Weekly oral paclitaxel as first-line treatment in patients with advanced gastric cancer

C. M. F. Kruijtzer1, H. Boot1, J. H. Beijnen1,2, H. L. Lochs3, F. X. Parnis4, A. S. T. Planting5, J. M. G. Pelgrims6, R. Williams7, R. A. A. Mathôt2, H. Rosing2, M. E. Schot1, H. van Tinteren1 and J. H. M. Schellens1,2,+

1 The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam; 2 The Netherlands Cancer Institute, Slotervaart Hospital, Amsterdam, The Netherlands; 3 Universitätsklinikum Charité der Humboldt, Berlin University, Berlin, Germany; 4 Ashford Cancer Center, Ashford, Australia; 5 Daniel den Hoed Kliniek, Rotterdam, The Netherlands; 6 Algemeen Ziekenhuis Stuyvenberg, Antwerpen, Belgium; 7 IVAX Research Inc., Miami, FL, USA

Received 25 June 2002; revised 21 October 2002; accepted 7 November 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

Pharmacokinetic study has shown that co-administration of cyclosporin A (CsA), which acts as a P-glycoprotein (P-gp) and CYP-3A blocker, resulted in an 8-fold increase in the systemic exposure of oral paclitaxel. Two doses of oral paclitaxel on 1 day in combination with CsA resulted in higher systemic exposure than single dose administration.

Patients and methods:

In this phase II study, chemonaïve patients with advanced gastric cancer received oral paclitaxel weekly in two doses of 90 mg/m2 on the same day; CsA (10 mg/kg) was given 30 min before each dose of oral paclitaxel.

Results:

In 25 patients, the main toxicities were: nausea CTC grade 2/3, 10 patients (40%); vomiting grade 2/3, 4 patients (20%); diarrhea grade 2/3, 6 patients (24%); neutropenia grade 3/4, 5 patients (20%). In the 24 evaluable patients, eight partial responses were observed, resulting in an overall response rate (ORR) of 33% [95% confidence interval (CI) 18% to 52%]. Eleven patients had stable disease (46%) and 5 patients showed progressive disease (21%). The ORR in the total population was 32% (95% CI 17% to 50%). The median time to progression was 16 weeks (95% CI 9–22). Pharmacokinetic analyses revealed that the mean area under the plasma concentration–time curve (AUC) of orally administered paclitaxel (± standard deviation) was 3757.6 ± 939.4 ng·h/ml in week 1 and 3928.4 ± 1281 ng·h/ml in week 2. The intrapatient variability in the AUC was 12%.

Conclusions:

Oral paclitaxel in combination with CsA is both active and safe in chemonaïve patients with advanced gastric cancer. Toxicities were mainly gastrointestinal.

Key words: advanced gastric cancer, chemotherapy, cyclosporin A, paclitaxel, toxicity


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Gastric cancer can be cured only by complete surgical excision of all neoplastic tissue. Unfortunately, at the time of presentation the disease is often at an advanced stage and not amenable to curative surgery. Chemotherapy with single agents for metastatic disease generally produces low response rates of short duration. Combination chemotherapy with agents such as 5-fluorouracil (5-FU), doxorubicin and either mitomycin (FAM regimen) or methotrexate (FAMTX regimen) may produce responses in approximately 20–50% of patients with advanced disease [1, 2]. More recently, the combination consisting of epirubicin, cisplatin and protracted i.v. infusion of 5-fluorouracil (ECF regimen) has been shown to be superior to FAMTX and has become widely used [3, 4]. With the ECF regimen, response rates of 45% were observed and median overall survival was 8.9 months. However, even with the ECF regimen, the 2-year survival rate is only 14% and the challenge remains to explore new and potentially more effective treatments [3].

The use of the taxanes (paclitaxel and docetaxel) in patients with advanced gastric cancer has been reported in several studies with response rates between 5% and 24% in first- and second-line treatment [59]. Higher response rates were found for combinations of paclitaxel with 5-FU or carboplatin, combined with radiotherapy [1013]. Weekly infusions of paclitaxel have a favorable toxicity profile, allowing dose intensification, and show promising activity in patients with breast and non-small-cell lung cancers (NSCLC) [1416]. Weekly schedules of monotherapy with paclitaxel in patients with advanced gastric cancer have not yet been reported.

Oral administration of paclitaxel is convenient and practical for patients and circumvents systemic exposure to the infusion vehicle (Cremophor EL), which is held responsible for hypersensitivity reactions. Moreover, oral administration may enable the development of chronic treatment schedules, resulting in sustained plasma concentrations of paclitaxel above the threshold level of pharmacological activity. Preclinical studies have shown that the oral bioavailability of paclitaxel is low due to its affinity for the membrane-bound drug efflux pump P-glycoprotein (P-gp) in the gastrointestinal tract. In addition, presystemic extraction in the liver by the cytochrome P450 system may also play an important role [17, 18].

Preclinical and clinical studies in our institute have shown that co-administration of oral cyclosporin A (CsA), an efficacious inhibitor of P-gp- as well as CYP-3A-mediated drug metabolism, resulted in a significant increase in the systemic exposure of oral paclitaxel [19, 20]. The apparent bioavailability of oral paclitaxel, calculated by the ratio of the oral area under the plasma concentration–time curve (AUC) of paclitaxel when CsA was co-administered and the AUC of paclitaxel after i.v. administration alone, increased from 4% to 47% [20], and P-gp inhibition by CsA was maximal at a single dose of 10 mg/kg [21]. In vitro data suggested that for paclitaxel the time period of drug exposure may be more important for the antitumor activity than an increase in the plasma concentration [22, 23]. In order to improve the systemic exposure to oral paclitaxel a schedule dosing twice on 1 day was investigated. The results of this study showed that the highest systemic exposure to paclitaxel was reached at the dose level of 2 x 90 mg/m2, with a good safety profile [24].

Based on these observations we initiated a phase II study and assessed response, time to progression and toxicity of the combination of oral paclitaxel and oral CsA given twice on 1 day on a weekly basis in chemonaïve patients with advanced gastric cancer. We also determined the pharmacokinetic parameters of this combination.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eligibility criteria
Patients with histologically confirmed, locally advanced unresectable or metastatic adenocarcinoma of the stomach or gastroesophageal junction were eligible. Prior chemotherapy was not permitted. At entry, patients were required to have measurable disease according to the RECIST criteria [25]. They had to have adequate hematological, renal and hepatic functions, and a WHO performance status of <2. Prior gastric resection was allowed. Exclusion criteria were: concomitant use of known P-gp inhibitors; chronic use of H2-receptor antagonists or proton pump inhibitors; known history of cerebral or leptomeningeal metastases; history of prior malignancy, except completely excised in situ carcinoma of the cervix or non-melanoma skin cancer; bowel obstruction or motility disorders that could influence the absorption of drugs; allergy to CsA; and serious concurrent disease, including heart disease. The study protocol was approved by the Medical Ethics Committees of all participating institutions and all patients gave written informed consent.

Treatment plan
On day 1 of each week, oral paclitaxel (Paxoral®; IVAX Research Inc., Miami, FL, USA) was dosed twice (90 mg/m2 x 2) with at least a seven but not more than 12 h dose interval. Cyclosporin A (CsA) 10 mg/kg was given 30 min before each dose of oral paclitaxel. CsA (Neoral®; Novartis, Basel, Switzerland) was supplied as capsules of 50 and 100 mg or as a liquid of 100 mg/ml. The oral paclitaxel solution contained 12 mg paclitaxel per ml and was added to at least 50 ml of tap water or juice (not grapefruit) in a plastic cup. The solution was shaken gently for ~1 min and had to be drunk within 2 h of preparation. The treatment was administered weekly until disease progression or unacceptable toxicity developed. Patients were advised to have a ‘light’ meal consisting of one cracker and a cup of tea prior to intake of the drugs and they started eating 1 h after the dose. No antiallergic premedications (dexamethasone, clemastine or ranitidine) were taken, because our previous phase I studies had revealed that this can be omitted [20, 26]. Oral granisetron was given 1 h before intake of the chemotherapy to prevent nausea and vomiting. Patients were informed that in the case of progressive disease or unacceptable toxicity they could switch to ECF chemotherapy.

Evaluation of response and toxicity
All toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) [27]. All patients who received at least one weekly cycle of therapy were evaluable for toxicity. Two dose reductions were allowed, first to 70 mg/m2 (x2), then to 55 mg/m2 (x2), but patients who required further dose reductions were withdrawn from the study. The first dose reduction was mandated for patients who experienced CTC grade 3 or 4 non-hematological toxicity, or hematological toxicity consisting of absolute neutrophil count (ANC) <0.5 x 109/l, neutropenic fever or thrombocytopenia <25 x 109/l. Treatment was postponed until recovery of thrombocytes to >100 x 109/l and ANC >1.5 x 109/l. When treatment delay was >2 weeks because of hematological toxicity, any further treatment was at the second dose reduction level. For patients who required dose reductions the dosage was not re-escalated in subsequent cycles. The CsA dose of 10 mg/kg remained constant despite dose reductions of paclitaxel.

Standard clinical measurements and radiological examinations were used to ensure measurable disease. Responses were evaluated according to the RECIST criteria [25] and confirmed by independent review. Patients who completed at least six weekly cycles were considered evaluable for response. The primary end point of the study was the response rate. We also determined the duration of response: the number of days between the onset of response and the date of last progression-free evaluation. For patients who had not progressed the date of last progression-free evaluation was censored. We determined the time to progression: the number of days between the date of first treatment and the date on which progression was clearly documented or death occurred.

Sample collection and analysis
Pharmacokinetic monitoring was performed in every patient during week 1 and week 2. For paclitaxel, blood samples of 5 ml each were collected in heparinized tubes at predosing, 30 and 60 min, and 2, 3, 4, 6, 7, 7.5, 8, 10, 12, 24 and 30 h after ingestion of oral paclitaxel. For the centers outside The Netherlands, blood samples of 5 ml were collected at predosing, 1, 3 and 4 h after paclitaxel intake. Blood samples were centrifuged, plasma was separated and stored at –20°C until analysis. Paclitaxel concentrations in the plasma were determined using a validated high performance liquid chromatography (HPLC) assay [28]. For CsA monitoring, blood sampling was performed only at The Netherlands Cancer Institute at the same sampling times as used for paclitaxel. Whole blood samples were stored at 4°C and analyzed within 1 week using a fluorescence polarization immunoassay (Abbott Laboratories, Amstelveen, The Netherlands) [29].

Pharmacokinetic analysis
A population pharmacokinetic model was developed for paclitaxel using the nonlinear mixed-effect modeling program, NONMEM (double precision; version V, level 1.1) [30]. The first-order conditional estimation method was applied. A two-compartment structural kinetic model with first-order absorption and elimination, and saturable transport between central and peripheral compartments, was used to describe the time profiles of plasma paclitaxel concentration. The following pharmacokinetic parameters of paclitaxel were calculated: absorption rate constant (Ka); volume of distribution of the central compartment (V); clearance from the central compartment (CL); maximal transport capacity from the central to the peripheral compartment (Tmax); concentration at which the transport is half maximal (Tm); and the rate constant for transport from the peripheral to the central compartments (k21). Since paclitaxel was administered orally, the terms relating to plasma (V, CL and Tmax) represent the ratio of these parameters to the unknown bioavailability.

Interpatient variability [coefficient of variation (CV)] of the pharmacokinetic parameters was estimated using a proportional error model. For instance, the interindividual CV in CL was estimated using: CLi = CLpop (1 + {eta}i), in which i represents the number of the individual, CLi is the CL of the ith individual, CLpop is the population value and {eta} is the interindividual random effect with mean 0 and variance {omega}2. The difference between the observed concentration (Cobs) and its respective prediction (Cpred) was modeled with a proportional error model: Cobs = Cpred x (1 + {varepsilon}), where {varepsilon} is an independent random variable with mean 0 and standard deviation {sigma}.

Since plasma paclitaxel concentration versus time profiles were assessed during two courses, an interoccasion (between course) CV was estimated. The following expression was used for CL: CLij = CLpop (1 + {eta}i + {kappa}ij), in which j represents the number of the course (1 or 2), CLij is the CL of the ith individual at occasion j, CLpop is the population value, and {eta} and {kappa} are the interindividual and interoccasion random effects with mean 0 and variances {omega}2 and {pi}2, respectively.

Individual pharmacokinetic parameters were generated by Bayesian analysis. On the basis of these parameters, individual plasma concentration–time profiles of paclitaxel were generated for assessment of the AUC, the maximal plasma concentration (Cmax), the time to maximal plasma concentration (Tmax), and the time above the previously defined threshold concentrations of 0.1 µM (T >0.1 µM) and 0.05 µM (T >0.05 µM). For CsA, the AUC parameter was determined.

Statistics
Patients were accrued according to a two-stage design [31] aiming at 25 eligible patients. We defined 30% as the target response rate to detect. Furthermore, we had determined that response rates of <=10% would be of no further interest. With this design, the study had 80% power for concluding that oral paclitaxel had sufficient activity level (more than five responses) if the true response rate is >=30%, whereas it will have <5% probability of concluding acceptable activity if the true response rate is <=10%. Analyses of response rate and time to progression were performed on all evaluable patients and on the total population. The time to progression curve was estimated using the Kaplan–Meier method.

We calculated the interpatient CV in the paclitaxel AUC by dividing the standard deviation by the mean measured values and multiplying by 100. The intrapatient CV in the AUC was defined as the AUC value in week 1 minus the AUC value in week 2, divided by the AUC value in week 1 and multiplied by 100. All the individual values were summed up and divided by the number of patients.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Table 1 lists the clinical characteristics of the 25 patients enrolled in this study between October 2000 and June 2001. Median age of the patients was 63 years (range 51–86). At entry, two patients (8%) had locally advanced unresectable disease (stage IIIB) and 23 patients (92%) had stage IV disease with distant metastases. Fifteen patients (60%) had undergone prior surgery: 10 patients had a primary curative resection before metastases were detected; three had a diagnostic laparotomy/laparoscopy; and in two patients a palliative resection had been performed.


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Table 1. Patient characteristics at baseline
 
Response
Twenty-four patients were evaluable for response (Table 2). One patient refused treatment after the first administration because of grade 2 nausea and was not evaluable for response. Partial responses were reported in eight patients, resulting in an overall response rate (ORR) of 33% [95% confidence interval (CI) 18% to 52%] in the 24 evaluable patients. Most responses were observed after the first response evaluation. The duration of response was 20 weeks (range 14–38). Furthermore, 11 patients (46% of the evaluable population) showed stabilization of the disease as their best response, for a median duration of 14 weeks (range 8–28). Five patients (21%) had progressive disease. In the total population, the ORR was 32% (95% CI 17% to 50%).


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Table 2. Best response (RECIST criteria) to weekly oral paclitaxel (two doses in 1 day) in combination with CsA
 
Dose intensity and dose reduction
The extent of exposure to oral paclitaxel is shown in Table 3. A total of 286 weekly administrations (comprising two doses taken on 1 day) of oral paclitaxel and CsA were administered, with a median of eight weekly administrations per patient (range 1–24). The median dose intensity was 141 mg/m2/week [standard deviation (SD) 31]. Sixteen patients had a total of 64 weeks delay of treatment, most of which were a result of mild neutropenia without sufficient recovery for retreatment.


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Table 3. Extent of exposure in all patients
 
One patient changed from the two-dose schedule to a one-dose schedule after the second administration, at the patient’s request. Five patients underwent a dose reduction from 90 to 70 mg/m2 (x2) after a median of six weekly administrations (range 2–11). The reason was neutropenia CTC grade 4 without recovery after 2 weeks delay of treatment.

Treatment duration
As of January 2002, all patients had discontinued treatment. Five patients discontinued as a result of disease progression and 17 because of secondary progression after an initial response or disease stabilization. Median treatment duration was 14 weeks (range 1–29). Three patients stopped treatment as a result of grade 2 toxicities, one for nausea, one for fatigue and one for vomiting, after 1, 22 and 26 weeks, respectively.

Time to progression and overall survival
As of January 2002, median time to progression for the 24 evaluable patients was 16 weeks (95% CI 9–22); median overall survival time had not been reached and 16 of the 24 patients (67%) were still alive.

Toxicity
The principal hematological toxicity was neutropenia, as 20% of patients experienced severe (grade 3–4) neutropenia (Table 4). However, no neutropenic fever was observed. Of the non-hematological toxicities, gastrointestinal toxicity was most frequently reported. Nausea and vomiting grade 3 were reported in 8% and 4% of the patients, respectively. Patients with gastric carcinoma still in situ experienced these symptoms with greater severity. Diarrhea grade 3 was also observed in 4% of patients. Serious neurotoxicity (>=grade 2), as commonly described for treatment with i.v. paclitaxel, was not observed in this study.


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Table 4. Toxicity, by patient (maximum severity grade)
 
One patient developed fever because of a dental abscess and pneumonia. After 2 days, this patient developed a renal insufficiency. Because treatment with CsA may be associated with renal toxicity we made additional measurements of CsA levels at 12 and 24 h in this patient. These were not elevated into the toxic range. The renal insufficiency we observed was reversible and possibly caused by transient hypotension. In this study, we did not observe any grade 4 non-hematological toxicity and no toxic deaths occurred.

Pharmacokinetics
Several pharmacokinetic-compartment models were applied to the data, including 2- and 3-compartment models with linear and/or saturable distribution and/or elimination. The data were adequately described by a 2-compartment model with first-order absorption, linear elimination and a saturable pathway to the peripheral compartment. Population parameters are given in Table 5. Structural parameters of the model were estimated with adequate precision (CV 8–32%). Interindividual CVs could only be estimated for V, CL and Tm. This should not be interpreted as an absence of variability for the parameters Ka, Tmax and k21, but simply that the data do not contain enough information to quantify these parameters. Interoccasion CVs could be quantified for CL and Tm. The model-based and Bayesian-predicted concentrations were symmetrically distributed around the line of identity, indicating the adequacy of the population model (data not shown). On the basis of individual Bayesian estimates, secondary pharmacokinetic parameters of weekly dosing of oral paclitaxel twice on 1 day were derived (Table 6). The mean AUC of orally administered paclitaxel was 3757.6 ± 939.4 ng·h/ml in week 1 and 3928.4 ± 1281 ng·h/ml in week 2. The calculated interpatient CV of the AUC of oral paclitaxel was 25% and 33% in weeks 1 and 2, respectively. The intrapatient CV of the AUC was 12%.


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Table 5. Population pharmacokinetic parameters of paclitaxel after oral administration of 90 mg/m2 twice in 1 day
 

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Table 6. Pharmacokinetic parameters of weekly dosing of oral paclitaxel twice on 1 day (mean ± standard deviation)
 
An important pharmacokinetic parameter of i.v. paclitaxel is the time period of exposure above a certain threshold level (T >0.1 µM). The mean T >0.1 µM values (±SD) were 9.1 ± 3.7 h in week 1 and 10.3 ± 4.2 h in week 2. The mean T >0.05 µM values (±SD) were 20.1 ± 8.2 h in week 1 and 21.2 ± 9.4 h in week 2. The mean Cmax values after the first and second dose were comparable between weeks 1 and 2, but a small, not significant increase in the Cmax value was noted after the second dose. Figure 1A and B shows plots of all observed paclitaxel concentrations over time and the mean Bayesian-predicted plasma concentration time profile in week 1 and week 2. For CsA, pharmacokinetic parameters were calculated in only five patients. The mean AUC of CsA was 19.1 ± 4.3 mg.h/l in week 1 and 19.6 ± 2.3 mg.h/l in week 2.



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Figure 1. Plots of all observed paclitaxel concentrations over time and the mean Bayesian-predicted plasma concentration–time profile for paclitaxel in (A) week 1 and (B) week 2.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Our phase II study with oral paclitaxel plus CsA revealed an ORR of 32% (95% CI 18% to 52%) in 24 evaluable patients with advanced gastric cancer who were not previously treated with chemotherapy. The median time to progression was 16 weeks (95% CI 9–22). The response rate and time to progression of the current study were comparable with combination regimens such as FAM/FAMTX and single agent paclitaxel administered i.v. every 3 weeks [17]. Based on the preclinical research which demonstrated that the bioavailability of oral paclitaxel can be increased by co-administration of CsA [1820], this phase II study was a logical step in translating the preclinical research into a clinical trial.

Response rates obtained with the ECF regimen are higher than those in our study [3, 4]. However, the ECF regimen consists of three chemotherapeutic agents in contrast with single agent paclitaxel in our study. A potential drawback of the ECF regimen is the implantation of a central venous line with an external pump for the continuous 5-FU infusion, because this is associated with an increased risk of catheter complications [3, 4]. Another disadvantage is that this treatment is not possible on an outpatient basis, because the i.v. administration of cisplatin requires an intensive hydration schedule.

The toxicity profile in our study is manageable and consisted mainly of gastrointestinal toxicity such as nausea and vomiting, but the majority of these patients had already complained of this before the start of treatment. However, these symptoms worsened during oral paclitaxel treatment. The high incidence of gastrointestinal toxicity in our study might be diminished by an optimized antiemetic treatment and the addition of dexamethasone around the time of paclitaxel intake. The occurrence of the diarrhea may be explained by local irritation of the intestinal mucosa by the oral formulation of paclitaxel. Notably, we did not observe serious neurotoxicity. We know from the literature that increased neurotoxicity is probably associated with high peak-plasma concentrations of paclitaxel [32]. In our study, the peak-plasma concentrations were significantly lower than those obtained with the conventional 3-week schedule, and this may contribute to the low incidence of neurotoxicity [32, 33]. However, it is not yet known how plasma levels of orally administered paclitaxel, without the presence of Cremophor EL, should be interpreted. The hematological toxicity was very mild compared with the literature data [5, 8]. A similar study in patients with advanced NSCLC, who were also treated with weekly oral paclitaxel (twice on 1 day), has shown moderate neutropenia [34]. A possible explanation might be that the patients with advanced gastric cancer were chemonaïve and their bone marrow reserve was still sufficient.

Our treatment can be given on an outpatient basis or at home, which might improve quality of life for this group of patients who are treated with palliative intent. The disadvantages of the oral formulation of this cytotoxic drug in combination with CsA are the possible interactions with concomitant medications, which are also substrates for the same drug transporter (P-gp) and/or CYP-3A. Pharmacokinetic parameters of orally administered paclitaxel have shown good reproducibility and the values of the AUC, Cmax and T >0.01 µM are in good accordance with a previously published study in which the same schedule was used [24]. The interpatient CVs of the AUC of 25% and 33% in week 1 and week 2, respectively, were somewhat higher than the i.v. data of 16% and 22%, respectively [33, 35]. The intrapatient CV of the AUC was very low (12%) and indicates limited variation within the same patient in absorption and elimination processes. The results show that absorption of oral paclitaxel might not be seriously influenced by the observed toxicity of vomiting, which mainly occurred ~24 h after intake. These findings are reassuring to both physicians and patients, because insufficient absorption due to vomiting is unlikely.

The weekly oral dose of CsA twice on 1 day was not associated with renal toxicity or infections due to immune-suppression. This can probably be attributed to the weekly administration schedule, whereas after organ transplantation CsA is administered on a continuous daily basis. We have also demonstrated, in a clinical study, that weekly administration of CsA plus docetaxel has no effect on immunological parameters (C. M. F. Kruijtzer, M. M. Malingré, J. H. Schornagel et al., unpublished data).

In conclusion, in this multicenter phase II study, promising clinical activity was seen (ORR 33%) in chemonaïve patients with advanced gastric cancer. Oral paclitaxel in combination with CsA is feasible and has a manageable toxicity profile. This combination provides an excellent basis for new studies on oral paclitaxel and CsA in combination with other oral drugs active in gastric cancer, for example capecitabine, in order to further increase efficacy. Studies that focus on optimizing the pharmaceutical formulation of oral paclitaxel to reduce gastrointestinal toxicity and improve tolerability will be initiated.


    Acknowledgements
 
The authors thank Ciska Koopman for performing the bioanalytical assays.


    Footnotes
 
+ Correspondence to: Dr J. H. M. Schellens, The Netherlands Cancer Institute, Department of Medical Oncology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel: +31-(0)205-122569, Fax: +31-(0)205-122572; E-mail: jhm{at}nki.nl Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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