Treatment Outcome of Pharmacokinetics-Based Dosing of Docetaxel and Fluorouracil in Advanced Head and Neck Cancer Patients

Introduction: Docetaxel, Cisplatin and 5-Fluorouracil (DPF) became the standard induction chemotherapy in advanced Head and Neck Cancer (HNC) but associated with high toxicity rate. Several studies reported higher response rates with better tolerability when chemotherapy dose is calculated based on Pharmacokinetics (PK) versus conventional Body Surface Area (BSA). Patien ts an d Methods: Thirty nine patients with stage III and IV HNC who received induction DPF were inc luded in the study. Dose of cycle 1 was BSA-based then Docetaxel and 5-FU doses were PK-adjusted starting from cycle 2 whereas Cisplatin dose was BSA-based throughout the study. Results: After median follow up period of 14 months the median overall survival (OS) and progression free survival (PFS) were 15.1 and 10.6 months respectively. Twenty nine patients were available for response assessment. Seven patients (24.1%) achieved complete response while partial response encountered in 19 patients (65.5%) with and Overall response rate of 89.6%. Both treatment related side effects and mortality significantly decreased after the application of PK dose adjustments (p-value 0.007 and 0.01 respectively). Conclusion: PK-guided dose adjustments of 5-FU and Docetaxel in DPF regimen can significantly decrease the treatment related side effects and mortality without compromising the tumor response rate. A randomized clinical trial is needed to compare the PK-guided dose adjustment with the standard BSA based protocol. How to cite this paper: Fouad, A.M., Saber, M.M., Ismail, Y.M., Sallam, Y.A., Shouman, T.M., Elshimy, R.A.A. and Gabal, A.A. (2018) Treatment Outcome of Pharmacokinetics-Based Dosing of Docetaxel and Fluorouracil in Advanced Head and Neck Cancer Patients. Journal of Cancer Therapy, 9, 998-1010. https://doi.org/10.4236/jct.2018.912082 Received: November 21, 2018 Accepted: December 15, 2018 Published: December 18, 2018 Copyright © 2018 by authors and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Open Access


Introduction
Head and Neck Cancers (HNCs) are heterogeneous group of cancers. That may differ in location, pathogenesis, tumor biology, treatment, prognosis and effect on quality of life [1]. It was estimated that HNCs comprise 2% -3% of all cancers in the United States and account for 1% -2% of all cancer deaths [2]. In Egypt, HNC represents about 5% of all malignant tumors [3].
The Docetaxel, Cisplatin and 5-fluorouracil (5-FU) regimen (DPF) is the standard induction regimen in advanced HNC since the publication of the TAX323 [4] and TAX324 studies [ 5]. On the other hand, they are associated with high hematologic toxicity and a high complication rate [4] [5].
Chemotherapy dosing is based on body surface area (BSA). The BSA-based dose for any drug is recommended by the manufacturer according to the maximum tolerated dose (MTD) achieved during phase I studies. But there is actually no exact scientific basis for the use of BSA for chemotherapeutic drugs, and several studies have shown that this approach is not valid. BSA-based dosing is associated with drug plasma leve l variability up to 30-fold. Solid evidence exists that this inter-and intra-patient pharmacokinetic (PK) variability of anticanceragents is a major contributor to toxicity and treatment failure [6]. whereas approximately 40% -60% and 10% -20% are under and over this therapeutic AUC threshold respectively. PK-guided 5-FU dosing has not been widely incorporated into clinical practice, because of the lack of data that support this approach [7]. Also there is lack of prospective studies that clarify the concept of modifying the Docetaxel dose based on drug PKs to achieve the target AUC. We proposed this study aiming to investigate the application of PKguided 5-FU and Docetaxe l dosing and to evaluate its effect on treatment outcome and toxicity profile.

Patients
This prospective study was conducted at the Medical Oncology department, Na-

Treatment and PK-Based Dose Adjustments
All of the patients were planned to receive three cycles of DPF regimen.

Follow up, Response and Toxicity Assessment
Patients were considered eligible for response analysis if they completed three cycles of planned DPF. Disease response was assessed at the end of cycle three then every 3 months. Responses were assessed using the Response Evaluation Criteria in Solid Tumors ( RECIST V1.1) criteria [11]. During follow up complete physical examinations was performed and local imaging (CT or MRI) was requested. Toxicity assessment was done using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [12].
Patients were followed-up for a minimum period of 12 months for survival assessment.

Statistical Methods
Statistical analysis was done using IBM© SPSS© Statistics version 22 (IBM© Corp., Armonk, NY, USA). Numerical data were expressed as mean and standard deviation or median and range as appropriate. Qualitative data were expressed as frequency and percentage. Chi-square test was used to compare toxicity between different cycles. Survival analysis was done using Kaplan-Meier method and comparison between survival curves was done usi ng log-rank test. All tests were two-tailed. A p-value < 0.05 was considered significant. Progression

Patients Characteristics
Thirty nine patients were enrolled in this study. The mean age of the patients was 46.7 ± 9.7 years (range 24 -68). More than half of the patients were females (53.8%). The majority of the patients at the study entry had PS 1 (97.4%) and the smoking history was depicted in 30.8% of them. Presentation with head and neck lump was the most common presenting complaint ( 66.7%). Patient characteristics were summarized at ( Table 2).

Tumor Characteristics
The tumor characteristics at the time of diagnosis are shown in (

Treatment
Three cycles of induction DPF were prescribed to all of the patients who were included in the study. The first cycle was delivered successfully to all of them however only 30 and 29 patients were able to receive the second and third cycles respectively. Eight of the te n patients who did not complete the treatment died and the other two patients lost follow up before the subsequent cyc les.

Drug Pharmacokinetic Characteristics and Dose Adjustments
Docetaxel: After the first cycle, the patients who had low, high and targeted plasma con-

5-FU:
After the first cycle, the patients who had low, high and targeted plasma concentration of 5-FU were 10, 9 and 7 respectively. Thirteen patients did not get their results due to lab error (i.e. beyond stability blood sample). Thirty patients were able to receive the second cycle of DPF and their plasma concentration of 5-FU was re-assessed. The patients who had low, high and targeted plasma concentration of 5-FU were 5, 7 and 11 respectively while it couldn't be measured for 7 patients due to lab error. The third cyc le was received by 29 patients.
Twenty patients had target plasma concentration, two patients had high plasma concentration and none of the patients had low plasma concentration of 5-FU.
Again, se ven patients did not get their results due to lab error (i.e. beyond stability blood sample). The median doses of 5-FU given in the first cycle, second and third cycle were 1700, 1685 and 1700 mg, respectively and the 5-FU dose necessary to achieve the target AUC at cycle 3 ranged from 31.2% to 147% of the standard dose. Cisplatin: Cisplatin dosage was based on BSA in the three cycles and was given as 75 mg/m2 on day 1.

Toxicity
The treatment related toxicity was evaluated after each cycle. Two patients lost follow up after the first cycle and were not included in the toxicity assessment.
Diarrhea, mucositis and neuropathy were the most frequent toxic events and

Discussion
While therapeutic options for HNCs have improved over the past 30 years, the survival for patients with advanced HNCs remained poor with high treatme nt related toxicity [13]. The DPF regimen is associated with extensive hematologic Santini et al. [14], Fety et al. [ 15] and Gamelin et al. [ 16] prospectively studied 5-FU dose adjustment based on PK aiming to predict safe dose intensification with less toxic adverse effects; however, there is lack of prospective studies that tried to c larify the concept of modifying the dose of Docetaxel-based PKs to improve its therapeutic index [ 10]. To the best of our knowledge, our study is the first to prospectively investigate PK-based dose adjustme nt of both Docetaxel and 5-FU in DPF regimen used in advanced HNC.
Santini et al. [14] and Fety et al. [ 15] compared the effect of PK-based 5-FU dose adjustment i n Cisplatin/5-FU (PF) regimen in advanced HNC to BSA-based PF (two arm studies).In the former study the CR i n PK arm was 47.0 vs 31.0% i n the BSA arm (P < 0.050), whereas in the second study ORR i n PK arm was 81.7 vs 77.2% in BSA arm (P = 0.030), while in our study ORR was 89.6%. ORR in our study was higher than that achieved by Vermorken et al. [4] (67.8%) and Posner et al. [5] (72.0%) who used BSA-based DPF dosing in advanced HNC. Our results concur with that reported in the meta-analysis done by Fang et al. [17] and indicated that PK-guided strategy si gnificantly improved the ORR compared with BSA-guided strategy (P < 0.0001). Matchi ng with these results; Game lin et al. [ 16] reported ORR i n the PK arm was 33.6% vs 18.3% in the BSA arm ( P = 0.0004).
In respect to DPF-associated toxicities observed in our study, they were consistent with that reported i n other literature used BSA-based dosing including myelosuppression, diarrhea, mucositis, hand and foot syndrome, nausea, vomiting, neuropathy and febrile neutropenia. In the curre nt study the treatme nt related serious side effects ( G III & IV) and treatment related mortality after second and third cycles( PK-based) were significantly lowered when compared to that occurred after first cycle (BSA-based) (P = 0.007 and 0.01, respectively).
These findings again are similar to the work of Santini et al. [14] and Fety et al. [15] where the i ncidence of GIII & IV toxicities were significantly lower i n PK arm vs BSA arm. The freque ncy of G III & IV myelosuppression (neutropenia) after the third cyc le in our study was lower in patients treated with PK-guided DPF dosing when compared with BSA-guided DPF dosing used in Vermorken et al. [4] and Posner et al. [5] ( 10.3% vs 76.9% vs 83%, respectively).
The correlation between age and PK dose adjustment was presented in ASCO 2005 by te n Tije et al. [18] and the y found that Docetaxel plasma PKs are unaltered in elderly patients, yet they appeared to be more sensitive to Docetaxel-induced neutropenia. In our trial this correlation was not done due to the percentage of patients aged ≥ 65 years was only 2.6%. In our study the Docetaxel dose necessary to successfully achieving the target AUC at cycle 3 ranged from 44.9% to 137.8% of the standard dose (75 mg/m 2 ).
While the 5-FU dose necessary to achieve the target AUC at cycle 3 ranged from 31.2% to 147% of the standard dose (1000 mg/m 2 ). We attributed this finding to A. M. Fouad et al.
the large intra-patient variability in Docetaxel and 5-FU exposure and this finding underline that no standard dose could be applied for all patients due to different plasma leve ls of drugs in each patient. The intra-patient variability may be due to admi nistration time (circadian rhythm), PK sampli ng time, diet, concomitant medications and other environmental factors [9].
The main limitation of our study is the si ngle-arm design, which did not allow for direct comparison of BSA& PK dosing strategies (in 2 different arms) regarding toxicity, tolerance and efficacy.
Also, the number of non evaluable (beyond stability) samples throughout the course of the study was high and this may be due to samples being withdrawn before or after the e xact time of i nfusion and infusion time error reflecting the challenges of conducting this dosi ng approach. This suggests that e xperience and training would be necessary to correctly implement this dosing approach.

Conclusion
PK-based dose adjustment of Docetaxel and 5-FU in DPF regimen in advanced HNC significantly lowered serious toxicities and treatment related mortality with excellent response to treatment. We suggest that this strategy may be promising in effectively and safely de livering more cycles of chemotherapy without unneeded dose delay or reductions particularly in the setting of metastatic cancers where chemotherapy is the main line of treatment.

Conflicts of Interest
The authors declare no conflicts of interest.