Dataset Information

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

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.

SUBMITTER: Watanabe D

PROVIDER: S-EPMC10634158 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Watanabe Daichi D Fujii Hironori H Ohata Koichi K Iihara Hirotoshi H Makiyama Akitaka A Kobayashi Ryo R Hirose Chiemi C Hishida Shiori S Matsuoka Serika S Tajima Jesse Yu JY Kiyama Shigeru S Takahashi Takao T Suzuki Akio A Matsuhashi Nobuhisa N

BMC cancer 20231108 1

<h4>Background</h4>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.<h4>Patients and methods</h4>We conducted ...[more]

PMID: 37940878

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Project description:Combined treatment with bevacizumab and trifluridine/tipiracil (TAS-102) leads to an increased chance of survival in patients with refractory metastatic colorectal cancer (mCRC); however, this treatment is associated with an increased frequency of severe neutropenia (number of neutrophils <1,000), which should ideally be managed without dose delays. The present study provided a retrospective review of 35 patients with mCRC, and aimed to elucidate the benefits of prophylactic pegfilgrastim for the treatment of severe neutropenia. Patients received TAS-102 (35 mg/m2) orally twice daily on days 1-5 and 8-12 of each 28-day treatment cycle, along with intravenous bevacizumab (5 mg/kg) on days 1 and 15. Moreover, the patients received 3.6 mg pegfilgrastim on day 15 of each cycle. The incidence of adverse events (AEs), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were assessed. In the first and subsequent cycles, 23 and 12 patients, respectively, received pegfilgrastim. The most common AE experienced was grade 3/4 neutropenia (8 patients; 22.9%). Among these 8 patients, 6 (17.1%) and 3 (8.6%) exhibited neutropenia prior to receiving pegfilgrastim or following discontinuation of pegfilgrastim administration, respectively. Moreover, 1 individual among these 8 patients (2.9%) demonstrated grade 3 neutropenia both prior to receiving pegfilgrastim and following discontinuation of pegfilgrastim. A total of 2 patients (5.7%) exhibited grade 3 bone pain, which prevented sustainable administration of pegfilgrastim and resulted in grade 3 neutropenia. Dose delays and dose reduction of TAS-102 due to neutropenia were required in 5 (14.3%) and 2 (5.7%) patients, respectively, during the treatment period. None of the patients exhibited severe neutropenia during chemotherapy after pegfilgrastim administration, thereby preventing dose delays and dose reduction of TAS-102. The relative dose intensity was 96.8% (65.0-100.0%), and the DCR was 54.3%. The median PFS and median OS were 4.4 and 14.9 months, respectively. In conclusion, prophylactic pegfilgrastim may facilitate the management of severe neutropenia without dose delays in patients with mCRC treated with TAS-102 plus bevacizumab.

Project description:BackgroundTAS-102 (trifluridine/tipiracil) plus bevacizumab demonstrated a significant survival benefit in patients with refractory metastatic colorectal cancer (mCRC). Physicians and patients are uncertain whether this treatment option is clinically acceptable in different countries, underscoring the need for analyses of the cost-effectiveness of this regimen.ObjectivesTo guide doctors and patients to choose TAS-102 plus bevacizumab or TAS-102 monotherapy in cancer treatment.DesignThe cost-effective analysis.MethodsA comprehensive Markov model of the 10-year horizon for three health states was established using data from the SUNLIGHT trial to evaluate the cost and health effects of TAS-102 with or without bevacizumab at particular willingness-to-pay (WTP) thresholds, analyzing parameters including quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), incremental net monetary benefit, as well as incremental net-health benefit (INHB). Sensitivity and subgroup analyses were additionally conducted.ResultsTreatment with TAS-102 plus bevacizumab versus TAS-102 monotherapy increased effectiveness (cost) by 0.39 ($151,474), 0.38 ($26,794), and 0.41 ($8596) QALYs, with an ICER of $388,171, $69,617, and $20,919 per QALY and an INHB of -0.62, -0.03, and 0.18 QALYs in the United States, United Kingdom, and China, respectively. The utility of progression-free survival was the most important factor in this model. At respective WTP thresholds of $150,000, $65,000, and $37,653 per QALY in the United States, United Kingdom, and China, the odds of TAS-102 plus bevacizumab being the dominant treatment were 0%, 49.6%, and 87.8%, respectively. In addition, mCRC patients with an Eastern Oncology Cooperative Group performance status ⩾ 1 may be the best candidates for treatment.ConclusionTAS-102 plus bevacizumab treatment represents a cost-effective third-line treatment for refractory mCRC from a Chinese payers' perspective, although the same was not true in the United States or United Kingdom at current drug prices.

Project description:ObjectiveTo compare theoretical strengths and limitations of common immortal time adjustment methods, propose a new approach using multiple imputation (MI), and provide practical guidance for using MI in precision medicine evaluations centered on a real-world case study.Study setting and designMethods comparison, guidance, and real-world case study based on previous literature. We compared landmark analysis, time-distribution matching, time-dependent analysis, and our proposed MI application. Guidance for MI spanned (1) selecting the imputation method; (2) specifying and applying the imputation model; and (3) conducting comparative analysis and pooling estimates. Our case study used a matched cohort design to evaluate overall survival benefits of whole-genome and transcriptome analysis, a precision medicine technology, compared to usual care for advanced cancers, and applied both time-distribution matching and MI. Bootstrap simulation characterized imputation sensitivity to varying data missingness and sample sizes.Data sources and analytic sampleCase study used population-based administrative data and single-arm precision medicine program data from British Columbia, Canada for the study period 2012 to 2015.Principal findingsWhile each method described can reduce immortal time bias, MI offers theoretical advantages. Compared to alternative approaches, MI minimizes information loss and better characterizes statistical uncertainty about the true length of the immortal time period, avoiding false precision. Additionally, MI explicitly considers the impacts of patient characteristics on immortal time distributions, with inclusion criteria and follow-up period definitions that do not inadvertently risk biasing evaluations. In the real-world case study, survival analysis results did not substantively differ across MI and time distribution matching, but standard errors based on MI were higher for all point estimates. Mean imputed immortal time was stable across simulations.ConclusionsPrecision medicine evaluations must employ immortal time adjustment methods for unbiased, decision-grade real-world evidence generation. MI is a promising solution to the challenge of immortal time bias.

Project description:BackgroundTAS-102 (trifluridine and tipiracil hydrochloride; a novel combination oral nucleoside anti-tumor agent) has recently received regulatory approval for patients with refractory metastatic colorectal cancer (mCRC). Internal review of data at a single-institution showed a trend towards better overall survival (OS) for patients who experienced chemotherapy-induced neutropenia at 1-month (CIN-1-month). To explore this finding further, a cohort study was designed based on outcome data from three centers in United States and one from Japan.MethodsCIN-1-month after starting TAS-102 was defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 as a neutrophil count decrease of ≥ grade 2 (absolute neutrophil count < 1500/mm(3)). Patients had confirmed mCRC that was refractory to standard therapies. Patient demographics and clinical characteristics were compared between patients with CIN-1-month (CIN-1-month positive) versus those who did not have CIN-1-month (CIN-1-month negative); with the median progression-free survival (PFS) and OS were calculated using the Kaplan-Meier method, and differences evaluated using the Log-rank test.ResultsOur cohort study had a total of 149 patients with data regarding their neutrophil assessment at 1-month mark. Patients who developed ≥ grade 2 CIN-1-month had a both longer PFS (median 3.0 months versus 2.4 months; Log-rank P-value = 0.01), as well as OS (14.0 versus 5.6 months; Log-rank P-value < 0.0001). Only CIN-1-month (adjusted HR: 0.21 (95 % CI: 0.11-0.38) and higher baseline CEA levels (adjusted HR: 2.00 (95 % CI: 1.22-3.35) were noted to be independent predictors of OS. Furthermore, the CIN-1-month was noted to be a statistically significantly predictor of OS over a wide range of cutoffs.ConclusionsOur observations are novel and hypothesis generating. Neutropenia after starting TAS-102 was associated with better prognosis in patients with refractory mCRC. It can be postulated that the dosage of TAS-102 potentially may need to be increased to achieve better outcomes in patients not experiencing any neutropenia. Further pharmacologic investigations should help elucidate these issues.

Dataset Information

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

Background

Patients and methods

Results

Conclusion

Publications

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

Similar Datasets

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