Abstract
Aim: To evaluate the treatment outcomes of irinotecan monotherapy for patients with advanced biliary tract cancer refractory to gemcitabine, cisplatin, and oral fluoropyrimidine. Patients and Methods: Irinotecan (100 mg/m2) was administered intravenously on days 1, 8, and 15, repeated every four weeks. Results: Thirteen patients were enrolled. The dose intensity was only 55.0%. The response rate and disease control rate were 1/13 (7.7%) and 3/13 (23.1%), respectively. The median overall survival and time-to-progression were 6.7 months (95% confidence interval=3.0-10.4 months) and 1.8 months (95% confidence interval=1.6-3.9 months), respectively. Grade 3/4 adverse events included leukopenia (7/13), neutropenia (8/13), anemia (6/13), nausea (1/13), vomiting (1/13), anorexia (2/13), diarrhea (1/13), and constipation (1/13). Conclusion: Irinotecan monotherapy had a modest antitumor effect even for patients who were refractory to gemcitabine, cisplatin, and oral fluoropyrimidine. However, this regimen was not fully tolerated as third-line or fourth-line therapy. Therefore, further evaluation of a modified irinotecan regimen is necessary.
Recently, the treatment outcomes of patients with advanced biliary tract cancer (BTC) have improved, and the median overall survival has reached almost one year (1, 2). Gemcitabine and cisplatin combination therapy has become the standard of care for advanced BTC (3, 4). S-1 is an oral fluoropyrimidine that is widely used in Asian countries, and this drug also has good antitumor effects on advanced BTC (5-8). Thus, these three drugs (gemcitabine, cisplatin, and S-1) are considered key drugs for the treatment of advanced BTC, and many studies have been conducted using these drugs (9-15). However, the treatment of patients with disease refractory to these three drugs has not been evaluated as far as we are aware.
Irinotecan is a chemotherapeutic drug that inhibits topoisomerase I. Irinotecan has been evaluated as a monotherapy and as part of combination therapies for first-line treatment, and its antitumor effect was considered only modest for advanced BTC (16-20). Therefore, irinotecan has not been actively developed as a first-line treatment. However, there are some patients who benefit from the use of irinotecan. Therefore, we conducted a pilot study to evaluate the use of irinotecan monotherapy to treat patients with BTC refractory to gemcitabine, cisplatin, and S-1.
Patients and Methods
Eligibility criteria. This study was conducted at the University of Tokyo Hospital in Japan. The protocol was approved by the Institutional Review Board at the University of Tokyo Hospital (P2008027), and informed consent was obtained from each participant. Patients with advanced BTC were eligible if they met the following criteria: i) histologically or cytologically proven BTC; ii) disease refractory to gemcitabine, cisplatin, and S-1; iii) an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; and iv) adequate bone marrow function (white blood count >3,000/mm3, hemoglobin >9.0 g/dl, and platelet count >100,000/mm3), liver function (total bilirubin less than three times the upper limit of normal (ULN) and aspartate/alanine transaminases less than five times the ULN), and renal function (creatinine <1.2 mg/dl or creatinine clearance >50 ml/min). In patients with obstructive jaundice, the total serum bilirubin was required to be within three times the ULN after biliary drainage. Exclusion criteria included an age less than 20 years, uncontrolled infection, uncontrolled massive pleural effusion or massive ascites, active ulcers of the gastrointestinal tract, pregnancy or lactation, a history of drug hypersensitivity, active concomitant malignancy, and concurrent severe medical conditions.
Treatment. Irinotecan (100 mg/m2) was administered intravenously for 90 min on days 1, 8, and 15, and this cycle was repeated every four weeks. Dose reductions were made based on adverse events that were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (21). Treatment was temporarily suspended in cases of grade 3/4 hematological toxicity or non-hematological toxicity of grade 2 or higher. After the toxicity was reduced to grade 1 or below, the treatment was restarted at a lower dose. The irinotecan dose was initially reduced to 80 mg/m2. If severe toxicity occurred again, the dose was reduced to 60 mg/m2. The treatment was stopped if the patients continued to experience further toxicity. Dose re-escalation was not performed. Treatment continued until disease progression, the development of unacceptable toxicity, or patient refusal.
Response and toxicity assessment. The pretreatment evaluation included a medical history and a physical examination, a complete blood count, serum biochemical tests, urinalysis, and an echocardiogram. The ECOG performance status was determined and laboratory tests were performed on days 1, 8, and 15. The levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were measured at the beginning of the study and on day 1 of each cycle. Pretreatment evaluation using contrast-enhanced computed tomography (CT) was conducted within the four weeks prior to the start of treatment. The tumor response was assessed every two cycles (eight weeks) using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (22). Toxicity was evaluated using CTCAE version 3.0.
Genotyping of uridine diphosphate-glucuronyl transferase 1 family, polypeptide A1 (UGT1A1). Genomic DNA was extracted from whole blood collected into a tube containing EDTA-2K by a Magtration System 6GC (Precision System Science, Chiba, Japan). The UGT1A1 genotype was then determined by direct sequencing. Genomic DNA was amplified using a GeneAmp PCR System 9700 (Applied Biosystems, Foster City, CA, USA) with the following forward and reverse primers: UGT1A1F, 5’-AGTGAACTCC CTGCTACCTTTG-3’, and UGT1A1R, 5’-ATTTTGGTGAAGGCAGTTGATT-3’. Amplification was conducted with 35 cycles of 30 s at 95°C, 1 min at 60°C, and 1 min at 72°C. The purified PCR products were directly sequenced using the primers UGT1A1S, 5’-TTGTATGTTTTGATCACACGC-3’, and UGT1A1R. Sequence analysis was performed on an ABI PRISM 310 Genetic Analyzer (Applied Biosystems). The relationship between UGT1A1 polymorphisms and toxicity was evaluated.
Statistical analysis. The response rate, disease control rate, time-to-progression, overall survival, and toxicity were evaluated. The tumor response and disease control rate were evaluated according to RECIST version 1.1 (22). The patients who stopped treatment before the first assessment were deemed “not evaluable” for tumor response. Time-to-progression and overall survival were calculated using the Kaplan–Meier method. Time-to-progression was calculated from the date of irinotecan treatment initiation until documented disease progression. Overall survival was calculated from the date of irinotecan treatment initiation to the date of death or the last follow-up. In subset analysis by UGT1A1 genotype, Fisher's exact test was used to compare the incidence of toxicity. The Mann-Whitney U-test was used to compare quantitative variables, as appropriate. The final analysis was based on the follow-up information, which was received up to the end of December 2012. The JMP 9.0 statistical program (SAS Institute Inc., Cary, NC, USA) was used for all statistical analyses.
Patients' characteristics.
Results
Patients' characteristics. Between November 2008 and October 2012, thirteen patients were enrolled in this study. The patient characteristics are listed in Table I. The median baseline sum of the longest tumor diameter (BSLD) was 9.9 cm measured using RECIST version 1.1. Most of the patients (9/13, 69%) received gemcitabine and S-1 combination therapy followed by gemcitabine and cisplatin combination therapy as prior chemotherapy regimens. Only one patient, who was considered intolerant to gemcitabine and cisplatin combination therapy, was treated with irinotecan monotherapy without prior cisplatin administration. The median duration from diagnosis to the start of irinotecan monotherapy was 12.5 months.
Efficacy and toxicity. In total, 36 cycles of irinotecan monotherapy were delivered, with a median of two cycles per patient (range=1-8 cycles). The dose intensity was only 55.0%. Eleven patients (85%) required dose reduction. The response rate and disease control rate were 1/13 (7.7%) and 3/13 (23.1%), respectively. No patient achieved a complete response. The median overall survival and time-to-progression were 6.7 months (95% confidence interval [CI]=3.0-10.4 months) and 1.8 months (95% CI=1.6-3.9 months), respectively (Figure 1). The major adverse events are presented in Table II. No treatment-related deaths occurred. Grade 3/4 adverse events included leukopenia (7/13, 54%), neutropenia (8/13, 62%), anemia (6/13, 46%), nausea (1/13, 8%), vomiting (1/13, 8%), anorexia (2/13, 15%), diarrhea (1/13, 8%), and constipation (1/13, 8%). Ten patients (77%) suffered from some type of grade 3/4 toxicity.
Time to progression (TTP) and overall survival (OS) curves.
All patients were tested for UGT1A1 polymorphisms, including the *6 and *28 polymorphisms. The UGT1A1 genotype was *1/*1 in eight patients (62%) and *1/*6 in five patients (38%). No patient had a *1/*28 or *28/*28 genotype. Grade 3/4 neutropenia occurred in 4/5 (80%) and 4/8 (50%) of patients with the *1/*6 and *1/*1 genotypes, respectively (p=0.56). The dose intensities for these patients were 46.4% and 59.1%, respectively (p=0.71).
Discussion
Irinotecan monotherapy had a modest antitumor effect even for patients with disease refractory to gemcitabine, cisplatin, and S-1. Although many patients experienced immediate tumor progression, three patients (21.4%) benefitted from irinotecan, even in a third-line or fourth-line setting. Therefore, irinotecan monotherapy might be a treatment option for patients with disease refractory to gemcitabine, cisplatin, and oral fluoropyrimidines.
The adverse events due to this regimen were severe. Ten patients (77%) suffered from some type of grade 3/4 toxicity. Moreover, the dose intensity was extremely low (55.0%). We adopted this regimen based on previous reports for advanced pancreatic cancer in a first-line setting (23). This regimen was well-tolerated and had a moderate efficacy in patients with refractory pancreatic cancer (24). Because the patients enrolled in the present study had disease at a more advanced stage, this regimen was not tolerated by patients who were refractory to gemcitabine, cisplatin, and oral fluoropyrimidine. If further evaluation is conducted with such patients, this regimen must be modified to ensure its safety.
The relationship between UGT1A1 polymorphisms and toxicity was also evaluated in this study. Grade 3/4 neutropenia occurred more frequently and the dose intensity of irinotecan was lower in patients with the *1/*6 genotype than those of the the *1/*1 genotype. However, the patients enrolled in this study might be too small to detect the differences significantly. Therefore, if further evaluation of irinotecan monotherapy using modified regimen will be conducted in the future, the relationship between UGT1A1 polymorphisms and toxicity should be evaluated with much more patients.
Toxicity experienced with irinotecan monotherapy.
Few patients with BTC are treated with third-line or fourth-line chemotherapy. However, most of these patients do not receive adequate benefit from these treatments. Some predictive factors are needed to select these patients who will benefit from chemotherapy. For irinotecan, the low expression of human mutL homolog 1 (hMLH1), a mismatch repair gene, has been reported to be a factor predictive of response to irinotecan chemotherapy in patients with BTC (25). These types of predictive factors should be evaluated in future studies using irinotecan to treat advanced BTC.
In conclusion, irinotecan monotherapy had a modest antitumor effect, even for patients who were refractory to gemcitabine, cisplatin, and S-1. However, this regimen was not fully tolerated by the patients when treated in a third-line or fourth-line setting. Therefore, further evaluation is needed using a modified irinotecan regimen.
Footnotes
-
Conflicts of Interest
None declared.
- Received April 25, 2013.
- Revision received May 14, 2013.
- Accepted May 15, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
