Research ArticlePROCEEDINGS OF THE 21st ANNUAL MEETING OF THE SOCIETY OF BIOTHERAPEUTIC APPROACHES

Biweekly Administration of TAS-102 for Neutropenia Prevention in Patients with Colorectal Cancer

YOICHIRO YOSHIDA, RYOHEI SAKAMOTO, RYUJI KAJITANI, TARO MUNECHIKA, YOSHIKO MATSUMOTO, AKIRA KOMONO, NAOYA AISU, KOJIMA DAIBO, FUMIHIKO KIYOMI and SUGURU HASEGAWA
Anticancer Research July 2018, 38 (7) 4367-4373; DOI: https://doi.org/10.21873/anticanres.12738

Abstract

Background/Aim: TAS-102 has led to a significant improvement in overall survival (OS) and progression-free survival (PFS) of patients with metastatic colorectal cancer (mCRC). Neutropenia is the most common adverse event and an important factor impacting chemotherapy continuation. In this retrospective study, factors associated with grade ≥3 neutropenia, that is frequently observed in TAS-102-treated patients, were examined. Patients and Methods: The medical records of 41 patients with CRC who received TAS-102 between October 2014 and June 2017 at the Fukuoka University Hospital were retrospectively reviewed. Response rate, PFS, OS, and adverse events were analyzed using KRAS mutation, administration method, concomitant drug administration, neutrophil-to-lymphocyte ratio (NLR), and Onodera's prognostic nutritional index (Onodera's index) as a stratification factors. Results: Both PFS and OS were significantly higher with TAS-102 plus bevacizumab combination therapy. Biweekly administration (7.1%) was associated with significantly less neutropenia compared to normal administration (44.4%). DCR with biweekly administration was better than that with normal administration, although without statistical significance. No significant difference was observed in OS rates between the biweekly and normal administration regimens; however, the biweekly regimen was associated with significantly prolonged PFS. By multivariate analysis, a significant difference was noted in the Onodera's index for OS and in the administration method and NLR for PFS. Conclusion: Biweekly administration without a change in the drug dose intensity was associated with reduced neutropenia in patients with mCRC. The effects and adverse events of TAS-102 were associated with concomitant drug administration, administration method, and nutritional status.

TAS-102 is an oral anticancer drug composed of trifluridine (FTD) and tipiracil hydrochloride (1). FTD is incorporated into the DNA of colorectal cancer cells to exert its antitumor effect (2), whereas tipiracil hydrochloride maintains blood FTD concentrations by inhibiting the FTD-degrading enzyme thymidine phosphorylase. In the global phase III RECOURSE trial, overall survival (OS) and progression-free survival (PFS) were significantly better in patients with colorectal cancer (CRC) treated with TAS-102 than those treated with placebo (3). However, grade ≥3 neutropenia (38%) was frequently observed in the TAS-102 arm (3). Furthermore, TAS-102 plus bevacizumab combination therapy was reported to be associated with grade ≥3 neutropenia in 72% of treated patients (4). Neutropenia is the most common adverse event (5, 6) and an important factor impacting chemotherapy continuation (7). Therefore, overcoming neutropenia is assumed to lead to improved survival rates. We previously reported the case of a patient in whom neutropenia could be avoided by changing TAS-102 administration method (8). Given that this was our experience in only one patient, we examined adverse events and factors associated with neutropenia in TAS-102-treated patients using multiple stratification factors.

Patients and Methods

Patients. The medical records of patients with CRC who received TAS-102 at Fukuoka University Hospital between October 2014 and June 2017 were retrospectively reviewed. Patients aged ≥20 years with histologically confirmed CRC who received at least two prior chemotherapeutic regimens for metastatic disease (mCRC) were eligible. The additional inclusion criteria were as follows: Eastern Cooperative Oncology Group (ECOG) performance status, 0-2; life expectancy, ≥12 weeks; white blood cell count, ≥3,000/mm3; neutrophil count, ≥1,500/mm3; platelet count, ≥75,000/mm3; hemoglobin level, ≥8.5 g/dl; total bilirubin level, ≤2.0 times the upper normal limit; serum aspartate aminotransferase and alanine aminotransferase levels, ≤3.0 times the upper normal limit; and serum creatinine level, ≤2.0 mg/dl. All patients provided written informed consent prior to chemotherapy.

Treatment. TAS-102 was orally administered at a dose of 35 mg/m2 twice daily on days 1-5 and 8-12 of every 28-day cycle (normal administration) with or without bevacizumab (5.0 mg/kg) on day 1 or on days 1-5 and 15-19 of every 28-day cycle (biweekly administration) with or without bevacizumab (5.0 mg/kg) on day 1. Treatment was continued until progressive disease, unacceptable toxicity, consent withdrawal, treatment discontinuation based on clinical indications, and at the investigator's discretion.

Evaluation of chemotherapeutic efficacy. Based on the collected data from the medical records at Fukuoka University, patient characteristics, response to treatment, adverse events, treatment compliance, PFS, and OS, were retrospectively analyzed. Before treatment initiation, all patients underwent physical examination, chest radiography, and computed tomography of the abdomen, pelvis, and chest. The National Cancer Institute Common Toxicity Criteria version 4.0 was used for evaluating the severity of adverse effects (9). Tumors were measured at 6-8-week intervals. The Response Evaluation Criteria for Solid Tumors version 1.1 was used for evaluating responses based on radiologist-reported measurements (10). Complete and partial responses were subsequently confirmed after at least 4-week intervals. Table I shows the histological classifications and other clinicopathological factors.

Statistical analysis. PFS was defined as the time from the initiation of TAS-102 administration to the first recorded occurrence of disease progression. OS was defined as the time from the initiation of TAS-102 administration to death from any cause. Survival curves were generated using the Kaplan–Meier method, and survival differences were evaluated using the log-rank test. Response rate, PFS, OS, and adverse events were analyzed using KRAS mutation, administration method, concomitantly administered drugs, neutrophil-to-lymphocyte ratio (NLR), and Onodera's index as stratification factors. Onodera's index was determined according the following formula: 10×serum albumin (g/dl)+0.005×total lymphocyte count (per mm3) (11). SPSS IBM version 23 statistical software (IBM, Armonk, NY, USA) was used for all calculations.

Results

In total, 47 patients received TAS-102 for mCRC in a late-line treatment setting. Six patients were excluded based on the selection criteria: two patients with ECOG PS of three and four patients with hematological, renal, and liver functions outside the study parameters.

All patients received prior chemotherapy regimens containing oxaliplatin, irinotecan, fluoropyrimidines, and bevacizumab; TAS-102 monotherapy and TAS-102 plus bevacizumab combination therapy was administered in 39% and 61% of patients, respectively. Third, fourth, fifth line treatments were received by 80%, 17%, 3% of patients respectively. The rates of those with wild-type and mutant KRAS-harboring CRC were almost equivalent. The overall response rate and disease control rate (DCR) were 4.9% and 48.8%, respectively (Table II). OS and PFS were 264 and 111 days, respectively (Figure 1). Grade ≥3 hematologic adverse events included leukopenia (12.2%), neutropenia (34.1%), thrombocytopenia (7.3%), and anemia (7.3%).

View this table:
Table I.

Baseline patient characteristics.

View this table:
Table II.

Overall response rates.

DCR of TAS-102 monotherapy was 25%, that was increased to 64% by TAS-102 plus bevacizumab combination therapy (p=0.015, Figure 2A). Both PFS and OS were significantly increased by TAS-102 plus bevacizumab combination therapy (Figure 2B). Analysis of outcomes by the administration method revealed that although not significant, DCR with biweekly administration was better than that with normal administration (Figure 3A). No significant difference was observed in the OS rates based on administration frequency; PFS was significantly prolonged in the biweekly regimen group compared with the normal administration group (Figure 3B).

Figure 1.
Figure 1.

Kaplan–Meier survival curve showing overall survival (OS) (A) and progression-free survival (PFS) (B).

Table III shows grade ≥3 hematologic adverse events according to the administration method. Biweekly administration was associated with significantly less neutropenia compared to normal administration. Univariate analysis by logistic regression revealed that bevacizumab and Onodera's index were significantly associated with response to therapy (Table IV). Bevacizumab and Onodera's index also emerged as significant factors associated with response based on multiple logistic regression analysis with stepwise variable selection (Table V). By multivariate analysis using Cox regression model with stepwise variable selection, a significant association was noted between Onodera's index and OS, and administration method and NLR were significantly associated with PFS (Table VI). Finally, OS was significantly prolonged with increasing Onodera's index, and biweekly administration method and low NLR were significant factors for PFS.

View this table:
Table III.

Grade ≥3 hematological adverse events due to administration method.

View this table:
Table IV.

Logistic regression analysis with stepwise variable selection for response rate.

View this table:
Table V.

Multiple logistic regression analysis with stepwise variable selection for response rate.

View this table:
Table VI.

Multiple cox regression analysis with stepwise variable selection for PFS and OS.

Figure 2.
Figure 2.

Association of concomitant drug administration on (A) disease control rate (DCR) and (B) progression-free survival (PFS) and overall survival (OS) in patients treated with TAS-102. Bmab: Bevacizumab; CR: complete response; PR: partial response; PD: progressive disease; RR: response rate; SD: stable disease.

Discussion

The administration schedule of TAS-102 was investigated in several phase I trials (12). Briefly, TAS-102 was orally administered once a day for 14 days with a 1-week rest period with repetition of the regimen every 3 weeks based on preclinical data. The maximum tolerated TAS-102 dose was determined as 50 mg/m2/day, whereas the dose-limiting toxicity was neutropenia with a TAS-102 dose of 60 mg/m2/day (13). Additional Phase I trials to determine optimal TAS-102 schedule to minimize hematologic toxicity investigated two TAS-102 schedules: once daily dose on days 1-5 and 8-12 every 28 days or once daily dose on days 1-5 every 21 days, and the recommended doses (RDs) were 100 and 160 mg/m2/day in the first and second regimens, respectively. These two doses (100 and 160 mg/m2/day) were subsequently evaluated in solid tumors resistant to 5-fluorouracil, though no objective responses were observed (14). Thereafter, phase I trials were conducted to compare twice and thrice daily administration, with TAS-102 treatments on days 1-5 and 8-12 every 28 days. One phase I trial with TAS-102 administration thrice a day determined an RD of 70 mg/m2/day (15). Based on these trials and considering its efficacy and toxicity, 50 mg/m2 TAS-102 twice daily for 5 days a week for 2 weeks was established as RD in the US. Phase I trials in Japan aimed to determine the optimal phase II dose and to examine the pharmacokinetic (PK) profile of TAS-102; in these trials, TAS-102 was administered twice daily for 1 day to 5 days and 8 days to 12 weeks for 4 weeks. PK data showed that the concentrations of FTD and TPI linearly increased with increasing oral doses, whereas dose-dependent increases were observed with doses up to 70 mg/m2/day. Although the current administration method was established based on these trials, it remains unclear whether the method of administration is optimal as few administration methods were examined in these clinical trials.

Figure 3.
Figure 3.

Effects of administration method on (A) DCR and (B) PFS and OS in patients treated with TAS-102. Bmab: Bevacizumab; CR: complete response; PR: partial response; PD: progressive disease; RR: response rate; SD: stable disease.

Kasi et al. proposed that several mechanisms might underlie the association of chemotherapy-induced neutropenia at 1-month mark (CIN-1m) and OS (16). First, patients with a high tumor burden might have a high baseline neutrophil count, which might decrease the likelihood of CIN-1m. Second, since TAS-102 incorporates into the tumor, there is a possibility that the standard drug dose might not be sufficient to exert myelotoxicity in patients with a high tumor burden. Finally, PK of TAS-102 and its metabolites might differ among individuals experiencing different levels of neutropenia. The highest tolerable FTD concentration was shown to be the one that provided the highest antitumor activity, with hematological toxicity as a potential surrogate marker for the efficacy of the drug (17). Therefore, if the hypothesis is valid, patients who do not develop chemotherapy-induced neutropenia should have a higher risk of death. Several studies have reported that chemotherapy-induced neutropenia was significantly correlated with survival in gastric cancer and mCRC (18, 19). However, the doses and concentrations of FTD incorporated into the DNA of cancer cells and white blood cells (WBC) are different (17). The FTD concentrations in cancer cells were approximately six times higher than those of WBC; therefore, it is possible that development of new administration methods can achieve maintenance of antitumor effects without bone marrow suppression. The ultimate and critical goal is to maintain the exposure of cancer cell DNA to FTD, which is hindered if the drug is discontinued due to neutropenia. Therefore, development of new administration methods is critical to reduce neutropenia without changing dose intensity.

Dose intensities of the normal method (TAS-102 on days 1-5 and 8-12 of the 28-day cycle) and the biweekly method (TAS-102 on days 1-5 and 15-19 of the 28-day cycle) are equal (8). In our results, the incidence of neutropenia is quite different despite equal drug dose intensity. Tanaka et al. reported on the relationship between FTD incorporated into the tumor cell DNA and the number of administration days (20) and showed that FTD uptake into the DNA of cancer cells increased with increasing dosing days, albeit worsening efficiency. Their data suggested that the most efficient method appears to be 3 to 5 days of administration. We suggest that biweekly administration might be beneficial for efficient incorporation of FTD into DNA of cancer cells. Bevacizumab results in altered tumor vascular physiology and can improve delivery and efficacy of chemotherapy (21). Therefore, it is possible that FTD can be incorporated into DNA in the center of the tumor mass in treatment protocols combining TAS-102 with bevacizumab.

The current study revealed that the effect and adverse events of TAS-102 were associated with concomitant drug, administration method and nutritional status. However, the low number of patients included in the study limits the elucidation of well-defined conclusions. To verify these findings, we recently initiated the phase II TAS-CC4 trial to assess TAS-102 and bevacizumab as third-line chemotherapy for CRC (UMIN000030030).

Acknowledgements

The Authors would like to thank the participating patients, their family members, and all researchers involved in this study. The Authors are also grateful to Aya Tanaka for collecting data.

Footnotes

  • Conflicts of Interest

    The Authors declare that they have no conflict of interest regarding this study.

  • Received April 11, 2018.
  • Revision received May 31, 2018.
  • Accepted June 4, 2018.

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Biweekly Administration of TAS-102 for Neutropenia Prevention in Patients with Colorectal Cancer
YOICHIRO YOSHIDA, RYOHEI SAKAMOTO, RYUJI KAJITANI, TARO MUNECHIKA, YOSHIKO MATSUMOTO, AKIRA KOMONO, NAOYA AISU, KOJIMA DAIBO, FUMIHIKO KIYOMI, SUGURU HASEGAWA
Anticancer Research Jul 2018, 38 (7) 4367-4373; DOI: 10.21873/anticanres.12738
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