Skip to main content
Download PDF

Prognostic impact of severe neutropenia in colorectal cancer patients treated with TAS-102 and bevacizumab, addressing immortal-time bias

BMC Cancer volume 23, Article number: 1078 (2023) Cite this article

Abstract

Background

Several studies have reported an association between severe neutropenia and long-term survival in patients treated with trifluridine-tipiracil (TAS-102). Because some of these studies failed to address immortality time bias, however, their findings should be interpreted with caution. Additionally, the association between severe neutropenia and survival in patients receiving TAS-102 in combination with bevacizumab (Bmab) remains unclear.

Patients and methods

We conducted a single-center retrospective cohort study in patients with colorectal cancer who received Bmab + TAS-102. We compared overall survival (OS) between patients who developed grade ≥ 3 neutropenia during the treatment period and those who did not. To account for immortal time bias, we used two approaches, time-varying Cox regression and landmark analysis.

Results

Median OS was 15.3 months [95% CI: 14.1–NA] in patients with grade ≥ 3 neutropenia and 10.0 months [95% CI: 8.1–NA] in those without. In time-varying Cox regression, onset grade ≥ 3 neutropenia was significantly related to longer survival after adjustment for age and modified Glasgow Prognostic Score. Additionally, 30-, 60-, 90-, and 120-day landmark analysis showed that grade ≥ 3 neutropenia was associated with longer survival after adjustment for age and modified Glasgow Prognostic Score, with respective HRs of 0.30 [0.10–0.90], 0.65 [0.30–1.42], 0.39 [0.17–0.90], and 0.41 [0.18–0.95].

Conclusion

We identified an association between long-term survival and the development of severe neutropenia during the early cycle of Bmab + TAS-102 using an approach that addressed immortality time bias.

Peer Review reports

Implications for practice

Our study found that the occurrence of grade ≥ 3 neutropenia during the treatment period of Bmab + TAS-102 was significantly associated with long-term survival in patients with colorectal cancer. For patients who do not develop neutropenia during the early cycle of Bmab + TAS-102, increasing TAS-102 dosage to improve treatment outcomes may warrant consideration.

Introduction

Trifluridine-tipiracil (TAS-102) is an oral antitumor agent composed of the thymidine-based nucleic acid analog trifluridine and the thymidine phosphorylase inhibitor tipiracil hydrochloride in a molar ratio of 1:0.5. In Phase III clinical trials, TAS-102 was clinically superior to placebo in overall survival (OS) in patients with metastatic colorectal cancer refractory to standard therapies, including fluoropyrimidines, irinotecan, and oxaliplatin [1, 2].

Our previous retrospective study compared TAS-102 in combination with bevacizumab (Bmab + TAS-102) and TAS-102 monotherapy using a propensity-matched cohort. Results indicated that Bmab + TAS-102 significantly improved OS in patients with metastatic colorectal cancer refractory to standard therapies (hazard ratio [HR], 0.24 [95% CI 0.12–0.52]; p < 0.001) [3]. Additionally, a randomized phase 2 study demonstrated that Bmab + TAS-102 prolonged progression-free survival (PFS) (HR 0.45 [95% CI 0.29–0.72]; p = 0.0015) compared with TAS-102 monotherapy [4].

The most common adverse event associated with TAS-102 monotherapy is neutropenia, with 37.9% of patients treated with TAS-102 monotherapy experiencing grade ≥ 3 neutropenia in the RECOURSE trial [1]. Moreover, the incidence of grade ≥ 3 neutropenia tended to be higher on combination of Bmab with TAS-102 compared with TAS-102 monotherapy (67% vs. 38%) [4].

Several retrospective cohort studies reported an association between the occurrence of neutropenia during TAS-102 monotherapy or Bmab + TAS-102 therapy and long-term survival [5,6,7,8]. These findings should be interpreted with caution, however, because classification of the group without neutropenia to the group with neutropenia group after treatment initiation may cause a problem known as immortal time bias [9].

In this study, we aimed to determine the association between the onset of severe neutropenia and survival in patients with colorectal cancer who received Bmab + TAS-102 using an approach that addresses immortal time bias.

Patients and methods

Study design

The study was conducted under a retrospective cohort design at a single center in patients diagnosed with metastatic colorectal cancer who were refractory to standard chemotherapy regimens and received Bmab + TAS-102. Survival duration was compared between patients with and without grade ≥ 3 neutropenia during the treatment period, with the onset of neutropenia considered as a time-dependent covariate.

Setting and participants

The data were obtained from electronic medical records at Gifu University Hospital. The study population consisted of patients with colorectal cancer who were refractory to standard therapies, including fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (in cases of tumors with wild-type RAS), and who received Bmab + TAS-102 between March 2016 and June 2021. The exclusion criterion for this study was a reduction in the initial dose of TAS-102.

Variables

The primary endpoint of the study was OS, defined as the time elapsed from the initiation of Bmab + TAS-102 to death. PFS was defined as the time from the initiation of Bmab + TAS-102 to the first date of radiological or clinical progression or time of death. For OS and PFS, patients who were lost to follow-up or survived until the end of the observation period were censored. Tumor response was assessed according to the guidelines outlined in Response Evaluation Criteria in Solid Tumors version 1.1 [10]. Disease control rate was defined as the proportion of patients with a complete or partial response, or stable disease. Neutropenia was graded according to the Common Terminology Criteria for Adverse Events version 5.0 [11], with grade ≥ 3 neutropenia defined as severe neutropenia. Potential confounding factors, such as age and modified Glasgow Prognostic Score (mGPS), were considered in the analysis. The latter is a widely recognized prognostic predictor of colorectal cancer which is calculated based on serum albumin and CRP levels: patients with a serum albumin level greater than 3.5 g/dL and CRP less than 1.0 mg/dL were classified as mGPS 0, those with either decreased albumin levels or increased CRP levels as mGPS 1, and those with both decreased albumin levels and elevated CRP levels as mGPS 2 [12].

Statistical methods

In the present study, the exposure group consisted of patients who experienced grade ≥ 3 neutropenia during the follow-up period. However, this raises concerns of immortal time bias [13]. To address this potential, our primary analysis utilized a time-varying Cox regression model rather than assuming that hazard ratios remained unchanged over time [13, 14]. The Simon and Makuch method [14] was employed to graphically depict survival curves for time-dependent covariates. This modified Kaplan–Meier survival curve is a more accurate representation of the difference in survival curves than simply assuming a fixed covariate and plotting Kaplan–Meier curves [15].

Additionally, landmark analysis was performed as sensitivity analysis [16, 17]. In our study, landmark time points were established at 30, 60, 90, and 120 days post-treatment initiation. Outcome events after each landmark were included in the analysis. Patients who developed grade ≥ 3 neutropenia prior to each landmark were classified into the neutropenia group, while those who did not develop grade ≥ 3 neutropenia prior to each landmark were classified into the non-neutropenia group. Hazard ratios for death between the two groups were calculated using Cox proportional hazards regression analysis.

As no specific hypothesis was predetermined regarding the anticipated effect in this study, no sample size calculation was performed. Data analysis was conducted using R software version 4.2.2. In all analyses, a two­tailed p value of less than 0.05 was deemed to be significant. Since the statistical analysis plan did not include a provision for correcting multiple comparisons for secondary outcomes, these results cannot be conclusively interpreted.

Results

Patients

An eligible cohort of 80 patients with metastatic colorectal cancer who underwent TAS-102 treatment was identified and assessed for inclusion (Fig. 1). Subsequently, 23 subjects were excluded due to a reduced initial dose of TAS-102. The study cohort was divided based on the onset of severe neutropenia during the follow-up period into 30 patients with severe neutropenia and 27 patients without severe neutropenia. All 57 subjects who met the eligibility criteria were included in the final analysis. Baseline demographics are shown in Table 1. Except for one patient with no RAS, BRAF, or MSI data, there were no missing baseline data.

Fig. 1
figure 1

Consolidated Standards of Reporting Trials (CONSORT) Flow Diagram. Abbreviation: Bmab, bevacizumab

Full size image
Table 1 Baseline characteristics of patients with and without grade ≥ 3 neutropenia
Full size table

Survival analysis and incidence of grade ≥ 3 neutropenia in the entire cohort

In all study subjects, the median duration of follow-up was 305 days, with an interquartile range of 217–432. Median OS was 14.2 months (95% CI [13.4 – 18.6]) and median PFS was 6.8 months (95% CI [5.2 – 10.2]).

The onset of severe neutropenia during the follow-up period was 52.6% (30/57). Among the 30 patients, the median onset time of severe neutropenia from the initiation of Bmab + TAS-102 was 56 days, with an interquartile range of 28 to 70.

Comparison of the efficacy of the combination TAS-102 and Bmab in patients with and without severe neutropenia

To prevent immortal-time bias in assessment of the association between neutropenia and survival, we implemented both a time-varying Cox regression model and landmark analysis. Median survival was determined using Simon and Makuch’s modified Kaplan–Meier survival curves. Results showed that median OS was 15.3 months [95% CI: 14.1–NA] for patients with severe neutropenia and 10.0 months [95% CI: 8.1–NA] for those without severe neutropenia. Time-varying Cox regression showed that severe neutropenia was significantly associated with longer survival after adjusting for age and mGPS (HR: 0.42; [95% CI: 0.19–0.89], p = 0.025) (Fig. 2A). Median PFS was 8.5 months [95% CI: 5.5–12.0] and 5.3 months [95% CI: 3.5–9.2] for patients with and without severe neutropenia, respectively. Although not significant, patients with severe neutropenia tended to have longer PFS (HR: 0.72; [95% CI: 0.40–1.32], p = 0.3) (Fig. 2B).

Fig. 2
figure 2

Simon and Makuch’s modified Kaplan–Meier curves for overall survival (A) and progression-free survival (B) in colorectal cancer patients who received a combination of trifluridine-tipiracil and bevacizumab. One curve (green line) shows patients who experienced grade ≥ 3 neutropenia during the treatment period (30 patients [52.6%] with grade ≥ 3 neutropenia), and the other curve (red line) shows those who did not (27 patients [47.4%] without grade ≥ 3 neutropenia). Abbreviations: Bmab + TAS-102, trifluridine-tipiracil in combination with bevacizumab. CI, confidence interval. HR, hazard ratio. mGPS, modified Glasgow prognostic score. NA, indicates calculation not possible. OS, overall survival. PFS, progression-free survival

Full size image

Next, 30-, 60-, 90-, and 120-day landmark analyses were performed. Median survival time between groups with and without neutropenia at the 30-, 60-, 90-, and 120-day landmarks was 19.6 [13.1-NA] and 13.1 [7.5–17.4], 16.1 [12.1-NA] and 12.2 [8.0–16.6], 15.1 [11.1-NA] and 10.7 [5.5–21.3], and 11.4 [10.2-NA] and 9.7 [4.5–20.4], respectively. Cox proportional hazards analysis showed HRs for the association between neutropenia and OS at the 30-, 60-, 90-, and 120-day landmarks of 0.30 [0.10–0.90], 0.65 [0.30–1.42], 0.39 [0.17–0.90], and 0.41 [0.18–0.95], respectively (Table 2).

Table 2 Survival analysis at 30, 60, 90, and 120-day landmarks
Full size table

Comparison of overall response rate, relative dose intensity, and usage of regorafenib following TAS-102 with bevacizumab between patients with and without severe neutropenia

Table 3 shows the overall response rate, disease control rate, relative dose intensity, and use of regorafenib following treatment with Bmab + TAS-102 in patients with and without severe neutropenia. Although not significant, patients with severe neutropenia tended to have higher disease control rates (90.0% vs. 70.4%, p = 0.093). Notably, the relative dose intensity of TAS-102 was significantly lower in patients with severe neutropenia (0.73 vs 0.84, p = 0.014). The proportion of patients who received regorafenib following Bmab + TAS-102 in the two groups was comparable (33.3% vs. 33.3%, p > 0.9). The occurrences of other adverse events among patients with and without severe neutropenia are shown in Supplemental Table 1.

Table 3 Comparison of overall response rate, relative dose intensity, and regorafenib use post-treatment
Full size table

Discussion

The objective of this study was to examine the impact of severe neutropenia on the efficacy of treatment with Bmab + TAS-102 while addressing the problem of immortal time bias. To overcome this challenge, we applied two strategies: a time-varying Cox regression model and landmark analysis [18]. The results of these two methods were consistent and indicated that grade ≥ 3 neutropenia onset was significantly associated with longer survival.

Two other studies have examined the relationship between neutropenia during Bmab + TAS-102 therapy and OS. Their results warrant caution, however, as they either did not adjust for confounding variables [8] or for the time-varying nature of neutropenia [6]. Our study is distinctive in that it addressed immortal time bias, and controlled for major confounding factors including age and mGPS by time-varying Cox proportional hazards regression. In addition, our 30-, 60-, 90-, and 120-day landmark analyses showed that neutropenia during the early period after the first cycle was associated with prognosis. These results provide novel evidence in support of these previous findings of an association between prognosis and neutropenia during the first cycle of TAS-102 monotherapy [7] and in combination with Bmab [8]. In this regard, our study addresses the limitations of prior research and contributes to a more robust evidence base.

In our study, patients with severe neutropenia exhibited significantly lower relative dose intensity for TAS-102 due to dose reductions in response to severe neutropenia. Nevertheless, disease control rates in these patients were higher, suggesting that reducing the dose in response to grade ≥ 3 neutropenia could be acceptable from a risk–benefit perspective. Conversely, for patients who do not experience neutropenia, the standard dose of TAS-102 may not be sufficient to induce myelotoxicity, and an increase in TAS-102 dosage as a potential strategy to improve treatment outcomes may be considered, as discussed by Kasi et al. [7, 19]. The relationship between neutropenia and patient outcomes may be explained by neutropenia's potential role as an indirect measure for the optimal dosage of Bmab + TAS-102. This marker could reflect various factors such as drug exposure, dose density, and metabolic activity, as indicated in prior studies on other colorectal cancer treatments [20, 21]. Specific gene variations related to the metabolism of trifluridine and the excretion of tipiracil have been shown to affect the effectiveness and toxicity of TAS-102 in patients with metastatic colorectal cancer [22, 23]. Interestingly, a higher incidence of neutropenia has been correlated with both a higher area under the curve for trifluridine plasma concentration and longer OS [24]. Consequently, use of body surface area alone to determine TAS-102 dosage may not be adequate, as it fails to consider individual differences in drug metabolism.

As one result of our study, we found that severe neutropenia exhibited a favorable yet statistically non-significant impact on PFS, with a more pronounced effect on OS. These findings lead us to hypothesize that Bmab + TAS-102 therapy, coupled with the onset of neutropenia, may modulate the tumor microenvironment. Recent research indicates that TAS-102 exerts its antitumor immune effect primarily by directly eliminating Tumor-Associated Macrophage 2 (TAM2) [25], which promotes tumor growth through mechanisms such as angiogenesis and immunosuppression [26, 27]. VEGF inhibitors, such as Bmab, enhance antitumor responses by inhibiting the infiltration of tumor-promoting immune cells, including TAM2 [28]. Neutrophils are also known to contribute to tumor growth by promoting angiogenesis and suppressing antitumor immune responses [29,30,31]. Therefore, neutropenia induced by Bmab + TAS-102 may alter the tumor microenvironment and potentially influence tumor evolution following treatment [32].

Our study has several limitations. First, it was conducted under a retrospective design at a single center. Second, due to the small sample size, the number of variables included in the multivariable analysis was restricted to avoid overfitting. As a result, we could not adjust for additional factors, such as comorbidities. Third, given that the OS and PFS in our study were longer than those reported in a previous phase III trial (median OS: 9.4 months, median PFS: 4.6 months) [4], it is possible the target population in this study had a relatively favorable overall health status that would be considered acceptable for Bmab combination therapy. Fourth, the mechanism underlying the relationship between myelosuppression and increased antitumor activity remains unresolved. In particular, it is yet to be established whether myelosuppression enhances antitumor activity by suppressing tumor-promoting cells, such as TAM, or whether severe neutropenia develops as a consequence of administering an optimal dose of TAS-102. Further investigation in larger cohorts is necessary to validate the outcomes of this study, clarify the molecular mechanisms underlying the impact of Bmab + TAS-102-induced severe neutropenia on prognosis, and evaluate the potential benefit of modifying subsequent TAS-102 doses in response to hematological toxicity during treatment.

Conclusion

Our study showed a significant association between the occurrence of severe neutropenia during Bmab + TAS-102 and long-term survival, utilizing an approach that addresses immortality time bias.

Availability of data and materials

The data that support the findings of this study are available from the study groups, but restrictions apply to the availability of these data, which were used under license for the current study; therefore, the data are not publicly available. However, data are available from the corresponding authors upon reasonable request and with permission from the study groups.

Abbreviations

Bmab + TAS-102:

Trifluridine-tipiracil in combination with bevacizumab

CI:

Confidence interval

HR:

Hazard ratio

mGPS:

Modified Glasgow prognostic score

NA:

Calculation not possible

OS:

Overall survival

PFS:

Progression-free survival

TAM2:

Tumor-associated macrophage 2

References

  1. Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372:1909–19.

    Article  PubMed  Google Scholar 

  2. Xu J, Kim TW, Shen L, Sriuranpong V, Pan H, Xu R, et al. Results of a randomized, double-blind, placebo-controlled, phase III Trial of Trifluridine/Tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: the TERRA study. J Clin Oncol. 2018;36:350–8.

    Article  CAS  PubMed  Google Scholar 

  3. Fujii H, Matsuhashi N, Kitahora M, Takahashi T, Hirose C, Iihara H, et al. Bevacizumab in combination with TAS-102 improves clinical outcomes in patients with refractory metastatic colorectal cancer: a retrospective study. Oncologist. 2020;25:e469–76.

    Article  CAS  PubMed  Google Scholar 

  4. Pfeiffer P, Yilmaz M, Möller S, Zitnjak D, Krogh M, Petersen LN, et al. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21:412–20.

    Article  CAS  PubMed  Google Scholar 

  5. Kimura M, Usami E, Iwai M, Teramachi H, Yoshimura T. Severe neutropenia: a prognosticator in patients with advanced/recurrent colorectal cancer under oral trifluridine-tipiracil (TAS-102) chemotherapy. Pharmazie. 2017;72:49–52.

    CAS  PubMed  Google Scholar 

  6. Nose Y, Kagawa Y, Hata T, Mori R, Kawai K, Naito A, et al. Neutropenia is an indicator of outcomes in metastatic colorectal cancer patients treated with FTD/TPI plus bevacizumab: a retrospective study. Cancer Chemother Pharmacol. 2020;86:427–33.

    Article  CAS  PubMed  Google Scholar 

  7. Kasi PM, Kotani D, Cecchini M, Shitara K, Ohtsu A, Ramanathan RK, et al. Chemotherapy induced neutropenia at 1-month mark is a predictor of overall survival in patients receiving TAS-102 for refractory metastatic colorectal cancer: a cohort study. BMC Cancer. 2016;16:467.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Kamiimabeppu D, Osumi H, Shinozaki E, Ooki A, Wakatsuki T, Yoshino K, et al. Effect of neutropenia on survival outcomes of patients with metastatic colorectal cancer receiving trifluridine/tipiracil plus bevacizumab. Oncol Lett. 2021;22:783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Suissa S. Immortal time bias in observational studies of drug effects. Pharmacoepidemiol Drug Saf. 2007;16:241–9.

    Article  PubMed  Google Scholar 

  10. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.

    Article  CAS  PubMed  Google Scholar 

  11. U.S. Department of Health and Human Services, National Institutes of Health National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 2017. Cited 1 Feb 2023. Available: https://www.eortc.be/services/doc/ctc/.

  12. Tsuchihashi K, Ito M, Moriwaki T, Fukuoka S, Taniguchi H, Takashima A, et al. Role of predictive value of the modified Glasgow prognostic score for later-line chemotherapy in patients with metastatic colorectal cancer. Clin Colorectal Cancer. 2018;17:e687–97.

    Article  PubMed  Google Scholar 

  13. Suissa S. Immortal time bias in pharmaco-epidemiology. Am J Epidemiol. 2008;167:492–9.

    Article  PubMed  Google Scholar 

  14. Simon R, Makuch RW. A non-parametric graphical representation of the relationship between survival and the occurrence of an event: application to responder versus non-responder bias. Stat Med. 1984;3:35–44.

    Article  CAS  PubMed  Google Scholar 

  15. Schultz LR, Peterson EL, Breslau N. Graphing survival curve estimates for time-dependent covariates. Int J Methods Psychiatr Res. 2002;11:68–74.

    Article  PubMed  Google Scholar 

  16. Gleiss A, Oberbauer R, Heinze G. An unjustified benefit: immortal time bias in the analysis of time-dependent events. Transpl Int. 2018;31:125–30.

    Article  PubMed  Google Scholar 

  17. Putter H, van Houwelingen HC. Understanding landmarking and its relation with time-dependent cox regression. Stat Biosci. 2017;9:489–503.

    Article  PubMed  Google Scholar 

  18. Giobbie-Hurder A, Gelber RD, Regan MM. Challenges of guarantee-time bias. J Clin Oncol. 2013;31:2963–9.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kasi PM, Grothey A. Should we optimize cytotoxic therapy by dosing to neutropenia? Lessons from TAS-102. Ann Oncol. 2020. 15–16.

  20. Tan X, Wen Q, Wang R, Chen Z. Chemotherapy-induced neutropenia and the prognosis of colorectal cancer: a meta-analysis of cohort studies. Expert Rev Anticancer Ther. 2017;17:1077–85.

    Article  CAS  PubMed  Google Scholar 

  21. Shitara K, Matsuo K, Takahari D, Yokota T, Inaba Y, Yamaura H, 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.

    Article  CAS  PubMed  Google Scholar 

  22. Suenaga M, Schirripa M, Cao S, Zhang W, Yang D, Dadduzio V, et al. Potential role of polymorphisms in the transporter genes ENT1 and MATE1/OCT2 in predicting TAS-102 efficacy and toxicity in patients with refractory metastatic colorectal cancer. Eur J Cancer. 2017;86:197–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sakamoto K, Yokogawa T, Ueno H, Oguchi K, Kazuno H, Ishida K, et al. Crucial roles of thymidine kinase 1 and deoxyUTPase in incorporating the antineoplastic nucleosides trifluridine and 2’-deoxy-5-fluorouridine into DNA. Int J Oncol. 2015;46:2327–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yoshino T, Cleary JM, Van Cutsem E, Mayer RJ, Ohtsu A, Shinozaki E, et al. Neutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trials. Ann Oncol. 2020;31:88–95.

    Article  CAS  PubMed  Google Scholar 

  25. Limagne E, Thibaudin M, Nuttin L, Spill A, Derangère V, Fumet J-D, et al. Trifluridine/Tipiracil plus Oxaliplatin Improves PD-1 blockade in colorectal cancer by inducing immunogenic cell death and depleting macrophages. Cancer Immunol Res. 2019;7:1958–69.

    Article  CAS  PubMed  Google Scholar 

  26. Pander J, Heusinkveld M, van der Straaten T, Jordanova ES, Baak-Pablo R, Gelderblom H, et al. Activation of tumor-promoting type 2 macrophages by EGFR-targeting antibody cetuximab. Clin Cancer Res. 2011;17:5668–73.

    Article  CAS  PubMed  Google Scholar 

  27. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11:889–96.

    Article  CAS  PubMed  Google Scholar 

  28. Hamada Y, Tanoue K, Kita Y, Tanabe K, Hokonohara K, Wada M, et al. Vascular endothelial growth factor inhibitors promote antitumor responses via tumor microenvironment immunosuppression in advanced colorectal cancer. Scand J Gastroenterol. 2023;58:1009–20.

    Article  CAS  PubMed  Google Scholar 

  29. Terzić J, Grivennikov S, Karin E, Karin M. Inflammation and colon cancer. Gastroenterology. 2010;138:2101-2114.e5.

    Article  PubMed  Google Scholar 

  30. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nozawa H, Chiu C, Hanahan D. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci U S A. 2006;103:12493–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hirata E, Sahai E. Tumor Microenvironment and Differential Responses to Therapy. Cold Spring Harb Perspect Med. 2017;7. https://doi.org/10.1101/cshperspect.a026781.

Download references

Acknowledgements

We appreciate the participants for their contribution to this study. We are also grateful to Takuma Ishihara from Gifu University Hospital Innovative and Clinical Research Promotion Center, Gifu University, Gifu, Japan, for providing many suggestions on statistical analysis methods.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

This study was funded by a Gifu University Hospital Pharmacy Department Operation Grant.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Gifu University Hospital, Yanagido 1-1, Gifu, 501-1194, Japan

    Daichi Watanabe, Hironori Fujii, Koichi Ohata, Hirotoshi Iihara, Ryo Kobayashi, Chiemi Hirose, Shiori Hishida, Serika Matsuoka & Akio Suzuki

  2. Cancer Center, Gifu University Hospital, Gifu, Japan

    Akitaka Makiyama

  3. Laboratory of Advanced Medical Pharmacy, Gifu Pharmaceutical University, Gifu, Japan

    Ryo Kobayashi & Akio Suzuki

  4. Department of Gastroenterological Surgery/Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Japan

    Jesse Yu Tajima, Shigeru Kiyama, Takao Takahashi & Nobuhisa Matsuhashi

  5. Department of Surgery, Ibi Kousei Hospital, Gifu-Seino Medical Center, Gifu, Japan

    Takao Takahashi

Authors
  1. Daichi Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hironori Fujii
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Koichi Ohata
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hirotoshi Iihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Akitaka Makiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ryo Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chiemi Hirose
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shiori Hishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Serika Matsuoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jesse Yu Tajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shigeru Kiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Takao Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Akio Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Nobuhisa Matsuhashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D.W., H.F., K.O., H.I., R.K., C.H., S.H., S.M., and A.S. conceived the study. D.W., H.F., C.H., S.H., S.M., and K.O. conducted the data analysis. D.W. performed the statistical analyses. A.M., J.T., S.K., T.T., A.S., and N.M. provided technical support. D.W., H.F., H.I., R.K., A.M., T.T., A.S., and N.M. contributed to the interpretation of data and assisted in the preparation of the manuscript. D.W. drafted the manuscript. H.F., K.O., H.I., R.K., A.M., J.T., S.K., T.T., A.S., and N.M. critically revised the manuscript. All authors reviewed the manuscript. The author(s) read and approved the final manuscript.

Corresponding author

Correspondence to Hironori Fujii.

Ethics declarations

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki and ethical guidelines for clinical studies. The study followed the guidelines for human studies established by the ethics committee of Gifu University Graduate School of Medicine and approved by the Japanese government (Institutional Review Board Approval No. 2021-A221). Due to the retrospective nature of this study and the anonymity of the presented data, the ethics committee of Gifu University Graduate School of Medicine waived the requirement for obtaining informed consent from the patients whose medical records are included in this study.

Consent for publication

Not applicable.

Competing interests

H Fujii has received honoraria for lectures from Ono Pharm., Chugai Pharm., and Taiho Pharm.

H Iihara has received honoraria for lectures from Taiho Pharm., Chugai Pharma., Yakult Honsha., Astellas Pharma., Eli Lilly and Company., Daiichi Sankyo., AstraZeneca plc, Nippon Kayaku, Ono Pharm., and Nippon Boehringer Ingelheim.

K Ohata has received honoraria for lectures from Chugai Pharma. and Nippon Boehringer Ingelheim.

C Hirose has received honoraria for lectures from Chugai Pharma., Eli Lilly Japan and Nippon Kayaku.

A Makiyama has received honoraria for lectures from Eli Lilly and Company, Taiho Pharm., and Takeda Pharma.

T Takahashi has received grants or research funds made to institutions from Yakult Honsha. A Makiyama has received honoraria for lectures from Eli Lilly Japan, Taiho Pharm., and Takeda Pharma.

N Matsuhashi has received honoraria for lectures from Asahi Kasei Pharma, Chugai Pharm., Covidien Japan, Daiichi Sankyo, Eli Lilly Japan, Johnson & Johnson, Kaken Pharm., Sanofi, Taiho Pharm., Takeda Pharm., and Yakult Honsha.; grants or research funds made to institution from Abbott, Asahi Kasei Pharma, Chugai Pharm., Covidien Japan, Daiichi Sankyo, Eisai, Eli Lilly Japan, EP‐CRSU, EPS Corporation, FUJIFILM, Johnson & Johnson, Kaken Pharm., Kyowa Kirin, MSD, Nippon Kayaku, Ono Pharm., Otsuka Pharm., Sanofi, ShiftZero K.K., Taiho Pharm., Takeda Pharm., Terumo, Tsumura, and Yakult Honsha.

A Suzuki has received honoraria for lectures from Toa Eiyo, Asahi Kasei Pharma, Daiichi Sankyo, Pfizer Eisai, Nippon Shinyaku, Celltrion Healthcare Japan, Otsuka Pharm., Sandoz, Daiichi Sankyo, Nipro, Taiho Pharm., Asahi Kasei Pharma, Nippon Chemiphar, Japan Blood Products Organization, Takeda Pharm., and Nippon Boehringer Ingelheim.; and grants made to institution from Nippon Kayaku, Asahi Kasei Pharma, Chugai Pharm., Taiho Pharm., Daiichi Sankyo, Japan Blood Products Organization, Mochida Pharm., and Sun Pharma.

The other authors have no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1: Table S1.

The occurrences of adverse events among patients with and without grade ≥3 neutropenia.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Watanabe, D., Fujii, H., Ohata, K. et al. Prognostic impact of severe neutropenia in colorectal cancer patients treated with TAS-102 and bevacizumab, addressing immortal-time bias. BMC Cancer 23, 1078 (2023). https://doi.org/10.1186/s12885-023-11618-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12885-023-11618-3

Keywords

BMC Cancer

ISSN: 1471-2407

Contact us