability. A bridging study of uracil/tegafur (UFT) plus an oral LV regimen in Japanese and American patients demonstrated that the incidence of diarrhea of grade 3 or higher in the Japanese was lower than that in the Americans (9 vs 22%, respectively) (14). Other reasons for the lower incidence of diarrhea in the Japanese patients receiving the modified IFL regimen might be associated with the lower dose of irinotecan at 100 mg/m2 weekly. The incidence of diarrhea of grade 3 or higher was 16.4% in patients receiving reduced-dose IFL treatment with weekly irinotecan 100 mg/m2, compared with 19–28% in patients with original IFL treatment in Western countries involving weekly irinotecan at 125 mg/m2 (3,8,9,12,13). Weekly irinotecan at 125 mg/m2 in the original IFL regimen would probably lead to early treatment discontinuation due to severe adverse events. On the other hand, grade 3 or higher neutropenia was observed in 50% of the patients in this study, in whom the incidence was considered to be higher than the incidence of 26.7% in the reduced-dose IFL regimen in the United States (8). Recently, a regional safety comparison between the United States and East Asia in a phase III trial of adjuvant stage III colon cancer, comparing a XELOX regimen (combined oxaliplatin plus capecitabine) with a 5-FU/LV regimen, demonstrated that the relative risk of grade 3 or 4 neutropenia in the United States is slightly lower than that in East Asia (0.96 vs 1.00, respectively) (15). That finding is consistent with this study. However, febrile neutropenia during the treatment did not occur in this study, perhaps because careful safety assessment and laboratory tests were performed weekly before the treatment. Thus, neutropenia of grade 3 or higher was manageable under careful clinical management. As a result, we achieved a longer treatment duration of 7.9 months as compared with 5.5 months originally reported in the United States. Moreover, the reduced-dose IFL regimen showed a similar survival benefit to the original IFL regime as a historical comparison, with a median overall survival time of 16.6 months to 14.8–17.6 months. Therefore, it is suggested that weekly irinotecan at 100 mg/m2 as examined in this study might be appropriate for Japanese patients.
The most impressive finding from this study is an overall survival in excess of 20 months, probably because of the longer progression-free survival of 8.3 months as compared with 7.0 months as originally reported. Additionally, overall survival of patients with advanced colorectal cancer was reported to be strongly correlated with the percentage of patients who received the three drugs, fluorouracil, irinotecan, and oxaliplatin, in the treatment of their disease (16,17). The predicted overall survival was calculated using a mathematical regression model: overall survival (months) = 13.2 + (% patients receiving three drugsx0.1). In our study, 63% of patients received all three drugs, and the predicted overall survival was calculated as 19.5 months (13.2 + 63 x 0.1). Moreover, six arms of four published phase III trials included more than 60% of the patients receiving all three drugs in the course of their treatment, and showed a median overall survival time of 19.3–21.5 months, which was comparable with the overall survival time of 20.3 months shown in our study (13,18–20).
A recent randomized phase III study comparing irinotecan in combination with bolus 5-FU (IFL) to infusion of 5-FU (FOLFIRI) as first-line treatment for metastatic colorectal cancer demonstrated that FOLFIRI was significantly better in terms of progression-free survival, and showed a trend to superior overall survival and a more favorable toxicity profile, as compared with an IFL regimen (9). N9741 randomized phase III studies demonstrated that FOLFOX4 led to superior response rate, time to progression, and overall survival compared with either original or reduced-dose IFL (13). At present, first-line FOLFIRI or FOLFOX have become standards of care for metastatic colorectal cancer patients worldwide. In time, neither original nor reduced-dose IFL regimes should be considered as appropriate treatments.
In conclusion, our results suggest that a modified IFL regimen was an active and well-tolerated treatment for Japanese patients with advanced colorectal cancer, and might show different toxicity profiles than in Western patients, such as a lower incidence of severe diarrhea and a higher incidence of neutropenia without fever.
Conflict of interest statement
None declared.
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References |
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