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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 10  |  Page : 656-660

Factors potentially associated with gemcitabine-based chemotherapy-induced thrombocytopenia in Chinese patients with nonsmall cell lung cancer


1 Department of Pharmacy, Zhejiang Cancer Hospital; Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, People's Republic of China
2 Department of Pharmacy, Integrated Chinese and Western Medicine Hospital of Zhejiang Province, Hangzhou 310003, Zhejiang, People's Republic of China
3 Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology, Zhejiang Cancer Hospital; Department of Chemotherapy Center, Zhejiang Cancer Hospital, Hangzhou 310022, People's Republic of China
4 Department of Clinical Laboratory, Zhejiang Cancer Hospital, Hangzhou 310022, People's Republic of China
5 Institute for Individualized Medicine, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006, People's Republic of China

Date of Web Publication24-Sep-2018

Correspondence Address:
Neng-Ming Lin
Institute for Individualized Medicine, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006
People's Republic of China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.187338

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 > Abstract 


Objective: To investigate the prevalence and characteristics of gemcitabine-based chemotherapy-induced thrombocytopenia in Chinese patients with nonsmall cell lung cancer (NSCLC).
Materials and Methods: Medical records of 197 patients with histologically proven NSCLC received gemcitabine-based chemotherapy from June 2011 to June 2013 in our hospital were collected. The relative risk factors were identified and evaluated by univariate and multivariate analyses.
Results: The incidence of gemcitabine-based chemotherapy-induced thrombocytopenia in these NSCLC patients was 85.8%. Between thrombocytopenia and nonthrombocytopenia patients, in patients with thrombocytopenia and thrombocytopenia, we found Stage III/IV patients got more probabilities for thrombocytopenia (P < 0.01). In addition, patients who received gemcitabine and cisplatin (GP) regimen resulted in more thrombocytopenia than gemcitabine and carboplatin (GC) and other regimens (P < 0.001). In addition, majority of the thrombocytopenia patients presented thrombocytopenia in their first cycle (P < 0.001). Whereas, other potential risk factors such as age, gender, performance status value, diabetes mellitus or not, and other underlying disease (hypertension and hepatopathy) were not showed such significance in this study. Further, the multivariate analysis revealed that stage (odds ratio [OR] 7.113, P < 0.01) and chemotherapy cycles (OR 0.543, P < 0.01) were also statistically significant independent risk factors for gemcitabine-based chemotherapy-induced thrombocytopenia.
Conclusion: This study shows that thrombocytopenia is common in Chinese NSCLC patients receiving gemcitabine-based regimens. Chemotherapy cycles and stage might be the important factors influencing the occurrence of gemcitabine-based regimens-induced thrombocytopenia.

Keywords: Gemcitabine-based regimens-induced thrombocytopenia, nonsmall cell lung cancer, risk factor


How to cite this article:
Wang Z, Cai XJ, Chen LY, Cheng B, Shi L, Lei L, Ye LQ, Lin NM. Factors potentially associated with gemcitabine-based chemotherapy-induced thrombocytopenia in Chinese patients with nonsmall cell lung cancer. J Can Res Ther 2018;14, Suppl S3:656-60

How to cite this URL:
Wang Z, Cai XJ, Chen LY, Cheng B, Shi L, Lei L, Ye LQ, Lin NM. Factors potentially associated with gemcitabine-based chemotherapy-induced thrombocytopenia in Chinese patients with nonsmall cell lung cancer. J Can Res Ther [serial online] 2018 [cited 2019 Sep 17];14:656-60. Available from: http://www.cancerjournal.net/text.asp?2018/14/10/656/187338




 > Introduction Top


Gemcitabine (2,2'-difluorodeoxycytidine), a nucleoside analog, has strong broad-spectrum antitumor activity, which has been widely applied in malignant tumor treatment.[1],[2] However, the application of gemcitabine also causes several adverse reaction, of which the bone marrow suppression occurred most commonly. In detail, the incidence of III and IV blood system adverse reactions are as follows: granulocyte fell by 17%, white blood cells decline in 9.5%, platelet decline in 8.5%, anemia, 8.5%.[3],[4],[5] Especially the platelet decline, after gemcitabine treatment 4–5 days, reaches its peak at 2 weeks, may lead to the postponement of chemotherapy cycles or dose reductions, as well as affecting patients' well-being.[6]

Several studies have reported the similar questions. Wu et al. conducted a descriptive study of anemia and thrombocytopenia in patients undergoing chemotherapy in a large outpatient oncology practice database (2000–2007) found that the most common cancer was breast cancer (19.5%), followed by nonsmall cell lung cancer (NSCLC) (14.9%), and the prevalence of thrombocytopenia ranged from 21.9% in patients treated with taxane-based regimens to 64.2% in patients treated with gemcitabine-based regimens.[7] Cassidy et al. evaluated the impact of schedule (21- vs. 28-day cycle) and cisplatin dose (100 vs. 475 mg/m2) of gemcitabine-based chemotherapy on the incidence of Grade 3 or 4 thrombocytopenia. They found that gemcitabine monotherapy produces less thrombocytopenia than gemcitabine combinations, and dose and schedule do influence the incidence of thrombocytopenia.[8] In addition, it was first concerned about the impact of gemcitabine on platelet, rather than white blood cells, neutrophils.

Lung cancer is a malignant tumor with the highest mortality rates, of which, NSCLC accounts for about 80%. As 70–80% NSCLC were in late stage when they initially treated; thus, they lost the radical cure operation opportunity and the chance of radical surgery. Therefore, palliative chemotherapy is the main treatment of advanced lung cancer.[9],[10] Gemcitabine in clinic is widely used in the treatment of NSCLC; however, the characteristics and relative impacted factors of gemcitabine-based chemotherapy-induced thrombocytopenia in NSCLC are unclear. Furthermore, data in Chinese patients are sparse. Thus, it is essential to predict the development of gemcitabine-based chemotherapy-induced thrombocytopenia in NSCLC and allow for earlier measures to effectively manage thrombocytopenia and prevent relative complications.

Here, we investigated the prevalence and characteristics of gemcitabine-based chemotherapy-induced thrombocytopenia in patients with NSCLC, and we aim to find out the main risk factors in those populations, so as to offer useful information for clinic and reduce the persistent and/or serious thrombocytopenia incidence.


 > Materials and Methods Top


Patients

From June 2011 to June 2013, data of 197 patients with histologically proven NSCLC received gemcitabine-based chemotherapy in our hospital were collected. This study was approved by our Institutional Review Board, and all data were rendered anonymous.

Collected data included age, gender, the stage and pathological type of the cancers, chemotherapy regimen and cycles, performance status (PS) (at diagnosis of just before chemotherapy), underlying disease status. Thrombocytopenia level at the start of cycle 1 was considered baseline, the appearance time, the severity of thrombocytopenia were recorded. Thrombocytopenia was categorized by the toxicity grade, according to Common Terminology Criteria for Adverse Events version 3.0.[11]

Inclusion criteria were as follows: Male or female aged 18 years or over; histologic or cytologic confirmation of NSCLC; received gemcitabine-based chemotherapy; no thrombocytopenia before gemcitabine-based chemotherapy (the blood platelet count c300 × 109 g/L); had complete data of medical history and treatment records.

The exclusion criterions were as follows: History of hematological system diseases (including hematological malignancies) or bone marrow or chronic renal diseases; those received blood transfusion, obvious bleeding during the course of treatment (as these patients were prone to platelet abnormalities).

Statistics analysis

Where appropriate, the univariate statistical analyses between dichotomous variables were determined by the Pearson Chi-square or Fisher's exact tests to compare the thrombocytopenia occurrence and severity in separate groups.

The two independent samples nonparametric test was undergone meantime to analyze the association between severity of thrombocytopenia and the respective variable. Binary logistic regression analysis was used to identify potentially risk factors for the prevalence of thrombocytopenia. SPSS statistics (version 15.0, IBM, New York, USA) was used for all analyses.


 > Results Top


The prevalence rate of thrombocytopenia and patient characteristics

Thrombocytopenia was observed in 169 of the 197 patients (85.8%). Of which, Grade 1–2 thrombocytopenia occurred in 44.7% of patients, and 41.1% of patients experienced Grade 3–4 thrombocytopenia [Table 1].
Table 1: The prevalence and severity of thrombocytopenia

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Of the 197 patients participated in the study, their median age was 60 (39–85) and 154 patients (78.2%) were males. Among them, 28 patients (13.8%) were diabetes mellitus and 46 patients (23.4%) had hypertension. Pathological Stage IV was diagnosed in 75.6% of patients. Pathological investigation revealed 80 adenocarcinomas (40.6%), 90 squamous cell carcinomas (45.7%), and 27 other cell types (13.7%). Patients whose PS <2 occupied 80.2%. As for chemotherapy regimen, platinum-based regimens (gemcitabine and cisplatin [GP] and gemcitabine and carboplatin [GC]) accounted for 89.3% of all chemotherapy regimens and were most common in patients with NSCLC. Of which, thrombocytopenia occurred in 106 patients when they just received one cycle chemotherapy [Table 2]. Moreover, the median number of chemotherapy lines was one (range: 1–6).
Table 2: Patient characteristics

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Relationship between the prevalence of thrombocytopenia and potential associated factors

To explore the potential risk factors for thrombocytopenia, thrombocytopenia, and nonthrombocytopenia, patients were compared to analyze the relationship of their characteristics and thrombocytopenia occurrence [Table 3]. We found that Stage III/IV patients have more probability of thrombocytopenia (P < 0.01). Moreover, GP regimen resulted in more thrombocytopenia than GC and other regimens (P < 0.001). In addition, the occurrence of thrombocytopenia was found to be a fluctuation state with the cycles of chemotherapy. Majority of the thrombocytopenia patients presented thrombocytopenia in their first cycle (P < 0.001), and all thrombocytopenia was found during their first 6 cycles. As for age, gender, PS value, diabetes mellitus or not, and other underlying disease (hypertension and hepatopathy), there was no difference between thrombocytopenia and nonthrombocytopenia groups. Further, the multivariate analysis revealed that stage and chemotherapy cycles results in synergistic effect in gemcitabine-based chemotherapy induced thrombocytopenia [Table 4].
Table 3: The associated risk factors for thrombocytopenia

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Table 4: Multivariate analysis of risk factors for gemcitabine-based regimens induced thrombocytopenia in NSCLC patients

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Meanwhile, to analyze the possible risk factors associated with the severity of thrombocytopenia, the patients with thrombocytopenia were divided into three groups (Grade 1/Grade 2, G1/G2; Grade 3, G3; and Grade 4, G4) according to the National Cancer Institute Common Toxicity Criteria thrombocytopenia scale [Table 5]. However, among the three groups, there was no statistically significant difference in the type of pathology, stage, chemotherapy cycles, chemotherapy, etc., (P > 0.05).
Table 5: Relationships between severity of CIA and potential associated factors

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 > Discussion Top


This study shows that thrombocytopenia occurs common in Chinese NSCLC patients receiving gemcitabine-based regimens. Chemotherapy cycles and stage might be the important factors influencing the occurrence of gemcitabine-based regimens-induced thrombocytopenia.

Thrombocytopenia, one kind of myelosuppression, has a significant effect on the treatment of cancer patients. The treatment-related thrombocytopenia is estimated to occur in ~10–36% of patients with solid tumors, and in 75% of those with hematologic cancers.[7] The clinical consequences of thrombocytopenia varies widely, from asymptomatic laboratory abnormalities to dose-limiting and life-threatening toxicities, which might lead to the postponement of chemotherapy cycles or dose reductions, as well as affecting patients' well-being.

Moreover, the incidence and extent of cancer-related, or primary, cytopenias depend on the characteristics, which might be unique to the patient and tumor type, and on the duration and stage of disease. In our study, thrombocytopenia was observed in 169 of the 197 patients (85.8%), which was higher than the prevalence of gemcitabine-based regimens reported by Wu et al. It may be associated with the race disparity and different chemotherapy regimens. Moreover, we found that majority of patients presented thrombocytopenia in their first cycles. One-hundred and nine (65.5%) patients treated by GP regimen suffered thrombocytopenia. Compared to carboplatin-containing regimen (GC), cisplatin-containing regimen (GP) was found to be associated with higher thrombocytopenia occurrence. These analogous results were also reported in large-scale USA and Chinese population.[12] It may be explained by the reason that cisplatin are known to cause more thrombocytopenia.

Remarkably, we found that patients with Stage III/IV were more likely to have a thrombocytopenia, and the patients who received the first cycle of chemotherapy were susceptible to thrombocytopenia than other cycles. This is associated with the prevention treatment in the next course of chemotherapy. In addition, for patients with multiple risk factors, it is necessary to give prophylaxis before the first chemotherapy cycle. However, other factors such as age, gender, pathological type as well as underlying disease (hypertension and hepatopathy) had no statistical relationship with the gemcitabine-based regimens-induced thrombocytopenia.

Further, the risk factors analysis of the severity of thrombocytopenia with gemcitabine-based regimen showed no differences in these factors among the three groups. That is, the opportunity to different patients suffer severe thrombocytopenia may be similar.

However, this retrospective study had several limitations. First, as single-institution experiences are not adequate to make universal conclusions, this is the major limitation of our study. Furthermore, the data were extracted from electronic medical records rather than being prospectively collected. The accuracy and completeness of the patient information cannot be confirmed. In addition, even a strong statistical association does not necessarily indicate a cause-and-effect relation. Thus, as a remedy for these limitations, a prospective randomized controlled trial is needed.


 > Conclusion Top


Thrombocytopenia is common in NSCLC patients receiving gemcitabine-based regimens, also in Chinese population. Chemotherapy cycles and stage might be the important factors influencing the occurrence of gemcitabine-based regimens-induced thrombocytopenia. These factors need more attention when gemcitabine used in clinic.

Acknowledgments

This work was sponsored by 1022 Talent Training Program of Zhejiang Cancer Hospital, Zhejiang Provincial Program for the cultivation of High-level Innovative Health talents (NO 2010-190-4), the general research program of medical health in Zhejiang Province (NO 2014KYB039), scientific research fund project of integrated Chinese and Western Medicine Institute in Zhejiang Province (2014LYK021), Science and technology in Zhejiang Province Chinese Medicine Program (2012ZA101, 2015ZA148, 2016ZA038), Hangzhou City Science and Technology Project Planning Guide (Social Development) (20130733Q15), Hangzhou City Health Science and Technology Project (2013A43) and Public Welfare Technology Application Studies Program of Zhejiang (2015C33286).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Yang F, Li X, Chen KZ, Jiang GC, Wang J. Tolerability and toxicity of adjuvant cisplatin and gemcitabine for treating non-small cell lung cancer. Chin Med J (Engl) 2013;126:2087-91.  Back to cited text no. 1
    
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Grigorescu AC, Bala C. Phase II study of erlotinib plus gemcitabine in first-line treatment of poor prognosis, advanced non-small cell lung cancer patients. J BUON 2013;18:188-94.  Back to cited text no. 5
    
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Morabito A, Gebbia V, Di Maio M, Cinieri S, Viganò MG, Bianco R, et al. Randomized phase III trial of gemcitabine and cisplatin vs. gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: The CAPPA-2 study. Lung Cancer 2013;81:77-83.  Back to cited text no. 6
    
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Wu Y, Aravind S, Ranganathan G, Martin A, Nalysnyk L. Anemia and thrombocytopenia in patients undergoing chemotherapy for solid tumors: A descriptive study of a large outpatient oncology practice database, 2000-2007. Clin Ther 2009;31 Pt 2:2416-32.  Back to cited text no. 7
    
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Cassidy CA, Peterson P, Cirera L, Roychowdhury DF. Incidence of thrombocytopenia with gemcitabine-based therapy and influence of dosing and schedule. Anticancer Drugs 2001;12:383-5.  Back to cited text no. 8
    
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Carnio S, Novello S, Mele T, Levra MG, Scagliotti GV. Extending survival of stage IV non-small cell lung cancer. Semin Oncol 2014;41:69-92.  Back to cited text no. 9
    
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Cuyún Carter G, Barrett AM, Kaye JA, Liepa AM, Winfree KB, John WJ. A comprehensive review of nongenetic prognostic and predictive factors influencing the heterogeneity of outcomes in advanced non-small-cell lung cancer. Cancer Manag Res 2014;6:437-49.  Back to cited text no. 10
    
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Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Available from: http://www.ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. [Last accessed on 2008 Feb 06].  Back to cited text no. 11
    
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Yang JJ, Zhou Q, Liao RQ, Huang YS, Xu CR, Wang Z, et al. Nedaplatin/gemcitabine versus carboplatin/gemcitabine in treatment of advanced non-small cell lung cancer: A randomized clinical trial. Chin J Cancer Res 2012;24:97-102.  Back to cited text no. 12
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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