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Importance: Primary analysis of the TRAIN-2 study showed high pathologic complete response rates after neoadjuvant chemotherapy with or without anthracyclines plus dual ERBB2 (formerly HER2) blockade., Objective: To evaluate 3-year event-free survival (EFS) and overall survival (OS) of an anthracycline-free and anthracycline-containing regimen with dual ERBB2 blockade in patients with stage II and III ERBB2-positive breast cancer., Design, Setting, and Participants: A total of 438 patients with stage II and III ERBB2-positive breast cancer were enrolled in this randomized, clinical, open-label phase 3 trial across 37 hospitals in the Netherlands from December 9, 2013, until January 14, 2016. Follow-up analyses were performed after a median follow-up of 48.8 months (interquartile range, 44.1-55.2 months). Analysis was performed on an intention-to-treat basis., Interventions: Participants were randomly assigned on a 1:1 basis, stratified by age, tumor stage, nodal stage, and estrogen receptor status, to receive 3 cycles of fluorouracil (500 mg/m2), epirubicin (90 mg/m2), and cyclophosphamide (500 mg/m2), followed by 6 cycles of paclitaxel and carboplatin or 9 cycles of paclitaxel (80 mg/m2 days 1 and 8) and carboplatin (area under the concentration-time curve, 6 mg/mL/min). Both groups received trastuzumab (6 mg/kg; loading dose 8 mg/kg) and pertuzumab (420 mg intravenously; loading dose 840 mg) every 3 weeks., Main Outcomes and Measures: Three-year EFS, OS, and safety., Results: A total of 438 women were randomized, with 219 per group (anthracycline group, median age, 49 years [interquartile range, 43-55 years]; and nonanthracycline group, median age, 48 years [interquartile range, 43-56 years]). A total of 23 EFS events (10.5%) occurred in the anthracycline group and 21 EFS events (9.6%) occurred in the nonanthracycline group (hazard ratio, 0.90; 95% CI, 0.50-1.63; favoring nonanthracyclines). Three-year EFS estimates were 92.7% (95% CI, 89.3%-96.2%) in the anthracycline group and 93.6% (95% CI, 90.4%-96.9%) in the nonanthracycline group and 3-year OS estimates were 97.7% (95% CI, 95.7%-99.7%) in the anthracycline group and 98.2% (95% CI, 96.4%-100%) in the nonanthracycline group. The results were irrespective of hormone receptor and nodal status. A decline in left ventricular ejection fraction of 10% or more from baseline to less than 50% was more common in patients who received anthracyclines than those who did not (17 of 220 [7.7%] vs 7 of 218 [3.2%]; P = .04). Two patients treated with anthracyclines developed acute leukemia., Conclusions and Relevance: This follow-up analysis of the TRAIN-2 study shows similar 3-year EFS and OS estimates with or without anthracyclines in patients with stage II and III ERBB2-positive breast cancer. Anthracycline use is associated with increased risk of febrile neutropenia, cardiotoxic effects, and secondary malignant neoplasms., Trial Registration: ClinicalTrials.gov Identifier: NCT01996267.

Background: The optimal chemotherapy backbone for dual HER2 blockade in the neoadjuvant setting for early breast cancer is unknown. We investigated whether the addition of anthracyclines would improve pathological complete response compared with a carboplatin-taxane regimen, when given in combination with the HER2-targeted agents trastuzumab and pertuzumab., Methods: The TRAIN-2 study is an open-label, randomised, controlled, phase 3 trial being done in 37 hospitals in the Netherlands. We recruited patients aged 18 years or older with previously untreated, histologically confirmed stage II-III HER2-positive breast cancer. Patients were randomly allocated using central randomisation software (1:1 ratio) with minimisation without a random component, stratified by tumour stage, nodal stage, oestrogen receptor status, and age, to receive 5-fluorouracil (500 mg/m 2 ), epirubicin (90 mg/m 2 ), and cyclophosphamide (500 mg/m 2 ) every 3 weeks for three cycles followed by paclitaxel (80 mg/m 2 on days 1 and 8) and carboplatin (area under the concentration-time curve [AUC] 6 mg/mL per min on day 1 or optionally, as per hospital preference, AUC 3 mg/mL per min on days 1 and 8) every 3 weeks for six cycles, or to receive nine cycles of paclitaxel and carboplatin at the same dose and schedule as in the anthracycline group. Patients in both study groups received trastuzumab (6 mg/kg, loading dose 8 mg/kg) and pertuzumab (420 mg, loading dose 840 mg) concurrently with all chemotherapy cycles. The primary endpoint was the proportion of patients who achieved a pathological complete response in breast and axilla (ypT0/is ypN0) in the intention-to-treat population. Safety was analysed in patients who received at least one treatment cycle according to actual treatment received. This trial is registered with ClinicalTrials.gov, number NCT01996267, and follow-up for long-term outcome is ongoing., Findings: Between Dec 9, 2013, and Jan 14, 2016, 438 patients were enrolled and randomly assigned to the two treatment groups (219 patients to each group), of whom 418 were evaluable for the primary endpoint (212 in the anthracycline group and 206 in the non-anthracycline group). The median follow-up for all patients was 19 months (IQR 16-23 months). A pathological complete response was recorded in 141 (67%, 95% CI 60-73) of 212 patients in the anthracycline group and in 140 (68%, 61-74) of 206 in the non-anthracycline group (p=0·95). One patient randomly allocated to the non-anthracycline group did receive anthracyclines and was thus included in the anthracycline group for safety analyses; therefore, for the safety analyses there were 220 patients in the anthracycline group and 218 in the non-anthracycline group. Serious adverse events were reported in 61 (28%) of 220 patients in the anthracycline group and in 49 (22%) of 218 in the non-anthracycline group. The most common adverse events of any cause were grade 3 or worse neutropenia (in 131 [60%] of 220 patients in the anthracycline group vs 118 [54%] of 218 in the non-anthracycline group), grade 3 or worse diarrhoea (26 [12%] vs 37 [18%]), and grade 2 or worse peripheral neuropathy (66 [30%] vs 68 [31%]), with no substantial differences between the groups. Grade 3 or worse febrile neutropenia was more common in the anthracycline group than in the non-anthracycline group (23 [10%] vs three [1%], p<0·0001). Symptomatic left ventricular systolic dysfunction was rare in both groups (two [1%] of 220 vs 0 of 218). One patient in the anthracycline group died because of a pulmonary embolism, which was possibly treatment related., Interpretation: In view of the high proportion of pathological complete responses recorded in both groups and the fact that febrile neutropenia was more frequent in the anthracycline group, omitting anthracyclines from neoadjuvant treatment regimens might be a preferred approach in the presence of dual HER2 blockade in patients with early HER2-positive breast cancer. Long-term follow-up is required to confirm these results., Funding: Roche Netherlands., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: The primary outcome of the current study is, whether there is a protective effect of prior chemotherapy or of prior granulocyte colony-stimulating factor (G-CSF) on the next cycle blood cell counts., Methods: Hematologic toxicity was evaluated, based on a randomized phase III study in breast cancer patients (n = 167) with >20% risk of febrile neutropenia. The primary endpoint was the nadir blood cell counts for patients treated with G-CSF given during all 6 chemotherapy cycles or limited to the first 2 chemotherapy cycles only., Results: For the present analyses, 47 patients were eligible. In the G-CSF 1-6 arm, the median white blood cell count (WBC) and absolute neutrophil count (ANC) nadir slowly decreased from 10.8 × 109/L in cycle 1 to 7.5 × 109/L in cycle 6 and from 7.1 × 109/L to 5.5 × 109/L, respectively. The median WBC nadir in the G-CSF 1-2 arm decreased from 1.2 × 109/L in cycle 3 to 0.9 × 109/L in cycle 6 and the ANC nadir showed a grade 4 neutropenia of 0.1 × 109/L in cycles 3-6. All patients had ANC recovery to normal levels (≥1.5 × 109/L) without delay on day 1 of the next cycle., Conclusion: We conclude that there is no protective effect of prior G-CSF or prior chemotherapy use on nadir blood cell counts in subsequent cycles., (The Author(s). Published by S. Karger AG, Basel.)

Background: The aim of this study was to evaluate the accuracy of clinical imaging of the primary breast tumour post-neoadjuvant chemotherapy (NAC) related to the post-neoadjuvant histological tumour size (gold standard) and whether this varies with breast cancer subtype. In this study, results of both magnetic resonance imaging (MRI) and ultrasound (US) were reported., Methods: Patients with invasive breast cancer were enrolled in the INTENS study between 2006 and 2009. We included 182 patients, of whom data were available for post-NAC MRI (n=155), US (n=123), and histopathological tumour size., Results: MRI estimated residual tumour size with <10-mm discordance in 54% of patients, overestimated size in 28% and underestimated size in 18% of patients. With US, this was 63%, 20% and 17%, respectively. The negative predictive value in hormone receptor-positive tumours for both MRI and US was low, 26% and 33%, respectively. The median deviation in clinical tumour size as percentage of pathological tumour was 63% (P25=26, P75=100) and 49% (P25=22, P75=100) for MRI and US, respectively (P=0.06)., Conclusions: In this study, US was at least as good as breast MRI in providing information on residual tumour size post-neoadjuvant chemotherapy. However, both modalities suffered from a substantial percentage of over- and underestimation of tumour size and in addition both showed a low negative predictive value of pathologic complete remission (Gov nr: NCT00314977)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The role of zoledronic acid (ZA) when added to the neoadjuvant treatment of breast cancer (BC) in enhancing the clinical and pathological response of tumors is unclear. The effect of ZA on the antitumor effect of neoadjuvant chemotherapy has not prospectively been studied before., Patients and Methods: NEOZOTAC is a national, multicenter, randomized study comparing the efficacy of TAC (docetaxel, adriamycin and cyclophosphamide i.v.) followed by granulocyte colony-stimulating factor on day 2 with or without ZA 4 mg i.v. q 3 weeks inpatients withstage II/III, HER2-negative BC. We present data on the pathological complete response (pCR in breast and axilla), on clinical response using MRI, and toxicity. Post hoc subgroup analyses were undertaken to address the predictive value of menopausal status., Results: Addition of ZA to chemotherapy did not improve pCR rates (13.2% for TAC+ZA versus 13.3% for TAC). Postmenopausal women (N = 96) had a numerical benefit from ZA treatment (pCR 14.0% for TAC+ZA versus 8.7% for TAC, P = 0.42). Clinical objective response did not differ between treatment arms (72.9% versus 73.7%). There was no difference in grade III/IV toxicity between treatment arms., Conclusions: Addition of ZA to neoadjuvant chemotherapy did not improve pathological or clinical response to chemotherapy. Further investigations are warranted in postmenopausal women with BC, since this subgroup might benefit from ZA treatment.

Aims: To report our clinical experience of panitumumab monotherapy as a second-line treatment for patients with metastatic colorectal cancer (mCRC)., Materials and Methods: This retrospective, descriptive study included a series of consecutive patients receiving panitumumab monotherapy (6 mg/kg 2 weekly) at a single centre in the Netherlands between June 2009 and November 2011. All patients had wild-type KRAS tumours, had progressed during first-line fluoropyrimidine-based therapy and were not candidates for, or refused, standard second-line therapy (usually irinotecan in the Netherlands). Prophylactic medication was given for epidermal growth factor receptor inhibitor-associated skin toxicities., Results: Thirty-one patients were treated during this period. The most commonly administered first-line mCRC regimen was capecitabine/oxaliplatin/bevacizumab (18/31 patients; 58.1%). Patients received a mean of 7.9 (range 1-18) panitumumab cycles. The median progression-free survival was 3.4 (95% confidence interval 2.4, 4.4) months. The median overall survival estimates were 11.4 (95% confidence interval 1.2, 21.6) months from the initiation of panitumumab monotherapy. Ten patients experienced partial responses according to Response Evaluation Criteria In Solid Tumors (RECIST; objective response rate: 32.3%); disease was controlled (objective response or stable disease) in 15 patients (48.4%). Carcinoembryonic antigen (CEA) responses (two consecutive ≥10% decreases from baseline) occurred in 11/29 patients (37.9%); all of whom had >50% decreases in CEA levels. All patients with an objective response at week 12 had CEA reductions at weeks 6 and 12. The only adverse events were grade 1/2 skin toxicities (61.3%) and gastrointestinal complaints (6.5%); three other patients (9.7%) experienced both skin and gastrointestinal complaints., Conclusion: Panitumumab monotherapy seems to be a safe and active second-line treatment for patients with wild-type KRAS mCRC, with activity in line with that seen for irinotecan monotherapy, but with less toxicity. CEA may provide a useful early indicator of response to panitumumab., (Copyright © 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Purpose: Guidelines advise primary granulocyte colony-stimulating factor (G-CSF) prophylaxis during chemotherapy if risk of febrile neutropenia (FN) is more than 20%, but this comes with considerable costs. We investigated the incremental costs and effects between two treatment strategies of primary pegfilgrastim prophylaxis., Methods: Our economic evaluation used a health care perspective and was based on a randomized study in patients with breast cancer with increased risk of FN, comparing primary G-CSF prophylaxis throughout all chemotherapy cycles (G-CSF 1-6 cycles) with prophylaxis during the first two cycles only (G-CSF 1-2 cycles). Primary outcome was cost effectiveness expressed as costs per patient with episodes of FN prevented., Results: The incidence of FN increased from 10% in the G-CSF 1 to 6 cycles study arm (eight of 84 patients) to 36% in the G-CSF 1 to 2 cycles study arm (30 of 83 patients), whereas the mean total costs decreased from € 20,658 (95% CI, € 20,049 to € 21,247) to € 17,168 (95% CI € 16,239 to € 18,029) per patient, respectively. Chemotherapy and G-CSF determined 80% of the total costs. As expected, FN-related costs were higher in the G-CSF 1 to 2 cycles arm. The incremental cost effectiveness ratio for the G-CSF 1 to 6 cycles arm compared with the G-CSF 1 to 2 cycles arm was € 13,112 per patient with episodes of FN prevented., Conclusion: We conclude that G-CSF prophylaxis throughout all chemotherapy cycles is more effective, but more costly, compared with prophylaxis limited to the first two cycles. Whether G-CSF prophylaxis throughout all chemotherapy cycles is considered cost effective depends on the willingness to pay per patient with episodes of FN prevented.

Background: Preclinical studies comparing paclitaxel formulated with polyethoxylated castor oil with the sonicated formulation of liposome-entrapped paclitaxel (LEP) have demonstrated that LEP was associated with reduced toxicity while maintaining similar efficacy. Preliminary studies on the pharmacokinetics in patients support earlier preclinical data, which suggested that the LEP Easy-to-Use (LEP-ETU) formulation and paclitaxel formulated with castor oil may have comparable pharmacokinetic properties., Objectives: Our objectives were: (1) to determine bioequivalence of paclitaxel pharmaceutically formulated as LEP-ETU (test) and paclitaxel formulated with castor oil (reference); and (2) to assess the tolerability of LEP-ETU following intravenous administration., Methods: Patients with advanced cancer were studied in a randomized, 2-period crossover bioequivalence study. Patients received paclitaxel 175 mg/m(2) administered as an intravenous infusion over 180 minutes, either as a single-treatment cycle of the test formulation followed by a single-treatment cycle of the reference formulation, or vice versa., Results: Thirty-two of 58 patients were evaluable and were included in the analysis for bioequivalence. Mean total paclitaxel Cmax values for the test and reference formulations were 4955.0 and 5108.8 ng/mL, respectively. Corresponding AUC0-∞ values were 15,853.8 and 18,550.8 ng·h/mL, respectively. Treatment ratios of the geometric means were 97% (90% CI, 91%-103%) for Cmax and 84% (90% CI, 80%-90%) for AUC0-∞. These results met the required 80% to 125% bioequivalence criteria. The most frequently reported adverse events after LEP-ETU administration were fatigue, alopecia, and myalgia., Conclusion: At the studied dose regimen, LEP-ETU showed bioequivalence with paclitaxel formulated with polyethoxylated castor oil., (© 2013 Elsevier HS Journals, Inc. All rights reserved.)

Purpose: Early breast cancer is commonly treated with anthracyclines and taxanes. However, combining these drugs increases the risk of myelotoxicity and may require granulocyte colony-stimulating factor (G-CSF) support. The highest incidence of febrile neutropenia (FN) and largest benefit of G-CSF during the first cycles of chemotherapy lead to questions about the effectiveness of continued use of G-CSF throughout later cycles of chemotherapy., Patients and Methods: In a multicenter study, patients with breast cancer who were considered fit enough to receive 3-weekly polychemotherapy, but also had > 20% risk for FN, were randomly assigned to primary G-CSF prophylaxis during the first two chemotherapy cycles only (experimental arm) or to primary G-CSF prophylaxis throughout all chemotherapy cycles (standard arm). The noninferiority hypothesis was that the incidence of FN would be maximally 7.5% higher in the experimental compared with the standard arm., Results: After inclusion of 167 eligible patients, the independent data monitoring committee advised premature study closure. Of 84 patients randomly assigned to G-CSF throughout all chemotherapy cycles, eight (10%) experienced an episode of FN. In contrast, of 83 patients randomly assigned to G-CSF during the first two cycles only, 30 (36%) had an FN episode (95% CI, 0.13 to 0.54), with a peak incidence of 24% in the third cycle (ie, first cycle without G-CSF prophylaxis)., Conclusion: In patients with early breast cancer at high risk for FN, continued use of primary G-CSF prophylaxis during all chemotherapy cycles is of clinical relevance and thus cannot be abandoned.

Background: This study was designed to determine whether delivering neo-adjuvant chemotherapy at a higher dose in a shorter period of time improves outcome of breast cancer patients., Patients and Methods: Women with newly diagnosed breast cancer were randomly assigned to neoadjuvant chemotherapy of four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC 60/600 - T 100 mg/m(2)) or six cycles of TAC (75/50/500 mg/m(2)) every 3 weeks. The primary endpoint was the pathologic complete response (pCR) rate, defined as no invasive tumour present in the breast., Results: In total, 201 patients were included. Baseline characteristics were well balanced. AC-T resulted in pCR in 21% and TAC in 16% of patients (odds ratio 1.44 (95% confidence interval (CI) 0.67-3.10). AC-T without primary granulocyte-colony stimulating factor (G-CSF) prophylaxis was associated with more febrile neutropenia compared to TAC with primary G-CSF prophylaxis (23% versus 9%), and with more grade 3/4 sensory neuropathy (5% versus 0%)., Conclusions: With a higher cumulative dose for the concurrent arm, no differences were observed between the two treatment arms with respect to pCR rate. The differential toxicity profile could partly be explained by different use of primary G-CSF prophylaxis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Results of existing studies are inconclusive concerning the relationship between chemotherapy and subjective cognitive functioning (SCF). The aim of this study was to evaluate SCF of breast cancer (BC) patients and to find predictors of impaired SCF. Both satisfaction and frequency of complaints about SCF were measured., Methods: BC patients who were about to receive chemotherapy (N = 74) and patients with a benign breast disease (BBD) (N = 63) participated. Before chemotherapy started (Time 1) and 3 months after ending chemotherapy (and at comparable moments for the BBD group) (Time 2), women completed validated questionnaires concerning the frequency of complaints and satisfaction with SCF, fatigue, perceived stress, anxiety, and depressive symptoms., Results: No differences were found between the BBD and BC patients concerning the frequency of complaints about SCF across time. Satisfaction with SCF decreased across time in BC patients but remained stable across time in BBD patients (p < 0.001; p = 0.003 after controlling for state anxiety and perceived stress). Correlation coefficients between the satisfaction and the frequency of complaints about SCF ranged between -0.26 and -0.49. Depressive symptoms and satisfaction with SCF (Time 1) predicted the frequency of complaints about SCF (Time 2). Diagnosis, frequency of complaints about SCF, and state anxiety (Time 1) predicted satisfaction with SCF (Time 2)., Conclusions: BC patients do not differ in the frequency of complaints about SCF compared with BBD patients, but their satisfaction with SCF decreased after treatment. Psychological factors predicted the frequency of complaints about SCF. Psychological factors and diagnosis predicted satisfaction with SCF., (Copyright © 2012 John Wiley & Sons, Ltd.)

Introduction: The use of neo-adjuvant chemotherapy has increased in the treatment of loco-regionally advanced primarily operable breast cancer. As a result of improved neo-adjuvant chemotherapy regimes the number of clinical as well as radiological responses have increased. In case of a complete response it is difficult to identify residual disease and to perform an adequate radical breast-conserving surgery. Therefore localization of the original tumour bed is mandatory. In this study we propose a novel technique with a seed containing radioactive 125 Iodine ((125)I). The (125)I has a half-time of 60 days and is therefore still recognisable with a gamma probe after admittance of several courses of neo-adjuvant chemotherapy., Material and Methods: In the period from July 2003 and November 2008, 47 consecutive patients had successful (125)I seed localization of a breast tumour before starting neo-adjuvant chemotherapy., Results: The overall clinical response rate to neo-adjuvant chemotherapy was 100%. Complete clinical response occurred in 34 patients, partial clinical response occurred in 13 patients. Complete radiological response occurred in 18 patients, partial radiological response occurred in 29 patients. The initial surgical treatment consisted of breast-conserving surgery for all 47 patients, after a mean of 170 days (range: 70-220) after (125)I seed localization. In 19 patients pathology revealed no residual tumour, 23 patients showed a partial response. Only 3 lumpectomies were irradical., Conclusion: This study has shown that (125)I seed localization is a novel and highly successful technique in localizing the tumour bed in patients who receive neo-adjuvant chemotherapy for breast cancer leading to a high percentage of radical margins in case of breast-conserving surgery., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

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.

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.

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.

Intoplicine, an antitumor drug which interacts with both topoisomerase enzymes I and II, has demonstrated a broad spectrum of activity in preclinical studies. This indicates further clinical evaluation. In the present phase I study, with the primary objective to determine the maximum tolerated dose, intoplicine was administered by a 24 h continuous infusion every 21 days to 32 patients with solid malignant tumors. The patients received 12-640 mg/m2 by a central venous catheter. Liver toxicity was dose limiting. One patient died in a hepatic coma after the first course (dose 640 mg/m2), which was associated with intoplicine treatment. Other side effects were sporadic and mild. Myelotoxicity was virtually absent. Twenty-two patients had stable disease for four to six courses of treatment. The plasma concentration-time curves were compatible with standard linear pharmacokinetic models, with a protracted terminal half-life (mean 115 h). Although one sudden death occurred probably due to intoplicine toxicity, we nevertheless feel that research with intoplicine should continue, mainly because of its preclinical activity and its unique mechanism of action. The recommended dose for phase II studies with intoplicine administered as a 24 h infusion is 384 mg/m2. Liver toxicity, also seen in studies employing other dosages and infusion durations, should be investigated extensively in further clinical studies.

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., (Copyright 1998 The Italian Pharmacological Society)

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'.

Dosages of anticancer agents are usually calculated from a uniform standard-the body surface area (BSA). Although the BSA is proportionate to many physiological functions, it is however only partially related to the overall drug clearance. Consequently, a wide variability in drug exposure and drug concentrations can be found between patients, by which some experience little toxicity, while others may show severe toxic symptoms. It seems clear that monitoring of plasma drug concentrations can be a useful tool to further optimize current cancer chemotherapy. The problem that pharmacokinetic parameters are usually generated from concentration-time profiles obtained after multiple venepunctures can be reduced by applying limited sampling models (LSM). Other tailor-made dosing strategies include the Calvert formula for carboplatin dosing and strategies based on the characteristics of the individual patient. It can be concluded that the determination of pharmacokinetic parameters and adjustment of the drug dose in each patient to a predefined 'target' value with an optimal therapeutic outcome, could contribute substantially to improvement of current chemotherapeutic treatment.

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.

Background: Recently the feasibility of combining carboplatin with paclitaxel has been demonstrated in dose-finding studies. Maximum tolerated doses were 550 mg/m2 and 200 mg/m2 (three hours), respectively. We report now a phase II study in ovarian cancer patients., Patients and Methods: Twenty-one chemo-naïve patients with optimally (n = 6) or suboptimally (n = 15) debulked stage III or IV ovarian cancer were treated every three weeks for six courses with paclitaxel (200 mg/m2) as a three-hour infusion, immediately followed by carboplatin (550 mg/m2) as a 30-minute infusion., Results: Uncomplicated neutropenia was the principal toxicity, with mild anemia occurring regularly. As observed in the preceding phase I study, a relative lack of thrombocytopenia, generally grade III was found. Other toxicities consisted of mild neurotoxicity, nausea and vomiting, alopecia, myalgia, and bone pain. All suboptimally debulked patients responded to therapy. Overall, 12 patients underwent second-look laparoscopy, which revealed a pathologically confirmed complete remission in six. The median follow-up interval at the time of analysis was 14 months. Twelve patients are currently free of progression, at 8+ to 19 +/- months after the start of therapy., Conclusion: The carboplatin/paclitaxel combination appears to be a well-tolerated regimen, yielding high response rates. This combination has now gone forward to be evaluated in prospective randomized trials versus the cisplatin/paclitaxel combination.

The clinical pharmacology of carboplatin (C) administered with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (P) was investigated in two phase I studies undertaken in 83 previously untreated patients with either non-small cell lung cancer or ovarian cancer. Carboplatin was administered over 30 minutes and paclitaxel over 3 hours. Both agents were given every 4 weeks. Non-small cell lung cancer patients were randomized to two administration sequences, either carboplatin followed by paclitaxel (C-->P) or the reverse (P-->C). Each patient received the alternate sequence during the second and subsequent courses. Ovarian cancer patients uniformly received paclitaxel before carboplatin. Platinum concentrations in plasma ultrafiltrate were measured via flameless atomic absorption spectrometry, and 122 concentration-time curves were obtained. For non-small cell lung cancer patients, the mean area under the concentration-time curve (AUC) per 300 mg/m2 carboplatin was 3.52 mg/mL x min (range, 1.94 to 5.83) for the sequence C-->P and 3.62 mg/mL x min (range, 1.91 to 5.01) for the sequence P-->C. No sequence-dependent effect was observed (P > .5). For ovarian cancer patients, the mean AUC per 300 mg/m2 carboplatin was 3.83 mg/mL x min (range, 2.72 to 6.10), showing no difference when compared with data derived from non-small cell lung cancer patients (P = .13). In addition, the carboplatin AUC was not influenced by increasing paclitaxel doses from 100 to 250 mg/m2. Neutropenia was the principal toxicity, and anemia was frequent. However, there was a striking lack of thrombocytopenia. Modeling of the relationship between the carboplatin AUC and the decrease in platelets revealed a 50% decrease in platelets at a carboplatin AUC (AUC50) of 6.3 mg/mL x min. This contrasts with historical data documenting a carboplatin AUC50 of 4.0 mg/mL x min. Our findings suggest that there is a considerable interaction of both drugs at the cellular level, with at least an additive effect of carboplatin on the main hematologic toxicity of paclitaxel (ie, neutropenia). There is also a protective effect exerted by paclitaxel on carboplatin-related toxicity (ie, thrombocytopenia). The clear protective effect of paclitaxel in this combination suggests that it is possible to reduce the dose interval to 3 weeks. Studies are in progress to test this hypothesis and to investigate the underlying pharmacologic interactions.

Topotecan (Hycamtin; SmithKline Beecham Pharmaceuticals, Philadelphia, PA), a topoisomerase I inhibitor, is a semisynthetic camptothecin that has been structurally modified for increased water solubility. The closed lactone ring predominates at acidic pH, but the reverse reaction of the parent into the metabolite predominates at physiologic pH. The pharmacokinetic profile of topotecan is usually characterized by a two-compartment model and is linear in the dose range of 0.5 to 3.5 mg/m2. Following intravenous administration for 5 days at doses of 0.5 to 1.5 mg/m2/d as a 30-minute infusion, topotecan has a volume of distribution of approximately 130 L. Mean plasma clearance for topotecan (total) was approximately 1,000 mL/min with a plasma half-life of 2 to 3 hours. Renal clearance is an important determinant of topotecan elimination, with approximately 30% of the dose excreted in the urine. In three phase I studies in which the schedule of five daily doses every 21 or 28 days was investigated, all found 1.5 mg/m2/d to be the maximum tolerated dose. Neutropenia (reversible and noncumulative over time) was the major dose-limiting toxicity; fevers and infections were infrequently reported. The magnitude of topotecan exposure was correlated to the observed myelosuppression.

Purpose: To investigate the pharmacokinetics and pharmacodynamics of paclitaxel (P) and carboplatin (C) in a sequence-finding and dose-escalating study in untreated non-small-cell lung cancer (NSCLC) patients., Patients and Methods: Fifty-five chemotherapy-naive patients with NSCLC were entered onto the pharmacokinetic part of a large phase I trial in which P was administered as a 3-hour infusion at dosages of 100 to 250 mg/m2, and C over 30 minutes at dosages of 300 to 400 mg/m2. Patients were randomized for the sequence of administration, first C followed by P or vice versa. Each patient received the alternate sequence during the second and subsequent courses., Results: The most important hematologic toxicity encountered-was neutropenia. Hematologic toxicity was not dependent on the sequence in which P and C were administered, but there was cumulative neutropenia. Nonhematologic toxicities consisted mainly of vomiting, myalgia, and arthralgia. No sequence-dependent pharmacokinetic interactions for the P area under the concentration-time curve (P-AUC), maximal plasma concentration (P-Cmax), or time above a threshold concentration of 0.1 mumol/L (P-T > or = 0.1 mumol/L) were observed. However, there was a significant difference for the metabolite 6 alpha-hydroxypaclitaxel AUC (6OHP-AUC). Higher 6OHP-AUCs were observed when C was administered before P. The mean plasma ultrafiltrate AUC of C (CpUF-AUC) at the dosage of 300 mg/m2 for the sequence C-->P was 3.52 mg/mL.min (range, 1.94 to 5.83) and 3.62 mg/mL.min for the sequence P-->C (range, 1.91 to 5.01), which is not significantly different (P = .55). Of 45 assessable patients, there were five major responders (three complete responders and two partial responders). Four of five responses occurred at dosages above dose level 4 (P 175 mg/m2 + C 300 mg/m2). The median survival duration was best correlated with the P dose (4.8 months for doses < 175 mg/m2 v 7.9 months for doses > or = 175 mg/m2, P = .07; P-T > or = 0.1 mumol/L, 4.8 months for < 15 hours v 8.2 months for > or = 15 hours, P = .06)., Conclusion: There was no pharmacokinetic-sequence interaction between C and P in this study. A clear dose-response relation with respect to response rate and survival was observed. The pharmacokinetic parameter P-T > or = 0.1 mumol/L was related to improved survival in this study.

The aim of this pharmacokinetic/pharmacodynamic study was to define the relationships of the carboplatin exposure with the toxicity in patients treated with high dose carboplatin (400 mg m-2 day-1), cyclophosphamide (1500 mg m-2 day-1) and thiotepa (120 mg m-2 day-1) for four consecutive days, followed by peripheral stem cell transplantation. Exposure to carboplatin was studied in 200 treatment days by measuring the area under the carboplatin plasma ultrafiltrate (pUF) concentration vs time curve (AUC). The AUC was obtained by using a previously validated limited sampling model. A total of 31 patients was studied who received one, two or three courses of this high-dose chemotherapy regimen. The unbound, plasma ultrafiltrate carboplatin was almost completely cleared from the body before each next treatment day in a course; the day-to-day AUC variation was 3.3%. The mean cumulative AUC over 4 days was 19.6 (range 14.1-27.2) mg ml-1 min-1. In 97 treatment days the carboplatin dose was calculated using the Calvert formula with the creatinine clearance as the measure for the glomerular filtration rate (GFR). For these courses, the inter-patient variability in pharmacokinetics was significantly reduced from 21% to 15% (P = 0.007) in comparison with the schemes where it was given as a fixed dose of 400 mg m-2. There were no relationships found between toxicity and the AUC of carboplatin, which may be due to the influence of overlapping toxicities of cyclophosphamide and thiotepa. However, the ototoxicity was strongly related to the cumulative carboplatin AUC. This toxicity was dose limiting for carboplatin in this schedule. It appeared that the carboplatin pharmacokinetics in these regimens were similar to those reported at conventional dosages. To reduce the inter-patient variation, the carboplatin dose can be calculated using the Calvert-formula with the creatinine clearance as the measure for the GFR.

Carboplatin is a chemotherapeutic agent frequently used in the treatment of various malignancies. An individual dosing strategy has been recommended to yield the most optimal exposure, expressed as the area under the concentration-time curve (AUC). The formula developed by Calvert et al. (dose = target-AUC x [GFR + 25]) can be used to achieve this. However, due to the inconvenient [51Cr]-ethylenediamine-tetraacetic acid ([51Cr]-EDTA)-based measurement of the glomerular filtration rate (GFR), its application in the clinic has thus far been limited. Chatelut and co-workers have recently proposed a formula to estimate carboplatin clearance using the serum creatinine concentration. We retrospectively tested the Chatelut equation and the Calvert formula using either the creatinine clearance based on 24-h urine collection or the creatinine clearance based on the formula of Cockcroft and Gault. The latter equations were shown to predict the carboplatin clearance reasonably well, although systematic overprediction and underprediction occurred. However, the formula proposed by Chatelut and co-workers had no significant bias and was precise. It is proposed that this formula be used to calculate the optimal carboplatin dosage after prospective validation has been performed.

Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ring-opened hydroxy acid, is essential for this activity. We performed a pharmacokinetics study as part of phase II clinical trials in patients with various types of solid tumors, giving topotecan at 1.5 mg/m2 per day by 30-min infusion for 5 consecutive days, with courses being repeated every 3 weeks. Previously validated limited-sampling models, using concentration measurements in samples obtained 2 h after infusion, were used to calculate the area under the plasma concentration-time curves (AUCs) for both chemical forms. Samples were obtained from a total of 36 patients over 136 treatment days. The mean AUC of the closed-ring form (AUC(closed)) was 8.74 (range 2.3-16.3 microM min per day, and the mean AUC of the ring-opened form (AUC(open)) was 11.5 (range 3.2-46.0) microM min per day (interpatient variability 34-61%). In each patient the AUC values achieved on the 1st day of administration were similar to and, thus, predictive for those achieved during the following days, with a day-to-day variation of 7.39% being recorded for the AUC(closed) and that of 12.6% for the AUC(open). There was no drug accumulation during the 5 consecutive treatment days of each cycle. However, despite the large interpatient pharmacokinetic variability, the importance of regular drug monitoring on this schedule can be questioned, as the pharmacodynamic variability was relatively small.

There is an increasing interest in using saliva as a biological matrix for drug monitoring, because it can be obtained by a noninvasive and patient-friendly means. In this article we describe our experience with respect to the practical use of saliva for pharmacokinetic monitoring of the anticancer agent carboplatin. Plasma ultrafiltrate (pUF), unstimulated, and citric acid-stimulated saliva samples were obtained from 17 patients receiving 175-350 mg/m2 carboplatin in different combination regimens. Platinum concentrations of carboplatin were determined by using a validated Zeeman atomic absorption spectrometric method. Carboplatin was detectable both in saliva and in pUF for at least 24 h after intravenous administration. Maximum concentrations in saliva ranged between 0.13 and 1.15 mg/L and were reached approximately 1.3 h (range 0-3.8 h) after the end of the infusion. The ratios of carboplatin levels in pUF and saliva were time dependent and patient dependent. The ratios of the clinically relevant carboplatin area under the concentration-time curve (AUC) in pUF and saliva varied between 11 and 150 (mean 45). Based on this large variation, we conclude that in this setup, saliva drug concentrations are not a reliable replacement for carboplatin analysis in pUF.

Purpose: To determine the maximum-tolerable dose (MTD) and to investigate the pharmacokinetics and pharmacodynamics of topotecan in a phase I study. Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. Broad preclinical activity rationalized further clinical evaluation., Patients and Methods: In this phase I trial, topotecan was administered by 24-hour continuous infusion every 21 days to patients with solid malignant tumors., Results: A total of 25 eligible patients, of whom 22 were pretreated, entered the study. They received the following dosages of topotecan: 2.5, 3.75, 5.60, 8.4, and 10.5 mg/m2 by 24-hour infusion. Reversible leukopenia and thrombocytopenia were dose-limiting, with mild anemia occurring regularly. Other toxicities, such as alopecia, mucositis, nausea, and vomiting were sporadic and mild. Responses were not observed. However, eight patients had stable disease. The plasma concentration-time curves were not compatible with standard linear pharmacokinetic models, and indications were found for the occurrence of nonlinear (saturation) kinetics at the dosages studied., Conclusion: The recommended dose for phase II studies is 8.4 mg/m2 when administered as a 24-hour infusion, which is well tolerated. Further studies will be necessary to account for the putative nonlinear behavior of the drug.

Carboplatin is a chemotherapeutic agent frequently used in the treatment of various malignancies. The myelotoxicity and clinical efficacy of carboplatin correlate with the clearance of the drug, which is correlated to the glomerular filtration rate (GFR). Dosing of this agent based solely upon the patients body surface area is therefore not accurate enough; the GFR, and thus the clearance of carboplatin differ in each patient irrespective of the body area. Consequently, some patients undergo a higher systemic exposure, expressed as the area under the plasma concentration/time curve (AUC), than others when dosages of carboplatin are given on the basis of the body surface area. A high AUC correlates with increased toxicity, thus increasing the risks of the treatment, but in the case of a low AUC the therapeutical efficacy decreases. This indicates that an individual dosing strategy is warranted to obtain the optimal AUC. In this article, the development and application of a simple equation, known as the Calvert formula, are discussed. This formula can be used to calculate the carboplatin dose accurately in order to obtain a target AUC by using only the GFR. The formula is: dose (mg) = AUC (mg ml-1 min) x [GFR (ml/min) + 25 (ml/min)]. This formula has proven to be, in both retrospective and prospective studies, a reliable tool to calculate the optimal dose of carboplatin Future studies should determine the value of the creatinine clearance as a measure for the GFR.

Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ring-opened hydroxy acid, is essential for this activity. The open form predominates at physiological pH. We performed a pharmacokinetic study as part of a phase I study in patients with various types of solid tumors, where topotecan was administered in a 30-min infusion daily on 5 consecutive days every 3 weeks. The plasma kinetics of topotecan could be described best using an open two-compartment model with t1/2(alpha) and t1/2(beta) of 8.1 (range 0.3 to 40.7) min and 132 (range 49 to 286) min, respectively. The plasma concentration-time profiles of the metabolite, however, could be described using a one-compartment model with t1/2(formation) of 29.0 (range 5.6-99.5) min and t1/2 (elimination of 123.2 (range 32-265) min, respectively. The lactone was the predominate form during the first hour from the start of infusion, but was rapidly converted into its ring-opened structure. The elimination rate of topotecan was independent of the dose. There were linear relationships between the dose (mg m-2 day-1), the area under the plasma concentration versus time curve (AUC) of topotecan and its metabolite, the total AUC, peak plasma lactone concentrations, and the time period that the topotecan concentrations remained above 10 nM. Different models were used to correlate pharmacokinetic and pharmacodynamic parameters. The percentage decrease in absolute neutrophil count (ANC) was related to these parameters and plots were well fitted by linear and sigmoidal Emax models.

Background: Limited sampling models for the estimation of the topotecan Area Under the concentration versus time Curve (AUC) and its lactone ring opened form (AUC Tm), from one or more plasma concentration determinations, are desired for further population-kinetic studies., Patients and Methods: The models were developed and validated using 34 pharmacokinetic curves in 19 patients who participated in a phase I study., Results: A single point model was selected as optimal: AUC (mumol/L.min) = 499 (min).C2h (mumol/L) +0.85 (m2/mg.mumol/L.min).dose(mg/m2), and for topotecan-metabolite (Tm), AUC Tm (mumol/L.min) = 55.1 (min).CTm2h (mumol/L) -0.011 (m2/mg.mg.mumol/L.min).dose (mg/m2), where C2h is the plasma concentration (mumol/L) of topotecan at 2 h after the end of a 30-min infusion, and CTm2h the concentration of the opened form at the same time point. The models are valid for dosages ranging from 0.5 to 1.5 mg/m2/day and proved to be unbiased (MPE% = -1.8% and -9.3%, respectively) and precise (RMSE% = 17.9% and 22.7%, respectively). From the predicted AUCs, the clearance (Cl = dose (mumol)/AUC(mumol/L.min)) could also reliably be predicted, as well as the total AUC (AUC+AUC Tm) RMSE% = 17.1% and MPE% = -0.02%). Half-life values could not be predicted with acceptable precision and accuracy., Conclusion: The limited sampling models presented may useful for future studies focused on pharmacokinetic/pharmacodynamic relationships of topotecan in large populations.

Patients and Methods: Twenty-one patients with metastatic ovarian cancer with minimal residual disease confined to the peritoneal cavity, were treated with intraperitoneal-administered carboplatin. Carboplatin was added to 2 liters of fluid and given via a Tenckoff-catheter. A dwell-time of 4 hours was allowed. After removal of fluid the amount of recovered carboplatin was determined., Results: It appeared that the median recovery of carboplatin was 25.5% (range 2%-56%). There was a great interpatient variability of carboplatin recovery but it was relatively constant during consecutive courses., Conclusions: Optimal dosing of intraperitoneal-administered carboplatin with a dwell-time is not possible because of the differences in recovery. This manifested itself in the fact that the absorbed dose, as well as a calculated Area Under the concentration versus time Curve (AUC), were much better related to toxicity than the administered dose.

A limited sampling model for the estimation of the carboplatin area under the concentration versus time curve (AUC), as developed by Sørensen et al., was validated prospectively for the use in a high-dose combination chemotherapy schedule. The model allows an estimation of the AUC on the basis of only one timed plasma drug concentration, sampled at exactly 2.75 h after a 1-h carboplatin infusion. Pharmacokinetic curves were obtained from nine patients receiving carboplatin (400 mg/m2 per day) combined with cyclophosphamide (1500 mg/m2 per day), thiotepa (120 mg/m2 per day), and mesna (3 g/day) for 4 consecutive days. Peripheral blood stem-cell transplantation (PBSCT) was performed 3 days later to restore hematopoiesis. Using this combination of high doses, the model proved to be unbiased (MPE -3.40%; SE, 1.22%) and highly precise [root mean squared prediction error (RMSE), 5.15%; SE, 0.17%] for estimation of the AUC during 4 consecutive days. The validated limited sampling model provides a starting point for future pharmacokinetic studies in a larger population of patients, which might lead to more insight into the relationships with the pharmacodynamic outcome of carboplatin and may help in achieving more rational dosing of patients on the basis of an AUC determination.

Pharmacokinetic parameters of antineoplastic drugs are usually generated from concentration/time profiles obtained after multiple venipunctures. With limited-sampling models (LSM) this number can be reduced to between one and three timed plasma samples. LSMs may facilitate population pharmacokinetic/pharmacodynamic studies, which eventually may lead to a dosing strategy based on the characteristics of the individual patient. In this article, the development, validation and application of several LSMs reported in the literature are reviewed.