Correlation between paclitaxel Tc > 0.05 and its therapeutic efficacy and severe toxicities in ovarian cancer patients

Shuyao Zhang; Muyin Sun; Yun Yuan; Miaojun Wang; Yuqi She; Li Zhou; Congzhu Li; Chen Chen; Shengqi Zhang

doi:10.4103/2395-3977.192930

ORIGINAL ARTICLE

Year : 2016 | Volume : 2 | Issue : 5 | Page : 131-136

Correlation between paclitaxel Tc > 0.05 and its therapeutic efficacy and severe toxicities in ovarian cancer patients

Shuyao Zhang¹, Muyin Sun², Yun Yuan³, Miaojun Wang⁴, Yuqi She¹, Li Zhou⁵, Congzhu Li⁵, Chen Chen¹, Shengqi Zhang⁴
¹ Department of Medicine, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
² Department of Digestive Medical Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
³ Nursing Department, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
⁴ Department of Lymphatic Blood Medical Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
⁵ Department of Women Surgical Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China

Date of Submission	10-Oct-2016
Date of Acceptance	13-Oct-2016
Date of Web Publication	24-Oct-2016

Correspondence Address:
Dr. Shengqi Zhang
Department of Lymphatic Blood Medical Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515031, Guangdong
China

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/2395-3977.192930

Abstract

Aim: Although paclitaxel (PTX) is a widely used chemotherapeutic agent across many cancer types, the correlation between its concentration and treatment efficacy and toxicity is yet to be clarified. Hence, the study aims to determine the correlation between PTX Tc > 0.05 and its therapeutic efficacy and toxicity.
Methods: Using MyPaclitaxel™, we measured the blood concentration of PTX in 96 ovarian cancer (stage IIIB to IV) patients, who were admitted to the Cancer Hospital of Shantou University Medical College in Chaoshan, China. PTX Tc > 0.05, the time during which PTX plasma concentration exceed 0.05 μmol/L, is calculated using nonlinear mixed effect model.
Results: (1) The PTX Tc > 0.05 was constant and significantly correlated with treatment response and the range of Tc > 0.05 of PTX was 14-36 h. (2) There was no correlation between relative PTX dose and the PTX Tc > 0.05. (3) There was a statistically significant difference in the PTX Tc > 0.05 between complete remission (CR) + partial remission (PR) and stable disease (SD) + progressive disease (P = 0.00185). The PTX Tc > 0.05 in most patients with CR and PR was in the range of 26-30 h. (4) The PTX Tc > 0.05 significantly correlated with the occurrence of leukopenia (P = 0.0002) and leukopenic fever (P = 0.0211), and higher PTX Tc > 0.05 correlated with increased incidence of severe leukopenia and leukopenic fever. (5) Occurrence and severity of peripheral neuropathy significantly correlated with the level of PTX Tc > 0.05 (P = 0.0003, 0.0118).
Conclusion: These results indicated that the PTX Tc > 0.05 correlated with therapeutic efficacy and drug toxicity. Therefore, monitoring the PTX Tc > 0.05 other than blood concentration of PTX is necessary to optimize individual treatment.

Keywords: Blood concentration, ovarian cancer, paclitaxel, Tc > 0.05

How to cite this article:
Zhang S, Sun M, Yuan Y, Wang M, She Y, Zhou L, Li C, Chen C, Zhang S. Correlation between paclitaxel Tc > 0.05 and its therapeutic efficacy and severe toxicities in ovarian cancer patients. Cancer Transl Med 2016;2:131-6

How to cite this URL:
Zhang S, Sun M, Yuan Y, Wang M, She Y, Zhou L, Li C, Chen C, Zhang S. Correlation between paclitaxel Tc > 0.05 and its therapeutic efficacy and severe toxicities in ovarian cancer patients. Cancer Transl Med [serial online] 2016 [cited 2019 Dec 9];2:131-6. Available from: http://www.cancertm.com/text.asp?2016/2/5/131/192930

Shuyao Zhang, Muyin Sun, Yun Yuan, Miaojun Wang, and Yuqi She contributed equally to this work and were co-first authors

Introduction

Paclitaxel (PTX) (brand name Taxol) is one of the most commonly used chemotherapeutic drugs in the treatment of ovarian cancer.^[1],[2] The most common side effects of PTX are peripheral neuropathy and hematologic toxicity. Studies have shown a high individual variability of blood PTX concentration when the conventional body surface area (BSA) was used to calculate the dosage.^[3],[4],[5] The pharmacokinetics of PTX is complex and follows a nonlinear three-compartment model.^[6],[7] A number of pharmacokinetic and pharmacodynamic studies on patients in the Western countries have demonstrated a significant correlation between the plasma PTX concentration and its treatment efficacy along with neuronal and blood toxicity when the PTX concentration exceeded 0.05 μmol/L. The time required to achieve this concentration is referred to as Tc > 0.05.^{[7],[8],[9],[10],[11]} Studies by Gianni et al.^[6] showed that the pharmacokinetic index Tc > 0.05 can be a predictor of neutropenia. So far, majority of the pharmacokinetic and pharmacodynamic studies on PTX have been carried out on patients in the Western countries, and there are, however, only a few studies on the Asian population.^{[9],[10],[12],[13],[14]}

Chaoshan area in China is densely populated with a unique genetic background of Han origin. There is a high incidence of esophageal cancer and ovarian cancer in this area.^[15],[16] Therefore, investigating the variability of blood PTX concentration and evaluating its effect on treatment efficacy and toxicity in this population could help to guide individualized chemotherapy. In the current study, the plasma PTX concentration in patients with ovarian cancer in Chaoshan area was examined and correlated with its treatment efficacy and toxicity to establish an optimal PTX concentration for this population. This study will be helpful for increasing the PTX treatment efficacy, reducing its toxicity, and therefore enhancing the quality of life of living patients.

Methods

Study subjects

A total of 96 female patients, with pathologically and cytologically confirmed diagnosis of ovarian cancer were enrolled in the study. Age of patients ranged from 46 to 68 (median 62) years. All patients were in stage IIIB to IV and received chemotherapy with PTX dosage calculated based on conventional BSA.

This study was approved by the Human Ethics Committee of Shantou University Medical College (No. 2014030915). Patients received detailed explanations of the study procedures and potential consequences. Written informed consents were obtained from all the patients.

Inclusion criteria

Patients were included in the study if they met all of the following criteria: (1) The diagnosis was pathologically or cytologically confirmed; (2) received at least four cycles of PTX treatment as recommended by a physician; (3) had at least one tumor; (4) Eastern Cooperative Oncology Group performance status score ≤ 1; (5) white blood cell > 4 × 10⁹ /L; platelet > 100 × 10⁹ /L; (6) normal liver, kidney, and heart functions.

Exclusion criteria

The exclusion criteria consisted of (1) receiving other medications 4 weeks before the study; (2) predicted survival time < 12 weeks; (3) female patients who are pregnant or lactating; (4) severe peripheral neuropathy; (5) allergies to medication or correlated components.

Regimen

Ninety-six patients with ovarian cancer (stage IIIB-IV) were given PTX 175 mg/m² and carboplatin dose based on the Calvert formula with target area under the plasma concentration-time curve = 6; BSA ranging from 1.18 to 1.94 m² . PTX was dissolved in 500 mL of 5% glucose solution and administered intravenously in 3 h. Standard premedications such as dexamethasone, diphenhydramine, and cimetidine were routinely given before PTX administration to prevent potential hypersensitivity reactions. Blood pressure and pulse were monitored during treatment with PTX.

Sample collection and evaluation

Blood sample collection

The name, dosage, starting time, ending time, and chemotherapy regimen were recorded at the beginning of drug administration. Venous blood was drawn and placed in K₂ EDTA tubes within 18-30 h of PTX administration, centrifuged at 1739 ×g for 10 min, and plasma was separated and stored in a refrigerator or freezer until used. The PTX concentrations were measured using the MyPaclitaxel™ kit (Changjiang Science Limited, Jiangsu, China) in an automated equipment according to the manufacturer's instructions. The PTX concentrations were monitored in all four cycles during treatment. Then, the PTX Tc > 0.05 which was the time when the plasma PTX concentration exceeded 0.05 μmol/L was calculated based on the dosage, the time of infusion, blood sampling, and concentration using computer software nonlinear mixed effect model (NONMEM).

Evaluation of therapeutic efficacy and toxicity

Therapeutic efficacy was evaluated every two treatment cycles by clinicians based on the Response Evaluation Criteria in Solid Tumors 1.0; the recording criteria were as follows: complete remission (CR) - the tumor is eradicated completely with no new foci for at least 4 weeks; partial remission (PR) - the largest diameter of the tumor is no > 20% of the original tumor size for at least 4 weeks; stable disease (SD) - the largest diameter of the tumor is greater than that of PR but smaller than that of progressive disease (PD) for at least 4 weeks; PD - the largest diameter of the tumor is > 30% of the original tumor size or an appearance of new tumor within 4 weeks. CR and PR were considered indicative of effective treatment; conversely, SD and PD were considered results of noneffective treatment. Therapeutic efficacy (response rate, RR) was calculated according to the WHO standards using the formula: RR = (CR + PR)/total cases × 100%. The results of the evaluation are shown in [Table 1].

Table 1. Correlation of paclitaxel Tc > 0.05 and therapeutic responses

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Toxicity was evaluated using the Common Terminology Criteria for Adverse Events 4.0 of the US Department of Public Health. The main focus of the assessment was on peripheral neuropathy and hematologic toxicity.

Statistical analysis

Statistical Product and Service Solutions version 19.0 software (IBM SPSS Co., Chicago, USA) was used for statistical analyses. Data with frequency distribution were analyzed with a nonparametric Kolmogorov-Smirnov test; data with normal distribution were analyzed using parametric Kolmogorov-Smirnov test. Data with a normal distribution were expressed as a mean and standard deviation. The differences in the variables were compared using Chi-square test or t-test. Data with a skewed distribution were expressed as median and interquartile range, and differences were compared using the Mann-Whitney U-tests. Correlation analysis was performed using Spearman correlation and linear regression analysis. P < 0.05 was considered statistically significant.

Results

Distribution of paclitaxel

All patients received the combination of PTX and carboplatin as a chemotherapy drug. The treatment regimen and the plasma concentrations of PTX are presented in [Table 2]. The PTX concentration remained constant in each cycle. The Tc > 0.05 which was the time when the plasma PTX concentration exceeded 0.05 μmol/L reflecting its distribution, was calculated using computer software NONMEM. The PTX Tc > 0.05 ranged from 14 to 36 h [Table 3].

Table 2. Medication used in each cycle

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Table 3. The Tc > 0.05 of paclitaxel in patients

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Correlation between relative paclitaxel dose and paclitaxel Tc > 0.05

The results presented in [Figure 1] reveal no correlation between relative PTX dose and the PTX Tc > 0.05. Although administration of PTX was based on BSA, there was still a large pharmacological difference among individuals. The phenomenon was mainly correlated to the nonlinear pharmacokinetic characteristics of PTX.

Figure 1. Correlation between paclitaxel dosage and paclitaxel Tc > 0.05

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Correlation of paclitaxel Tc > 0.05 and therapeutic responses

There was a statistically significant difference in the PTX Tc > 0.05 between CR + PR and SD + PD (P = 0.00185). The PTX Tc > 0.05, in most patients, with CR and PR ranged from 26 to 30 h which suggests that the distribution of PTX could be an indicator of treatment efficacy [Table 1].

Correlation between paclitaxel Tc > 0.05 and leukopenia

Analysis revealed that PTX Tc > 0.05 closely correlated with the occurrence of leukopenia and leukopenic fever. The average PTX Tc > 0.05 in patients with grade 0-2 leukopenia was 24.26 h that was significantly shorter than that in patients with grade 3-4 leukopenia (27.16 h) (P = 0.0002). Likewise, the average PTX Tc > 0.05 in patients with leukopenic fever was 25.71 h that was significantly longer than those without leukopenic fever (24.30 h) (P = 0.0211) [Table 4]. These results indicated that PTX Tc > 0.05 correlated with leukopenia and leukopenic fever.

Table 4. Correlation of paclitaxel Tc > 0.05 with leukopenia and leukopenic fever

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Correlation between paclitaxel Tc > 0.05 and peripheral nerve toxicity

The average PTX Tc > 0.05 in patients without neuropathy was 24.25 h that was significantly shorter than 26.98 h in those with peripheral nerve toxicity (P = 0.0003). The average PTX Tc > 0.05 is 24.38 h in patients with mild neuropathy that was significantly shorter than 26.53 h in patients with grade 2-4 peripheral nerve toxicity (P = 0.0118). The results are summarized in [Table 5] which indicated that severe neuropathy correlated with higher PTX Tc > 0.05.

Table 5. Correlation of paclitaxel Tc > 0.05 and peripheral nerve toxicity

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Discussion

Classically, dosages of some chemotherapeutic agents are determined by BSA. The distribution of drugs was found to vary greatly among individuals due to pharmacokinetic differences, resulting in different PTX plasma concentrations. However, the therapeutic range of drug concentration for cancer treatment is very narrow. The drug plasma concentrations of majority of the patients are out of therapeutic window.^[17] In the advanced stages of cancer treatments, the drug dose is not always adjusted until the occurrence of serious chemotherapy side effects due to the drug blood concentrations that are either too low or too high to combat cancer cells.^{[11],[17],[18]} Therefore, immediate attention is necessary to monitor the blood concentration of tumor chemotherapy drug, so as to scientifically and rationally calculate the dosage for individual medication.

The results of the present study indicated that: (1) The PTX Tc > 0.05, ranged from 14 to 36 h, was constant in patients and significantly correlated with treatment response. (2) There was no correlation between relative PTX dose and the PTX Tc > 0.05. (3) The PTX Tc > 0.05 correlated with therapeutic response. There was a statistically significant difference in the PTX Tc > 0.05 between CR + PR and SD + PD (P = 0.00185). The PTX Tc > 0.05 in most patients with CR and PR was in the range of 26-30 h. (4) The PTX Tc > 0.05 was closely correlated with the occurrence of leukopenia (P = 0.0002) and leukopenic fever (P = 0.0211). Higher PTX Tc > 0.05 was associated with higher incidence of severe leucopenia and leukopenic fever. (5) The occurrence of peripheral neuropathy and its severity are significantly correlated with the level of PTX Tc > 0.05 (P = 0.0003 and 0.0118, respectively).

It is known that the blood PTX is the total PTX which exists in both bound and free states. However, only free PTX can enter tumor cells to exert its tumor-killing effect.^[11] There are a lot of factors that affect the binding of PTX to proteins that could hinder the concentration measured in this study. The limitation is that we cannot monitor the concentration of PTX inside the tumor cells. Further studies are needed to assess the effective PTX concentration in patients. Our results suggested that monitoring the drug distribution in the body is a better parameter than blood drug concentration for optimizing individual treatment. The PTX Tc > 0.05 obtained from this study will be helpful in guiding chemotherapy using PTX, particularly in Chaoshan, China.

PTX is a commonly used chemotherapeutic agent in many cancer types. It is often combined with a platinum agent for combination therapy in the current chemotherapy regimen.^[19] The degree of pharmacokinetic variability in each patient makes it difficult to assess the therapeutic outcome and concomitant drug adverse toxicity. Further research is needed to understand the pharmacokinetics of PTX to optimize its treatment results in individual patients.

Financial support and sponsorship

This work was supported by the Key Project of Science and Technology Planning in Shantou City (C201400122).

Conflicts of interest

There are no conflicts of interest.

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Figures

[Figure 1]

Tables

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

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