|Year : 2016 | Volume
| 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|
Dr. Shengqi Zhang
Department of Lymphatic Blood Medical Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515031, Guangdong
Source of Support: None, Conflict of Interest: None
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 Mar 26];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., 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.,, The pharmacokinetics of PTX is complex and follows a nonlinear three-compartment model., 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.,,,, Studies by Gianni et al. 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.,,,,
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., 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|| |
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.
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.
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.
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].
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 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].
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|
Click here to view
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 |
Click here to view
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 |
Click here to view
| 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. 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.,, 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. 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. 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.
| References|| |
Huizing MT, Giaccone G, van Warmerdam LJ, Rosing H, Bakker PJ, Vermorken JB, Postmus PE, van Zandwijk N, Koolen MG, ten Bokkel Huinink WW, van der Vijgh WJ, Bierhorst FJ, Lai A, Dalesio O, Pinedo HM, Veenhof CH, Beijnen JH. Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. J Clin Oncol
1997; 15 (1): 317-29.
Miller AA, Rosner GL, Egorin MJ, Hollis D, Lichtman SM, Ratain MJ. Prospective evaluation of body surface area as a determinant of paclitaxel pharmacokinetics and pharmacodynamics in women with solid tumors: cancer and leukemia group B study 9763. Clin Cancer Res
2004; 10 (24): 8325-31.
Zhang Z, Mei L, Feng SS. Paclitaxel drug delivery systems. Expert Opin Drug Deliv
2013; 10 (3): 325-40.
Jiko M, Yano I, Sato E, Takahashi K, Motohashi H, Masuda S, Okuda M, Ito N, Nakamura E, Segawa T, Kamoto T, Ogawa O, Inui K. Pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine, and effects of CYP3A5 and MDR1 polymorphisms in patients with urogenital cancers. Int J Clin Oncol
2007; 12 (4): 284-90.
Mielke S, Sparreboom A, Steinberg SM, Gelderblom H, Unger C, Behringer D, Mross K. Association of paclitaxel pharmacokinetics with the development of peripheral neuropathy in patients with advanced cancer. Clin Cancer Res
2005; 11 (13): 4843-50.
Gianni L, Kearns CM, Giani A, Capri G, Viganó L, Lacatelli A, Bonadonna G, Egorin MJ. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol
1995; 13 (1): 180-90.
Ohtsu T, Sasaki Y, Tamura T, Miyata Y, Nakanomyo H, Nishiwaki Y, Saijo N. Clinical pharmacokinetics and pharmacodynamics of paclitaxel: a 3-hour infusion versus a 24-hour infusion. Clin Cancer Res
1995; 1 (6): 599-606.
Joerger M, Baty F, Früh M, Droege C, Stahel RA, Betticher DC, von Moos R, Ochsenbein A, Pless M, Gautschi O, Rothschild S, Brauchli P, Klingbiel D, Zappa F, Brutsche M. Evaluation of a pharmacology-driven dosing algorithm of 3-weekly paclitaxel using therapeutic drug monitoring. Clin Pharmacokinet
2012; 51 (9): 607-17.
Nakajima M, Fujiki Y, Kyo S, Kanaya T, Nakamura M, Maida Y, Tanaka M, Inoue M, Yokoi T. Pharmacokinetics of paclitaxel in ovarian cancer patients and genetic polymorphisms of CYP2C8, CYP3A4, and MDR1. J Clin Pharmacol
2005; 45 (6): 674-82.
Joerger M, Huitema AD, Richel DJ, Dittrich C, Pavlidis N, Briasoulis E, Vermorken JB, Strocchi E, Martoni A, Sorio R, Sleeboom HP, Izquierdo MA, Jodrell DI, Calvert H, Boddy AV, Hollema H, Féty R, Van der Vijgh WJ, Hempel G, Chatelut E, Karlsson M, Wilkins J, Tranchand B, Schrijvers AH, Twelves C, Beijnen JH, Schellens JH. Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients: a study by the European organization for research and treatment of cancer-pharmacology and molecular mechanisms group and new drug development group. Clin Cancer Res
2007; 13 (21): 6410-8.
Mould DR, Fleming GF, Darcy KM, Spriggs D. Population analysis of a 24-h paclitaxel infusion in advanced endometrial cancer: a gynaecological oncology group study. Br J Clin Pharmacol
2006; 62 (1): 56-70.
Kobayashi M, Oba K, Sakamoto J, Kondo K, Nagata N, Okabayashi T, Namikawa T, Hanazaki K. Pharmacokinetic study of weekly administration dose of paclitaxel in patients with advanced or recurrent gastric cancer in Japan. Gastric Cancer
2007; 10 (1): 52-7.
de Jonge ME, van den Bongard HJ, Huitema AD, Mathôt RA, Rosing H, Baas P, van Zandwijk N, Beijnen JH, Schellens JH. Bayesian pharmacokinetically guided dosing of paclitaxel in patients with non-small cell lung cancer. Clin Cancer Res
2004; 10 (7): 2237-44.
Woo MH, Relling MV, Sonnichsen DS, Rivera GK, Pratt CB, Pui CH, Evans WE, Pappo AS. Phase I targeted systemic exposure study of paclitaxel in children with refractory acute leukemias. Clin Cancer Res
1999; 5 (3): 543-9.
Li K, Yu P, Zhu YF, Zhang ZY, Huang SS, Huang G, Ma XH. Study of risk factors for esophageal carcinoma in high incidental area of Chaoshan region of China. Chin Oncol
2011; 10 (11): 634-6. (in Chinese)
Li K, Yu P, Zhu YF, Zhang ZY, Huang SS, Huang G, Ma XH. Relationship between Congou tea and esophageal cancer in Chaoshan region of Guangdong, China. Chin J Dis Control Prev
2002; 6 (1): 47-9. (in Chinese)
Henningsson A, Karlsson MO, Viganò L, Gianni L, Verweij J, Sparreboom A. Mechanism-based pharmacokinetic model for paclitaxel. J Clin Oncol
2001; 19 (20): 4065-73.
Engels FK, Loos WJ, van der Bol JM, de Bruijn P, Mathijssen RH, Verweij J, Mathot RA. Therapeutic drug monitoring for the individualization of docetaxel dosing: a randomized pharmacokinetic study. Clin Cancer Res
2011; 17 (2): 353-62.
Huang TC, Campbell TC. Comparison of weekly versus every 3 weeks paclitaxel in the treatment of advanced solid tumors: a meta-analysis. Cancer Treat Rev
2012; 38 (6): 613-7.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
|This article has been cited by|
||Analytical and clinical validation of a dried blood spot assay for the determination of paclitaxel using high-performance liquid chromatography-tandem mass spectrometry
| ||Natália B. Andriguetti,Roberta Z. Hahn,Lilian F. Lizot,Suziane Raymundo,Jose L. Costa,Kelly F. da Cunha,Ramon M.M. Vilela,Helena M. Kluck,Gilberto Schwartsmann,Marina V. Antunes,Rafael Linden |
| ||Clinical Biochemistry. 2018; |
|[Pubmed] | [DOI]|