The exploding tumour on breast magnetic resonance imaging: an infected skin comedo.

A 61-year-old woman with a histologically proven invasive lobular carcinoma entered a clinical trial, which involved repeat magnetic resonance imaging (MRI). The protocol of the repeated MRI described a T4 breast cancer with involvement of the skin (Fig 1). There were only 17 days between the first and second MRI and during this short time it appeared that there had been rapid disease progression. On the initial MRI, a skin comedo could be seen in the left breast close to the tumour. The patient had squeezed the skin comedo, which had become infected. The second MRI captured the infected skin comedo, which had the appearance of an extensive breast cancer with skin involvement. The patient could be mismanaged if the clinician does not correlate the clinical findings with the radiological findings.

The smooth and bumpy road of trastuzumab administration: from intravenous (IV) in a hospital to subcutaneous (SC) at home.

Trastuzumab has become standard of care in the treatment of early and metastatic HER2-positive breast cancer. Initially trastuzumab could only be administered intravenously (IV), however since a few years there is also a subcutaneous (SC) formulation. The efficacy and the safety profile of both formulations is the comparable. The administration logistics however have an impact on the patients, the health care professionals (HCPs), the hospital and the government. The preference for the patients (89%) and the HCPs (77%) is in favour of the SC formulation. The patient chair time per cycle, as defined by the time between entry and exit of infusion chair, is between 53 and 122 minutes shorter for SC administration. Also, the time actively dedicated by the HCP on preparation and administration SC, is between 17 and 50 minutes shorter per cycle. These time savings may increase the capacity of an oncological day clinic and reduce waiting lists. An additional benefit is that the use of SC formulation reduces the consumables and the waste. When the SC form was given at home instead of in the hospital the safety profile remained the same, but the satisfaction rate improved further for both the patients and the HCPs. The next and final step will be potentially to invest in teaching the patients to self-administer the medication. The home administration and the education of the patients and the HCPs will have a cost price and it will be interesting to see how the hospital financial authorities and the government will deal with this situation in the time of budgetary restrictions.

The socio-economical impact of intravenous (IV) versus subcutaneous (SC) administration of trastuzumab: future prospectives.

Trastuzumab was the first targeted therapy for HER2 positive breast cancer. It has become the standard of care for HER2 positive metastatic breast cancer since 2000 and in the adjuvant setting since 2006. Adjuvant it is given for a year and in patients with metastatic disease until progression. The standard mode of administration is intravenous. Recently a subcutaneous form has become available. A phase III study showed that there is no difference between the intravenous and subcutaneous form in terms of safety and efficacy. The patient's preference however significantly favoured the subcutaneous form. It is estimated that the use of the SC form could contribute to a cost saving between 758 and 2576 euro per annual course. For Belgium alone this could mean an estimated saving of 1.4 to 4.6 million euros per year. The potential benefit of the SC administration for healthcare facilities could be further increased when applied in a LEAN working day-care chemotherapy unit. After reviewing the existing literature we suggest to further validate the potential financial impact of SC trastuzumab compared to the traditional IV form and to introduce a scientific proposal incorporating the benefits of this formulation in a LEAN working healthcare unit.

Desmoplastic small round cell tumor (DSRCT) arising in the ovary: report of a case diagnosed at an early stage and review of the literature.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare sarcoma tumor affecting mainly young adult males. It rarely has an ovarian involvement. CASE: A 29-year-old woman presented to her gynecologist for amenorrhoea. The laboratory results demonstrated a menopausal status and the ultrasound revealed a large mass of the right ovary. The right ovary was completely removed by laparoscopy. Pathology, cytology and immunochemistry revealed a DSRCT. In January 2009 a left salpingo-oophorectomy and a right salpingectomy were performed via laparoscopy. After 35 months from diagnosis there was no clinical evidence of disease recurrence. CONCLUSION: DSRCT is a rare ovarian tumor in adolescence with a general poor outcome. Every ovarian mass regardless of age should be approached with caution.

Initial experience with conservative treatment in cancer patients with osteonecrosis of the jaw (ONJ) and predictors of outcome.

BACKGROUND: Overall survival (OS) and outcome of cancer patients with bisphosphonate-associated osteonecrosis of the jaw (ONJ) using conservative treatment (chlorhexidine 0.12% rinse, intermittent antibiotics, and careful sequestrectomy) are unknown. DESIGN: In all, 33 ONJ patients were studied for OS and ONJ outcome. RESULTS: Median duration of bisphosphonate treatment was 27 months (range 4-115) and was stopped in 25 (76%) patients. Nine (27%) cases presented with stage 1, 21 (64%) with stage 2, and 3 (9%) with stage 3 disease. During median follow-up of 23 months, 11 patients (33%) died (median survival 39 months), with no ONJ-related fatalities. Out of 30 assessable patients, 53% no longer had exposed bone, 37% had stable lesions, and 10% showed progressive necrosis. The hazard ratio for healing with doubling of bisphosphonate exposure was 0.419 [95% confidence interval (CI) 0.178-0.982; P = 0.045], stage 2 versus stage 1 disease 0.216 (95% CI 0.063-0.738; P = 0.015), and stage 3 versus stage 1 disease 0.084 (95% CI 0.008-0.913; P = 0.042). Cessation of bisphosphonate treatment did not influence outcome. CONCLUSIONS: Conservative treatment of ONJ leads to mucosal closure in 53% of patients. Doubling the exposure time to bisphosphonates and higher stages of ONJ significantly reduce ONJ healing rates.

Safety and pharmacology of paclitaxel in patients with impaired liver function: a population pharmacokinetic-pharmacodynamic study.

AIMS: To assess quantitatively the safety and pharmacology of paclitaxel in patients with moderate to severe hepatic impairment. METHODS: Solid tumour patients were enrolled into five liver function cohorts as defined by liver transaminase and total bilirubin concentrations. Paclitaxel was administered as a 3-h intravenous infusion at doses ranging from 110 to 175 mg m(-2), depending on liver impairment. Covariate and semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) population modelling was used to describe the impact of liver impairment on the pharmacology and safety of paclitaxel. RESULTS: Thirty-five patients were included in the study, and PK data were assessed for 59 treatment courses. Most patients had advanced breast cancer (n = 22). Objective responses to paclitaxel were seen in four patients (11%). Patients in higher categories of liver impairment had a significantly lower paclitaxel elimination capacity (R2 = -0.38, P = 0.05), and total bilirubin was a significant covariate to predict decreased elimination capacity with population modelling (P = 0.002). Total bilirubin was also a significant predictor of increased haematological toxicity within the integrated population PK-PD model (P < 10(-4)). Data simulations were used to calculate safe initial paclitaxel doses, which were lower than the administered doses for liver impairment cohorts III-V. CONCLUSIONS: Total bilirubin is a good predictor of paclitaxel elimination capacity and of individual susceptibility to paclitaxel-related myelosuppression in cancer patients with moderate to severe liver impairment. The proposed, adapted paclitaxel doses need validation in prospective trials.

Phase II feasibility study of concurrent radiotherapy and gemcitabine in chemonaive patients with squamous cell carcinoma of the head and neck: long-term follow up data.

BACKGROUND: Radiotherapy (RT) with concurrent chemotherapy is the current standard of care for patients with unresectable locally advanced squamous cell carcinoma of the head and neck (SCCHN). Gemcitabine (GEM) is a potent radiosensitizer and in addition has activity as an anticancer agent in SCCHN. PATIENTS AND METHODS: Twenty-six patients with locally far advanced SCCHN were enrolled in a chemoradiation feasibility study between November 1998 and September 2003. Use was made of conventionally fractionated RT and GEM 100 mg/m(2), which was given within 2 h prior to radiotherapy on a weekly basis starting on day 1 of RT. Response was assessed according to WHO criteria, toxicity according to NCI-CTC version 2. RESULTS: The patients received a median of 7 (2-8) weekly cycles of gemcitabine and a median cumulative RT dose of 70 Gy (66-84.75). Hematologic toxicity was mild, but non-hematologic toxicity was severe: grade 3-4 stomatitis occurred in 85% of patients, dermatitis in 69%, pharyngitis/esophagitis in 81% and 80% of the patients needed a feeding tube during treatment. All 22 evaluable patients responded (50% complete, 50% partial). Median follow up of the surviving patients is 46 months. Median disease-free and overall survival is 13 months and 19 months, respectively; 27% of the patients are alive without evidence of recurrence beyond 3 years. CONCLUSIONS: Conventionally fractionated RT in combination with GEM 100 mg/m(2) weekly is feasible and highly active in the treatment of locally advanced SCCHN. In particular, long-term local control rate is promising. Acute mucosal toxicities are significant but manageable. Long-term toxicity interferes with normal food intake.

Bisphosphonates and osteonecrosis of the jaw: cause and effect or a post hoc fallacy?

BACKGROUND: An increasing amount of reports are being published suggesting a relationship between the use of bisphosphonates (BPs) and the development of osteonecrosis of the jaw (ONJ). We reviewed the currently available evidence and explore the potential mechanisms of action based on the known effects of the concerned BP. DESIGN: The MEDLine, Current Contents and Science Citation Index Expanded databases were queried and the results augmented by analyzing cited references and recent congress proceedings. RESULTS: 22 papers were included detailing 225 patients, all based on retrospective chart review without control groups. The prevalence of ONJ was estimated at 1.5%. The involved BPs were pamidronate, zoledronic acid, alendronate and risedronate, all potent nitrogen-containing agents. The most common symptom was pain (81.7%), although 12.2% of cases were asymptomatic. In 69.3% of patients ONJ was preceded by a dental extraction. At the time of diagnosis, 74.5% of patients were receiving chemotherapy and in 38.2% of cases corticosteroids were administered. Although various conservative and surgical treatment modalities were reported, residual sites of ONJ persisted in 72.5% of cases. CONCLUSION: Although not enough evidence is available to prove a causal link, it seems that under specific circumstances local defenses can become overwhelmed resulting in ONJ.

Cremophor EL pharmacokinetics in a phase I study of paclitaxel (Taxol) and carboplatin in non-small cell lung cancer patients.

The purpose of our study was to investigate the pharmacokinetics of Cremophor EL following administration of escalating doses of Taxol (paclitaxel dissolved in Cremophor EL/ethanol) to non-small cell lung cancer (NSCLC) patients. Patients with NSCLC stage IIIb or IV without prior chemotherapy treatment were eligible for treatment with paclitaxel and carboplatin in a dose-finding phase I study. The starting dose of paclitaxel was 100 mg/m2 and doses were escalated with steps of 25 mg/m2, which is equal to a starting dose of Cremophor EL of 8.3 ml/m2 with dose increments of 2.1 ml/m2. Carboplatin dosages were 300, 350 or 400 mg/m2. Pharmacokinetic sampling was performed during the first and the second course, and the samples were analyzed using a validated high-performance liquid chromatographic assay. A total of 39 patients were included in this pharmacokinetic part of the study. The doses of paclitaxel were escalated up to 250 mg/m2 (20.8 ml/m2 Cremophor EL). Pharmacokinetic analyses revealed a low elimination-rate of Cremophor EL (CI=37.8-134 ml/h/m2; t 1/2=34.4-61.5 h) and a volume of distribution similar to the volume of the central blood compartment (Vss=4.96-7.85 l). In addition, a dose-independent clearance of Cremophor EL was found indicating linear kinetics. Dose adjustment using the body surface area, however, resulted in a non-linear increase in systemic exposure. The use of body surface area in calculations of Cremophor EL should therefore be re-evaluated.

Pharmacokinetics and metabolism of docetaxel administered as a 1-h intravenous infusion.

Docetaxel, a taxane antitumor agent, was administered to 24 patients by a 1-h intravenous infusion at a dose level of 100 mg/m(2) with pharmacokinetic monitoring. The plasma concentration-versus-time data were fitted with a three-compartment model. The mean area under the curve (AUC) for docetaxel was 3.1 +/- 0.9 h. mg/l and the clearance was 34.8 +/- 9.3 l/h per m(2). There was considerable interpatient pharmacokinetic variability. In 33% of the patient population, metabolites were detected in plasma samples collected 5-30 min after the end of the infusion. The cyclized oxazolidinedione metabolite M4 was most frequently present and was detected in 8 out of 24 patients with maximal concentrations between 0.022 and 0.23 mg/l. Logistic regression analysis was performed to predict M4 docetaxel metabolism. In the final model, alanine aminotransferase and alkaline phosphatase levels were the strongest predictors. No relationship was found between M4 metabolism and percentage decrease in neutrophil count in this study. Three patients with high M4 concentrations in plasma during course 1 suffered from most pronounced fluid retention (grade 2-3) after two to five courses.

A limited-sampling model for the pharmacokinetics of carboplatin administered in combination with paclitaxel.

PURPOSE: Carboplatin doses are often determined by using modified Calvert formulas. It has been observed that the area under the concentration versus time curve (AUC) for free carboplatin is lower than expected when modified formulas are used for carboplatin/paclitaxel chemotherapy combination regimens. By using limited-sampling models, the carboplatin AUC actually reached can easily be verified, and the dose adjusted accordingly. METHODS: In this report, we describe the development and validation of a limited-sampling model for carboplatin from 77 pharmacokinetic curves, when carboplatin is used in combination with paclitaxel. RESULTS: The following single-point model was selected as optimal: AUC carboplatin (min mg(-1) ml(-1)) = 418. c(2.5 h)(mg/ml) + 0.43 (min mg(-1) ml(-1)), where c(2.5 h) is the concentration (mg/ml) of carboplatin 2.5 h after the start of a 30-min infusion. This model proved to be unbiased (mean prediction error = 3.4 +/- 1.6%) and precise (root mean square error = 10.1 +/- 1.5%). CONCLUSIONS: The proposed model can be very useful for ongoing and future carboplatin/paclitaxel studies aimed to optimise and individualize treatment.

Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients.

The non-linear plasma pharmacokinetics of paclitaxel in patients has been well established, however, the exact underlying mechanism remains to be elucidated. We have previously shown that the non-linear plasma pharmacokinetics of paclitaxel in mice results from Cremophor EL. To investigate whether Cremophor EL also plays a role in the non-linear pharmacokinetics of paclitaxel in patients, we have established its pharmacokinetics in patients receiving paclitaxel by 3-, 24- or 96-h intravenous infusion. The pharmacokinetics of Cremophor EL itself was non-linear as the clearance (Cl) in the 3-h schedules was significantly lower than when using the longer 24- or 96-h infusions (Cl175-3 h = 42.8+/-24.9 ml h(-1) m(-2); CI175-24 h = 79.7+/-24.3; P = 0.035 and Cl135-3 h = 44.1+/-21.8 ml h(-1) m(-1); Cl140-96 h = 211.8+/-32.0; P < 0.001). Consequently, the maximum plasma levels were much higher (0.62%) in the 3-h infusions than when using longer infusion durations. By using an in vitro equilibrium assay and determination in plasma ultrafiltrate we have established that the fraction of unbound paclitaxel in plasma is inversely related with the Cremophor EL level. Despite its relatively low molecular weight, no Cremophor EL was found in the ultrafiltrate fraction. Our results strongly suggest that entrapment of paclitaxel in plasma by Cremophor EL, probably by inclusion in micelles, is the cause of the apparent nonlinear plasma pharmacokinetics of paclitaxel. This mechanism of a (pseudo-)non-linearity contrasts previous postulations about saturable distribution and elimination kinetics and means that we must re-evaluate previous assumptions on pharmacokinetics-pharmacodynamics relationships.

A single 24-hour plasma sample does not predict the carboplatin AUC from carboplatin-paclitaxel combinations or from a high-dose carboplatin-thiotepa-cyclophosphamide regimen.

PURPOSE: It has been observed that the area under the free carboplatin concentration in plasma ultrafiltrate versus time curve (AUC) is related to toxicity and tumour response. For this reason, it can be important to measure the carboplatin AUC and subsequently adjust the dose to achieve a predefined target AUC. The use of limited sampling strategies enables relatively simple measurement and calculation of actual carboplatin AUCs. METHODS: We studied the performance of a limited sampling model, based on a single 24-h sample (the Ghazal-Aswad model). in 52 patients who received carboplatin in two different chemotherapy regimens (a carboplatin-paclitaxel combination and a high-dose carboplatin-thiotepa-cyclophosphamide combination). RESULTS: The measured mean AUC in our population was 4.1 min x mg/ml (median 3.9, range 1.9 6.3, SD 1.0 min x mg/ml). With the limited sampling model, the predicted mean AUC was 4.4 min x mg/ml (median 4.2, range 2.4-8.4, SD 1.2 min x mg/ml). Statistical analysis revealed that the model was slightly biased (MPE%, 6.5%), but imprecise (RMSE%, 20.6%) in our study population. CONCLUSION: Although easy and attractive to use, the Ghazal-Aswad formula is not precise enough to predict the carboplatin AUC, and needs to be evaluated prospectively in other patient populations.

Pharmacologic study of 3-hour 135 mg M-2 paclitaxel in platinum pretreated patients with advanced ovarian cancer.

Paclitaxel (Taxol(R)) is an active agent in platinum-refractory ovarian cancer. Since the available pharmacokinetic data of 135 mg m-2 paclitaxel administered by 3-h infusion are scarce and fragmented, we now describe a comprehensive pharmacologic study in a group of 13 patients who were pretreated with platinum for advanced ovarian cancer. The mean paclitaxel AUC was 10.3+/-2.4 h micromol l-1 (range 6.8-13.9 h micromol l-1). Quantification of the two major paclitaxel metabolites, 6alpha-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel yielded AUCs of 0.44+/-0.30 h micromol l-1 and 0.31+/-0.20 h micromol l-1, respectively. The AUC of 3'-p-hydroxypaclitaxel was significantly different from that of patients with an altered hepatic function. The administration of 135 mg m-2 single-paclitaxel was safe, and the toxicities observed at higher doses in earlier studies were absent in this study. This is important, because the schedule and paclitaxel dose of 135 mg m-2 given by a 3-h infusion is expected to be used more frequently in combination with other cytotoxic agents with the aim of improving efficacy.

Influence of Cremophor EL on the quantification of paclitaxel in plasma using high-performance liquid chromatography with solid-phase extraction as sample pretreatment.

For the quantitative determination of paclitaxel in human plasma reversed-phase high-performance liquid chromatographic (HPLC) methods with solid-phase extraction (SPE) as sample pretreatment procedure are frequently used. Recovery problems arose during the quantification of paclitaxel in plasma samples of patients. The major problems were a large batch-to-batch difference in performance of the SPE columns and the effects of the pharmaceutical vehicle Cremophor EL on the performance of the SPE. Cremophor EL concentrations exceeding 1.0% (v/v) had a great impact on the absolute recovery of paclitaxel from human plasma with the SPE procedure. The recoveries decreased approximately 10 to 40% depending on the quality of the batch SPE columns. The problems are avoided by using 2'-methylpaclitaxel as the internal standard. This study points out the importance of including the effects of a pharmaceutical vehicle, like Cremophor EL, in the validation programme of a bioanalytical assay and the use of an internal standard in HPLC paclitaxel assays preceded by SPE as sample pretreatment procedure.

Carboplatin dosage formulae can generate inaccurate predictions of Carboplatin exposure in carboplatin/paclitaxel combination regimens.

Carboplatin is a frequently used antitumour agent recommended to be administered according to the Calvert formula: dose = AUC x (GFR+25), where GFR is the glomerular filtration rate as measured by (51)Cr-EDTA clearance and AUC is the targeted area under the carboplatin concentration versus time curve. In several modified Calvert formulae, the GFR is estimated on the basis of serum creatinine levels. We compared AUCs of carboplatin that were predicted by modified Calvert formulae with actual measured AUCs in 75 courses in patients with non-small cell lung cancer or ovarian cancer who were treated with the combination of carboplatin-paclitaxel. Predictions were made using two modified Calvert formulae, in which the GFR was calculated by serum creatinine level-based equations, according to Jelliffe (Eq. 1) and Cockroft-Gault (Eq. 2). We also studied the performance of a formula for the clearance of carboplatin, as proposed by Chatelut (Eq. 3). The actual measured mean AUC was 4.6 mg/ml.min (range 1.9 to 10.4 mg/ml.min, SD 1.7). Equation 1 overestimated the AUC by 32.9% with an imprecision of 43.0%, and equation 2 overestimated the AUC by 27.6% with an imprecision of 33.4%. For equation 3, an AUC overestimation of only 10.2%, but with an imprecision of 25.3%, was observed. In conclusion, all three equations overestimated the carboplatin AUCs and had poor precisions. We concluded that the real carboplatin AUCs were lower than calculated, using the three tested formulae. This may have important consequences for ongoing and future phase II and III studies with carboplatin-paclitaxel combinations, utilising these formulae to calculate the carboplatin dose. Thus far, the original Calvert dosage formula remains the 'golden standard'.

Hepatic metabolism of paclitaxel and its impact in patients with altered hepatic function.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been demonstrated to be an active anticancer agent, including in platinum-refractory ovarian cancer. The pharmacokinetics of paclitaxel have been extensively described. It displays nonlinear pharmacokinetics in humans, especially when administered in shorter infusion times and at higher doses. Several relationships have been established between pharmacokinetics and pharmacodynamics. In both animal and human studies, hepatic metabolism and biliary excretion have been identified as the main elimination pathways of paclitaxel. It thus can be expected that hepatic dysfunction will have a major impact on the pharmacokinetics of paclitaxel and its main metabolite 6alpha-hydroxypaclitaxel and, thus, on pharmacodynamic outcome (toxicities and responses). Because patients with an altered hepatic function were excluded from most phase I and II studies conducted thus far, little is known about the pharmacokinetics and pharmacodynamics in this group of patients. This report summarizes paclitaxel's metabolism and clinical observations concerning its pharmacokinetics and pharmacodynamics in patients with altered hepatic function. It has been shown that hepatic impairment has a great influence on the systemic exposure of paclitaxel and metabolites with pharmacodynamic consequences. A decrease of biliary elimination is probably the major mechanistic effect that influences paclitaxel metabolism and elimination. Specific dosing guidelines in the treatment of patients with altered hepatic function are required.

Phase I and pharmacologic study of the combination paclitaxel and carboplatin as first-line chemotherapy in stage III and IV ovarian cancer.

PURPOSE: To determine the maximum-tolerated dose for the combination paclitaxel and carboplatin administered every 4 weeks and to gain more insight into the pharmacokinetics and pharmacodynamics of this combination in previously untreated ovarian cancer patients. PATIENTS AND METHODS: Thirty-five chemotherapy-naive patients with suboptimally debulked stage III (tumor masses > 3 cm) and stage IV ovarian cancer were entered onto this phase I trial in which paclitaxel was administered as a 3-hour intravenous (IV) infusion at dosages of 125 to 225 mg/m2 immediately followed by carboplatin over 30 minutes at dosages of 300 to 600 mg/m2. A total of six courses was planned, followed by a second-look laparoscopy/laparotomy. Patients with a response and/or minimal residual disease at second-look laparoscopy received three additional courses. Twenty-six patients participated in the pharmacokinetic part of the study. RESULTS: The most important hematologic toxicity encountered was neutropenia. Neutropenia was more pronounced for the higher dose levels (DLs) and was cumulative. Thrombocytopenia was mild in the first eight DLs, but increased during the treatment courses. Nonhematologic toxicities consisted mainly of vomiting, neuropathy, fatigue, rash, pruritus, myalgia, and arthralgia. Dose-limiting toxicities (DLTs) in this trial were neutropenic fever, thrombocytopenia that required platelet transfusions, and cumulative neuropathy. Of 33 patients assessable for response, 26 major responders (78%, 20 complete response [CR] and six partial response [PR]) were documented. The maximal concentration (Cmax) of paclitaxel and the area under the concentration-time curve (AUC) were not different from the historical data for paclitaxel as a single agent. Retrospective analysis using a modified Calvert formula showed that the measured carboplatin AUCs in plasma ultrafiltrate (pUF) were 30% +/- 3.4% less than the calculated carboplatin AUC. Neutropenia was more pronounced than could be expected on the basis of the historical times above a threshold concentration greater than 0.1 mumol/L (T > or = 0.1 mumol/L) or 0.05 mumol/L (T > or = 0.05 mumol/L), and thrombocytopenia was less than could be expected from historical sigmoidal Emax models. CONCLUSION: The combination of paclitaxel 200 mg/ m2 and carboplatin 550 mg/m2 every 4 weeks is a well-tolerated treatment modality. The paclitaxel-carboplatin combination is highly active in stage III (bulky) and stage IV ovarian cancer. No indications for a pharmacokinetic drug-drug interaction between carboplatin and paclitaxel were found.