- Email: [email protected]
Neutropenia as a Predictive Factor in Metastatic Colorectal Cancer Treated With TAS-102
Original Study
Neutropenia as a Predictive Factor in Metastatic Colorectal Cancer Treated With TAS-102 Satoshi Hamauchi,1 Kentaro Yamazaki,1 Toshiki Masuishi,2 Yosuke Kito,1 Azusa Komori,2 Takahiro Tsushima,1 Yukiya Narita,2 Akiko Todaka,1 Makoto Ishihara,3 Tomoya Yokota,1 Tsutomu Tanaka,3 Nozomu Machida,1 Shigenori Kadowaki,2 Akira Fukutomi,1 Takashi Ura,2 Yusuke Onozawa,4 Masashi Ando,2 Masahiro Tajika,3 Kei Muro,2 Hirofumi Yasui,1 Keita Mori,5 Hiroya Taniguchi2 Abstract The most common treatment-related adverse event of TAS-102 monotherapy for colorectal cancer is bone marrow suppression, which leads to neutropenia. A retrospective study of 95 patients at 2 institutions was performed to evaluate the association between efficacy and neutropenia. Our findings indicate that neutropenia caused by TAS-102 was associated with better efficacy. Background: TAS-102 significantly improves overall survival in patients with metastatic colorectal cancer. The most common treatment-related adverse event of TAS-102 is bone marrow suppression, which leads to neutropenia. The potential predictive value of neutropenia caused by cytotoxic drugs has been reported in various types of cancer. Methods: We retrospectively analyzed 95 consecutive patients with metastatic colorectal cancer who received TAS102 at 2 Japanese institutions between May 2014 and May 2015. To evaluate the association between efficacy and neutropenia, patients were divided into 4 categories according to the grade of neutropenia during the first cycle of TAS-102: Category A (grade 0-1), B (grade 2-4), C (grade 0-2), and D (grade 3-4). Results: Patient characteristics were as follows: median age, 64 years; male, 58%; Eastern Cooperative Oncology Group performance status 0 to 1, 91%; primary site colon, 49%; KRAS exon 2 wild, 57%; and number of metastatic site 3, 55%. The disease control rate was significantly different between Category A and B (29.2% vs. 52.6%; P ¼ .045) and between Category C and D (30.9% vs. 72.2%; P ¼ .002). In multivariate analysis, Category D remained a significant predictive factor for progression-free survival compared with Category C (4.3 vs. 2.0 months; hazard ratio, 0.45; P ¼ .01). Conclusion: Neutropenia caused by TAS-102 during the first cycle was associated with better efficacy. Neutropenia may be a surrogate marker for adequate antitumor doses of TAS-102. Clinical Colorectal Cancer, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: Chemotherapy, Metastatic colorectal cancer, Neutropenia, Predictive factor, TAS-102
Introduction 1
Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan Department of Clinical Oncology Department of Endoscopy, Aichi Cancer Center Hospital, Nagoya, Japan 4 Division of Clinical Oncology 5 Clinical Research Center, Shizuoka Cancer Center, Shizuoka, Japan 2 3
Submitted: May 2, 2016; Revised: Jun 23, 2016; Accepted: Jul 5, 2016 Address for correspondence: Kentaro Yamazaki, MD, Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntogun, Shizuoka 411-8777, Japan E-mail contact: [email protected]
1533-0028/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clcc.2016.07.005
Systemic chemotherapy has improved outcomes in patients with solid cancer, but not in all cases. Therefore, a considerable amount of clinical and basic research has focused on seeking factors that predict the outcome of chemotherapy. In some molecular targeted therapies for solid tumors, predictive biomarkers, such as HER2 overexpression for HER2 inhibitor in breast cancer1 and gastric cancer2 and RAS mutations for epidermal growth factor receptor (EGFR) antibody in colorectal cancer,3,4 have been established. Furthermore, the association of treatment efficacy with adverse events, such as skin rash caused by EGFR inhibitor and
Clinical Colorectal Cancer Month 2016
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Neutropenia and TAS-102 hypertension caused by vascular endothelial growth factor (VEGF) inhibitor, has been reported.5,6 It has also been reported that neutropenia during chemotherapy with cytotoxic agents is associated with favorable outcomes for several types of cancer.7-9 Regarding gastrointestinal cancer, Yamanaka et al reported that patients with advanced gastric cancer who experienced neutropenia caused by an oral fluoropyrimidine S-1 had longer survival than those who did not.10 A similar result has also been reported for metastatic colorectal cancer (mCRC) treated with fluorouracil plus folinic acid and oxaliplatin (FOLFOX).11 However, almost all of these studies involved chemo-naive patients, and the clinical impact of neutropenia on heavily pretreated patients has not yet been reported. TAS-102 is an oral antitumor drug containing trifluridine and tipiracil hydrochloride. Trifluridine is incorporated into DNA, and this process might result in its antitumor effects. Tipiracil hydrochloride assists in maintaining the blood concentrations of trifluridine by inhibiting thymidine phosphorylase that degrades trifluridine. In the global phase III REfractory COLoREctal cancer Study (RECOURSE) trial, patients who were given TAS-102 demonstrated a significant improvement in overall survival (OS) and progression-free survival (PFS) compared with those given placebo (hazard ratio [HR], 0.68 and 0.48 for OS and PFS, respectively; both P < .0001).12 Grade 3 or higher adverse events frequently observed in the TAS-102 arm included neutropenia (38%) and leukopenia (21%). Based on the above, we hypothesized that neutropenia is a predictor of efficacy of TAS-102 and conducted a retrospective analysis of patients with mCRC.
Drug-related adverse events according to the National Cancer Institute Common Toxicity Criteria version 4.0 were evaluated at least once every 2 weeks during chemotherapy. The most severe grade of neutropenia was based on the lowest recorded neutrophil count during the first cycle and was graded according to National Cancer Institute Common Toxicity Criteria version 4.0 regardless of the baseline neutrophil count. Tumor response was assessed by computed tomography every 8 to 12 weeks according to the guidelines of the Response Evaluation Criteria in Solid Tumors, version 1.1.
Statistical Methods
This was a retrospective study of patients with mCRC who received TAS-102 monotherapy at 2 Japanese institutions (Shizuoka Cancer Center and Aichi Cancer Center Hospital) from May 2014 to May 2015. Inclusion criteria were as follows: presence of histologically proven, inoperable metastatic colorectal adenocarcinoma; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2; sufficient bone marrow function (neutrophil count 1500/mm3, platelet count 75,000/mm3); adequate renal and liver function (serum creatinine [Cr] 1.5 mg/dL, aspartate transaminase/alanine aminotransferase 100 IU/L, total bilirubin 1.5 mg/dL); at least 2 prior regimens; and refractory to or intolerant of fluoropyrimidines, oxaliplatin, irinotecan, antiVEGF antibodies, and anti-EGFR antibodies (if KRAS exon 2 wild-type tumors). Patients could be included if they refused or were inappropriate candidates for oxaliplatin, irinotecan, anti-VEGF antibodies, and anti-EGFR antibody. This study was approved by the institutional review committees of the Shizuoka Cancer Center and the Aichi Cancer Center Hospital, and complied with the Declaration of Helsinki. Written informed consent was obtained from all patients before starting TAS-102 therapy.
Treatment Delivery
Results
TAS-102 (35 mg/m2) was administered twice daily, after breakfast and dinner, for 5 days a week with 2 days of rest for 2 weeks, followed by a 14-day rest period (1 treatment cycle). This treatment cycle was repeated every 4 weeks.
Patient Characteristics
Patients
-
Evaluation and Supportive Therapy
The objective of this study was to evaluate the association between grade of neutropenia caused by TAS-102 and efficacy (tumor response, PFS, and OS). PFS was calculated from the date of the start of TAS-102 until progressive disease (PD), death from any cause, or censoring at the last follow-up. OS was calculated from the start of TAS-102 until death from any cause or censoring at the last follow-up. We evaluated the grade of neutropenia during the first cycle to avoid lead-time bias, which produces a false-positive association between chemotherapy-induced neutropenia and longer survival. To evaluate the association between efficacy and neutropenia, patients were divided into 4 categories according to the grade of neutropenia during the first cycle of TAS-102: Category A (grade 0-1), B (grade 2-4), C (grade 0-2), and D (grade 3-4). To evaluate the association between neutropenia and efficacy, both univariate and multivariate analysis were applied. First, we performed a univariate analysis to examine the association between neutropenia during the first cycle and tumor response, PFS, and OS (category A vs. B, and C vs. D). The Fisher exact test was applied for tumor response and the log-rank test for PFS and OS. Nine patient background factors were selected for univariate analysis: ECOG PS (0-1 vs. 2), age ( 65 years vs. 64 years), gender (male vs. female), primary site of tumor (rectum vs. colon), number of prior regimens ( 3 vs. 2), time from start of first-line chemotherapy ( 18 months vs. < 18 months), KRAS exon 2 status (wild vs. mutant), number of metastatic organs ( 3 vs. 2), and prior history of regorafenib therapy (yes vs. no). Second, multivariate analysis was performed using confounding variables selected among the above 9 factors that showed P-value < .05 in univariate analysis. All reported P-values are 2-tailed, and P < .05 was considered statistically significant. All analyses were performed using R (version 3.1.1).
Patients and Methods
2
Treatment was discontinued if the tumor progressed, severe toxicity occurred, or the patient requested. Dose modification was made in decrements of 5 mg/m2 when hematologic adverse events at grade 4 or non-hematologic reactions at grade 3 or 4 appeared, and administration was temporarily discontinued.
Clinical Colorectal Cancer Month 2016
A total of 107 patients were treated with TAS-102 monotherapy for mCRC at Shizuoka Cancer Center and Aichi Cancer Center Hospital between May 2014 and May 2015. Twelve patients were
Satoshi Hamauchi et al excluded from this study for the following reasons: only 1 prior regimen (n ¼ 4), increase in blood bilirubin (n ¼ 4), decrease in platelet count (n ¼ 2), ECOG PS of 3 (n ¼ 1), and increase in Cr level (n ¼ 1). Our study therefore included 95 patients. Baseline characteristics are shown in Table 1. This study included 9 patients with an ECOG PS of 2 (9%). Almost all the patients had received prior chemotherapy regimens containing a fluoropyrimidine, oxaliplatin, irinotecan, anti-VEGF antibody, and anti-EGFR antibody (if KRAS exon 2 wild-type tumors). About half of the patients had received regorafenib.
patients (21%) discontinued this treatment due to PD by computed tomography (n ¼ 13) or clinical findings (n ¼ 7) in the first cycle. We diagnosed as PD by computed tomography or clinical findings as soon as the patients’ condition turned worse during the first cycle. Relative dose intensity (dose intensity/planned dose intensity 100) of TAS-102 in the first cycle was 88%. The median time to treatment failure of TAS-102 was 2.0 months, and the median number of cycles of TAS-102 administration was 2 (range, 1-13).
Toxicity Treatment Exposure The starting dose of TAS-102 was reduced in 6 patients for the following reasons: PS of 2 (n ¼ 3), older age (n ¼ 2), and renal impairment (n ¼ 1). Ninety-one patients (96%) discontinued TAS-102 due to PD (n ¼ 89) or adverse events (n ¼ 2). Twenty
Table 1 Baseline Patient Characteristics Characteristics
N (%)
Age (years) Median (range)
64 (32-90)
Gender Male
55 (58)
Female
40 (42)
ECOG PS 0
35 (37)
1
51 (54)
2
9 (9)
Primary site Colon
47 (49)
Rectum
48 (51)
Toxicities observed during chemotherapy are listed in Table 2. The median complete blood count (CBC) test times for all patients during the first cycle were 3 (range, 2-4), and 93 patients (98%) were given CBC tests in the third or the fourth week from the start of TAS-102 treatment, whereas 80 patients (84%) were given CBC tests in the first, second, and fourth weeks during the first cycle. The common grade 3 or 4 hematologic toxicities were neutropenia (42%) and anemia (22%). Grade 3 non-hematologic toxicities were anorexia (8%), nausea (4%), diarrhea (2%), and febrile neutropenia (2%). No grade 4 non-hematologic toxicity or treatment-related death was observed. We used granulocyte-colony stimulating factor for 3 patients owing to the grade 4 neutropenia during the first cycle. Incidences of grades of neutropenia during the first cycle were as follows: grade 0, 41% (n ¼ 39); grade 1, 16% (n ¼ 15); grade 2, 22% (n ¼ 21); grade 3, 15% (n ¼ 14); and grade 4, 6% (n ¼ 6).
Efficacy At the median follow-up time of 9.1 months (range, 1.4-16.1 months), the median PFS was 2.0 months, and the median survival time (MST) was 5.9 months (Figure 1).
KRAS exon 2 status Wild
54 (57)
Mutant
40 (42)
Unknown
1 (1)
Number of metastatic sites 1
14 (15)
2
29 (31)
3
52 (54)
Time from start of first-line chemotherapy <18 months
19 (20)
18 months
76 (80)
Number of prior regimens Median (range)
3 (2-7)
Prior chemotherapeutic agents Fluoropyrimidine
95 (100)
Oxaliplatin
94 (99)
Irinotecan
91 (96)
Anti-VEGF antibody
89 (94)
Anti-EGFR antibody (if wild KRAS exon 2)
50 (93)
Regorafenib
47 (49)
Abbreviations: ECOG PS ¼ Eastern Cooperative Oncology Group performance status; EGFR ¼ epidermal growth factor receptor; VEGF ¼ vascular endothelial growth factor.
Table 2 Adverse Events All Grade N (%)
Grade 3 or Higher N (%)
White blood cell decreased
62 (65)
17 (18)
Neutrophil count decreased
64 (67)
40 (42)
Anemia
80 (84)
21 (22)
Platelet count decreased
40 (42)
5 (5)
Anorexia
68 (72)
8 (8)
Fatigue
76 (80)
0 (0)
Nausea
59 (62)
4 (4)
Diarrhea
25 (26)
2 (2)
Mucositis oral
25 (26)
0 (0)
Adverse event Hematologic
Non-hematologic
Febrile neutropenia
2 (2)
2 (2)
AST increased
36 (38)
0 (0)
ALT increased
17 (18)
0 (0)
Blood bilirubin
20 (21)
1 (1)
Creatinine increased
11 (12)
0 (0)
Abbreviations: ALT ¼ Alanine aminotransferase; AST ¼ aspartate aminotransferase.
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Neutropenia and TAS-102
0.4
baseline characteristics and DCR, there was no factor showing a P-value < .05. Therefore, multivariate analysis was not performed for DCR. Regarding PFS and OS, the period from the start of firstline chemotherapy and number of metastatic sites, which showed a P-value < .05 in the univariate analysis examining the association between baseline characteristics and PFS and OS, were selected as confounding variables for multivariate analysis. In multivariate analysis, grade 3 or 4 neutropenia during the first cycle remained a significant factor that was predictive of PFS. Although neutropenia during the first cycle did not remain a significant factor for OS, this analysis showed a trend toward better survival in patients with neutropenia.
0.2
Discussion
Figure 1 Kaplan-Meier Curves Showing Progression-Free Survival (PFS) and Overall Survival (OS) (n [ 95)
1.0
OS: 5.9 months PFS: 2.0 months
Probability
0.8 0.6
0.0 0
6
12
Survival (months)
Tumor response was evaluated in 87 patients who had a measurable lesion. No complete response or partial response was observed. Thirty-four patients had stable disease, resulting in an objective response rate of 0%, and the disease control rate (DCR) was 39.1%.
Association Between Efficacy and Chemotherapy-Induced Neutropenia
The association between DCR and neutropenia during the first cycle according to each category is shown in Table 3. Comparison of category A (n ¼ 48) with B (n ¼ 38) and C (n ¼ 68) with D (n ¼ 18) showed that the category with a higher grade of neutropenia had significantly better DCR compared with the category with a lower grade. Kaplan-Meier curves for PFS and OS according to the each category are shown in Figure 2. In a comparison of category A (n ¼ 51) versus B (n ¼ 44) and C (n ¼ 75) versus D (n ¼ 20), the category with a higher grade of neutropenia demonstrated a significantly better PFS compared with the category with a lower grade. Although OS was also better in the category with a higher grade of neutropenia compared with a lower grade, the difference was not significant. Table 4 shows the findings of univariate and multivariate analyses of baseline characteristics, including the presence of neutropenia, as prognostic factors. In univariate analysis of the association between
Table 3 Association Between Neutropenia and Disease Control Rate Neutropenia (Category) Disease control rate (%) Odds ratio P-value (95% confidence interval)
A vs. B
C vs. D
29.2 vs. 52.6 2.67 0.045 (1.01-7.24)
30.9 vs. 72.2 5.69 0.002 (1.64-23.12)
N ¼ 86a with a measurable lesion. a One patient was excluded because of the change of hospital.
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Clinical Colorectal Cancer Month 2016
In this study, we showed that a higher grade of neutropenia caused by TAS-102 during the first cycle of chemotherapy was associated with better efficacy after adjustment for baseline factors. To our knowledge, this is the first report showing the predictive value of neutropenia caused by TAS-102 in patients with mCRC. Although other reports evaluated neutropenia occurring during all cycles of chemotherapy, we evaluated neutropenia in the first cycle of TAS-102 to avoid lead-time bias. Furthermore, we performed blood tests frequently and mainly during the third or fourth week from the start of TAS-102 treatment to detect the nadir of hematologic toxicities, because it was reported that the nadir of neutropenia due to TAS-102 tended to be observed about 21 days after the first administration in each course.13 From our results, we speculate that the absence of neutropenia may indicate insufficient doses of chemotherapeutic agents that do not produce a sufficient antitumor effect. The use of neutropenia as a pharmacodynamic marker could be used to individualize a biologically effective dose. The recommended doses (RD) of cytotoxic agents are generally determined by dose-finding studies, and the administration doses of the agents for clinical use are calculated on the basis of body surface area or Cr clearance. However, the sample sizes in these studies are insufficient for examining individual differences in drug metabolism, and therefore, toxicity profiles are likely to be highly variable.14 In addition, the poor correlation between body surface area and the pharmacokinetics of cytotoxic agents has been pointed out.15 It is known that neutropenia correlates with the plasma or blood concentration of cytotoxic agents.16,17 However, it is expensive and impractical to examine the plasma concentration of drugs in many patients. It has been reported that hematologic toxicity could be a measure of the biologic activity of cytotoxic agents in various types of cancer. From these results, a dose escalation study of cytotoxic agents has been attempted to evaluate neutropenia as a predictive factor. Shitara et al conducted a randomized phase II study comparing dose-escalated weekly paclitaxel, with the dose based on neutropenia, versus a standard dose of weekly paclitaxel for patients with previously treated advanced gastric cancer. They reported that the dose-escalated arm showed a significant improvement in PFS and tumor response compared with the standard dose arm, and there was no significant difference in grade 3 or more adverse events.18 In a Japanese phase I study of TAS-102 for patients with solid tumors refractory to standard chemotherapy, dose-limiting
Satoshi Hamauchi et al Figure 2 Kaplan-Meier Curves Showing Progression-Free Survival (PFS) and Overall Survival (OS) According to Each Category (n [ 95). A, PFS in Category A (Grade 0-1; n [ 51) and B (Grade 2-4; n [ 44). B, OS in Category A (Grade 0-1; n [ 51) and B (Grade 2-4; n [ 44). C, PFS in Category C (Grade 0-2; n [ 75) and D (Grade 3-4; n [ 20). D, OS in Category C (Grade 0-2; n [ 75) and D (Grade 3-4; n [ 20)
Category A: 2.0 months Category B: 2.7 months
0.8
HR, 0.59; 95% CI, 0.38-0.91; P=0.017 0.6 0.4
B 1.0 OS Probability
PFS Probability
A 1.0
0.2
Category A: 5.0 months Category B: 6.7 months HR, 0.68; 95% CI, 0.42-1.10; P=0.11
0.8 0.6 0.4 0.2
0.0
0.0 0
12
6
0
Survival (months)
C
D
1.0 Category C: 2.0 months Category D: 4.3 months
0.6
0.4
0.2
1.0
Category C: 5.7 months Category D: 8.0 months HR, 0.59; 95% CI, 0.32-1.07; P=0.084
0.8
HR, 0.41; 95% CI, 0.24-0.72; P=0.002 OS Probability
PFS Probability
0.8
6 12 Survival (months)
0.6
0.4
0.2
0.0
0.0 0
6
12
Survival (months)
0
6
12
Survival (months)
Abbreviations: CI ¼ Confidence interval; HR ¼ hazard ratio.
toxicities, such as grade 4 leucopenia, grade 4 neutropenia, and grade 4 thrombocytopenia, were observed in 2 patients at doses of 30 mg/m2 and 70 mg/m2. Consequently, the RD of TAS-102 monotherapy was determined as 70 mg/m2/day.13 Although the maximum tolerated dose was not reached in this study, 70 mg/m2/ day was determined as the RD of TAS-102 because of the increased tendency for grade 3 and 4 neutropenia. Therefore, we considered the possibility of an insufficient dose of TAS-102 with the current RD for some patients. Because increasing the doses of cytotoxic agents induces not only hematologic toxicity but also severe non-hematologic toxicity, the dose-escalating procedure of cytotoxic agents is not always safe for some cytotoxic agents. Non-hematologic toxicity caused by TAS102 is relatively mild compared with hematologic toxicity. In our study, there was no statistically significant difference in the worst grade of non-hematologic toxicity (mainly gastrointestinal toxicity) between patients with grade 3 to 4 neutropenia and those with grade 0 to 2 neutropenia. Therefore, dose escalation of TAS-102 according to the grade of neutropenia during the first cycle may be useful for patients with mCRC. For the safety and efficacy compared with other prospective studies such as J-00319 and RECOURSE, our study showed similar
outcomes in grade 3 or 4 neutropenia (42%, 50%, and 38% in our study, J-003, and RECOURSE, respectively) and median PFS (2.0 months, 1.9 months, and 2.0 months in our study, J-003, and RECOURSE, respectively). On the other hand, our study showed shorter MST compared with previous reports (5.9 months, 9.0 months, and 7.1 months in our study, J-003, and RECOURSE, respectively). The reason for this difference of MST is assumed that the prevalence rate of patients who had an ECOG PS 2 (9%), 3 or more metastatic sites (> 3, 54%), and the history of prior regorafenib treatment (49%) in our study were higher than those in previous reports. Although this study has limitations, such as a small number of patients, a retrospective design, a lack of serum drug levels, and performance at 2 institutions, this is the first report on the association between neutropenia caused by TAS-102 and efficacy for patients with advanced mCRC as late-line therapy.
Conclusion Neutropenia during the first cycle caused by TAS-102 was associated with better efficacy. Neutropenia may be a surrogate marker for adequate antitumor doses of TAS-102. To verify this hypothesis, it is necessary to validate the association by analyzing the
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6
DCR
PFS
Univariate Analysis Univariate Analysis
OS
Multivariate Analysis A vs. B
C vs. D
HR (95% CI); P-Value
HR (95% CI); P-Value
Univariate Analysis
HR (95% CI); P-Value
OR (95% CI); P-Value
HR (95% CI); P-Value
2.16 (0.34-15.76); .43
1.02 (0.49-2.14); .95
1.11 (0.48-2.58); .80
0.74 (0.61-4.19); .37
0.74 (0.49-1.12); .16
0.89 (0.55-1.42); .61
1.28 (0.49-3.42); .66
1.01 (0.67-1.54); .95
0.91 (0.56-1.46); .68
1.00 (0.39-2.59); 1.00
1.04 (0.69-1.58); .84
0.86 (0.54-1.38); .54
1.23 (0.43-3.70); .81
1.21 (0.76-1.92); .42
1.34 (0.75-2.38); .32
2.48 (0.67-11.49); .17
0.47 (0.28-0.80); .01
1.49 (0.57-3.98); .39
0.81 (0.53-1.23); .31
0.52 (0.19-1.35); .18
1.66 (1.09-2.55); .02
0.93 (0.36-2.40); 1.00
1.05 (0.69-1.58); .83
Multivariate Analysis A vs. B
C vs. D
HR (95% CI); P-Value
HR (95% CI); P-Value
0.49 (0.27-0.88); .02
0.48 (0.27-0.87); .01
2.10 (1.28-3.43); .01
2.07 (1.27-3.39); .01
0.78 (0.48-1.28); .33
0.69 (0.37-1.27); .23
ECOG PS 2 vs. 1 Age 65 years vs. 64 years Gender Male vs. female Primary site Rectum vs. colon Number of prior regimens 3 vs. 2 Time from start of first-line chemotherapy 18 mos vs. <18 mos
0.56 (0.32-0.97); .04
0.56 (0.33-0.97); .04
0.44 (0.25-0.78); .01
KRAS exon 2 status Wild vs. mutant
0.70 (0.44-1.13); .15
Number of metastatic sites 3 vs. 2
1.59 (1.04-2.55); .03
1.61 (1.05-2.47); .03
2.19 (1.34-3.57); .01
Prior regorafenib Yes vs. no
1.15 (0.71-1.85); .57
Neutropenia Yes vs. no
0.68 (0.43-1.07); .09
0.45 (0.26-0.79); .01
Abbreviations: CI ¼ Confidence interval; DCR ¼ disease control rate; ECOG PS ¼ Eastern Cooperative Oncology Group performance status; HR ¼ hazard ratio; OR ¼ odds ratio; OS ¼ overall survival; PFS ¼ progression-free survival.
Neutropenia and TAS-102
Clinical Colorectal Cancer Month 2016
Table 4 Univariate and Multivariate Analysis Regarding DCR, PFS, and OS
Satoshi Hamauchi et al clinical data of former trials such as RECOURSE and to conduct a well-defined prospective trial that evaluates the clinical benefit of dose escalation of TAS-102 in patients with mCRC without neutropenia during the first cycle.
3. 4.
Clinical Practice Points The potential predictive value of neutropenia caused by cytotoxic
5.
drugs has been reported in various types of cancer, including colorectal cancer. Neutropenia caused by TAS-102, a novel antitumor agent for mCRC, is the most common treatment-related adverse event, and there has been no report concerning the association between efficacy and neutropenia about this agent. In this study, neutropenia during the first cycle caused by TAS102 was associated with better efficacy. Dose escalation of TAS-102 according to the grade of neutropenia during the first cycle may be useful for patients with mCRC.
6.
Disclosure Satoshi Hamauchi has received honoraria from Taiho; Kentaro Yamazaki has received honoraria from Taiho; Toshiki Masuishi has received honoraria from Taiho; Yukiya Narita has received honoraria from Taiho and Aichi Cancer Center Hospital; Shigenori Kadowaki has received research funding from Taiho; Kei Muro has received honoraria from Taiho; and Hiroya Taniguchi has received honoraria from Taiho. All other authors state that they have no conflicts of interest.
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7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
19.
HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376:687-97. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008; 359:1757-65. Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013; 369:1023-34. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007; 357:2040-8. Scartozzi M, Galizia E, Chiorrini S, et al. Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab. Ann Oncol 2009; 20:227-30. Di Maio M, Gridelli C, Gallo C, et al. Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: a pooled analysis of three randomised trials. Lancet Oncol 2005; 6:669-77. Tewari KS, Java JJ, Gatcliffe TA, et al. Chemotherapy-induced neutropenia as a biomarker of survival in advanced ovarian carcinoma: an exploratory study of the gynecologic oncology group. Gynecol Oncol 2014; 133:439-45. Han Y, Yu Z, Wen S, et al. Prognostic value of chemotherapy-induced neutropenia in early-stage breast cancer. Breast Cancer Res Treat 2012; 131:483-90. Yamanaka T, Matsumoto S, Teramukai S, et al. Predictive value of chemotherapyinduced neutropenia for the efficacy of oral fluoropyrimidine S-1 in advanced gastric carcinoma. Br J Cancer 2007; 97:37-42. Shitara K, Matsuo K, Takahari D, et al. Neutropaenia as a prognostic factor in metastatic colorectal cancer patients undergoing chemotherapy with first-line FOLFOX. Eur J Cancer 2009; 45:1757-63. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 2015; 372:1909-19. Doi T, Ohtsu A, Yoshino T, et al. Phase I study of TAS-102 treatment in Japanese patients with advanced solid tumours. Br J Cancer 2012; 107:429-34. Gurney H. How to calculate the dose of chemotherapy. Br J Cancer 2002; 86: 1297-302. Baker SD, Verweij J, Rowinsky EK, et al. Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001. J Natl Cancer Inst 2002; 94: 1883-8. Bruno R, Hille D, Riva A, et al. Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 1998; 16: 187-96. Minami H, Kawada K, Sasaki Y, et al. Pharmacokinetics and pharmacodynamics of protein-unbound docetaxel in cancer patients. Cancer Sci 2006; 97: 235-41. Shitara K, Yuki S, Tahahari D, et al. Randomised phase II study comparing dose-escalated weekly paclitaxel vs standard-dose weekly paclitaxel for patients with previously treated advanced gastric cancer. Br J Cancer 2014; 110:271-7. Yoshino T, Mizunuma N, Yamazaki K, et al. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol 2012; 13:993-1001.
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Neutropenia as a Predictive Factor in Metastatic Colorectal Cancer Treated With TAS-102 Satoshi Hamauchi,1 Kentaro Yamazaki,1 Toshiki Masuishi,2 Yosuke Kito,1 Azusa Komori,2 Takahiro Tsushima,1 Yukiya Narita,2 Akiko Todaka,1 Makoto Ishihara,3 Tomoya Yokota,1 Tsutomu Tanaka,3 Nozomu Machida,1 Shigenori Kadowaki,2 Akira Fukutomi,1 Takashi Ura,2 Yusuke Onozawa,4 Masashi Ando,2 Masahiro Tajika,3 Kei Muro,2 Hirofumi Yasui,1 Keita Mori,5 Hiroya Taniguchi2 Abstract The most common treatment-related adverse event of TAS-102 monotherapy for colorectal cancer is bone marrow suppression, which leads to neutropenia. A retrospective study of 95 patients at 2 institutions was performed to evaluate the association between efficacy and neutropenia. Our findings indicate that neutropenia caused by TAS-102 was associated with better efficacy. Background: TAS-102 significantly improves overall survival in patients with metastatic colorectal cancer. The most common treatment-related adverse event of TAS-102 is bone marrow suppression, which leads to neutropenia. The potential predictive value of neutropenia caused by cytotoxic drugs has been reported in various types of cancer. Methods: We retrospectively analyzed 95 consecutive patients with metastatic colorectal cancer who received TAS102 at 2 Japanese institutions between May 2014 and May 2015. To evaluate the association between efficacy and neutropenia, patients were divided into 4 categories according to the grade of neutropenia during the first cycle of TAS-102: Category A (grade 0-1), B (grade 2-4), C (grade 0-2), and D (grade 3-4). Results: Patient characteristics were as follows: median age, 64 years; male, 58%; Eastern Cooperative Oncology Group performance status 0 to 1, 91%; primary site colon, 49%; KRAS exon 2 wild, 57%; and number of metastatic site 3, 55%. The disease control rate was significantly different between Category A and B (29.2% vs. 52.6%; P ¼ .045) and between Category C and D (30.9% vs. 72.2%; P ¼ .002). In multivariate analysis, Category D remained a significant predictive factor for progression-free survival compared with Category C (4.3 vs. 2.0 months; hazard ratio, 0.45; P ¼ .01). Conclusion: Neutropenia caused by TAS-102 during the first cycle was associated with better efficacy. Neutropenia may be a surrogate marker for adequate antitumor doses of TAS-102. Clinical Colorectal Cancer, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: Chemotherapy, Metastatic colorectal cancer, Neutropenia, Predictive factor, TAS-102
Introduction 1
Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan Department of Clinical Oncology Department of Endoscopy, Aichi Cancer Center Hospital, Nagoya, Japan 4 Division of Clinical Oncology 5 Clinical Research Center, Shizuoka Cancer Center, Shizuoka, Japan 2 3
Submitted: May 2, 2016; Revised: Jun 23, 2016; Accepted: Jul 5, 2016 Address for correspondence: Kentaro Yamazaki, MD, Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntogun, Shizuoka 411-8777, Japan E-mail contact: [email protected]
1533-0028/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clcc.2016.07.005
Systemic chemotherapy has improved outcomes in patients with solid cancer, but not in all cases. Therefore, a considerable amount of clinical and basic research has focused on seeking factors that predict the outcome of chemotherapy. In some molecular targeted therapies for solid tumors, predictive biomarkers, such as HER2 overexpression for HER2 inhibitor in breast cancer1 and gastric cancer2 and RAS mutations for epidermal growth factor receptor (EGFR) antibody in colorectal cancer,3,4 have been established. Furthermore, the association of treatment efficacy with adverse events, such as skin rash caused by EGFR inhibitor and
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Neutropenia and TAS-102 hypertension caused by vascular endothelial growth factor (VEGF) inhibitor, has been reported.5,6 It has also been reported that neutropenia during chemotherapy with cytotoxic agents is associated with favorable outcomes for several types of cancer.7-9 Regarding gastrointestinal cancer, Yamanaka et al reported that patients with advanced gastric cancer who experienced neutropenia caused by an oral fluoropyrimidine S-1 had longer survival than those who did not.10 A similar result has also been reported for metastatic colorectal cancer (mCRC) treated with fluorouracil plus folinic acid and oxaliplatin (FOLFOX).11 However, almost all of these studies involved chemo-naive patients, and the clinical impact of neutropenia on heavily pretreated patients has not yet been reported. TAS-102 is an oral antitumor drug containing trifluridine and tipiracil hydrochloride. Trifluridine is incorporated into DNA, and this process might result in its antitumor effects. Tipiracil hydrochloride assists in maintaining the blood concentrations of trifluridine by inhibiting thymidine phosphorylase that degrades trifluridine. In the global phase III REfractory COLoREctal cancer Study (RECOURSE) trial, patients who were given TAS-102 demonstrated a significant improvement in overall survival (OS) and progression-free survival (PFS) compared with those given placebo (hazard ratio [HR], 0.68 and 0.48 for OS and PFS, respectively; both P < .0001).12 Grade 3 or higher adverse events frequently observed in the TAS-102 arm included neutropenia (38%) and leukopenia (21%). Based on the above, we hypothesized that neutropenia is a predictor of efficacy of TAS-102 and conducted a retrospective analysis of patients with mCRC.
Drug-related adverse events according to the National Cancer Institute Common Toxicity Criteria version 4.0 were evaluated at least once every 2 weeks during chemotherapy. The most severe grade of neutropenia was based on the lowest recorded neutrophil count during the first cycle and was graded according to National Cancer Institute Common Toxicity Criteria version 4.0 regardless of the baseline neutrophil count. Tumor response was assessed by computed tomography every 8 to 12 weeks according to the guidelines of the Response Evaluation Criteria in Solid Tumors, version 1.1.
Statistical Methods
This was a retrospective study of patients with mCRC who received TAS-102 monotherapy at 2 Japanese institutions (Shizuoka Cancer Center and Aichi Cancer Center Hospital) from May 2014 to May 2015. Inclusion criteria were as follows: presence of histologically proven, inoperable metastatic colorectal adenocarcinoma; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2; sufficient bone marrow function (neutrophil count 1500/mm3, platelet count 75,000/mm3); adequate renal and liver function (serum creatinine [Cr] 1.5 mg/dL, aspartate transaminase/alanine aminotransferase 100 IU/L, total bilirubin 1.5 mg/dL); at least 2 prior regimens; and refractory to or intolerant of fluoropyrimidines, oxaliplatin, irinotecan, antiVEGF antibodies, and anti-EGFR antibodies (if KRAS exon 2 wild-type tumors). Patients could be included if they refused or were inappropriate candidates for oxaliplatin, irinotecan, anti-VEGF antibodies, and anti-EGFR antibody. This study was approved by the institutional review committees of the Shizuoka Cancer Center and the Aichi Cancer Center Hospital, and complied with the Declaration of Helsinki. Written informed consent was obtained from all patients before starting TAS-102 therapy.
Treatment Delivery
Results
TAS-102 (35 mg/m2) was administered twice daily, after breakfast and dinner, for 5 days a week with 2 days of rest for 2 weeks, followed by a 14-day rest period (1 treatment cycle). This treatment cycle was repeated every 4 weeks.
Patient Characteristics
Patients
-
Evaluation and Supportive Therapy
The objective of this study was to evaluate the association between grade of neutropenia caused by TAS-102 and efficacy (tumor response, PFS, and OS). PFS was calculated from the date of the start of TAS-102 until progressive disease (PD), death from any cause, or censoring at the last follow-up. OS was calculated from the start of TAS-102 until death from any cause or censoring at the last follow-up. We evaluated the grade of neutropenia during the first cycle to avoid lead-time bias, which produces a false-positive association between chemotherapy-induced neutropenia and longer survival. To evaluate the association between efficacy and neutropenia, patients were divided into 4 categories according to the grade of neutropenia during the first cycle of TAS-102: Category A (grade 0-1), B (grade 2-4), C (grade 0-2), and D (grade 3-4). To evaluate the association between neutropenia and efficacy, both univariate and multivariate analysis were applied. First, we performed a univariate analysis to examine the association between neutropenia during the first cycle and tumor response, PFS, and OS (category A vs. B, and C vs. D). The Fisher exact test was applied for tumor response and the log-rank test for PFS and OS. Nine patient background factors were selected for univariate analysis: ECOG PS (0-1 vs. 2), age ( 65 years vs. 64 years), gender (male vs. female), primary site of tumor (rectum vs. colon), number of prior regimens ( 3 vs. 2), time from start of first-line chemotherapy ( 18 months vs. < 18 months), KRAS exon 2 status (wild vs. mutant), number of metastatic organs ( 3 vs. 2), and prior history of regorafenib therapy (yes vs. no). Second, multivariate analysis was performed using confounding variables selected among the above 9 factors that showed P-value < .05 in univariate analysis. All reported P-values are 2-tailed, and P < .05 was considered statistically significant. All analyses were performed using R (version 3.1.1).
Patients and Methods
2
Treatment was discontinued if the tumor progressed, severe toxicity occurred, or the patient requested. Dose modification was made in decrements of 5 mg/m2 when hematologic adverse events at grade 4 or non-hematologic reactions at grade 3 or 4 appeared, and administration was temporarily discontinued.
Clinical Colorectal Cancer Month 2016
A total of 107 patients were treated with TAS-102 monotherapy for mCRC at Shizuoka Cancer Center and Aichi Cancer Center Hospital between May 2014 and May 2015. Twelve patients were
Satoshi Hamauchi et al excluded from this study for the following reasons: only 1 prior regimen (n ¼ 4), increase in blood bilirubin (n ¼ 4), decrease in platelet count (n ¼ 2), ECOG PS of 3 (n ¼ 1), and increase in Cr level (n ¼ 1). Our study therefore included 95 patients. Baseline characteristics are shown in Table 1. This study included 9 patients with an ECOG PS of 2 (9%). Almost all the patients had received prior chemotherapy regimens containing a fluoropyrimidine, oxaliplatin, irinotecan, anti-VEGF antibody, and anti-EGFR antibody (if KRAS exon 2 wild-type tumors). About half of the patients had received regorafenib.
patients (21%) discontinued this treatment due to PD by computed tomography (n ¼ 13) or clinical findings (n ¼ 7) in the first cycle. We diagnosed as PD by computed tomography or clinical findings as soon as the patients’ condition turned worse during the first cycle. Relative dose intensity (dose intensity/planned dose intensity 100) of TAS-102 in the first cycle was 88%. The median time to treatment failure of TAS-102 was 2.0 months, and the median number of cycles of TAS-102 administration was 2 (range, 1-13).
Toxicity Treatment Exposure The starting dose of TAS-102 was reduced in 6 patients for the following reasons: PS of 2 (n ¼ 3), older age (n ¼ 2), and renal impairment (n ¼ 1). Ninety-one patients (96%) discontinued TAS-102 due to PD (n ¼ 89) or adverse events (n ¼ 2). Twenty
Table 1 Baseline Patient Characteristics Characteristics
N (%)
Age (years) Median (range)
64 (32-90)
Gender Male
55 (58)
Female
40 (42)
ECOG PS 0
35 (37)
1
51 (54)
2
9 (9)
Primary site Colon
47 (49)
Rectum
48 (51)
Toxicities observed during chemotherapy are listed in Table 2. The median complete blood count (CBC) test times for all patients during the first cycle were 3 (range, 2-4), and 93 patients (98%) were given CBC tests in the third or the fourth week from the start of TAS-102 treatment, whereas 80 patients (84%) were given CBC tests in the first, second, and fourth weeks during the first cycle. The common grade 3 or 4 hematologic toxicities were neutropenia (42%) and anemia (22%). Grade 3 non-hematologic toxicities were anorexia (8%), nausea (4%), diarrhea (2%), and febrile neutropenia (2%). No grade 4 non-hematologic toxicity or treatment-related death was observed. We used granulocyte-colony stimulating factor for 3 patients owing to the grade 4 neutropenia during the first cycle. Incidences of grades of neutropenia during the first cycle were as follows: grade 0, 41% (n ¼ 39); grade 1, 16% (n ¼ 15); grade 2, 22% (n ¼ 21); grade 3, 15% (n ¼ 14); and grade 4, 6% (n ¼ 6).
Efficacy At the median follow-up time of 9.1 months (range, 1.4-16.1 months), the median PFS was 2.0 months, and the median survival time (MST) was 5.9 months (Figure 1).
KRAS exon 2 status Wild
54 (57)
Mutant
40 (42)
Unknown
1 (1)
Number of metastatic sites 1
14 (15)
2
29 (31)
3
52 (54)
Time from start of first-line chemotherapy <18 months
19 (20)
18 months
76 (80)
Number of prior regimens Median (range)
3 (2-7)
Prior chemotherapeutic agents Fluoropyrimidine
95 (100)
Oxaliplatin
94 (99)
Irinotecan
91 (96)
Anti-VEGF antibody
89 (94)
Anti-EGFR antibody (if wild KRAS exon 2)
50 (93)
Regorafenib
47 (49)
Abbreviations: ECOG PS ¼ Eastern Cooperative Oncology Group performance status; EGFR ¼ epidermal growth factor receptor; VEGF ¼ vascular endothelial growth factor.
Table 2 Adverse Events All Grade N (%)
Grade 3 or Higher N (%)
White blood cell decreased
62 (65)
17 (18)
Neutrophil count decreased
64 (67)
40 (42)
Anemia
80 (84)
21 (22)
Platelet count decreased
40 (42)
5 (5)
Anorexia
68 (72)
8 (8)
Fatigue
76 (80)
0 (0)
Nausea
59 (62)
4 (4)
Diarrhea
25 (26)
2 (2)
Mucositis oral
25 (26)
0 (0)
Adverse event Hematologic
Non-hematologic
Febrile neutropenia
2 (2)
2 (2)
AST increased
36 (38)
0 (0)
ALT increased
17 (18)
0 (0)
Blood bilirubin
20 (21)
1 (1)
Creatinine increased
11 (12)
0 (0)
Abbreviations: ALT ¼ Alanine aminotransferase; AST ¼ aspartate aminotransferase.
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Neutropenia and TAS-102
0.4
baseline characteristics and DCR, there was no factor showing a P-value < .05. Therefore, multivariate analysis was not performed for DCR. Regarding PFS and OS, the period from the start of firstline chemotherapy and number of metastatic sites, which showed a P-value < .05 in the univariate analysis examining the association between baseline characteristics and PFS and OS, were selected as confounding variables for multivariate analysis. In multivariate analysis, grade 3 or 4 neutropenia during the first cycle remained a significant factor that was predictive of PFS. Although neutropenia during the first cycle did not remain a significant factor for OS, this analysis showed a trend toward better survival in patients with neutropenia.
0.2
Discussion
Figure 1 Kaplan-Meier Curves Showing Progression-Free Survival (PFS) and Overall Survival (OS) (n [ 95)
1.0
OS: 5.9 months PFS: 2.0 months
Probability
0.8 0.6
0.0 0
6
12
Survival (months)
Tumor response was evaluated in 87 patients who had a measurable lesion. No complete response or partial response was observed. Thirty-four patients had stable disease, resulting in an objective response rate of 0%, and the disease control rate (DCR) was 39.1%.
Association Between Efficacy and Chemotherapy-Induced Neutropenia
The association between DCR and neutropenia during the first cycle according to each category is shown in Table 3. Comparison of category A (n ¼ 48) with B (n ¼ 38) and C (n ¼ 68) with D (n ¼ 18) showed that the category with a higher grade of neutropenia had significantly better DCR compared with the category with a lower grade. Kaplan-Meier curves for PFS and OS according to the each category are shown in Figure 2. In a comparison of category A (n ¼ 51) versus B (n ¼ 44) and C (n ¼ 75) versus D (n ¼ 20), the category with a higher grade of neutropenia demonstrated a significantly better PFS compared with the category with a lower grade. Although OS was also better in the category with a higher grade of neutropenia compared with a lower grade, the difference was not significant. Table 4 shows the findings of univariate and multivariate analyses of baseline characteristics, including the presence of neutropenia, as prognostic factors. In univariate analysis of the association between
Table 3 Association Between Neutropenia and Disease Control Rate Neutropenia (Category) Disease control rate (%) Odds ratio P-value (95% confidence interval)
A vs. B
C vs. D
29.2 vs. 52.6 2.67 0.045 (1.01-7.24)
30.9 vs. 72.2 5.69 0.002 (1.64-23.12)
N ¼ 86a with a measurable lesion. a One patient was excluded because of the change of hospital.
4
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Clinical Colorectal Cancer Month 2016
In this study, we showed that a higher grade of neutropenia caused by TAS-102 during the first cycle of chemotherapy was associated with better efficacy after adjustment for baseline factors. To our knowledge, this is the first report showing the predictive value of neutropenia caused by TAS-102 in patients with mCRC. Although other reports evaluated neutropenia occurring during all cycles of chemotherapy, we evaluated neutropenia in the first cycle of TAS-102 to avoid lead-time bias. Furthermore, we performed blood tests frequently and mainly during the third or fourth week from the start of TAS-102 treatment to detect the nadir of hematologic toxicities, because it was reported that the nadir of neutropenia due to TAS-102 tended to be observed about 21 days after the first administration in each course.13 From our results, we speculate that the absence of neutropenia may indicate insufficient doses of chemotherapeutic agents that do not produce a sufficient antitumor effect. The use of neutropenia as a pharmacodynamic marker could be used to individualize a biologically effective dose. The recommended doses (RD) of cytotoxic agents are generally determined by dose-finding studies, and the administration doses of the agents for clinical use are calculated on the basis of body surface area or Cr clearance. However, the sample sizes in these studies are insufficient for examining individual differences in drug metabolism, and therefore, toxicity profiles are likely to be highly variable.14 In addition, the poor correlation between body surface area and the pharmacokinetics of cytotoxic agents has been pointed out.15 It is known that neutropenia correlates with the plasma or blood concentration of cytotoxic agents.16,17 However, it is expensive and impractical to examine the plasma concentration of drugs in many patients. It has been reported that hematologic toxicity could be a measure of the biologic activity of cytotoxic agents in various types of cancer. From these results, a dose escalation study of cytotoxic agents has been attempted to evaluate neutropenia as a predictive factor. Shitara et al conducted a randomized phase II study comparing dose-escalated weekly paclitaxel, with the dose based on neutropenia, versus a standard dose of weekly paclitaxel for patients with previously treated advanced gastric cancer. They reported that the dose-escalated arm showed a significant improvement in PFS and tumor response compared with the standard dose arm, and there was no significant difference in grade 3 or more adverse events.18 In a Japanese phase I study of TAS-102 for patients with solid tumors refractory to standard chemotherapy, dose-limiting
Satoshi Hamauchi et al Figure 2 Kaplan-Meier Curves Showing Progression-Free Survival (PFS) and Overall Survival (OS) According to Each Category (n [ 95). A, PFS in Category A (Grade 0-1; n [ 51) and B (Grade 2-4; n [ 44). B, OS in Category A (Grade 0-1; n [ 51) and B (Grade 2-4; n [ 44). C, PFS in Category C (Grade 0-2; n [ 75) and D (Grade 3-4; n [ 20). D, OS in Category C (Grade 0-2; n [ 75) and D (Grade 3-4; n [ 20)
Category A: 2.0 months Category B: 2.7 months
0.8
HR, 0.59; 95% CI, 0.38-0.91; P=0.017 0.6 0.4
B 1.0 OS Probability
PFS Probability
A 1.0
0.2
Category A: 5.0 months Category B: 6.7 months HR, 0.68; 95% CI, 0.42-1.10; P=0.11
0.8 0.6 0.4 0.2
0.0
0.0 0
12
6
0
Survival (months)
C
D
1.0 Category C: 2.0 months Category D: 4.3 months
0.6
0.4
0.2
1.0
Category C: 5.7 months Category D: 8.0 months HR, 0.59; 95% CI, 0.32-1.07; P=0.084
0.8
HR, 0.41; 95% CI, 0.24-0.72; P=0.002 OS Probability
PFS Probability
0.8
6 12 Survival (months)
0.6
0.4
0.2
0.0
0.0 0
6
12
Survival (months)
0
6
12
Survival (months)
Abbreviations: CI ¼ Confidence interval; HR ¼ hazard ratio.
toxicities, such as grade 4 leucopenia, grade 4 neutropenia, and grade 4 thrombocytopenia, were observed in 2 patients at doses of 30 mg/m2 and 70 mg/m2. Consequently, the RD of TAS-102 monotherapy was determined as 70 mg/m2/day.13 Although the maximum tolerated dose was not reached in this study, 70 mg/m2/ day was determined as the RD of TAS-102 because of the increased tendency for grade 3 and 4 neutropenia. Therefore, we considered the possibility of an insufficient dose of TAS-102 with the current RD for some patients. Because increasing the doses of cytotoxic agents induces not only hematologic toxicity but also severe non-hematologic toxicity, the dose-escalating procedure of cytotoxic agents is not always safe for some cytotoxic agents. Non-hematologic toxicity caused by TAS102 is relatively mild compared with hematologic toxicity. In our study, there was no statistically significant difference in the worst grade of non-hematologic toxicity (mainly gastrointestinal toxicity) between patients with grade 3 to 4 neutropenia and those with grade 0 to 2 neutropenia. Therefore, dose escalation of TAS-102 according to the grade of neutropenia during the first cycle may be useful for patients with mCRC. For the safety and efficacy compared with other prospective studies such as J-00319 and RECOURSE, our study showed similar
outcomes in grade 3 or 4 neutropenia (42%, 50%, and 38% in our study, J-003, and RECOURSE, respectively) and median PFS (2.0 months, 1.9 months, and 2.0 months in our study, J-003, and RECOURSE, respectively). On the other hand, our study showed shorter MST compared with previous reports (5.9 months, 9.0 months, and 7.1 months in our study, J-003, and RECOURSE, respectively). The reason for this difference of MST is assumed that the prevalence rate of patients who had an ECOG PS 2 (9%), 3 or more metastatic sites (> 3, 54%), and the history of prior regorafenib treatment (49%) in our study were higher than those in previous reports. Although this study has limitations, such as a small number of patients, a retrospective design, a lack of serum drug levels, and performance at 2 institutions, this is the first report on the association between neutropenia caused by TAS-102 and efficacy for patients with advanced mCRC as late-line therapy.
Conclusion Neutropenia during the first cycle caused by TAS-102 was associated with better efficacy. Neutropenia may be a surrogate marker for adequate antitumor doses of TAS-102. To verify this hypothesis, it is necessary to validate the association by analyzing the
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6
DCR
PFS
Univariate Analysis Univariate Analysis
OS
Multivariate Analysis A vs. B
C vs. D
HR (95% CI); P-Value
HR (95% CI); P-Value
Univariate Analysis
HR (95% CI); P-Value
OR (95% CI); P-Value
HR (95% CI); P-Value
2.16 (0.34-15.76); .43
1.02 (0.49-2.14); .95
1.11 (0.48-2.58); .80
0.74 (0.61-4.19); .37
0.74 (0.49-1.12); .16
0.89 (0.55-1.42); .61
1.28 (0.49-3.42); .66
1.01 (0.67-1.54); .95
0.91 (0.56-1.46); .68
1.00 (0.39-2.59); 1.00
1.04 (0.69-1.58); .84
0.86 (0.54-1.38); .54
1.23 (0.43-3.70); .81
1.21 (0.76-1.92); .42
1.34 (0.75-2.38); .32
2.48 (0.67-11.49); .17
0.47 (0.28-0.80); .01
1.49 (0.57-3.98); .39
0.81 (0.53-1.23); .31
0.52 (0.19-1.35); .18
1.66 (1.09-2.55); .02
0.93 (0.36-2.40); 1.00
1.05 (0.69-1.58); .83
Multivariate Analysis A vs. B
C vs. D
HR (95% CI); P-Value
HR (95% CI); P-Value
0.49 (0.27-0.88); .02
0.48 (0.27-0.87); .01
2.10 (1.28-3.43); .01
2.07 (1.27-3.39); .01
0.78 (0.48-1.28); .33
0.69 (0.37-1.27); .23
ECOG PS 2 vs. 1 Age 65 years vs. 64 years Gender Male vs. female Primary site Rectum vs. colon Number of prior regimens 3 vs. 2 Time from start of first-line chemotherapy 18 mos vs. <18 mos
0.56 (0.32-0.97); .04
0.56 (0.33-0.97); .04
0.44 (0.25-0.78); .01
KRAS exon 2 status Wild vs. mutant
0.70 (0.44-1.13); .15
Number of metastatic sites 3 vs. 2
1.59 (1.04-2.55); .03
1.61 (1.05-2.47); .03
2.19 (1.34-3.57); .01
Prior regorafenib Yes vs. no
1.15 (0.71-1.85); .57
Neutropenia Yes vs. no
0.68 (0.43-1.07); .09
0.45 (0.26-0.79); .01
Abbreviations: CI ¼ Confidence interval; DCR ¼ disease control rate; ECOG PS ¼ Eastern Cooperative Oncology Group performance status; HR ¼ hazard ratio; OR ¼ odds ratio; OS ¼ overall survival; PFS ¼ progression-free survival.
Neutropenia and TAS-102
Clinical Colorectal Cancer Month 2016
Table 4 Univariate and Multivariate Analysis Regarding DCR, PFS, and OS
Satoshi Hamauchi et al clinical data of former trials such as RECOURSE and to conduct a well-defined prospective trial that evaluates the clinical benefit of dose escalation of TAS-102 in patients with mCRC without neutropenia during the first cycle.
3. 4.
Clinical Practice Points The potential predictive value of neutropenia caused by cytotoxic
5.
drugs has been reported in various types of cancer, including colorectal cancer. Neutropenia caused by TAS-102, a novel antitumor agent for mCRC, is the most common treatment-related adverse event, and there has been no report concerning the association between efficacy and neutropenia about this agent. In this study, neutropenia during the first cycle caused by TAS102 was associated with better efficacy. Dose escalation of TAS-102 according to the grade of neutropenia during the first cycle may be useful for patients with mCRC.
6.
Disclosure Satoshi Hamauchi has received honoraria from Taiho; Kentaro Yamazaki has received honoraria from Taiho; Toshiki Masuishi has received honoraria from Taiho; Yukiya Narita has received honoraria from Taiho and Aichi Cancer Center Hospital; Shigenori Kadowaki has received research funding from Taiho; Kei Muro has received honoraria from Taiho; and Hiroya Taniguchi has received honoraria from Taiho. All other authors state that they have no conflicts of interest.
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Clinical Colorectal Cancer Month 2016
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