Japanese Journal of Clinical Oncology Advance Access published online on May 30, 2007
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hym033
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© 2007 Foundation for Promotion of Cancer Research
Serum Total Bilirubin as a Predictive Factor for Severe Neutropenia in Lung Cancer Patients Treated with Cisplatin and Irinotecan
Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, Japan
For reprints and all correspondence: Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. E-mail: isekine{at}ncc.go.jp
Received September 29, 2006; accepted January 5, 2007
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Abstract |
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Objective: To clarify the association between pre-treatment total bilirubin (PTB) level and severe toxicity in patients receiving cisplatin and irinotecan.
Methods: We analyzed retrospectively the relationships of grade 4 neutropenia or grade 3–4 diarrhea and clinical variables including PTB and pre-treatment neutrophil counts (PNC) using a logistic regression model.
Results: One hundred and twenty-seven patients (93 men, 34 women; median age: 61 years; range: 24–74 years) received cisplatin (60 or 80 mg/m2) on day 1 and irinotecan (60 mg/m2) on days 1 and 8 every 3 weeks or on days 1, 8 and 15 every 4 weeks. Grade 4 neutropenia occurred in 29 patients (23%) and grade 3–4 diarrhea occurred in 13 patients (10%). Grade 4 neutropenia was associated with a higher PTB level (odds ratio: 4.9; 95% confidence interval: 1.4–17.7), a higher cisplatin dose (2.8, 1.0–7.8) and a lower PNC (1.5, 1.0–2.3). Grade 3–4 diarrhea was associated with liver metastasis (11.2, 2.2–57.4), a higher cisplatin dose (5.0, 1.2–21.3) and a lower PNC (2.0, 1.1–3.6).
Conclusions: PTB level was associated with the severity of neutropenia caused by cisplatin and irinotecan.
Key Words: irinotecan • toxicity • lung cancer
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Although irinotecan is an active agent against several solid tumors, it sometimes exhibits serious adverse effects, the most common being bone marrow toxicity, in particular leucopenia and neutropenia, and ileocolitis, which leads to diarrhea (1–4). The severity of these toxicities varies greatly between individuals, and thus identifying pre-treatment factors that predict an increased risk for severe toxicities is a critical issue in the treatment of cancer patients undergoing chemotherapy.
Irinotecan needs to be activated by systemic carboxylesterases to SN-38 to exert its anti-tumor activity, which is mediated by the inhibition of topoisomerase I (5). Glucuronidation of SN-38 (SN-38G) by UDP- glucuronosyltransferase (UGT) 1A1 during biliary excretion is the primary route of detoxification and elimination. A higher ratio of plasma SN-38 to SN38-G has been correlated with severe diarrhea, suggesting that the efficiency of SN-38 glucuronidation is an important determinant of toxicity (6–8).
Genetic polymorphisms of the UGT 1A1 gene, such as the number of TA repeats in the TATA box that are associated with reduced transcriptional efficiency and functional activity, have been reported previously (7). Some studies have demonstrated an association between UGT1A1 polymorphisms and the risk for severe toxicity from irinotecan (6, 8–11).
The UGT1A1 enzyme is also responsible for hepatic bilirubin glucuronidation. Serum bilirubin levels, therefore, may reflect UGT1A1 activity and may also be associated with irinotecan activity and toxicity. The pre-treatment serum total bilirubin (PTB) level has been shown to be related to severe neutropenia in patients receiving 350 mg/m2 of irinotecan (8). We extended this observation in patients receiving cisplatin and irinotecan to clarify the association between PTB and severe toxicity, including neutropenia and diarrhea, in these patients.
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PATIENTS AND METHODS |
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Treatment Schedule
The subjects consisted of consecutive lung cancer patients who had received cisplatin and irinotecan therapy at the National Cancer Centre Hospital between February 1999 and May 2004. Irinotecan, diluted in 500 ml of normal saline, was given intravenously over 90 min at a dose of 60 mg/m2 on days 1 and 8 or on days 1, 8 and 15. Cisplatin was given intravenously over 60 min after the irinotecan infusion at a dose of 60 or 80 mg/m2 on day 1 with at least 2500 ml of hydration. The first phase I trial of irinotecan and cisplatin showed that 80 mg/m2 of cisplatin on day 1 and 60 mg/m2 of irinotecan on days 1, 8, and 15 were the recommended dose for phase II trials (12), and this dose schedule was used for subsequent phase II and phase III trials of non-small cell lung cancer (NSCLC) (13,4,14). The second phase I trial of this combination showed that 60 mg/m2 of cisplatin on day 1 and 80 mg/m2 of irinotecan on days 1, 8, and 15 were the recommended dose (15). A phase II trial for small cell lung cancer, however, showed that this dose schedule was too toxic, and thereafter the dose of irinotecan was reduced from 80 to 60 mg/m2 (16). From the above, we used 80 mg/m2 of cisplatin and 60 mg/m2 of irinotecan for patients with NSCLC, and 60 mg/m2 of cisplatin and 60 mg/m2 of irinotecan for the other patients. Administration of irinotecan was omitted if any of the following toxicities were noted on days 8 and 15: a white blood cell count <2.0 x 109/l, a platelet count <75 x 109/l, or grade 1–3 diarrhea. Each course was repeated every 3 or 4 weeks until the occurrence of unacceptable toxicity, disease progression, patient's refusal to continue treatment, or the investigator's medical decision to stop treatment. To control for cisplatin-induced emesis, a 5-HT3 receptor antagonist and dexamethasone were given prior to cisplatin administration.
Study Design
We retrospectively reviewed the patients' clinical records, including patient characteristics (age, sex, Eastern Cooperative Oncology Group performance status, histology of primary disease, clinical stage, prior treatment, evidence of liver metastasis), the dose and schedule of chemotherapy, and pre-treatment complete blood counts and serum chemistry profiles. We defined ‘severe toxicity’ as grade 4 neutropenia or grade 3–4 diarrhea during the first cycle of chemotherapy, in accordance with the NCI-CTC Version 2.0 criteria. All patients were treated as in-patients, and complete blood counts and serum chemistry profiles were assessed at least once a week. PTB was defined as the serum total bilirubin level at fasting just prior to the administration of cisplatin and irinotecan.
Statistical Methods
The Mann–Whitney U test was used to compare the PTB levels of patients who developed severe toxicity and those who did not. Possible explanatory factors were compared using a logistic regression model. A PTB threshold of 
0.7 mg/dl was selected to categorize this variable because a total bilirubin level higher than 0.7 mg/dl has been correlated with a mutated UGT1A1 genotype and the occurrence of grade 4 neutropenia (8). Furthermore, sex, performance status, liver metastasis, prior chemotherapy, treatment schedule and cisplatin dose were defined as categorized variables, and age, AST, ALT and pre-treatment neutrophil count (PNC) were examined as continuous variables. Variables that seemed to be associated with severe toxicity (P < 0.1) were considered for inclusion in a multivariate analysis using a backward stepwise regression model. We performed these analyses using the SPSS statistical package (SPSS version 11.0 for Windows; SPSS Inc., Chicago, IL, USA).
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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A total of 127 consecutive patients with thoracic malignancy received cisplatin and irinotecan therapy. The patient characteristics are listed in Table 1. In all, two patients (1.5%) had stage IIA disease, seven patients (5.5%) had stage IIIA disease, 26 patients (20%) had stage IIIB disease and 85 patients (67%) had stage IV disease. The median PTB level was 0.6 (range, 0.2–2.4) mg/dl and the median PNC was 4.1 (range 1.8–8.5) x 109/l. A total of 93 patients (73%) received the planned doses without skipping the irinotecan administrations on day 8 or 15. Among the remaining 34 patients, the irinotecan on day 8 or 15 was omitted in 27 of 164 (16.5%) planned doses in patients with PTB level
0.7 mg/dl, while in 11 of 34 (32.4%) planned doses in patients with PTB level >0.7 mg/dl (P = 0.053). Thus, the actual irinotecan dose delivered was lower with marginal significance in patients with PTB level >0.7 mg/dl. Grade 4 neutropenia occurred in 29 (23%) patients and grade 3–4 diarrhea occurred in 13 (10%) patients.
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The median PTB level was higher in patients who developed grade 4 neutropenia than in those who did not (0.7 and 0.5 mg/dl, respectively; P = 0.03) (Fig. 1), but PTB was not correlated with the presence or absence of grade 3–4 diarrhea (P = 0.22).
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In a univariate analysis, grade 4 neutropenia was associated with only the PTB level (
0.7 versus >0.7 mg/dl; P = 0.01, Table 2). When PTB level was analyzed as a continuous variable, the association was not significant (OR: 3.74; 95% CI: 0.70–19.9; P = 0.12). In a multivariate analysis, grade 4 neutropenia was associated with the PTB level (0.7 versus >0.7 mg/dl; P = 0.02), the cisplatin dose (P = 0.04), and PNC (P = 0.04, Table 3). In a univariate analysis, grade 3–4 diarrhea was associated with only liver metastasis (P = 0.01, Table 3). We analyzed serum levels of PTB and pre-treatment AST and ALT between patients with (n = 18) or without (n = 109) liver metastasis. The median (range) PTB was 0.6 (0.4–2.4) mg/dl in patients with liver metastasis and 0.6 (0.2–1.2) mg/dl in patients without liver metastasis (p = 0.19). In contrast, the median (range) levels of pre-treatment AST and ALT were 30 (16–114) IU/l and 30 (11–84) IU/l, respectively, in patients with liver metastasis and 21 (11–161) IU/l and 17 (5–266) IU/l, respectively, in patients without liver metastasis (P = 0.0054). In a multivariate analysis, grade 3–4 diarrhea was associated with liver metastasis (P = 0.004), the cisplatin dose (P = 0.03) and PNC (P = 0.03, Table 3).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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This study showed that the PTB level was significantly associated with severity of neutropenia in patients treated with cisplatin and weekly irinotecan. Although irinotecan- induced toxicity can be reduced by skipping irinotecan on day 8, 15, or both, this dose modification is not enough to eliminate severe toxicity completely. In this study irinotecan was more frequently omitted on days 8 and 15 in patients with PTB level >0.7 mg/dl, and therefore, the association between PTB and irinotecan-induced toxicity may be underestimated. Thus, the PTB level, a simple routine measure in clinical practice, can be a useful predictive marker for irinotecan-induced toxicity.
The most compelling evidence for a genetic marker of toxicity caused by irinotecan therapy is seen with the UGT gene. In some retrospective pharmacogenetic studies, patients with at least one UGT1A1*28 allele encountered severe irinotecan-induced toxicity, compared with those with the wild-type genotype who were homozygous for the 6 TA repeat allele (6,9,10). In a prospective study, the UGT1A1 genotype was strongly associated with severe neutropenia in patients treated with irinotecan (8). More than 30 polymorphic variations have been reported to date for the UGT1A1 gene (17). Novel polymorphisms (*1, *6, *28,*60 and so on) in UGT1A1 and the functional characterization of known variants are helpful in elucidating the role of UGT1A1 genetic variation in irinotecan toxicity (18). The FDA has approved a UGT1A1 molecular assay test to detect polymorphisms in the UGT1A1 gene in clinical practice, so that patients with particular UGT1A1 gene variations that raise the risk of certain adverse effects can receive safer doses of irinotecan. This assay is intended to aid physicians to make decisions for individualized patient. Nevertheless, other important factors that affect dosing should also be considered, because severe toxicity sometimes occurs even in patients without particular UGT1A1 gene variations that place them at risk.
The UGT1A1 enzyme is responsible for hepatic bilirubin glucuronidation. A polymorphism in the UGT1A1 promoter has been linked with reduced UGT1A1 expression and is consequently associated with familiar hyperbilirubinemia. Accordingly, bilirubin levels may be associated with UGT1A1 function. The PTB level may reflect the total function of some polymorphisms in the UGT1A1 region and may be used as a simple and available surrogate marker for UGT1A1 function.
Recent studies have revealed that two major hepatic UGT, UGT1A1 and UGT1A9, and extra-hepatic UGT1A7 are involved in SN-38 glucuronidation (SN-38G) (7,19). The efficacy of irinotecan is possibly affected by the activity of these genes. Thus, the product of some genetic polymorphisms in several genes may be a better pharmacogenetic marker for selecting patients who may not respond favorably to irinotecan-containing chemotherapy.
Cisplatin and irinotecan therapy is a standard regimen for both advanced non-small cell and small cell lung cancer (4). A randomized trial of irinotecan with or without cisplatin in patients with non-small cell lung cancer showed that grade 4 neutropenia was observed more frequently in the cisplatin–irinotecan arm (37%) than in the irinotecan-alone arm (8%), whereas grade 3 and 4 diarrhea was observed at the same frequency in both arms. In the present study, a higher cisplatin dose was associated with both grade 4 neutropenia and grade 3 and 4 diarrhea. The addition of cisplatin to another anti-cancer agent aggravated diarrhea in phase III studies (20), although diarrhea was moderate in cisplatin monotherapy observed in clinical trials (21). Thus, a higher dose of cisplatin seems to be associated with diarrhea, but the mechanism for this association remains unclear.
In this study PTB level was associated with the severity of neutropenia, but not with severity of diarrhea. When SN-38G is excreted in the bile and intestines, the bacteria-derived enzyme beta-glucuronidase converts SN-38G back into SN-38 (22,23). Presence of SN-38 in the stool is associated with the occurrence of severe diarrhea as a result of the direct enteric injury caused by SN-38 (24). This phenomenon probably occurs because UGT1A1 is not involved in this step.
Liver metastasis was associated with the development of grade 3–4 diarrhea in both univariate and multivariate analyses in this study. This may be explained by small, but statistically significant differences in the pre-treatment transaminase levels between patients with or without liver metastasis. However, in contradiction to this explanation are that: (1) neither the pre-treatment AST nor ALT level was associated with grade 3–4 diarrhea in this study, and (2) in dose-finding studies of irinotecan monotherapy in patients with liver dysfunction, patients were categorized into subgroups by the PTB and serum AST and ALT levels, criteria of which were three times or five times the upper limit of normal (25,26). Thus, the small difference in the AST and ALT levels in this study is unlikely to be significant from the medical point of view.
The PNC in patients who developed grade 3–4 diarrhea was slightly lower than that in the other patients and the PNC was associated with grade 3–4 diarrhea in the multivariate analysis. Neutrophils play an important role in maintaining the mucosal barrier of the intestine and inflammatory responses against mucosal damage (27). Thus, reduced number, dysfunction, or both, of neutrophils may lead to impairment of the mucosal integrity, rendering these patients prone to develop diarrhea. In addition, the decreased number of neutrophils in the blood is closely related to malnutrition associated with cancer (28), which may in turn be associated with enhanced toxicity during chemotherapy with irinotecan and cisplatin.
In conclusion, the PTB level was significantly associated with severity of neutropenia in patients treated with cisplatin and weekly irinotecan. This will provide a simple and useful marker required for individualized therapy to reduce the risk of harmful chemotherapy.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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Acknowledgments |
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We thank Mika Nagai for her assistance with the preparation of the manuscript.
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References |
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