Abstract
An association between UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) polymorphisms and irinotecan-induced neutropenia has been previously reported. In this study, we assessed the clinical usefulness of testing for UGT1A1 polymorphisms prior to the initiation of irinotecan-based chemotherapy, as this remains a controversial subject. A total of 136 lung cancer patients who were treated with a combination of nedaplatin and irinotecan as initial chemotherapy were assessed. Following exclusion of patients exhibiting low UGT1A1 enzyme activity, 70 patients were treated after UGT1A1 polymorphism testing (test group) and 66 patients were treated without UGT1A1 polymorphism testing (non-test group). We retrospectively analyzed and compared the adverse events between the test and the non-test groups and observed no reduction in hematological or non-hematological toxicities in the test group compared to that in the non-test group. Of the 9 patients with grade 4 or 5 non-hematological toxicity, 6 patients had febrile neutropenia (FN). All the patients with FN were aged >70 years. The incidence of adverse events was significantly higher among patients aged >70 years compared to that among younger patients. In conclusion, in patients treated with nedaplatin and irinotecan combination chemotherapy, UGT1A1 polymorphism testing prior to the initiation of chemotherapy did not reduce the incidence of adverse events. Therefore, UGT1A1 polymorphism testing alone may not be sufficient to predict the occurrence of severe adverse events and it may be more important to effectively manage adverse events, particularly in elderly patients.
Keywords: lung cancer, UDP glucuronosyltransferase 1 family, polypeptide A1, irinotecan, nedaplatin, diarrhea, neutropenia
Introduction
Irinotecan is currently used as the standard chemotherapeutic agent for lung and colorectal cancer and its efficacy is dependent upon its activation by liver carboxyesterases to form the active metabolite SN-38. SN-38 is eliminated predominantly by a glucuronidation reaction to SN-38G. This glucuronidation reaction is mediated primarily by UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) (1). Irinotecan, SN-38 and SN-38G are all secreted into the bile by hepatocytes, with subsequent excretion into the small intestine (2). Dose-limiting toxicities of irinotecan are diarrhea and neutropenia and reduced enzyme activity and SN-38G formation is closely associated with severe toxicities (3). Genetic polymorphisms of UGT1A1 result in reduced enzyme activity, leading to decreased glucuronidation of SN-38 and, ultimately, in increased toxicity by irinotecan (3).
The association between UGT1A1*28 polymorphism and irinotecan-induced toxicities has been investigated (4). In East Asian populations, including the Japanese, the association between UGT1A1*28 and *6 polymorphisms and irinotecan-induced toxicities was previously investigated (3,5,6). In colorectal cancer, irinotecan-induced grade 3/4 neutropenia occurs more frequently in patients with the homozygous UGT1A1*28 mutation (*28/*28), the homozygous UGT1A1*6 mutation (*6/*6) or the double heterozygous mutation (*1/*28 and *1/*6), compared to patients with the wild-type of UGT1A1*28 and *6 (*1/*1 and *1/*1), the heterozygous UGT1A1*28 mutation (*1/*28) or the heterozygous UGT1A1*6 mutation (*1/*6) (7–9). These findings were similar for Japanese patients (9,10) and individuals with low enzyme activity constitute ~10% of the Japanese population (10,11).
The usefulness of UGT1A1 polymorphism testing prior to the initiation of chemotherapy in patients with lung cancer has not been clearly determined. Therefore, in this study, we aimed to assess the effect of excluding patients with low enzyme activity on the frequency and severity of irinotecan-induced toxicities.
Materials and methods
Study design
We retrospectively analyzed the treatment-related adverse events in patients receiving nedaplatin and irinotecan combination chemotherapy and compared the incidence of adverse events between two patient groups, according to whether the patients underwent UGT1A1 polymorphism testing prior to treatment. The patients in one group (test group) were those who underwent UGT1A1 polymorphism testing prior to treatment initiation and were found not to have low enzyme activity. Patients with low enzyme activity were excluded from the study. In the second group (non-test group) the patients proceeded to receive treatment without prior UGT1A1 polymorphism testing.
The adverse events were assessed according to the Common Terminology Criteria for Adverse Events, version 4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). Hematological (leukopenia, neutropenia, thrombocytopenia and anemia) as well as non-hematological toxicities [diarrhea and febrile neutropenia (FN)] were assessed.
Patients
Between November, 2007 and February, 2011, a total of 136 patients with lung cancer were assessed. The patients were all treated with a combination of nedaplatin and irinotecan as initial chemotherapy in the Kanagawa Cancer Center. Patients who received adjuvant chemotherapy were included in this study. No patient developed severe major organ dysfunction. A total of 70 patients were finally included in the test group and 66 patients in the non-test group.
Treatment
All the patients were treated with nedaplatin and irinotecan combination chemotherapy. The regimen consisted of four cycles of 50 mg/m2 nedaplatin on days 1 and 8 and 50 mg/m2 irinotecan on days 1 and 8, every 4 weeks (12,13). Cisplatin and irinotecan combination chemotherapy is known to be effective for small-cell and non-small-cell lung cancer (14,15). In Japan, cisplatin and irinotecan combination chemotherapy is one of the standard chemotherapy regimens used for the treatment of lung cancer. Nedaplatin is an analogue of cisplatin, with relatively low neurotoxicity and nephrotoxicity and high in vivo bioavailability. Three-dimensional analysis models have demonstrated a remarkable synergistic interaction of platinum administration concurrently with irinotecan; this synergistic interaction has also been observed with the combination of nedaplatin and irinotecan (16).
Testing for UGT1A1 polymorphism
UGT1A1 polymorphisms were identified with a modified loop-hybrid mobility shift assay. When loop-hybrids using a Cy5-tagged probe for the *28 and *6 locus were combined and used for mobility shift assay, simultaneous typing of the *28 and *6 variants was achieved in a single lane (17).
Statistical analysis
Differences between groups were assessed with the t-test and the Chi-square test. P<0.05 was considered to indicate statistically significant differences.
Results
UGT1A1 polymorphism
We tested for UGT1A1 polymorphisms in 134 lung cancer patients in the Kanagawa Cancer Center and identified 9 patients (6.7%) with low enzyme activity. The results of the UGT1A1 polymorphism testing are presented in Table I.
Table I.
Results of UGT1A1 polymorphism testing.
| UGT1A1*6 | |||
|---|---|---|---|
|
|
|||
| UGT1A1*28 | *1/*1 (wild-type) | *1/*6 (heterozygous) | *6/*6 (homozygous) |
| *1/*1 (wild-type) | 72 | 27 | 4 |
| *1/*28 (heterozygous) | 26 | 4 | - |
| *28/*28 (homozygous) | 1 | - | - |
Of the 134 lung cancer patients who were tested for UGT1A1 polymorphisms, 9 (6.7%) exhibited low enzyme activity. UGT1A1, UDP glucuronosyltransferase 1 family, polypeptide A1.
Following exclusion of the 9 patients exhibiting low enzyme activity, 70 patients were treated with a combination of nedaplatin and irinotecan as initial chemotherapy after UGT1A1 polymorphism testing. The remaining 64 patients were administered a different therapy or were not treated. A further 66 patients were also treated with a combination of nedaplatin and irinotecan as initial chemotherapy, but without UGT1A1 polymorphism testing prior to treatment initiation.
Patient characteristics
The characteristics of the 136 study patients (test group, n=70; non-test group, n=66) who were treated with a combination of nedaplatin and irinotecan as initial chemotherapy are summarized in Table II. The median age of the total study group was 66 years (range, 37–83 years). The median age of the test group was higher compared to that of the non-test group, but there was no difference in age distribution. The tumors were classified as 68 adenocarcinomas, 27 squamous cell carcinomas and 23 small-cell carcinomas. A total of 98 patients had clinical stage III–IV disease, according to the criteria of the Union for International Cancer Control, version 7 (18). After surgery, 30 patients received adjuvant chemotherapy. The median number of treatment cycles was 3 (range, 1–4 cycles). Adjuvant chemotherapy was administered to 27 patients (38%) in the test group and to only 3 patients (5%) in the non-test group.
Table II.
Patient characteristics.
| Characteristics | Total, no. (%) (n=136) | Test groupa, no. (%) (n=70) | Non-test groupb, no. (%) (n=66) |
|---|---|---|---|
| Age, years median (range) | 66 (37–83) | 68 (37–80) | 64 (39–83) |
| Gender | |||
| Male | 91 (67) | 45 (64) | 46 (70) |
| Female | 45 (33) | 25 (36) | 20 (30) |
| ECOG performance status | |||
| 0–1 | 130 (96) | 69 (99) | 61 (92) |
| 2 | 6 (4) | 1 (1) | 5 (8) |
| Pathology | |||
| Adenocarcinoma | 68 (50) | 35 (50) | 33 (50) |
| Squamous cell carcinoma | 27 (20) | 15 (22) | 12 (18) |
| Small-cell carcinoma | 23 (17) | 10 (14) | 13 (20) |
| Others | 18 (13) | 10 (14) | 8 (12) |
| Clinical stage (UICC-7) | |||
| I/II | 2 (2) | 0 (0) | 2 (3) |
| III | 33 (24) | 11 (16) | 22 (33) |
| IV | 65 (48) | 28 (40) | 37 (56) |
| Reccurence | 6 (4) | 4 (6) | 2 (3) |
| Adjuvant | 30 (22) | 27 (38) | 3 (5) |
| UGT1A1 polymorphism | |||
| Wild-type | 44 (32) | 44 (63) | 0 (0) |
| Heterozygous | 26 (19) | 26 (37) | 0 (0) |
| Non-test | 66 (49) | 0 (0) | 66 (100) |
Patients who underwent testing for UGT1A1 polymorphism prior to treatment and were not found to exhibit low enzyme activity.
Patients who did not undergo UGT1A1 polymorphism testing.
ECOG, Eastern Cooperative Oncology Group; UICC, Union for International Cancer Control; UGT1A1, UDP glucuronosyltransferase 1 family, polypeptide A1.
Toxicities
The adverse events are listed in Table III. Of the total study population, grade 4 neutropenia occurred in 27 patients (19.9%), ≥grade 3 diarrhea in 9 patients (6.6%) and ≥grade 3 FN in 12 patients (8.8%). There were 4 treatment-related deaths (2.9%): 2 patients succumbed to FN and diarrhea and 2 patients succumbed to interstitial pneumonitis (IP). In the test group, grade 4 neutropenia occurred in 14 patients (20.0%), ≥grade 3 diarrhea in 6 patients (8.6%) and ≥grade 3 FN in 5 patients (7.1%). In the non-test group, grade 4 neutropenia occurred in 13 patients (19.7%), ≥grade 3 diarrhea in 3 patients (4.5%) and ≥grade 3 FN in 7 patients (10.6%). There was no significant reduction in any of the adverse effects in the test group compared to the non-test group.
Table III.
Comparison of adverse events between patient groups.
| Adverse events | Total, no. (%) (n=136) | Test group, no. (%) (n=70) | Non-test group, no. (%) (n=66) | P-value |
|---|---|---|---|---|
| Leukopenia | ||||
| Grade ≥3 | 37 (22.1) | 19 (27.1) | 18 (27.2) | 0.99 |
| Grade ≥4 | 8 (5.9) | 7 (10.0) | 1 (1.5) | 0.037 |
| Neutropenia | ||||
| Grade ≥3 | 78 (57.3) | 38 (54.3) | 40 (60.6) | 0.46 |
| Grade ≥4 | 27 (19.9) | 14 (20.0) | 13 (19.7) | 0.96 |
| Thrombocytopenia | ||||
| Grade ≥3 | 28 (20.6) | 14 (20.0) | 14 (21.2) | 0.83 |
| Grade ≥4 | 11 (8.1) | 8 (11.4) | 3 (4.5) | 0.14 |
| Anemia | ||||
| Grade ≥3 | 20 (14.7) | 10 (14.3) | 10 (15.1) | 0.88 |
| Grade ≥4 | 1 (0.7) | 1 (1.4) | 0 (0.0) | 0.51 |
| Hematological toxicities | ||||
| Grade ≥3 | 83 (61.0) | 40 (57.1) | 43 (65.2) | 0.34 |
| Grade ≥4 | 28 (20.6) | 15 (21.4) | 13 (19.6) | 0.80 |
| Febrile neutropeniaa | ||||
| Grade ≥3 | 12 (8.8) | 5 (7.1) | 7 (10.6) | 0.48 |
| Grade ≥4 | 6 (4.4) | 4 (5.7) | 2 (3.0) | 0.37 |
| Diarrhea | ||||
| Grade ≥3 | 9 (6.6) | 6 (8.6) | 3 (4.5) | 0.28 |
| Grade ≥4 | 3 (2.2) | 2 (2.9) | 1 (1.5) | 0.52 |
| Non-hematological toxicities | ||||
| Grade ≥3 | 38 (27.9) | 24 (34.3) | 14 (21.2) | 0.089 |
| Grade ≥4 | 9 (6.6) | 7 (10.0) | 2 (3.0) | 0.097 |
| Treatment-related mortality | 4 (2.9) | 3 (4.3) | 1 (1.5) | 0.33 |
The comparisons between the two groups were performed with the Chi-square test. Adverse events were evaluated with Common Terminology Criteria for Adverse Events, version 4.0.
Febrile neutropenia was treated as a non-hematological toxicity.
We evaluated grade 4 or 5 non-hematological toxicities separately, since, when severe, these toxicities are considered to be the most important in the clinical field. Of the total study population, grade 4 or 5 non-hematological toxicities occurred in 9 patients (6.6%), with 6 patients developing FN and 3 patients developing IP or bowel perforation (Table IV). All 6 patients with FN were elderly (aged ≥70 years) and 5 of these patients developed FN concurrently with ≥grade 3 diarrhea.
Table IV.
Characteristics of 9 patients with severe non-hematological toxicities.
| Patient characteristics | Grade of adverse eventsa | |||||||
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| Age (years) | Gender | UGT1A1 | PS | Pathology | cStage | FN | Diarrhea | Other severe NH toxicitiesb |
|
|
|
|||||||
| 73 | Female | Non-test | 1 | SCC | IV | 4 | - | - |
| 83 | Male | Non-test | 1 | NSCLC | IIIB | 5 | 5 | - |
| 56 | Male | Wild-type | 1 | Adenocarcinoma | IV | - | - | 5c |
| 69 | Male | Wild-type | 1 | SCC | IV | - | - | 5c |
| 72 | Male | Wild-type | 1 | Adenocarcinoma | IV | 5 | 5 | - |
| 73 | Male | Wild-type | 1 | SCC | IV | 4 | 3 | - |
| 77 | Male | *28 heterozygous | 0 | Adenocarcinoma | IV | 4 | 4 | - |
| 67 | Male | *6 heterozygous | 1 | LCNEC | IV | - | - | 4d |
| 78 | Male | *6 heterozygous | 1 | SCLC | IV | 4 | 3 | - |
Adverse events ≥grade 3.
Other grade 4 and 5 adverse events.
Interstitial pneumonitis.
Bowel perforation.
LCNEC, large-cell neuroendocrine carcinoma; FN, febrile neutropenia; NH, non-hematological; UGT1A1, UDP glucuronosyltransferase 1 family, polypeptide A1; PS, performance status; SCC, squamous cell carcinoma; SCLC, small-cell lung cancer; NSCLC, non-small-cell lung cancer.
Comparison of adverse events between elderly and non-elderly patients
We hypothesized that the incidence of severe toxicities may be higher among elderly patients and we compared the incidence of adverse events between the 46 elderly (≥70 years) and the 90 non-elderly (<70 years) patients (Table V). It should be noted that more patients were tested for UGT1A1 polymorphisms in the non-elderly group. The adverse events are listed in Table VI. In the elderly group, grade 4 neutropenia occurred in 14 patients (30.4%), ≥grade 3 diarrhea in 6 patients (13.0%) and ≥grade 3 FN in 8 patients (17.4%). In the non-elderly group, grade 4 neutropenia occurred in 13 patients (14.4%), ≥grade 3 diarrhea in 3 patients (3.3%) and ≥grade 3 FN in 4 patients (4.4%). These adverse events were significantly more frequent among elderly rather than among non-elderly patients. Similarly, other hematological and non-hematological toxicities were more frequent among elderly patients. Therefore, elderly patients exhibited a higher risk for toxicities associated with nedaplatin and irinotecan combination chemotherapy.
Table V.
Characteristics of the elderly and non-elderly patients.
| Characteristics | Total, no. (%) (n=136) | Elderly, no. (%) (n=46) | Non-elderly, no. (%) (n=90) |
|---|---|---|---|
| Age, years median (range) | 66 (37–83) | 74 (70–83) | 63 (37–69) |
| Gender | |||
| Male | 91 (67) | 32 (70) | 59 (66) |
| Female | 45 (33) | 14 (30) | 31 (34) |
| ECOG performance status | |||
| 0–1 | 130 (96) | 44 (96) | 86 (96) |
| 2 | 6 (4) | 2 (4) | 4 (4) |
| Pathology | |||
| Adenocarcinoma | 68 (50) | 26 (57) | 42 (47) |
| Squamous cell carcinoma | 27 (20) | 8 (17) | 19 (21) |
| Small-cell carcinoma | 23 (17) | 7 (15) | 16 (18) |
| Others | 18 (13) | 5 (11) | 13 (14) |
| Clinical stage (UICC-7) | |||
| I/II | 2 (2) | 2 (4) | 0 (0) |
| III | 33 (24) | 12 (26) | 39 (44) |
| IV | 65 (48) | 19 (41) | 28 (31) |
| Recurrence | 6 (4) | 3 (7) | 3 (3) |
| Adjuvant | 30 (22) | 10 (22) | 20 (22) |
| UGT1A1 polymorphism | |||
| Wild-type | 44 (32) | 20 (43) | 24 (27) |
| Heterozygous | 26 (19) | 10 (22) | 16 (18) |
| Non-test | 66 (49) | 16 (35) | 50 (55) |
ECOG, Eastern Cooperative Oncology Group; UICC, Union for International Cancer Control; UGT1A1, UDP glucuronosyltransferase 1 family, polypeptide A1.
Table VI.
Comparison of adverse events between elderly (≥70 years) and non-elderly (<70 years) patients.
| Adverse events | Total, no. (%)(n=136) | Elderly, no. (%)(n=46) | Non-elderly, no. (%)(n=90) | P-value |
|---|---|---|---|---|
| Leukopenia | ||||
| Grade ≥3 | 37 (22.1) | 15 (32.6) | 22 (24.4) | 0.31 |
| Grade ≥4 | 8 (5.9) | 8 (17.4) | 0 (0.0) | 0.001 |
| Neutropenia | ||||
| Grade ≥3 | 78 (57.3) | 31 (67.4) | 47 (52.2) | 0.091 |
| Grade ≥4 | 27 (19.9) | 14 (30.4) | 13 (14.4) | 0.027 |
| Thrombocytopenia | ||||
| Grade ≥3 | 28 (20.6) | 12 (26.1) | 16 (17.8) | 0.26 |
| Grade ≥4 | 11 (8.1) | 7 (15.2) | 4 (4.4) | 0.035 |
| Anemia | ||||
| Grade ≥3 | 20 (14.7) | 8 (17.4) | 12 (13.3) | 0.53 |
| Grade ≥4 | 1 (0.7) | 1 (2.2) | 0 (0.0) | 0.34 |
| Hematological toxicities | ||||
| Grade ≥3 | 83 (61.0) | 33 (71.7) | 50 (55.6) | 0.057 |
| Grade ≥4 | 28 (20.6) | 15 (32.6) | 13 (14.4) | 0.013 |
| Febrile neutropenia | ||||
| Grade ≥3 | 12 (8.8) | 8 (17.4) | 4 (4.4) | 0.016 |
| Grade ≥4 | 6 (4.4) | 6 (13.0) | 0 (0.0) | 0.001 |
| Diarrhea | ||||
| Grade ≥3 | 9 (6.6) | 6 (13.0) | 3 (3.3) | 0.040 |
| Grade ≥4 | 3 (2.2) | 3 (6.5) | 0 (0.0) | 0.037 |
| Non-hematological toxicities | ||||
| Grade ≥3 | 38 (27.9) | 18 (39.1) | 20 (22.2) | 0.037 |
| Grade ≥4 | 9 (6.6) | 6 (13.0) | 3 (3.3) | 0.040 |
| Treatment-related mortality | 4 (2.9) | 2 (4.3) | 2 (2.2) | 0.42 |
When the adverse events were compared by other background factors, such as gender, PS, adjuvant chemotherapy and UGT1A1 polymorphisms, no significant differences in incidence were observed between groups.
Discussion
The association between UGT1A1 polymorphism and the risk of irinotecan-induced toxicity is dose-dependent. In 2005, the US Food and Drug Administration recommended testing for UGT1A1*28 polymorphism for dose regulation of irinotecan. As regards colorectal cancer, studies on the optimal dose of irinotecan for the treatment of patients with low enzyme activity have been conducted (19,20). However, the optimal dose of irinotecan for lung cancer patients with low enzyme activity has not been determined and remains a subject of controversy.
In the present study, we observed no reduction in the incidence of adverse events among patients in the test group compared to those in the non-test group, which may be explained as follows: First, since the number of patients exhibiting low enzyme activity was low, the exclusion of such patients exerted a limited effect on the overall incidence of adverse results. In our UGT1A1 polymorphism testing of 134 patients, only 9 patients (6.7%) exhibited low enzyme activity. In the Japanese population, the frequency of individuals with low enzyme activity was reported to be ~10% (11).
Second, the dose of irinotecan in our study was low, which may explain the lack of significant between-group differences in adverse events. A previous meta-analysis demonstrated that the risks of adverse events with low-dose irinotecan (<150 mg/m2) were similar between patients with UGT1A1 (*1/*1 or *1/*28) (21). However, a later meta-analysis reported that the risk of adverse events was higher, even at low doses of irinotecan (<150 mg/m2), in patients with UGT1A1*28 (*28/*28) compared to those with UGT1A1*28 (*1/*1 or *1/*28) (22). In the present study, the regimen consisted of four cycles of 50 mg/m2 nedaplatin on days 1 and 8 and 50 mg/m2 irinotecan on days 1 and 8, every 4 weeks.
The higher ratio of adverse events in the test group may be attributed to the number of elderly patients in that group. Although there was no between-group difference in age distribution, there were 30 (42%) elderly patients in the test group, but only 16 (24%) in the non-test group. Therefore, elderly patients may be at a higher risk of developing nedaplatin and irinotecan combination chemotherapy-related toxicities compared to non-elderly patients.
Several of the patients with severe toxicities synchronously developed FN and diarrhea. All 9 patients with ≥grade 3 diarrhea had fever. Among the 14 patients with grade 2 diarrhea, 9 patients had fever. Among the 113 patients with grade 0 or 1 diarrhea, 14 patients had fever. Patients with ≥grade 2 diarrhea had fever more frequently compared to patients with grade 0 or 1 diarrhea (P<0.001). Diarrhea may lead to dehydration, which is a risk of severe FN, as is an age of ≥60 years (23,24). Patients with diarrhea are also considered to be at high risk of infection and severe FN.
A meta-analysis demonstrated that the risk of irinotecan-induced diarrhea in patients with UGT1A1 (*28/*28 or *1/*28) was higher compared to that in patients with UGT1A1 (*1/*1) at medium and high doses (25). However, the association between UGT1A1 polymorphism and irinotecan-induced diarrhea has been controversial. In addition to UGT1A1 polymorphisms, an association between irinotecan-induced gastrointestinal toxicity and polymorphisms of the ABCC5, ABCG1 and SLCO1B1 genes has also been reported (26).
The dose-limiting toxicities of irinotecan are diarrhea and neutropenia. Patients with diarrhea are also at a high risk of infection. Therefore, it is important to effectively manage irinotecan-induced diarrhea and neutropenia. High-dose loperamide has been shown to be efficient for managing delayed diarrhea (27,28). Furthermore, the efficacy of oral alkalization for the prevention of irinotecan-induced diarrhea has been reported (29).
Patients with low enzyme activity are at high risk of severe neutropenia. However, with UGT1A1 polymorphism testing alone, it may be difficult to predict the onset of severe adverse events. Regarding the safety and efficacy of irinotecan administration, it is more important to manage adverse events effectively in the clinical field. For elderly patients, in particular, their management while administering irinotecan and nedaplatin combination chemotherapy should be handled with caution. Further investigation on the prevention of irinotecan-induced diarrhea is required.
References
- 1.Iyer L, King CD, Whitington PF, Green MD, Roy SK, Tephly TR, Coffman BL, Ratain MJ. Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest. 1998;101:847–854. doi: 10.1172/JCI915. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Lokiec F, Canal P, Gay C, Chatelut E, Armand JP, Roché H, Bugat R, Gonçalvès E, Mathieu-Boué A. Pharmacokinetics of irinotecan and its metabolites in human blood, bile, and urine. Cancer Chemother Pharmacol. 1995;36:79–82. doi: 10.1007/BF00685737. [DOI] [PubMed] [Google Scholar]
- 3.Minami H, Sai K, Saeki M, Saito Y, Ozawa S, Suzuki K, Kaniwa N, Sawada J, Hamaguchi T, Yamamoto N, Shirao K, Yamada Y, Ohmatsu H, Kubota K, Yoshida T, Ohtsu A, Saijo N. Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese: roles of UGT1A1*6 and *28. Parmacogenet Genomics. 2007;17:497–504. doi: 10.1097/FPC.0b013e328014341f. [DOI] [PubMed] [Google Scholar]
- 4.Iyer L, Das S, Janisch L, Wen M, Ramírez J, Karrison T, Fleming GF, Vokes EE, Schilsky RL, Ratain MJ. UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J. 2002;2:43–47. doi: 10.1038/sj.tpj.6500072. [DOI] [PubMed] [Google Scholar]
- 5.Sai K, Saeki M, Saito Y, Ozawa S, Katori N, Jinno H, Hasegawa R, Kaniwa N, Sawada J, Komamura K, Ueno K, Kamakura S, Kitakaze M, Kitamura Y, Kamatani N, Minami H, Ohtsu A, Shirao K, Yoshida T, Saijo N. UGT1A1 haplotypes associated with reduced glucuronidation and increased serum bilirubin in irinotecan-administered Japanese patients with cancer. Clin Pharmacol Ther. 2004;75:501–515. doi: 10.1016/j.clpt.2004.01.010. [DOI] [PubMed] [Google Scholar]
- 6.Han JY, Lim HS, Shin ES, Yoo YK, Park YH, Lee JE, Jang IJ, Lee DH, Lee JS. Comprehensive analysis of UGT1A1 polymorphisms predictive for pharmacokinetics and treatment outcome in patients with non-small-cell lung cancer treated with irinotecan and cisplatin. J Clin Oncol. 2006;24:2237–2244. doi: 10.1200/JCO.2005.03.0239. [DOI] [PubMed] [Google Scholar]
- 7.Glimelius B, Garmo H, Berglund A, Fredriksson LA, Berglund M, Kohnke H, Byström P, Sørbye H, Wadelius M. Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer. Pharmacogenomics J. 2011;11:61–71. doi: 10.1038/tpj.2010.10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Shulman K, Cohen I, Barnett-Griness O, Kuten A, Gruber SB, Lejbkowicz F, Rennert G. Clinical implications of UGT1A1*28 genotype testing in colorectal cancer patients. Cancer. 2011;117:3156–3162. doi: 10.1002/cncr.25735. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Okuyama Y, Hazama S, Nozawa H, Kobayashi M, Takahashi K, Fujikawa K, Kato T, Nagata N, Kimura H, Oba K, Sakamoto J, Mishima H. Prospective phase II study of FOLFIRI for mCRC in Japan, including the analysis of UGT1A1*28/*6 polymorphisms. Jpn J Clin Oncol. 2011;41:477–482. doi: 10.1093/jjco/hyr001. [DOI] [PubMed] [Google Scholar]
- 10.Yamamoto N, Takahashi T, Kunikane H, Masuda N, Eguchi K, Shibuya M, Takeda Y, Isobe H, Ogura T, Yokoyama A, Watanabe K. Phase I/II pharmacokinetic and pharmacogenomic study of UGT1A1 polymorphism in elderly patients with advanced non-small cell lung cancer treated with irinotecan. Clinical Pharmacol Ther. 2009;85:149–154. doi: 10.1038/clpt.2008.152. [DOI] [PubMed] [Google Scholar]
- 11.Akiyama Y, Fujita K, Nagashima F, Yamamoto W, Endo H, Sunakawa Y, Yamashita K, Ishida H, Mizuno K, Araki K, Ichikawa W, Miya T, Narabayashi M, Kawara K, Sugiyama M, Hirose T, Ando Y, Sasaki Y. Genetic testing for UGT1A1*28 and *6 in Japanese patients who receive irinotecan chemotherapy. Ann Oncol. 2008;19:2089–2094. doi: 10.1093/annonc/mdn645. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Oshita F, Saito H, Yamada K. Feasible combination chemotherapy with nedaplatin and irinotecan for patients with non-small cell lung cancer and multiple risk factors. J Exp Ther Oncol. 2007;6:251–256. [PubMed] [Google Scholar]
- 13.Oshita F, Yamada K, Kato Y, Ikehara M, Noda K, Tanaka G, Nomura I, Suzuki R, Saito H. Phase I/II study of escalating doses of nedaplatin in combination with irinotecan for advanced non-small-cell lung cancer. Cancer Chemother Pharmacol. 2003;52:73–78. doi: 10.1007/s00280-003-0615-y. [DOI] [PubMed] [Google Scholar]
- 14.Noda K, Nishiwaki Y, Kawahara M, Negoro S, Sugiura T, Yokoyama A, Fukuoka M, Mori K, Watanabe K, Tamura T, Yamamoto S, Saijo N Japan Clinical Oncology Group. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002;346:85–91. doi: 10.1056/NEJMoa003034. [DOI] [PubMed] [Google Scholar]
- 15.Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol. 2007;18:317–323. doi: 10.1093/annonc/mdl377. [DOI] [PubMed] [Google Scholar]
- 16.Kanzawa F, Koizumi F, Koh Y, Nakamura T, Tatsumi Y, Fukumoto H, Saijo N, Yoshioka T, Nishio K. In vitro synergistic interactions between the cisplatin analogue nedaplatin and the DNA topoisomerase I inhibitor irinotecan and the mechanism of this interaction. Clin Cancer Res. 2001;7:202–209. [PubMed] [Google Scholar]
- 17.Matsukuma S, Saito H, Yamada K, Okamoto N, Ishikawa T, Yoshihara M, Koizume S, Sakuma Y, Miyagi Y. Simple and precise detection of UGT1A1 polymorphisms with a modified loop-hybrid mobility shift assay using Cy5-labeled loop probes. Clin Chim Acta. 2011;412:1668–1672. doi: 10.1016/j.cca.2011.05.021. [DOI] [PubMed] [Google Scholar]
- 18.Sobin LH, Gospodarowicz MK, Wittekind C, editors. TNM Classification of Malignant Tumors. 7th edition. Wiley-Blackwell; NY: 2009. [Google Scholar]
- 19.Satoh T, Ura T, Yamada Y, Yamazaki K, Tsujinaka T, Munakata M, Nishina T, Okamura S, Esaki T, Sasaki Y, Koizumi W, Kakeji Y, Ishizuka N, Hyodo I, Sakata Y. Genotype-directed, dose-finding study of irinotecan in cancer patients with UGT1A1*28 and/or UGT1A1*6 polymorphisms. Cancer Sci. 2011;102:1868–1873. doi: 10.1111/j.1349-7006.2011.02030.x. [DOI] [PubMed] [Google Scholar]
- 20.Marcuello E, Páez D, Paré L, Salazar J, Sebio A, del Rio E, Baiget M. A genotype-directed phase I–IV dose-finding study of irinotecan in combination with fluorouracil/leucovorin as first-line treatment in advanced colorectal cancer. Br J Cancer. 2011;105:53–57. doi: 10.1038/bjc.2011.206. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Hoskins JM, Goldberg RM, Qu P, Ibrahim JG, McLeod HL. UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. J Natl Cancer Inst. 2007;99:1290–1295. doi: 10.1093/jnci/djm115. [DOI] [PubMed] [Google Scholar]
- 22.Hu ZY, Yu Q, Pei Q, Guo C. Dose-dependent association between UGT1A1*28 genotype and irinotecan-induced neutropenia: low doses also increase risk. Clin Cancer Res. 2010;16:3832–3842. doi: 10.1158/1078-0432.CCR-10-1122. [DOI] [PubMed] [Google Scholar]
- 23.Klastersky J, Paesmans M, Rubenstein EB, Boyer M, Elting L, Feld R, Gallagher J, Herrstedt J, Rapoport B, Rolston K, Talcott J. The multinational association for supportive care in cancer risk index. A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol. 2000;18:3038–3051. doi: 10.1200/JCO.2000.18.16.3038. [DOI] [PubMed] [Google Scholar]
- 24.Klastersky J, Paesmans M, Georgala A, Muanza F, Plehiers B, Dubreucq L, Lalami Y, Aoun M, Barette M. Outpatient oral antibiotics for febrile neutropenic cancer patients using a score predictive for complications. J Clin Oncol. 2006;24:4129–4134. doi: 10.1200/JCO.2005.03.9909. [DOI] [PubMed] [Google Scholar]
- 25.Hu ZY, Yu Q, Zhao YS. Dose-dependent association between UGT1A1*28 polymorphism and irinotecan-induced diarrhoea: a meta-analysis. Eur J Cancer. 2010;46:1856–1865. doi: 10.1016/j.ejca.2010.02.049. [DOI] [PubMed] [Google Scholar]
- 26.Di Martino MT, Arbitrio M, Leone E, Guzzi PH, Rotundo MS, Ciliberto D, Tomaino V, Fabiani F, Talarico D, Sperlongano P, Doldo P, Cannataro M, Caraglia M, Tassone P, Tagliaferri P. Single nucleotide polymorphisms of ABCC5 and ABCG1 transporter genes correlate to irinotecan-associated gastrointestinal toxicity in colorectal cancer patients: a DMET microarray profiling study. Cancer Biol Ther. 2011;12:780–787. doi: 10.4161/cbt.12.9.17781. [DOI] [PubMed] [Google Scholar]
- 27.Bleiberg H, Cvitkovic E. Characterisation and clinical management of CPT-11 (irinotecan)-induced adverse events: the European perspective. Eur J Cancer. 1996;32A(Suppl 3):S18–S23. doi: 10.1016/0959-8049(96)00293-6. [DOI] [PubMed] [Google Scholar]
- 28.Merrouche Y, Extra JM, Abigerges D, Bugat R, Catimel G, Suc E, Marty M, Hérait P, Mahjoubi M, Armand JP. High dose-intensity of irinotecan administered every 3 weeks in advanced cancer patients: A feasibility study. J Clin Oncol. 1997;15:1080–1086. doi: 10.1200/JCO.1997.15.3.1080. [DOI] [PubMed] [Google Scholar]
- 29.Takeda Y, Kobayashi K, Akiyama Y, Soma T, Handa S, Kudoh S, Kudo K. Prevention of irinotecan (CPT-11)-induced diarrhea by oral alkalization combined with control of defecation in cancer patients. Int J Cancer. 2001;92:269–275. doi: 10.1002/1097-0215(200102)9999:9999<::aid-ijc1179>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]