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Background: TLD-1 is a novel liposomal doxorubicin that compared favorably to conventional doxorubicin liposomal formulations in preclinical models. This phase I first-in-human study aimed to define the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and preliminary activity of TLD-1 in patients with advanced solid tumors., Patients and Methods: We recruited patients with advanced solid tumors who failed standard therapy and received up to 3 prior lines of palliative systemic chemotherapy. TLD-1 was administered intravenously every 3 weeks up to a maximum of 9 cycles (6 for patients with prior anthracyclines) from a starting dose of 10 mg/m 2 , according to an accelerated titration design followed by a modified continual reassessment method., Results: 30 patients were enrolled between November 2018 and May 2021. No dose-limiting toxicities (DLT) were observed. Maximum administered dose of TLD-1 was 45 mg/m 2 , RP2D was defined at 40 mg/m 2 . Most frequent treatment-related adverse events (TRAE) of any grade included palmar-plantar erythrodysesthesia (PPE) (50% of patients), oral mucositis (50%), fatigue (30%) and skin rash (26.7%). Most common G3 TRAE included PPE in 4 patients (13.3%) and oral mucositis in 2 (6.7%). Overall objective response rate was 10% in the whole population and 23.1% among 13 patients with breast cancer; median time-to-treatment failure was 2.7 months. TLD-1 exhibit linear pharmacokinetics, with a median terminal half-life of 95 h., Conclusions: The new liposomal doxorubicin formulation TLD-1 showed a favourable safety profile and antitumor activity, particularly in breast cancer. RP2D was defined at 40 mg/m 2 administered every 3 weeks. (NCT03387917)., Competing Interests: Declaration of Competing Interest Ilaria Colombo: Travel grants: Tesaro, Janssen, AZ, GSK. Honoraria for consultancy or expert opinion: AZ, GSK, Novartis, MSD, BionTech. Institutional grants for clinical trials (PI): MSD, Bayer, Vivesto, Incyte, AZ, Orion. Kira-Lee Koster: Travel grants for congress visits from Takeda Pharma AG und Janssen-Cilag AG (paid to institution). Lisa Holer: no conflict of interest. Simon Haefliger: no conflict of interest. Manuela Rabaglio: no conflict of interest. Sara Bastian: no conflict of interest. Michael Schwitter: no conflict of interest. Katrin Eckhardt: no conflict of interest. Stefanie Hayoz: no conflict of interest. Anna M. Mc Laughlin: current employee of Pharmetheus AB and a paid consultant to multiple pharmaceutical companies. Charlotte Kloft: no conflict of interest. Marian Klose: no conflict of interest. Stefan Halbherr: Stefan Halbherr owns shares of InnoMedica Holding AG and functions as part of the executive management of the firm. Christian Baumgartner: Christian Baumgartner hold shares of Innomedica and is a former employee of the firm. He has received advisory fees from Boehringer Ingelheim. Cristiana Sessa: no conflict of interest. Anastasios Stathis: Institutional funding for clinical trials: Innomedica, Abbvie; ADC Therapeutics; Amgen, Astra Zeneca; Bayer; Cellestia; Incyte, Loxo Oncology; Merck MSD; Novartis; Pfizer; Philogen; Roche. Consultant/expert testimony/advisory board (institutional): Debiopharm, Janssen, AstraZeneca, Incyte, Eli Lilly, Novartis, Roche, Loxo Oncology. Travel grant: Incyte; Astra Zeneca. Dagmar Hess: no conflict of interest. Markus Joerger: Advisory role (institutional): Novartis, Astra Zeneca, Basilea Pharmaceutica, Bayer, BMS, Debiopharm, MSD, Roche, Sanofi; research funding: Swiss Cancer Research; travel grants: Roche, Sanofi, Takeda., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The classical taxanes (paclitaxel, docetaxel), the newer taxane cabazitaxel and the nanoparticle-bound nab-paclitaxel are among the most widely used anticancer drugs. Still, the optimal use and the value of pharmacological personalization of the taxanes is still controversial. We give an overview on the pharmacological properties of the taxanes, including metabolism, pharmacokinetics-pharmacodynamic relations and aspects in the clinical use of taxanes. The latter includes the ongoing debate on the most effective and safe regimen, the recommended initial dose, and pharmacological dosing individualization. The taxanes are among the most widely used anticancer drugs in patients with solid malignancies. Despite their longtime use in clinical routine, the optimal dosing strategy (weekly versus 3-weekly) or optimal average dose (cabazitaxel, nab-paclitaxel) has not been fully resolved, as it may differ according to tumour entity and line of treatment. The value of pharmacological individualization of the taxanes (TDM, TCI) has been partly explored for 3-weekly paclitaxel and docetaxel, but remains mostly unexplored for cabazitaxel and nab-paclitaxel at present., (© 2020 British Pharmacological Society.)

Endoxifen is one of the most important metabolites of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (C SS,min ENDX ) is observed under tamoxifen standard dosing and patients with breast cancer who do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at a 26% higher recurrence risk compared with patients with endoxifen concentrations exceeding this value. In this investigation, 10 clinical tamoxifen studies were pooled (1,388 patients) to investigate influential factors on C SS,min ENDX using nonlinear mixed-effects modeling. Age and body weight were found to significantly impact C SS,min ENDX in addition to CYP2D6 phenotype. Compared with postmenopausal patients, premenopausal patients had a 30% higher risk for subtarget C SS,min ENDX at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1-13.8-fold higher risk for subtarget C SS,min ENDX compared with elderly low-weight patients. Considering ever-rising obesity rates and the clinical importance of tamoxifen for premenopausal patients, this subpopulation may benefit most from individualized tamoxifen dosing., (© 2020 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Levels of endoxifen, the most active metabolite of tamoxifen, vary by the highly polymorphic cytochrome P450 (CYP) 2D6 enzyme. We prospectively investigated tamoxifen efficacy by serum endoxifen levels and the tamoxifen activity score (TAS). Experimental Design: A prospective observational multicenter study included postmenopausal women with an estrogen receptor-positive breast cancer receiving first-line tamoxifen, 20 mg daily in the neoadjuvant or metastatic setting, recruited between February 2009 and May 2014. The primary endpoint was the objective response rate (ORR) using RECIST criteria 1.0. Secondary endpoints were clinical benefit (CB), progression-free survival (PFS), and tolerability of tamoxifen. The main analysis used logistic regression to relate ORR to serum endoxifen levels after 3 months. Endpoints were also related to other tamoxifen metabolites and to TAS. Results: Endoxifen levels were available for 247 of all 297 patients (83%), of which 209 with target lesions (85%). Median follow-up time for PFS was 32.5 months, and 62% progressed. ORR and CB were 45% and 84%, respectively. ORR was not related to endoxifen, and the OR of ORR was 1.008 per μg/L increase in endoxifen (95% confidence interval, 0.971-1.046; P = 0.56 ). In general, none of the endpoints was associated with endoxifen levels, tamoxifen metabolites, or TAS. Conclusions: Under the prespecified assumptions, the results from this prospective clinical trial do not suggest therapeutic drug monitoring of endoxifen to be of clinical value in postmenopausal women treated with tamoxifen for breast cancer in the neoadjuvant or metastatic setting. Clin Cancer Res; 24(10); 2312-8. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background and Objectives: A better understanding of the highly variable pharmacokinetics (PK) of tamoxifen and its active metabolite endoxifen in breast cancer patients is crucial to support individualised treatment. This study used a modelling and simulation approach to quantitatively assess the influence of cytochrome P450 (CYP) 2D6 activity and other relevant factors on tamoxifen and endoxifen PK to identify subgroups at risk for subtherapeutic endoxifen concentrations., Methods: Simulations were performed using two previously published PK models jointly describing tamoxifen and endoxifen with CYP2D6 and CYP3A4/5 enzyme activities implemented as covariates. Steady-state predictions were compared between models and with the literature values. Factors potentially causing between-model discrepancies were explored. A previously published threshold (6 ng/mL) was used to identify patients with subtherapeutic endoxifen concentrations and to perform a dose adaptation study., Results: Steady-state predictions of tamoxifen and endoxifen were considerably different between the models. The factors, differences in sampling time, adherence and bioavailability, were not able to fully capture between-model variability. Endoxifen steady-state fluctuations within a dosing interval were minimal (<6%). Poor (97%) and intermediate (54%) CYP2D6 metabolisers failed to achieve therapeutic endoxifen concentrations, suggesting adapted doses of tamoxifen 80 and 40 mg, respectively, achieving therapeutic endoxifen concentrations in 89.7% of patients (standard dosing 45.2%). However, interindividual variability remained., Conclusions: To achieve therapeutic endoxifen concentrations early in treatment, it is advisable to initiate treatment by CYP2D6 genotype/phenotype-guided dosing, followed by therapeutic drug monitoring at steady-state. We strongly advocate to adequately measure, report and prospectively investigate influential factors (i.e. adherence, bioavailability, time to PK steady-state) in clinical trials.

Background: There is an ongoing debate about the relationship between breast implants and secondary malignancies., Methods: Breast cancer patients undergoing surgical reconstruction after mastectomy by either implants or autologous flap were identified in the Surveillance, Epidemiology and End Results registry between 1998 and 2002. The occurrence of secondary malignancies at least 1 year after diagnosis was compared between breast reconstruction with implants vs autologous flap., Results: Of 7955 women, 3727 underwent reconstruction using implants and 4228 using autologous flap. The incidence of secondary tumours was similar in both the groups (hazards ratio (HR)=1.02, 95% confidence interval (CI): 0.82-1.26, P=0.880). For lung cancer, a significantly increased risk for implants (HR=2.51, 95% CI: 1.28-4.95, P=0.005) was observed., Conclusions: Except for lung cancer, no association between implants and secondary malignancies including lymphomas was observed.

Background: There is ongoing debate about nonpalliative primary tumor surgery in metastatic breast cancer patients. This issue has become even more relevant with the introduction of increasingly sensitive imaging modalities., Methods: Metastatic breast cancer patients were identified in the SEER registry between 1998 and 2009. The effect of primary tumor surgery on overall and cancer-specific mortality using risk-adjusted Cox proportional hazard regression modeling and stratified propensity score matching was assessed., Results: Overall, 16,247 women with metastatic breast cancer were included. Of those 7600 women underwent primary tumor surgery although 8647 did not have any surgery at all. Primary tumor surgery decreased from 62.0% in 1998 to 39.1% in 2009 (P < 0.001). Primary tumor surgery was associated with decreased overall mortality (hazard ratio (HR) = 0.53, 95% CI 0.50-0.55, P < 0.001) and cancer-specific mortality (HR = 0.51, 95% CI 0.48-0.54, P < 0.001) in the propensity score-matched model. The benefit of primary tumor surgery increased from 1998 to 2009 for overall mortality (1998: HR = 0.72, 95% CI 0.59-0.89, 2009: HR = 0.42, 95% CI 0.35-0.50) and cancer-specific mortality (1998: HR = 0.72, 95% CI 0.58-0.89, 2009: HR = 0.40, 95% CI 0.33-0.48)., Conclusions: The present study-the first population-based analysis using propensity score methods-provides evidence of a favorable impact of primary tumor surgery on mortality in metastatic breast cancer patients. Most importantly, the benefit of primary tumor surgery increased over time from 1998 to 2009. Although the final results of ongoing randomized studies are awaited, currently available evidence should be discussed with metastatic breast cancer patients.

The addition of adjuvant chemotherapy in early breast cancer improves overall survival by approximately 10%. Recommendations favor the use of anthracyclines and taxanes in patients with luminal B disease, while the use of an anthracycline, taxane and alkylating agent is recommended in triple-negative disease. In luminal B disease, the addition of chemotherapy to endocrine treatment depends on estrogen receptor expression and overall risk. Chemotherapy is not recommended in most patients with luminal A (highly hormone-sensitive and low proliferation) breast cancer. A major controversy is the addition of adjuvant chemotherapy to endocrine treatment in patients with estrogen receptor-positive breast cancer. In some of these patients, multigene signatures such as the 21-gene recurrence score may be a useful addition to histopathology. The introduction of molecular subtypes and gene signatures improves the complexity of early breast cancer treatment, and individual institutes have to find their policy based on their histopathological information and the availability of gene signatures.

Objectives: The primary objective of this population-based study is to describe the patterns of care of elderly patients with breast cancer (BC), and evaluate potential causative factors for the decrease in BC-specific survival (BCSS) in the elderly., Patients and Methods: We included all or representative samples of patients with newly diagnosed BC from seven Swiss cancer registries between 2003 and 2005 (n=4820). Surgical and non-surgical BC treatment was analyzed over 5 age groups (<65, 65 to <70, 70 to <75, 75 to <80 and ≥80years), and the predictive impact of patient age on specific treatments was calculated using multivariate logistic regression analysis., Results: The proportion of locally advanced, metastatic and incompletely staged BC increased with age. The odds ratio for performing breast-conserving surgery (BCS) in stages I-II BC (0.37), sentinel lymph node dissection (SLND) in patients with no palpable adenopathy (0.58), post-BCS radiotherapy (0.04) and adjuvant endocrine treatment (0.23) were all in disfavor of patients ≥80years of age compared to their younger peers. Only 36% of patients ≥80years of age with no palpable adenopathy underwent SLND. In the adjusted model, higher age was a significant risk factor for omitting post-BCS radiotherapy, SLND and adjuvant endocrine treatment., Conclusions: This study found an increase in incomplete diagnostic assessment, and a substantial underuse of BCS, post-BCS radiotherapy, SLND and adjuvant endocrine treatment in elderly patients with BC. There is a need for improved management of early BC in the elderly even in a system with universal access to health care services., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: There is considerable heterogeneity in the use of chemotherapy in early breast cancer (BC), despite international recommendations issued from the NCCN, NIH and the St.Gallen bi-annual conference., Methods: We included 1,535 patients from seven Swiss cancer registries between 2003 and 2005 receiving chemotherapy for stage I to III BC. Chemotherapy was categorised into (a) FAC/FEC, anthracyclines followed by CMF or anthracycline-taxane combinations (FAC-T) (781 patients) and (b) other chemotherapy regimens such as CMF/AC (EC) (754 patients). Predictors for choosing FAC-T over non-FAC-T chemotherapy were separately determined in all patients and in ER-negative patients (n = 496) by multivariate logistic regression analysis., Results: The use of FAC-T increased significantly over time, from 44% in 2003 to 55% in 2005. BC stage III (versus stage I-II) and nodal positivity were the predominant predictors for using FAC-T chemotherapy in the adjusted model (odds ratio (OR) 4.1, 95%-confidence intervals (CI) 2.6-6.3 and OR 3.0, 95%-CI 2.0-4.4, respectively). In high-risk ER-negative BC patients, poor histological differentiation was more important to choose FAC-T chemotherapy (OR 3.8, 95%-CI 1.9-7.5) than tumour stage or nodal status. The use of FAC-T chemotherapy varied substantially among the seven geographic regions, from 20% in rural Grisons-Glarus to 73% in Zurich., Conclusions: Tumour biology is a predominant factor for choosing FAC-T over older chemotherapy regimens in patients with ER-negative early BC, but improvements should be made to reduce the substantial regional heterogeneity. Further epidemiological studies should assess how the use of FAC-T chemotherapy is affecting clinical outcome in patients with early BC and different risk profiles.

Background: There is considerable heterogeneity in the use of chemotherapy for patients with early breast cancer (BC), despite international recommendations issued from the National Comprehensive Cancer Network (NCCN), National Institutes of Health (NIH), and the St. Gallen biannual conference. This population-based study assessed the patterns of chemotherapy use in early BC., Patients and Methods: The study included all or representative samples of patients with stage I-III BC from 7 Swiss cancer registries between 2003 and 2005. Factors modifying chemotherapy use were determined by logistic regression, considering patients receiving chemotherapy as cases (n = 1535) and the others as controls (n = 2004)., Results: Nodal involvement was by far the strongest predictor for the use of chemotherapy (adjusted odds ratio [OR], 9.7; 95% confidence interval [CI], 7.2-13.0). Tumor biological characteristics such as histologic differentiation (OR, 4.4; 95% CI, 3.2-6.2), estrogen receptor (ER) status (OR, 3.8; 95% CI, 2.6-5.5), human epidermal growth factor receptor 2 (HER2) status (OR, 1.9; 95% CI, 1.3-2.7), and patient age (OR, 4.6; 95% CI, 3.5-6.2) were less important predictors for chemotherapy use. Socioeconomic and provider-related factors, such as patient education, affluence, insurance, breast surgeon's annual caseload, and case presentation at a multidisciplinary tumor conference did not predict the use of chemotherapy, with the exception of the health care provider's participation in clinical research (OR, 2.1; 95% CI, 1.6-2.8). The patient's region of residence did not predict the use of chemotherapy, but it was associated with the specific type of chemotherapy used., Conclusion: Nodal status, rather than surrogate markers for tumor biological features, was the predominant factor for choosing chemotherapy in patients with early BC in this large population study. Improvements should be made to increase the weight of tumor biological features in choosing chemotherapy in early BC., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aim: We report a case of bevacizumab-associated hyperlipoproteinemia in a patient with advanced breast cancer., Case Summary: A 57-year-old woman with advanced invasive-ductal breast cancer was administered bevacizumab from March 2008 to February 2009. Pretreatment laboratory showed borderline hypercholesterolemia (5.1 mmol/L, 197 mg/dL) and normal triglycerides (1.3 mmol/L, 115 mg/dL). Three months on treatment with bevacizumab, both serum cholesterol (11.9 mmol/L, 460 mg/dL) and triglycerides (7.4 mmol/L, 655 mg/dL) increased substantially, and remained well above the normal range for a period of bevacizumab treatment. From March 2008 to August 2008, the patient also received anticancer treatment with liposomal doxorubicin that was stopped early due to hand-foot syndrome. No concurrent hyperlipidemic drugs have been taken by the patient at the time of bevacizumab treatment. In February 2009, bevacizumab was stopped and the patient went on to receive paclitaxel for hepatic tumor progression. By December 2009, both serum triglycerides (1.3 mmol/L, 115 mg/dL) and cholesterol (3.2 mmol/L, 123 mg/dL) had normalized., Discussion: This is the first published case of bevacizumab-associated hyperlipoproteinemia. By applying the Naranjo ADR probability scales, at least a possible relationship between hyperlipoproteinemia type IIb and bevacizumab in this patient is supported by the data (Naranjo score 4). No hyperlipidemic drugs were given concurrently with bevacizumab, and the serum cholesterol and triglycerides decreased quickly after bevacizumab was discontinued., Conclusions: This study describes a case of bevacizumab-associated hyperlipidemia. Patients receiving bevacizumab should have their cholesterol and triglycerides checked for potential worsening.

Background: The aim of this study was to investigate predictors of state-of-the-art management of early breast cancer in Switzerland., Patients and Methods: The study included 3499 women aged 25-79 years diagnosed with invasive breast cancer stages I-IIIA in 2003-2005. Patients were identified through population-based cancer registries and treated in all kinds of settings. Concordance with national and international recommendations was assessed for 10 items covering surgery, radiotherapy, systemic adjuvant therapy and histopathology reporting. We used multivariate logistic regression to identify independent predictors of high (10 points) and low (≤7 points) concordance., Results: In one-third of the patients, management met guidelines in all items, whereas in about one-fifth, three or more items did not comply. Treatment by a surgeon with caseload in the upper tercile and team involved in clinical research were independent predictors of a high score, whereas treatment by a surgeon with a caseload in the lower tercile was associated with a low score. Socioeconomic characteristics such as income and education were not independent predictors, but patient's place of residence and age independently predicted management according to recommendations., Conclusion: Specialization and involvement in clinical research seem to be key elements for enhancing the quality of early breast cancer management at population level.

Adjuvant treatment of early-stage breast cancer with combined trastuzumab and chemotherapy has become standard in patients with HER2-positive tumors and a diameter of >1 cm or positive lymph nodes. Currently, there are no data directly supporting the use of adjuvant treatment, including trastuzumab, in patients with HER2-positive tumors, a diameter of ≤1 cm and no nodal involvement (pT1a,bpN0M0). However, 6%-10% of these small tumors are HER2 positive, and there is good evidence for an inferior clinical outcome in these patients, with recurrence rates of up to 30% after 5-10 years. Assumed that the relative risk reduction is similar to larger tumors, the absolute benefit should be large enough to consider adjuvant treatment. This review addresses current data regarding the prognosis of small HER2-positive tumors and discusses potential factors to individualize adjuvant treatment in patients with small HER2-positive tumors.

Background and Methods: There is accumulating data on the clinical benefit of aromatase inhibitors in the adjuvant treatment of early-stage breast cancer in postmenopausal women. The Breast International Group (BIG) 1-98 study is a randomized, phase 3, double-blind trial comparing four adjuvant endocrine treatments of 5 years duration in postmenopausal women with hormone-receptor-positive breast cancer: letrozole or tamoxifen monotherapy, sequential treatment with tamoxifen followed by letrozole, or vice versa. This article summarizes data presented at the 2009 St. Gallen early breast cancer conference: an update on the monotherapy arms of the BIG 1-98 study, and results from the sequential treatment arms. Implications for daily practice from BIG 1-98 and from other adjuvant trials will be discussed., Results: Despite cross-over from tamoxifen to letrozole by 25% of the patients after unblinding of the tamoxifen monotherapy arm, the improvement of disease-free survival (HR 0.88, 0.78-0.99, p = 0.03) and time to distant recurrence (HR 0.85, 0.72-1.00, p = 0.05) for letrozole monotherapy as compared to tamoxifen monotherapy remained significant in the intention-to-treat (ITT) analysis. A trend for an overall survival advantage for letrozole was seen in the ITT analysis (HR 0.87, 0.75-1.02, p = 0.08). No statistically significant differences were found for the sequential treatment arms versus letrozole monotherapy, with respect to disease-free survival, time to distant recurrence or overall survival. Cumulative incidence analysis of breast cancer recurrence favors the initiation of adjuvant endocrine treatment with letrozole instead of tamoxifen, especially in patients at higher risk for early recurrence. Similarly, data suggest that patients commenced on letrozole can be switched to tamoxifen after 2 years, if required., Conclusions: The BIG 1-98 study update with median follow up of 76 months confirms a significant reduction in the risk of breast cancer recurrence and a trend towards improved overall survival with letrozole as compared to tamoxifen, and no unexpected safety concerns with letrozole. Adjuvant endocrine treatment should preferentially be initiated with letrozole. For patients unable to continue letrozole, switching to tamoxifen appears to be an acceptable alternative.

Aims: To investigate the population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients., Patients and Methods: Sixty-five female patients with early or advanced breast cancer received doxorubicin 60 mg/m(2) over 15 minutes followed by cyclophosphamide 600 mg/m(2) over 15 minutes. The plasma concentration-time data of both drugs were measured, and the relationship between drug pharmacokinetics and neutrophil counts was evaluated using nonlinear mixed-effect modelling. Relationships were explored between drug exposure (the area under the plasma concentration-time curve [AUC]), toxicity and tumour response., Results: Fifty-nine patients had complete pharmacokinetic and toxicity data. In 50 patients with measurable disease, the objective response rate was 60%, with complete responses in 6% of patients. Both doxorubicin and cyclophosphamide pharmacokinetics were associated with neutrophil toxicity. Cyclophosphamide exposure (the AUC) was significantly higher in patients with at least stable disease (n = 44) than in patients with progressive disease (n = 6; 945 micromol . h/L [95% CI 889, 1001] vs 602 micromol . h/L [95% CI 379, 825], p = 0.0002). No such correlation was found for doxorubicin. Body surface area was positively correlated with doxorubicin clearance; AST and patient age were negatively correlated with doxorubicin clearance; creatinine clearance was positively correlated with doxorubicinol clearance; and occasional concurrent use of carbamazepine was positively correlated with cyclophosphamide clearance., Conclusions: The proposed inhibitory population pharmacokinetic-pharmacodynamic model adequately described individual neutrophil counts after administration of doxorubicin and cyclophosphamide. In this patient population, exposure to cyclophosphamide, as assessed by the AUC, might have been a predictor of the treatment response, whereas exposure to doxorubicin was not. A prospective study should validate cyclophosphamide exposure as a predictive marker for the treatment response and clinical outcome in this patient group.