Clin Pharmacokinet (2014) 53:103–110 DOI 10.1007/s40262-013-0102-5

ORIGINAL RESEARCH ARTICLE

The Effect of St John’s Wort on the Pharmacokinetics of

Andrew K. L. Goey • Irma Meijerman • Hilde Rosing • Serena Marchetti • Marja Mergui-Roelvink • Marianne Keessen • Jacobus A. Burgers • Jos H. Beijnen • Jan H. M. Schellens

Published online: 26 September 2013 Ó Springer International Publishing Switzerland 2013

Abstract 14 days of supplementation with SJW (300 mg extract Background and Objective St John’s wort (SJW), a her- [HyperiplantÒ] three times daily). bal antidepressant, is commonly used by cancer patients, Results SJW supplementation resulted in a statistically and its component hyperforin is a known inducer of the significant decrease in the mean area under the docetaxel cytochrome P450 (CYP) isoenzyme 3A4. Here, the plasma concentration–time curve extrapolated to infinity potential pharmacokinetic interaction between SJW and the (AUC?) from 3,035 ± 756 to 2,682 ± 717 ng Á h/mL sensitive CYP3A4 substrate docetaxel was investigated. (P = 0.045). Furthermore, docetaxel clearance signifi- Methods In ten evaluable cancer patients, the pharma- cantly increased from 47.2 to 53.7 L/h (P = 0.045) after cokinetics of docetaxel (135 mg administered intrave- SJW intake. The maximum plasma concentration and nously over 60 min) were compared before and after elimination half-life of docetaxel were (non-significantly) decreased after SJW supplementation. In addition, the incidence of docetaxel-related toxicities was lower after SJW supplementation. A. K. L. Goey (&) Á J. H. Beijnen Á J. H. M. Schellens Division of Pharmacoepidemiology and Clinical Pharmacology, Conclusion These results suggest that concomitant use of Department of Pharmaceutical Sciences, Utrecht University, docetaxel and the applied SJW product should be avoided Utrecht, The Netherlands to prevent potential undertreatment of cancer patients. e-mail: [email protected]

Present Address: A. K. L. Goey 1 Introduction Clinical Pharmacology Program, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA The herbal antidepressant St John’s wort (SJW; Hypericum I. Meijerman perforatum) is one of the top-selling herbal supplements in Division of Pharmacology, Department of Pharmaceutical the USA and Europe [1, 2]. The popularity of SJW among Sciences, Utrecht University, Utrecht, The Netherlands cancer patients is reflected by its ranking in the top eight alternative medicines [3]. H. Rosing Á J. H. Beijnen Department of Pharmacy and Pharmacology, Slotervaart To date, SJW has been known to cause many pharma- Hospital/The Netherlands Cancer Institute, Amsterdam, cokinetic herb–drug interactions [4]. The SJW constituent The Netherlands hyperforin is a well-known activator of the pregnane X receptor (PXR) [5], which results in increased transcription S. Marchetti Á M. Mergui-Roelvink Á M. Keessen Á J. H. M. Schellens of the cytochrome P450 3A4 isoenzyme (CYP3A4) and the Department of Clinical Pharmacology, The Netherlands Cancer drug efflux transporter ABCB1 (P-glycoprotein). Conse- Institute, Amsterdam, The Netherlands quently, induction of CYP3A4 and/or ABCB1 increases the metabolism and excretion of drug substrates, eventually J. A. Burgers Department of Thoracic Oncology, The Netherlands Cancer leading to decreased systemic exposure and possibly also Institute, Amsterdam, The Netherlands to decreased therapeutic efficacy. 104 A. K. L. Goey et al.

As CYP3A4 is involved in the metabolism of many criteria were alcoholism; drug addiction; psychotic disor- anticancer drugs (e.g. docetaxel, , imatinib, iri- ders leading to non-adequate follow-up; concomitant use of notecan), concomitant use of SJW may have serious clin- multidrug resistance (MDR)- and CYP3A-modulating ical consequences, especially undertreatment. In vitro drugs; uncontrolled infectious disease; human immunode- results have already shown that hyperforin increases the ficiency virus (HIV)-1 or -2; unresolved ([grade 1) tox- metabolism of docetaxel [6]. To date, however, no clinical icities from previous ; bowel obstruction or studies have been executed to determine the clinical rele- motility disorders that might influence the absorption of vance of this interaction. On the basis of significant clinical drugs; pregnancy; chronic use of H2-receptor antagonists interactions between SJW and the sensitive CYP3A4 sub- or proton pump inhibitors; neurological disease that might strate midazolam [7–12] and the anticancer drugs imatinib render a patient at increased risk of peripheral or central [13, 14] and irinotecan [15], a pharmacokinetic interaction neurotoxicity; and the presence of symptomatic cerebral or study of SJW and docetaxel should also be performed. leptomeningeal metastases. All patients provided written Compared with the metabolism of imatinib and irinotecan, informed consent prior to study entry and were treated in which enzymes and drug transporters other than between May 2010 and October 2011. CYP3A4 are involved [16, 17], docetaxel is more exclu- The study protocol (EudraCT number 2008-000886-41) sively metabolized by CYP3A4 [18] and is thus a good was approved by the Medical Ethical Committee of substrate for studying CYP3A4-mediated pharmacokinetic The Netherlands Cancer Institute (NKI; Amsterdam, interactions. The Netherlands) and was conducted in accordance with Therefore, this clinical study was designed to determine current standards of Good Clinical Practice, the WHO whether there is a significant pharmacokinetic interaction Declaration of Helsinki and the Medical Research Involv- between SJW and docetaxel. The secondary objective was ing Human Subjects Act (WMO). to determine whether the incidence of docetaxel-related toxicities would be affected if a herb–drug interaction 2.2 Study Design and Treatment occurred. This open-label, non-randomized, crossover study was conducted at the NKI. On day 1, docetaxel (TaxotereÒ; 2 Methods Aventis Pharma SA, Antony, France) was administered as an absolute dose of 135 mg (60 min intravenously). The 2.1 Patients dose of 135 mg was based on a safe dose of 75 mg/m2 and an average body surface area of 1.8 m2. From day 7 until Patients with histological or cytological proof of cancer for the morning of day 22, patients received SJW tablets whom treatment with docetaxel was considered to be of (HyperiplantÒ 300 mg dry SJW extract standardized to potential therapeutic benefit—for example, patients with 0.36–0.84 mg hypericin and 9–19 mg hyperforin; VSM advanced breast, gastric, oesophageal, bladder, ovarian, Geneesmiddelen BV, Alkmaar, The Netherlands) at the non-small cell lung, prostate, or head and neck cancer— recommended dose of one tablet three times daily. On the were included. Other inclusion criteria were age morning of day 22, the second cycle of docetaxel was C18 years; performance status B2 according to the World administered according to the same dosing schedule as that Health Organization (WHO) scale; life expectancy used on day 1 (Fig. 1). [3 months; absolute neutrophil count (ANC) C1.5 9 109/ Standard docetaxel pre-treatment consisted of oral L; platelet count C100 9 109/L; haemoglobin level dexamethasone 8 mg twice daily for three consecutive C6.0 mmol/L; impaired hepatic function as defined by days: 1 day before, on the day of docetaxel administration serum bilirubin B1.5 times the upper limit of normal and 1 day after. (ULN) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) B2.5 times the ULN; impaired 2.3 Pharmacokinetic Analysis of Docetaxel renal function as defined by serum creatinine B1.5 times the ULN or creatinine clearance C50 mL/min; and ability During the two docetaxel cycles, blood samples were and willingness to swallow and retain oral , to collected for pharmacokinetic analysis of docetaxel in comply with the protocol procedures and to follow dietary plasma. Blood samples were drawn at predose and at 0.25, restrictions. 0.5, 0.75, 1, 1.5, 2, 4, 7, 10, 24 and 48 h after the start of Patients were excluded if they had received any treat- the docetaxel infusion. Within 1 h after collection, samples ment with investigational drugs within 30 days before the were centrifuged at 1,500 9 g for 10 min at 4 °C, and start of the study or had used herbal supplements within plasma was isolated and stored at -20 °C until analysis. 6 weeks prior to the study treatment. Other exclusion Docetaxel plasma concentrations were determined using a Effect of St John’s Wort on the Pharmacokinetics of Docetaxel 105

Fig. 1 Study design. On day 1, the first docetaxel cycle was pharmacokinetic (PK) analysis of docetaxel were collected from administered. From day 7 until the morning of day 22, St John’s time 0 until 48 h after the start of the infusion. On days 7, 14 and 22, wort was supplemented, followed by a second cycle of docetaxel on blood samples were collected for hyperforin analysis. IV intravenous day 22. During both docetaxel cycles, blood samples for validated assay based on liquid chromatography coupled plasma samples were protected from ambient light during with tandem mass spectrometry (LC–MS/MS) [19]. In sample preparation. short, in this assay, docetaxel was extracted from the LC was carried out using a Polaris 3 C18-A column matrix using liquid–liquid extraction with tert-butyl methyl (50 mm 9 2 mm ID, particle size 3 lm; Varian, Middel- ether. Paclitaxel was used as the internal standard. Sample burg, The Netherlands) with a Polaris 3 C18-A pre-column injections (25 lL) were made on a C18 column (10 mm 9 2 mm ID, particle size 3 lm; Varian). Further, (150 9 2.1 mm ID, particle size 5 lm) coupled to a guard the LC equipment consisted of a DGU-14A degasser, a column (10 9 2 mm). The mobile phase consisted of CTO-10Avp column oven, a Sil-HTc autosampler and two methanol—10 mM NH4OH (7:3, v/v) which was delivered LC10-ADvp-l pumps (all from Shimadzu, Kyoto, Japan). at a flow rate of 0.2 mL/min. The run time was 7.5 min. Isocratic elution (25 % A, 75 % B), delivered at a flow rate Subsequently, positive ionization electrospray MS/MS was of 0.4 mL/min, was applied with mobile phase A consist- performed using a triple quadrupole mass spectrometer ing of 5 mM ammonium acetate and 0.1 % acetic acid in equipped with a turbo-ionspray interface. The method was water, while mobile phase B consisted of acetonitrile. successfully validated according to the US Food and Drug Subsequently, MS/MS analysis on a Finnigan TSQ Administration (FDA) guidelines on bioanalytical method Quantum Discovery Max triple quadrupole mass spec- validation. The validated range for docetaxel was trometer (Thermo Fischer Scientific, Waltham, MA, USA) 0.25–1,000 ng/mL. Interassay inaccuracy was between with electrospray ionization (ESI) was performed in the -10.2 and 1.02 %, and interassay precision did not exceed negative ion mode. For hyperforin, the mass transitions 12.8 %. from m/z 535 to 383 were optimized, and for the internal standard reserpine, responses from m/z 607 to 211 were 2.4 Pharmacokinetic Analysis of Hyperforin monitored. In order to indicate the extent of hyperforin exposure, a Adherence of SJW intake by the patients was assessed by calibration curve consisting of three hyperforin concen- checking the patients’ diaries and by measuring the pre- trations (37.5, 75 and 150 ng/mL) was prepared by spiking sence of hyperforin in plasma samples obtained at three hyperforin working solutions (Sigma-Aldrich, St Louis, timepoints. The first plasma sample was collected on the MO, USA) to blank human plasma (Sera Laboratories morning of day 7 before ingestion of the first SJW tablet. International Ltd, Haywards Heath, UK) measured in Seven days later on the morning or afternoon of day 14, the duplicate after each set of patient samples. Patient samples second sample was drawn during routine laboratory tests. were also processed and analyzed in duplicate. Subse- The third hyperforin sample was taken on the morning of quently, the average hyperforin concentrations in these day 22 before intake of the last SJW tablet. samples were calculated. For analysis of hyperforin, an LC–MS/MS assay was used. In short, after addition of 50 lL of 5,000 ng/mL 2.5 Pharmacokinetic and Statistical Analysis reserpine (internal standard), a 100 lL plasma sample underwent liquid–liquid extraction with 1 mL ethyl ace- On the basis of statistical power of 80 %, a significance tate-n-hexane (70:30, v/v). After evaporation of the organic level of 5 %, an estimated intra-subject standard deviation phase, the dry extract was reconstituted with 200 lL ace- in docetaxel clearance of 25 % and a detectable effect size tonitrile–water (75:25, v/v), and 20 lL was injected into of 25 %, a sample size of ten evaluable patients was the LC–MS/MS system. Since hyperforin is photosensitive, required. This calculation was performed with the 106 A. K. L. Goey et al.

Power.T.Test package in R version 2.14.0 software Table 1 Baseline patient characteristics (R Development Core Team, Vienna, Austria). Characteristic Value The following pharmacokinetic parameters of docetaxel were calculated using non-compartmental analysis with R: Patients (n)11 the area under the plasma concentration–time curve Sex (n) extrapolated to infinity (AUC?), total body clearance (CL), Female 7 elimination half-life (t‘) and maximum plasma concen- Male 4 tration (Cmax). Age (years) After logarithmic transformation of these parameters, a Median 62 paired Student’s t test (a = 0.05) was performed using R to Range 40–67 detect statistically significant differences between the two Race (n) treatment cycles. Caucasian 11 Primary tumour (n) 2.6 Docetaxel-Related Adverse Events Bladder 6 Non-small cell lung carcinoma 3 Docetaxel-related adverse events during cycles 1 and 2 Ovarian 1 were registered according to the National Cancer Institute Ureteral 1 Common Terminology Criteria for Adverse Events (NCI Previous treatment (n) CTCAE) version 3.0. Adverse events were considered to Chemotherapy 11 be docetaxel related if they were rated as possibly, prob- Radiation therapy 4 ably or definitely related by the investigator. Hormonal therapy 1

3 Results Table 2 Summary of docetaxel pharmacokinetic parameter a 3.1 Baseline Patient Characteristics estimates Parameter Day 1 Day 22 P value Eleven patients with advanced cancer were included in this AUC (ng Á h/mL) 3,035 ± 756 2,682 ± 717 0.045 study. The patients’ baseline characteristics are shown in ? CL (L/h) 47.2 ± 12.2 53.7 ± 14.7 0.045 Table 1. Because of a hypersensitivity reaction to doce- taxel, one patient did not completely receive the second Cmax (ng/mL) 2,000 ± 685 1,873 ± 710 0.468 docetaxel infusion and was therefore not evaluable for t‘ (h) 41 ± 35 31 ± 10 0.185 pharmacokinetic analysis. Exclusion of this patient resulted AUC? area under the plasma concentration–time curve extrapolated in a number of ten patients eligible for the final analysis. to infinity, CL total body clearance, Cmax peak plasma concentration, t‘ elimination half-life a 3.2 Pharmacokinetic Analysis of Docetaxel Pharmacokinetic data are given as means ± standard deviations and were obtained on day 1 (docetaxel alone) and on day 22 (14 days after the start of St John’s wort). P values were obtained from a paired Pharmacokinetic parameters of docetaxel before and after Student’s t test SJW intake are shown in Table 2. A paired Student’s t test revealed that the mean AUC? of docetaxel significantly decreased from 3,035 ± 756 ng Á h/mL in cycle 1 to 2,682 ± 717 ng Á h/mL in cycle 2 (P = 0.045). Figure 2 displays the mean plasma concentration–time curves of docetaxel before and after SJW supplementation. Individ- ual changes in the AUC? are depicted in Fig. 3. In eight out of ten patients, a decrease in the AUC? was observed. Furthermore, docetaxel clearance was significantly increased from 47.2 ± 12.2 to 53.7 ± 14.7 L/h (P =

0.045) after SJW supplementation. Further, the mean t‘ and Cmax decreased from 41 ± 35 to 31 ± 10 h (P = 0.185) and from 2,000 ± 685 to 1,873 ± 710 ng/mL Fig. 2 Mean (± standard deviation) plasma concentration–time (P = 0.468), respectively. These changes, however, were curves of docetaxel before and after St John’s wort (SJW) supple- not statistically significant. mentation (n = 10) Effect of St John’s Wort on the Pharmacokinetics of Docetaxel 107

Table 4 Incidence of docetaxel-related adverse events (National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0) Cycle 1 Cycle 2 (without SJW, n = 10) (with SJW, n = 10) Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4

Patients with 8180 adverse events (n) Fig. 3 Comparison of individual docetaxel area under the plasma Adverse events (n) concentration–time curve extrapolated to infinity (AUC?) values Fatigue 7 – 4 – obtained before St John’s wort (SJW) administration and 14 days after SJW intake (n = 10) Myalgia 4 – 3 – Alopecia 5 6 3.3 Hyperforin Analysis in Plasma Nausea 3 – 3 – Fever 3 – 3 – As expected, before the start of SJW supplementation, no Hypersensitivity 1–2– hyperforin was detected in the majority of the patients reaction (Table 3). In one patient, however, a relatively high hy- Constipation 3 – – – perforin concentration ([75 ng/mL) was found, which was Pain (bone) 1 – 1 – caused by the fact that the first tablet of SJW was acci- AST elevation 2 – – – dentally ingested before baseline pharmacokinetic blood ALT elevation – 1 – – sampling. As this patient ingested all other SJW doses Anaemia – – 1 – according to the protocol, this patient was considered Ocular ––1– (irritation) evaluable for pharmacokinetic analysis. After 7 and 14 days of SJW intake, hyperforin was Pain (ear) 1 – – – detected in all patient samples. In addition to the patients’ Dry mouth 1 – – – diaries, this result confirmed that all patients were com- Pain (throat) 1 – – – pliant with SJW intake. Neuropathy 1––– (fingers) Concerning the relationship between measured hyper- Watery eye 1–1– forin levels and the extent of CYP3A4 induction, it is worth (right) noting that the two patients with the highest hyperforin Tinnitus 1 – – – levels on day 1 of cycle 2 also showed the greatest Stomatitis 1 – – – decrease in the AUC? of docetaxel (data not shown). For Rash/pruritus 1 – – – the other patients, however, no apparent correlation Diarrhoea 1 – – – between hyperforin levels and the docetaxel AUC was ? Total adverse 38 1 25 0 observed. events (n)

ALT alanine aminotransferase, AST aspartate aminotransferase, 3.4 Docetaxel-Related Adverse Events SJW St John’s wort

The incidence of docetaxel-related toxicities according to Nine out of ten patients suffered from docetaxel-related NCI CTCAE version 3.0 are displayed in Table 4. adverse events, which were mainly grade 1–2 toxicities. The most common adverse events were fatigue, myalgia, alopecia, nausea and fever. Overall, the incidence of Table 3 Hyperforin plasma concentrations obtained at predose (day 7) and 7 days (day 14) and 14 days (day 22) after the start of docetaxel-related adverse events was lower after SJW St John’s wort supplementation supplementation (25 adverse events) than before Mean hyperforin plasma Day 7 Day 14 Day 22 (39 adverse events). In 50 % of the patients, the decrease concentration (predose) in the AUC? was accompanied by a decrease in docetaxel- related adverse events and also a decrease in co-medication a \37.5 ng/mL (n)926 use (data not shown). 37.5–75 ng/mL (n)054Objective toxicities, such as elevated serum AST and [75 ng/mL (n)130ALT levels and anaemia, occurred more frequently in a Not detectable cycle 1 (three adverse events) than in cycle 2 (one adverse 108 A. K. L. Goey et al. event); however, as this finding involved small numbers in in our study. For example, the AUC of irinotecan’s active a small population, these data cannot be interpreted further. metabolite SN-38 significantly decreased by 42% after supplementation with SJW [15], and the AUC? of imatinib was reduced by 30–32 % [13, 14]. Compared with imati-

4 Discussion nib, the less evident 12 % decrease in the AUC? of docetaxel in our study can be explained by differences in This study was intended to investigate whether supple- the route of administration. Imatinib is administered orally, mentation of SJW affected the pharmacokinetics of doce- thus additional induction of intestinal CYP3A4 and taxel. SJW has already been shown to be a potent CYP3A4 ABCB1 may have increased the potency of the interaction. inducer in in vitro studies [5, 20, 21] and in clinical studies It has already been shown that hyperforin has more potent [7–12]; thus, increased hepatic clearance and reduced CYP3A4-inducing effects in the intestinal wall than in the systemic exposure to docetaxel were expected. Pharma- liver [7, 8, 11, 26]. Consequently, administration of SJW is cokinetic analysis showed that the results were in concor- expected to have a more potent effect on the pharmaco- dance with this hypothesis. Supplementation of the kinetics of orally administered CYP3A4 substrates. commercial SJW product HyperiplantÒ for 2 weeks at the Regarding irinotecan, SJW may have affected carb- recommended dose of one tablet three times daily resulted oxylesterases [27] and uridine diphosphate glucuronosyl- in a reduction in exposure to docetaxel. The AUC? of transferase 1A (UGT1A) [28], which are (in contrast to docetaxel decreased by 12 % on average, which was sta- CYP3A4) directly involved in the formation and metabo- tistically significant (P \ 0.05). This outcome most likely lism of the active metabolite SN-38. Thus, besides resulted from increased elimination, as indicated by a mean CYP3A4 induction, SJW could affect the pharmacokinetics 14 % increase in docetaxel clearance after SJW supple- of irinotecan in more ways than docetaxel, which is mainly mentation (P \ 0.05). Furthermore, the t‘ and Cmax values metabolized by CYP3A4. decreased by 24 and 6 %, respectively, after SJW supple- Theoretically, the 3-day pretreatment period with mentation. Although these changes were not statistically dexamethasone could have partially masked the inductive significant, they were in line with increased elimination of effect of SJW, since dexamethasone is also a CYP3A4 docetaxel. Hyperforin levels that significantly induced the inducer [29]. However, short-term administration of metabolism of docetaxel via CYP3A4 in vitro (*50 ng/ dexamethasone for 3 days did not significantly alter the mL) [6] were also reached in the majority of the patients in pharmacokinetics of docetaxel [30]. Therefore, dexameth- this study (Table 3). This finding indicates that induction of asone pretreatment was not likely to have substantially CYP3A4 and docetaxel metabolism by hyperforin was affected docetaxel pharmacokinetics in our study. highly likely in the current study. Interestingly, the two Besides inducing CYP3A4, St John’s wort also induces patients who unexpectedly showed an increase in the the drug efflux transporter ABCB1 [31–34], which is

AUC? of docetaxel displayed the lowest hyperforin levels involved in the hepato-biliary excretion of docetaxel [35]. on day 1 of cycle 2. Conversely, the patients with the Differentiation of CYP3A4 or ABCB1 effects by SJW was greatest decrease in the docetaxel AUC? had the highest not possible in our study, because no CYP3A4-mediated hyperforin levels. These results support the previously metabolites of docetaxel or docetaxel levels in faeces were reported finding that the extent of CYP3A4 induction measured. However, induction of ABCB1 is not likely to depends on the content of hyperforin in SJW products [22]. significantly affect docetaxel plasma concentrations, which

The observed decrease in the AUC? of docetaxel after was demonstrated by the absence of significant pharma- SJW supplementation could affect the therapeutic effect of cokinetic interactions between docetaxel and the potent docetaxel, since systemic exposure to docetaxel is directly ABCB1 inhibitors laniquidar [35, 36] and zosuquidar [37]. related to its efficacy and toxicity [23, 24]. Cancer patients In addition, no significant correlations between ABCB1 receiving docetaxel and SJW could thus be at risk of un- polymorphisms and docetaxel clearance were observed dertreatment. The clinical relevance of the statistically [38]. significant interaction in the present study deserves further Significant clinical interactions between SJW and the investigation in a greater number of patients, using bio- CYP3A4 and CYP3A5 substrate midazolam [7–12, 26] equivalence acceptance limits [25]. indicate that SJW may also interact with CYP3A5. Both In addition to the clinical interaction studies combining CYP3A4 and CYP3A5 are regulated by PXR and are SJW with imatinib [13, 14] and irinotecan [15], our study is involved in the metabolism of docetaxel [39]. However, the fourth study investigating the pharmacokinetic inter- induction of CYP3A5 is not likely to significantly affect action between SJW and an anticancer drug. In comparison docetaxel pharmacokinetics, because docetaxel’s affinity with the imatinib and irinotecan interaction studies, SJW for CYP3A4 is approximately ten times higher than that for had a smaller effect on the pharmacokinetics of docetaxel CYP3A5 [40]. In agreement with these results, no Effect of St John’s Wort on the Pharmacokinetics of Docetaxel 109 significant correlation was observed between the inactive recommended that concomitant use of this SJW product CYP3A5*3 genotype and docetaxel clearance in cancer and docetaxel should be avoided. Considering the inter- patients [30, 38]. product variability in hyperforin content, it is also advis- In the present interaction study, patients were not ran- able not to combine SJW products and docetaxel in domized for the sequence of treatment, because it was in general. the patients’ interest to start docetaxel chemotherapy as soon as possible. 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