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Pemetrexed is a newer antifolate drug that has been approved as first-line treatment for patients with advanced non-squamous, non-small cell lung cancer (NSCLC) in combination with cisplatin, and as single agent for relapsed or chemotherapy refractory NSCLC after platinum-containing chemotherapy, at a dose of 500 mg/m(2). Pemetrexed undergoes intracellular activation by poly-gamma-glutamylation, that is essential for its antiproliferative activity. Polyglutamate derivatives mainly inhibit three key enzymes of intracellular folate metabolism, i.e. thymidylates synthase (TYMS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), with TYMS being the most relevant target. Pemetrexed undergoes rapid renal elimination as unchanged parent compound, with a terminal half-life of between two to five hours. In later clinical development, the usefulness of supplementation with folic acid and vitamin B(12) became evident, to control pemetrexed-related toxicity. The results from the phase III upfront registration study, a retrospective observational data, and a recent maintenance study of pemetrexed in NSCLC suggest histological subtype to be the most important predictive marker for clinical outcome in patients receiving pemetrexed, Pemetrexed is active in patients with non-squamous cell NSCLC while no benefit is seen in patients with squamous-cell histology, possibly as a result of different expression of intratumoral TYMS. These are important steps towards individualisation of anticancer treatment in patients with advanced NSCLC.

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.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.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.

Background For men with advanced castration-resistant prostate cancer (CRPC), several treatment options are available, including androgen receptor (AR) pathway inhibitors (abiraterone acetate, enzalutamide), taxanes (docetaxel, cabazitaxel) and the radionuclide (radium-223). However, cross-resistance is a clinically relevant problem. Platinum compounds have been tested in a number of clinical trials in molecularly unselected prostate cancer patients. Advances in CRPC molecular profiling have shown that a significant proportion of patients harbour DNA repair defects, which may serve as predictive markers for sensitivity to platinum agents. Objective To systematically identify and analyse clinical trials that have evaluated platinum agents in advanced prostate cancer patients. Methods PubMed was searched to identify published clinical trials of platinum agents in advanced prostate cancer. The PRIMSA statement was followed for the systematic review process. Identified trials are analysed for study design, statistical plan, assessments of anti-tumour activity and the potential value of predictive biomarkers. Results A total of 163 references were identified by the literature search and 72 publications that met the selection criteria were included in this review; of these 33 used carboplatin, 27 cisplatin, 6 satraplatin, 4 oxaliplatin and 2 other platinum compounds. Overall, anti-tumour activity varies in the range of 10%–40% for objective response and 20%–70% for PSA decline ≥50%. Response seemed highest for the combinations of carboplatin with taxanes or oxaliplatin with gemcitabine. The interpretation of the clinical data is limited by differences in response criteria used and patient populations studied. Conclusion Platinum compounds have moderate anti-tumour activity in molecularly unselected patients with advanced prostate cancer. Translational evidence of DNA repair deficiency should be leveraged in future studies to select prostate cancer patients most likely to benefit from platinum-based therapy.

AimsTo assess quantitatively the safety and pharmacology of paclitaxel in patients with moderate to severe hepatic impairment.MethodsSolid 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.ResultsThirty-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 (R-2 = -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 ConclusionsTotal 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.

Bleomycin is an antineoplastic agent that is mainly used in combination regimens. Dose-limiting toxicity is the bleomycin-induced pneumonitis (BIP) that can be diagnosed by clinical and radiological findings. The early diagnosis of BIP is often challenging.We report the occurrence of a diffuse pulmonary increase of FDG uptake in the FDG-PET scan in association with suspected BIP in a patient treated for relapsed seminoma. A retroperitoneal relapse was treated with a combination chemotherapy containing cisplatin, etoposide, and bleomycin. After 3 cycles of this regimen the patient developed mild clinical signs of early BIP. A following FDG-PET in order to evaluate treatment response showed a diffuse increased FDG uptake of the right lung. The subsequent HRCT revealed pathological findings consistent with BIP. After cessation of bleomycin and a systemic steroid trial a prompt normalization of the abnormal radiological and clinical findings occurred together with a disappearance of the increased pulmonary FDG uptake.FDG-PET can be used for evaluation of residual disease in patients treated for advanced seminoma. In cases of otherwise unexplained increased pulmonary FDG uptake in patients under treatment with bleomycin an evaluation for early BIP as a possible cause of this finding is warranted.

Traditionell wird bei Auftreten von Metastasen solider Tumoren von einem palliativen Krankheitsstadium ausgegangen. Lungenmetastasen sind eine haufige Erstmanifestation eines metastasierenden Tumorleidens und entwickeln sich im Krankheitsverlauf bei rund einem Drittel der Patienten.

La survenue de metastases de tumeurs solides indique generalement que la maladie se trouve a un stade palliatif. Les metastases pulmonaires sont une premiere manifestation frequente de cancer metastatique, et elles se developpent chez environ un tiers des patients au cours de la maladie.

The main treatment for advanced gastric cancer is fluoropyrimidine and platinum-based chemotherapy. We investigated the clinical validitiy of 19 candidate pharmacogenetic variants in ENOSF1 (enolase superfamily member 1), TYMS, CDA, MTHFR, TYMP, DPYD, ERCC1, ERCC2, GSTP1, GSTT1, GSTM1, CYP3A4 and CYP3A5 in relation to overall survival (OS), progression-free survival, objective response rate (ORR) and toxicity in 185 patients receiving triplet chemotherapy. The formal significance threshold was P

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.

The amount of sample available for clinical and biological proteomic research is often limited and thus significantly restricts clinical and translational research. Recently, we have integrated pressure cycling technology (PCT) assisted sample preparation and SWATH-MS to perform reproducible proteomic quantification of biopsy-level tissue samples. Here, we further evaluated the minimal sample requirement of the PCT-SWATH method using various types of samples, including cultured cells (HeLa, K562, and U251, 500 000 to 50 000 cells) and tissue samples (mouse liver, heart, brain, and human kidney, 3-0.2 mg). The data show that as few as 50 000 human cells and 0.2-0.5 mg of wet mouse and human tissues produced peptide samples sufficient for multiple SWATH-MS analyses at optimal sample load applied to the system. Generally, the reproducibility of the method increased with decreasing tissue sample amounts. The SWATH maps acquired from peptides derived from samples of varying sizes were essentially identical based on the number, type, and quantity of identified peptides. In conclusion, we determined the minimal sample required for optimal PCT-SWATH analyses, and found smaller sample size achieved higher quantitative accuracy.

Background Neutropenia is a frequent and severe adverse event in patients receiving paclitaxel chemotherapy. The time above a paclitaxel threshold concentration of 0.05 μmol/L (Tc > 0.05 μmol/L) is a strong predictor for paclitaxel-associated neutropenia and has been proposed as a target pharmacokinetic (PK) parameter for paclitaxel therapeutic drug monitoring and dose adaptation. Up to now, individual Tc > 0.05 μmol/L values are estimated based on a published PK model of paclitaxel by using the software NONMEM. Because many clinicians are not familiar with the use of NONMEM, an Excel-based dosing tool was developed to allow calculation of paclitaxel Tc > 0.05 μmol/L and give clinicians an easy-to-use tool. Methods Population PK parameters of paclitaxel were taken from a published PK model. An Alglib VBA code was implemented in Excel 2007 to compute differential equations for the paclitaxel PK model. Maximum a posteriori Bayesian estimates of the PK parameters were determined with the Excel Solver using individual drug concentrations. Concentrations from 250 patients were simulated receiving 1 cycle of paclitaxel chemotherapy. Predictions of paclitaxel Tc > 0.05 μmol/L as calculated by the Excel tool were compared with NONMEM, whereby maximum a posteriori Bayesian estimates were obtained using the POSTHOC function. Results There was a good concordance and comparable predictive performance between Excel and NONMEM regarding predicted paclitaxel plasma concentrations and Tc > 0.05 μmol/L values. Tc > 0.05 μmol/L had a maximum bias of 3% and an error on precision of 0.05 μmol/L values between both programs was 1%. Conclusions The Excel-based tool can estimate the time above a paclitaxel threshold concentration of 0.05 μmol/L with acceptable accuracy and precision. The presented Excel tool allows reliable calculation of paclitaxel Tc > 0.05 μmol/L and thus allows target concentration intervention to improve the benefit-risk ratio of the drug. The easy use facilitates therapeutic drug monitoring in clinical routine.

Clinical specimens are each inherently unique, limited and nonrenewable. Small samples such as tissue biopsies are often completely consumed after a limited number of analyses. Here we present a method that enables fast and reproducible conversion of a small amount of tissue (approximating the quantity obtained by a biopsy) into a single, permanent digital file representing the mass spectrometry (MS)-measurable proteome of the sample. The method combines pressure cycling technology (PCT) and sequential window acquisition of all theoretical fragment ion spectra (SWATH)-MS. The resulting proteome maps can be analyzed, re-analyzed, compared and mined in silico to detect and quantify specific proteins across multiple samples. We used this method to process and convert 18 biopsy samples from nine patients with renal cell carcinoma into SWATH-MS fragment ion maps. From these proteome maps we detected and quantified more than 2,000 proteins with a high degree of reproducibility across all samples. The measured proteins clearly distinguished tumorous kidney tissues from healthy tissues and differentiated distinct histomorphological kidney cancer subtypes.

Phenytoin dosing is critical in cancer patients as to decreased absorption secondary to chemotherapy-induced gastrointestinal toxicity, increased phenytoin metabolism in the liver secondary to chemotherapy, extreme patient profile that falls outside the predicted pharmacokinetic population, frequent hypoalbuminaemia and polydrug treatment. A retrospective study to assess the variability of free phenytoin and the free fraction of phenytoin, as well as the influence of comedication on these parameters was performed in cancer patients by using a population approach. Two hundred fifty-eight data pairs of total phenytoin and free phenytoin were analysed from 155 cancer patients on stable phenytoin using non-linear mixed-effect modeling (NONMEM). Total and free phenytoin were determined using a fluorescence polarization immunoassay. An extensive model building procedure was subsequently used for covariate testing on the free fraction of phenytoin. Mean total phenytoin concentration was 11.7 mg/l, free phenytoin 1.25 mg/l and phenytoin free fraction 0.107. Free phenytoin was1 mg/l on 132 occasions (51.2%) and2 mg/l on 37 occasions (14.3%). Total and free phenytoin were significantly correlated (r(S)=0.827, P0.01). The free fraction of phenytoin was independent of time after drug intake. Serum albumin concentrations and comedication with valproic acid or carbamazepine were identified by NONMEM as significant determinants of phenytoin free fraction. Co-medication with valproic acid and carbamazepine led to a 52.5% and 38.5% increase of the free fraction of phenytoin, respectively, and a 10 g/l decrease of serum albumin to a 15.1% increase of the free fraction of phenytoin. Phenytoin pharmacokinetics could reliably be estimated from oral doses and steady-state concentrations of protein-bound and free phenytoin. The variability in the free fraction of phenytoin could partly be explained by the influence of albumin concentrations and antiepileptic comedication. Significant alterations of the free fraction of phenytoin and free phenytoin by co-administration of valproic acid or carbamazepine suggest therapeutic drug monitoring of free phenytoin to be of potential benefit in cancer patients.

Deoxycytidine kinase (DCK) is the rate-limiting enzyme of the intracellular phosphorylation of nucleoside anticancer drugs, including gemcitabine and β-arabinofuranosylcytosine, to their active triphosphates. This study was performed to assess the occurrence and frequency of DCK polymorphisms in a predominantly Caucasian population and to choose candidate polymorphisms for subsequent functionality studies. All seven DCK exons and the promoter region were sequenced from 100 healthy volunteers (79 females and 21 males). With respect to ethnicity, the study cohort comprised 93 Caucasian, one Asian, one African, and five mixed-race individuals. Six novel single nucleotide polymorphisms (SNPs) were found (−243G>T, −135G>C, 261G>A, 364C>T, 727A>C, IVS6+41T>A). Two SNPs are nonsynonymous and lead to changes in the amino acid sequence [C364T in exon 3 (P121S) and A727C in exon 6 (K242Q)]. The presence of the linked promoter polymorphism −360C>G/−201C>T was confirmed in Caucasians, but was less frequent than what has been reported from Asians (allele frequencies 2 versus 15.6%). The most prevalent haplotype was the wild-type plus IVS6+41TT (85.8%). This study found novel DCK polymorphisms, including nonsynonymous SNPs, in exons 3 and 6. A comparison of the data obtained in this study with those reported in a previous study on Asians [Shi et al. (2004) Pharmacogenetics 14:759–768] illustrates marked inter-ethnic differences in the occurrence and frequency of DCK polymorphisms. The higher allelic frequency of the promoter polymorphism -C360G/-C201T in Asians than in Caucasians might predispose Asians to nucleoside drug-associated toxicity. These data will be used to assess the effect of DCK candidate SNPs (promoter, exons 3 and 6) in patients receiving gemcitabine anticancer treatment.

A method for sensitive determination of the anti-cancer agent oxaliplatin in human plasma and human plasma ultrafiltrate (pUF) is presented. The method is based on the quantification of platinum by graphite-furnace atomic-absorption spectrometry, with Zeeman correction and an atomisation temperature of 2,700 degrees C. Sample pretreatment involves dilution of the samples with a solution containing 0.15 mol L(-1) NaCl and 0.20 mol L(-1) HCl in water. Validation was performed in accordance with the most recent FDA guidelines for bioanalytical method validation. All results were within requirements. The validated ranges of quantification were 0.10-400 micromol L(-1) for human pUF and 0.50-400 micromol L(-1) for plasma. The assay is now successfully used to support pharmacokinetic studies of cancer patients treated with oxaliplatin.

Systemic chemotherapy is the treatment of choice for AIDS-related advanced Kaposi sarcoma. One principal schedule combines adriamycin (doxorubicin), bleomycin, and vincristine (ABV). We analysed the plasma concentrations of low-dose doxorubicin (Dx) and its metabolites doxorubicinol, 7-deoxydoxorubicinone, doxorubicinone, doxorubicinolone, and 7-deoxydoxorubicinolone in AIDS-patients to define patient-group and dose-specific pharmacokinetic parameters.A previously described high-performance liquid chromatographic (HPLC) method and a population approach with non-linear mixed effects modelling (NONMEM) were used for analysis and subsequent modelling of the time-concentration data of low-dose Dx and metabolites in seven patients with AIDS-related advanced Kaposi sarcoma. Patients received Dx 20 mg m(-2), bleomycin 15 U m(-2) and vincristine 2 mg as a 30-min intravenous infusion each. Blood samples were collected up to 72 h after the start of Dx treatment. WinNonlin software version 4.1 was used for non-compartmental analysis and NONMEM software version V for compartmental analysis. Covariate analysis was performed for various clinical and laboratory parameters.Non-compartmental analysis yielded an area under the plasma concentration-time curve (AUC) for Dx of 566 mug h L(-1), a maximum plasma concentration (c(max)) of 599 mug L(-1) and an elimination half-life (t(1/2)) of 30.8 h. Compartmental analysis resulted in a two-compartment model with first-order elimination, which best fitted the concentration-time data. Model estimate for Dx clearance was 61.8 L h(-1), for intercompartmental clearance (Q) 112 L h(-1), for the volume of the central compartment (V(1)) 23.3 L, and for the volume of the peripheral compartment (V(2)) 1,130 L. Metabolite data could adequately be estimated by NONMEM using single-compartment models. Graphical plots of residuals versus time for all metabolites yielded no evidence of non-linear pharmacokinetic behaviour. Laboratory parameters of liver and renal function were all in the normal range and their inclusion in the pharmacokinetic model did not improve data fit. A final jack-knife analysis was performed.Concentration-time data for low-dose Dx and metabolites in the ABV-regimen are best described by a two-compartment model with first-order elimination. The results confirm that the aglycones doxorubicinone, 7-deoxydoxorubicinone, and doxorubicinolone can be reliably detected in the studied patient group and implemented into a common metabolic model. Model estimates suggest that pharmacokinetic parameters are similar for low-dose Dx and higher-dosed Dx. As the role of the aglycones is still poorly understood, despite their potential clinical relevance, their analysis should be implemented in future pharmacokinetic and pharmacodynamic studies of Dx.

PurposeCirculating cell-free DNA is present in increased amounts in the blood of cancer patients, but the clinical relevance of this phenomenon remains unclear. We conducted a clinical study to assess the value of circulating DNA as a prognostic marker in patients with non–small-cell lung cancer (NSCLC).Patients and MethodsA standard protocol for the quantification of circulating DNA by real-time polymerase chain reaction was set up and validated at two oncology units. One hundred eighty-five informed patients with NSCLC and 46 healthy controls were included in the study. DNA concentrations were determined in paired plasma and serum samples and analyzed for a relationship with leukocyte counts and lactate dehydrogenase (LDH) levels. DNA concentrations in healthy controls and in patients were compared, and cutoff levels for plasma and serum DNA were determined. Patient survival was analyzed relative to baseline DNA concentrations, and the relationship between tumor responses and changes in DNA concentrations was assessed in patients receiving chemotherapy.ResultsWe found a significant correlation between increased plasma DNA concentrations and elevated LDH levels (P = .009), advanced tumor stage (P < .003), and poor survival (P < .001). Tumor progression after chemotherapy was significantly (P = .006) associated with increasing plasma DNA concentrations. Serum DNA concentrations strongly correlated (P < .001) with leukocyte counts.ConclusionOur data demonstrate that quantification of plasma DNA is an accurate technique amenable to standardization, which might complement current methods for the prediction of patient survival. This approach might be considered for evaluation in large prospective studies.

BACKGROUND: This study was initiated to explore the impact of organic cation transporter 1 (OCT1) and multidrug and toxin extrusion transporter 1 (MATE1) genetic polymorphisms on toxicity, and clinical activity of metformin in patients with castration-resistant prostate cancer (CRPC). METHODS: The SAKK 08/09 trial included 44 patients with CRPC to receive single-agent metformin 1000 mg two times a day until disease progression or unwanted toxicity. Drug pathway-associated gene polymorphisms of OCT1 (rs622342) and MATE1 (rs2289669) were assessed. The primary objective of this study was to define the relationship between mutations in OCT1, MATE1 and progression-free survival (PFS) at 12 weeks absolute PFS and PSA response in consenting patients of SAKK 08/09. The secondary objective of this study was to analyze the association between mutations in OCT1, MATE1, metformin-related toxicity, PSA response at 12 weeks and overall survival. RESULTS: Thirty-six patients were evaluable for pharmacogenetic analysis. Homozygous carriers of the polymorphic OCT1 C-allele had no metformin-related toxicity as compared with 41.9% for any metformin-related toxicity in carriers of at least one wild-type A-allele (P = 0.07). Disease progression according to RECIST (Response Evaluation Criteria In Solid Tumors) was significantly more frequent in homozygous carriers of the polymorphic OCT1 C-allele (80%) as compared with carriers of at least one wild-type A-allele (28.6%) (P = 0.002). Disease progression according to RECIST was also more frequent in carriers of at least one polymorphic MATE1 A-allele (44%) as compared with homozygous carriers of the wild-type G-allele (12.5%) (P = 0.07). OCT1 and MATE1 were not associated with PFS. CONCLUSIONS: The polymorphic OCT1 C-allele has been shown to be associated with less metformin-related toxicity and a higher risk of tumor progression in patients with CRPC receiving metformin as an anticancer treatment. Polymorphisms in metformin drug transporters are attractive molecular markers to serve as potential predictors of efficacy in future clinical studies.

BAY 1163877 is a potent and selective, oral, small molecule pan-FGFR inhibitor with anti-tumor activity in a wide range of cancer types. In vivo profiling in xenograft models identified tumor FGFR mRNA levels as a predictor of drug efficacy. Anti-tumor efficacy was largely independent of the tumor type surveyed or the FGFR isoform being overexpressed. Preclinical models included a patient-derived squamous head and neck cancer (HNSCC) xenograft (PDx) model overexpressing FGFR3 mRNA, a bladder cancer PDx model overexpressing FGFR2 mRNA, and a squamous esophageal cancer PDx model overexpressing FGFR1 mRNA. Against this background, clinical proof-of-concept was assessed by enrolling patients into the stratified expansion cohort of a Phase 1 study of BAY 1163877 (NCT01976741) based on tumor FGFR1-3 mRNA levels. FGFR1-3 mRNA was quantified in archival or newly obtained FFPE tumor biopsies by RNA in situ hybridization (RNAscope, ACD) and digital transcript counting (NanoString). In total, biopsies from > 500 patients were studied for FGFR1-3 mRNA expression levels. Based on preclinical xenograft experiments showing that low to moderate FGFR1-3 mRNA overexpression was not sufficient for a robust drug response, only patients with an RNAscope score of 3 or 4 (range 0-4) or a normalized Nanostring signal of 800 counts were eligible for enrollment. By applying these stringent criteria, FGFR1-3 mRNA positivity was on average observed with a 2- to 3-fold higher prevalence than published data for genetic aberrations of FGFRs in the respective tumor types (including amplifications, translocations, mutations). We further identified FGFR mRNA(+) tumor types in which genetic FGFR aberrations have not been previously reported. FGFR1-3 mRNA positivity ranged from 10% in lung adenocarcinoma to 45% in squamous non-small cell lung cancer (sqNSCLC) and 54% in HNSCC. As of August 2016, 57 FGFR mRNA(+) patients were enrolled and treated with BAY 1163877. Six patients experienced a partial remission (PR) by RECIST v1.1 criteria; including an FGFR3 mRNA(+) HNSCC patient without FGFR3 amplification or translocation, an FGFR1 mRNA(+) adenoid cystic carcinoma patient, and an FGFR1 mRNA(+) sqNSCLC patient (both without FGFR1 gene amplification), as well as an FGFR3 mRNA(+) bladder cancer patient without FGFR3 amplification, mutation or translocation. These results suggest that high FGFR1-3 mRNA expression identifies patients sensitive to FGFR inhibition. This population includes patients with and without genetic aberrations of FGFR1-3 encoding genes. In summary, an mRNA expression-based selection approach may identify a broader patient population with potential benefit from BAY 1163877, including tumor types not previously associated with altered FGFR signaling. Citation Format: Peter Ellinghaus, Matthias Ocker, Sebastian Bender, Christoph Kneip, Stuart Ince, Markus Joerger, Martin Schuler. Use of tumor mRNA expression for patient selection in a phase I study of the pan-fibroblast growth factor receptor inhibitor BAY 1163877 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3738. doi:10.1158/1538-7445.AM2017-3738

104 Background: BMS-986156 is a fully human IgG1 agonist mAb that binds GITR and promotes T effector cell activation and possible reduction/inactivation of T regulatory cells. Preclinical data show enhanced antitumor T-cell activity with anti-GITR + anti–programmed death-1 (PD-1). Here we describe preliminary dose escalation data from a phase I/IIa study of BMS-986156 ± nivolumab (anti–PD-1 mAb) in pts with advanced solid tumors (NCT02598960). Methods: During dose escalation, pts received BMS-986156 (10–800 mg) or BMS-986156 (30–800 mg) + nivolumab (240 mg) every 2 weeks. Objectives included safety (primary), immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Results: As of Dec 12, 2016, 66 pts were treated with BMS-986156 (n = 29) or BMS-986156 + nivolumab (n = 37).No dose-limiting toxicities (DLTs) were reported during dose escalation. The most common treatment-related adverse events reported with BMS-986156/BMS-986156 + nivolumab included pyrexia (21%/30%), chills (10%/16%), and fatigue (14%/14%); events were G1/2 in all pts except for 4 pts (6%) treated with the combination (G3 lipase [n = 1], G3 lung infection [n = 1], G3 fatigue [n = 1], and G3 aspartate aminotransferase with G4 creatine phosphokinase [n = 1; leading to discontinuation of treatment]). Preliminary data indicate that the incidence of immunogenicity to BMS-986156 was low when BMS-986156 ± nivolumab was administered. Preliminary data also indicate that BMS-986156 ± nivolumab exhibits linear PK with dose proportionality after a single dose, and BMS-986156 ± nivolumab is biologically active in PD analyses in peripheral blood. Initial antitumor activity has been observed in several pts treated with the combination; these data will be reported. Conclusions: This is the first report of clinical data with an anti-GITR mAb ± a PD-1 inhibitor.BMS-986156 ± nivolumab was well tolerated, with no DLTs and low immunogenicity. Antitumor activity was observed with BMS-986156 + nivolumab at doses predicted to be biologically active. Further evaluation of this combination in pts with advanced solid tumors is ongoing. Clinical trial information: NCT02598960.

386 Background: FGFRs play a role in a variety of malignancies, including urothelial bladder cancer (UBC). Whereas genetic alterations of FGFRs in UBC are known, non-genetic and epigenetic activation of FGFR gene expression have also been described. BAY 1163877 is an oral inhibitor of FGFRs 1-3 with antitumor activity in FGFR mRNA overexpressing xenograft models not limited to DNA alterations. We report the results from a phase I expansion cohort in UBC patients pre-screened for treatment with BAY 1163877 based on FGFR1-3 mRNA overexpression and/or activating mutations in the FGFR3 gene. Methods: FGFR mRNA levels were assessed in paraffin-embedded archival or fresh biopsy specimens by RNAscope and NanoString technology and activating mutations by RT-PCR-based mutation assay. Tumor response to treatment was assessed by RECIST, v1.1. Adverse events were assessed using CTCAE v4.03 criteria. Results: A total of 80 patients from multiple indications were enrolled in the phase I study; 800 mg BID was established as the recommended phase 2 dose. Sixty seven UBC patients were screened, with 31 tumor biopsies (46%) determined to overexpress FGFR mRNA: 2 patients each with FGFR1 and FGFR2, and 27 patients with FGFR3. Of the 27 patients with FGFR3 mRNA overexpression, 5 had in parallel an activating mutation in FGFR3 gene. Eight UBC patients met eligibility criteria and entered treatment; all had elevated FGFR3 mRNA expression and 4 had alterations in FGFR3 DNA (3 mutations and 1 translocation). Seven patients (87.5%) had tumor shrinkage in target lesions as best response, with 3/8 partial responses (PR; 37.5%). One patient with a PR presented with elevated FGFR3 mRNA without evidence of aberrant DNA. BAY 1163877 was generally well tolerated and AEs manageable with dose modification. The most common AEs in the overall population were increased phosphorus (66% all grade, 1 grade-3 event) and diarrhea (33% all grade, 2 grade-3 events). Conclusions: Selection of patients for treatment with BAY 1163877 based on FGFR mRNA expression levels in archival tissue was feasible. BAY 1163877 had a favorable safety profile and promising anti-tumor activity in UBC patients. Clinical trial information: NCT01976741.

Aim: Decreased DPD activity is a major cause of 5-fluorouracil (5-FU) toxicity, but known reduced-function variants in the DPD gene (DPYD) explain only a part of DPD-related 5-FU toxicities. Here, we evaluated the baseline (pretherapeutic) plasma 5,6-dihydrouracil:uracil (UH2:U) ratio as a marker of DPD activity in the context of DPYD genotypes. Materials & methods: DPYD variants were genotyped and plasma U, UH2 and 5-FU concentrations were determined by liquid chromatography-tandem mass spectrometry in 320 healthy blood donors and 28 cancer patients receiving 5-FU-based chemotherapy. Results: Baseline UH2:U ratios were strongly correlated with generally low and highly variable U concentrations. Reduced-function DPYD variants were only weakly associated with lower baseline UH2:U ratios. However, the interindividual variability in the UH2:U ratio was reduced and a stronger correlation between ratios and 5-FU exposure was observed in cancer patients during 5-FU administration. Conclusion: These results suggest that the baseline UH2:U plasma ratio in most individuals reflects the nonsaturated state of DPD and is not predictive of decreased DPD activity. It may, however, be highly predictive at increased substrate concentrations, as observed during 5-FU administration. Original submitted 9 May 2014; Revision submitted 20 August 2014

We present the case of a patient with rapidly accelerated fibrosarcoma gene F (BRAF) mutated adenocarcinoma of the lung, responding to BRAF inhibitor dabrafenib after progressing on vemurafenib followed by docetaxel. The present case illustrates the potential benefit of successful rechallenge with a BRAF inhibitor, a well known phenomenon observed in other oncogenic driven molecular subtypes of non-small cell lung cancer (NSCLC) such as epidermal growth factor receptor mutation. Rechallenge with a BRAF inhibitor in BRAF mutated NSCLC should be considered, particularly in the absence of alternative therpateutic options.

We investigated the clinical relevance of dihydropyrimidine dehydrogenase gene (DPYD) variants to predict severe early-onset fluoropyrimidine (FP) toxicity, in particular of a recently discovered haplotype hapB3 and a linked deep intronic splice site mutation c.1129-5923C>G. Selected regions of DPYD were sequenced in prospectively collected germline DNA of 500 patients receiving FP-based chemotherapy. Associations of DPYD variants and haplotypes with hematologic, gastrointestinal, infectious, and dermatologic toxicity in therapy cycles 1-2 and resulting FP-dose interventions (dose reduction, therapy delay or cessation) were analyzed accounting for clinical and demographic covariates. Fifteen additional cases with toxicity-related therapy delay or cessation were retrospectively examined for risk variants. The association of c.1129-5923C>G/hapB3 (4.6% carrier frequency) with severe toxicity was replicated in an independent prospective cohort. Overall, c.1129-5923G/hapB3 carriers showed a relative risk of 3.74 (RR, 95% CI = 2.30-6.09, p = 2 × 10(-5)) for severe toxicity (grades 3-5). Of 31 risk variant carriers (c.1129-5923C>G/hapB3, c.1679T>G, c.1905+1G>A or c.2846A>T), 11 (all with c.1129-5923C>G/hapB3) experienced severe toxicity (15% of 72 cases, RR = 2.73, 95% CI = 1.61-4.63, p = 5 × 10(-6)), and 16 carriers (55%) required FP-dose interventions. Seven of the 15 (47%) retrospective cases carried a risk variant. The c.1129-5923C>G/hapB3 variant is a major contributor to severe early-onset FP toxicity in Caucasian patients. This variant may substantially improve the identification of patients at risk of FP toxicity compared to established DPYD risk variants (c.1905+1G>A, c.1679T>G and c.2846A>T). Pre-therapeutic DPYD testing may prevent 20-30% of life-threatening or lethal episodes of FP toxicity in Caucasian patients.

There is no personalized anticancer treatment without individualized dosing. Clearly, BSA-based chemotherapy dosing does not improve the substantial pharmacokinetic variability of individual drugs. Similarly, the new oral kinase inhibitors and endocrine compounds exhibit a marked pharmacokinetic variability due to variable absorption, hepatic metabolism and potential drug-drug and food-drug interactions. Therapeutic drug monitoring and genotyping may allow more individualized dosing of anticancer compounds in the future. However, the large number of anticancer drugs that are newly approved or undergoing preclinical development are a substantial challenge for the development of substance-specific dosing algorithms. It will be necessary to implement individual dosing strategies in the early clinical development of new anticancer drugs to inform clinicians at the time of first approval.Die individualisierte Dosierung ist wesentlicher Teil der «personalisierten Onkologie». Von den klassischen Zytostatika ist bekannt, dass die Dosierung nach BSA keine Verbesserung der stark variablen, individuellen Plasmakonzentrationen bringt. Die neuen oralen Kinaseinhibitoren wie auch die endokrinen Substanzen weisen eine erhebliche Variabilität der individuellen Plasmakonzentrationen aus, bedingt durch variable Absorption, hepatische Metabolisierung, sowie eine Vielfalt möglicher Interaktionen. Therapeutisches Drug Monitoring und die Genotypisierung sind wichtige Werkzeuge, die in Zukunft eine individualisierte Dosierung in der Onkologie erlauben könnten. Die grosse Anzahl neu zugelassener und in Entwicklung sich befindender Onkologika bedeutet aber eine grosse Herausforderung an die Entwicklung entsprechender Dosisalgorithmen. Nur wenn individualisierte Dosisstrategien bereits in die frühe klinische Entwicklung einbezogen werden, können Substanz-spezifische Empfehlungen rechtzeitig in die klinische Praxis einfliessen.Il n'existe pas de traitement personnalisé du cancer sans individualisation de la dose. La détermination de la dose de chimiothérapie tenant compte de la surface corporelle n'améliore pas substantiellement la variabilité pharmacocinétique des médicaments individuels. Par ailleurs, les nouveaux inhibiteurs de la tyrosine kinase actifs par voie orale et les substances endocriniennes montrent une grande variabilité sur le plan de la pharmacocinétique en raison de la variabilité de l'absorption, du métabolisme hépatique et des interactions potentielles entre différents médicaments et la nourriture. Le monitorage thérapeutique des médicaments et le typage génétique peuvent améliorer dans le futur le dosage individualisé des médicaments anticancéreux. Néanmoins, un grand nombre de ces médicaments approuvés récemment pour un usage clinique ou en phase de développement préclinique représentent un challenge important en ce qui concerne le développement d'algorithmes tenant compte du dosage spécifique de chaque substance. Il va être nécessaire d'implémenter des stratégies de dosage spécifique précocement au cours du développement clinique des nouveaux médicaments anticancéreux afin d'en informer les cliniciens au moment de leur mise à disposition sur le marché.

627^ Background: Preclinical data show PI3K-pathway inhibition can enhance the efficacy of anticancer therapy, such as PTX or TZ. In this 4-arm Ph Ib study (NCT01285466), buparlisib (pan-PI3K inhib...

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.

Penile cancer is rare in Western countries. High-risk patients are considered for prophylactic inguinal lymphadenectomy. For advanced disease, a triplet drug regimen consisting of bleomycin, methotrexate, and cisplatin is the most active combination tested so far. A 62-year-old man with penile cancer underwent partial penile amputation but presented 10 months later with inguinal nodal metastasis. He received three cycles of paclitaxel/carboplatin with marked clinical and radiologic (computed tomography and positron emission tomography) tumor regression. Later, complete resection of the inguinal nodal metastasis was performed. The paclitaxel/carboplatin combination has potential activity in penile cancer. Positron emission tomography may be used for screening of nodal metastases.

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.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 to70, 70 to75, 75 to80 and ≥80years), and the predictive impact of patient age on specific treatments was calculated using multivariate logistic regression analysis.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.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.

523Background: Tamoxifen is commonly used to treat estrogen receptor (ER)-positive breast cancers, though the response to tamoxifen and its adverse event profile have a high degree of inter-individ...

Background: Optimal management of elderly patients (≥70 years) with non-small cell lung cancer (NSCLC) remains debatable. We compared survival and treatment of advanced NSCLC between elderly and younger patients. Methods: From the cancer registry, we identified 188 patients treated with chemotherapy for stage IV NSCLC. Patient characteristics, survival, toxicity, chemotherapy regimen and response were compared between age groups (patients 50-69 vs. ≥70 years). Results: There were 96 young and 92 elderly patients. The majority were male (70%) and had adenocarcinoma (53%). More elderly had an ECOG performance status >1 (59 vs. 42%, p = 0.04). Median survival was longer for young patients (11.5 vs. 10.8 months, hazard ratio, HR 1.43, p = 0.04). Patients ≥75 years had a significantly worse outcome compared to the young and patients aged 70-74 years (11.5 vs. 12.8 vs. 7.7 months, HR 1.71, p = 0.01). Hospitalization rate did not differ. Elderly had more hematological toxicities (56 vs. 32%, p = 0.01) and less frequently received first-line platinum combinations (96 vs. 69%, p < 0.001). Conclusions: Elderly patients had a marginally worse survival compared to young patients. Despite the less frequent use of combination chemotherapy, elderly patients experienced toxicity more often. Survival of those ≥75 years was significantly worse, indicating the urgent need of further research particularly in this age group.

This study was initiated to assess the quantitative impact of patient anthropometrics and dihydropyrimidine dehydrogenase (DPYD) mutations on the pharmacokinetics (PK) of 5-fluorouracil (5FU) and to explore limited sampling strategies of 5FU.We included 32 patients with gastrointestinal malignancies, receiving 46-h continuous-infusional 5FU and performed PK-sampling at baseline, 15, 30, 45 min, 1 and 2 h after the start of infusion and at the end of infusion, for 2 subsequent cycles. Plasma concentrations of 5FU, 5-fluorodihydrouracil (5FUH2), uracil (U) and 5,6-dihydrouracil (UH2) were determined using LC-MS/MS and submitted to population PK analysis using nonlinear mixed-effects modeling. Broad genotyping of DPYD was performed, and the potential impact of the DPYD genotype on the elimination of 5FU was assessed. Limited sampling strategies were evaluated for their accuracy to predict steady-state concentrations of 5FU (CSS(5FU)), using data simulations based on the final PK-model.The area-under-the concentration-time curve of 5FU (AUC(5FU)) was found to be20 mg h/L in 33 occasions (58 %), between 20 and 30 mg h/L in 17 occasions (30 %) and30 mg h/L in 7 occasions (12 %). Men had a 26 % higher elimination of 5FU and a 18 % higher apparent elimination of 5FUH2. Accordingly, women had a higher AUC(5FU) compared to men (22 vs. 18 mg h/L, p = 0.04). No DPYD risk variants were found, and the DPYD variants detected (c.496AG, c.1601GA, c.1627AG) were not significantly associated with the elimination of 5FU. Individual baseline UH(2)/U ratio was significantly associated with AUC(5FU) (R = -0.49, p0.001). Limited sampling strategies with time-points3 h after the start of infusion were not adequate to predict CSS(5FU). Female gender was the only predictor of nausea/emesis in the multivariate model.Gender-specific elimination of 5FU is supported by the present data and may partly explain the gender-specific association between DPYD risk variants and 5FU-specific toxicity.

Methotrexate (MTX) at a dose of ≥1 g/m(2) remains the most efficient treatment against primary central nervous system lymphoma (PCNSL), and is the most widely used drug in prospective clinical trials. MTX is a folate analog that inhibits dihydrofolate reductase, thereby blocking de novo purine synthesis. MTX as well as 7-hydroxy-MTX, its main metabolite in serum, are both eliminated by the kidneys. The elimination of MTX is prolonged in patients with renal impairment and third-space fluid collections, and in patients receiving concurrent non-steroidal antirheumatic drugs, benzimidazoles and sulfonamides, among others. Main adverse events with high-dose MTX include severe myelosuppression, renal dysfunction and stomatitis. Supportive measures such as rigorous hydration, urine alkalinization and careful drug monitoring with supplemental leucovorin rescue are crucial to avoid significant toxicity. Strategies to optimize clinical efficacy of high-dose MTX in patients with PCNSL include administration of 3 h instead of longer infusions, potentially supplemented with an additional intravenous MTX bolus, and maintaining MTX dose intensity over the course of four treatment cycles. Some pharmacological studies suggest that achieving an MTX area under the plasma concentration-time curve (AUC(MTX)) of between 1000 and 1100 μmol.h/L may improve clinical outcome, but clinical data are not conclusive at present. In this review, we analyze the impact of patient, lymphoma and pharmacokinetic variables on the antitumor activity of high-dose MTX in patients with PCNSL, summarize recommendations for daily clinical practice and give some suggestions for future trials.

The use of bone turnover markers in oncology includes monitoring of anticancer treatment in patients with malignant disease metastatic to the bones (therapeutic monitoring), predicting the risk of bone relapse in patients with a first diagnosis of potentially curative, early-stage malignant tumors (prognostic use), and making an early diagnosis of (microscopic) malignant bone disease in patients with a known malignant tumor to start early bone-targeted treatment and avoid skeletal-related events (diagnostic use). Concerning prognostic use, there is limited evidence for bone turnover markers to predict the occurrence of metachronous bone metastases in patients with early-stage malignant tumors, with serum PINP (N-terminal propeptide of procollagen type 1), ICTP (Carboxyterminal cross-linked telopeptide of type I collagen), bone sialoprotein (BSP), and tumor immunoexpression of BSP being the most promising candidates. Concerning diagnostic use, serum bone-specific alkaline phosphatise (BSAP), PINP and osteoprotegerin (OPG) were repeatedly shown to be associated with synchronous bone metastases in patients with breast or lung cancer, but sensitivity of these markers was too low to suggest that they might be preferred over conventional bone scans for the diagnosis of bone metastases. A somewhat higher sensitivity for the diagnosis of bone metastases was found for urinary NTx (N-terminal cross-linked telopeptide of type I collagen) and serum ICTP in solid tumor patients, serum TRAcP-5b (Tartrate-resistant acid phosphatase type 5b) in patients with breast cancer and serum BSAP, PINP and OPG in prostate cancer patients. Both prognostic and diagnostic use of bone turnover markers are reviewed in this chapter.

When modeling pharmacokinetic (PK) data, identifying covariates is important in explaining interindividual variability, and thus increasing the predictive value of the model. Nonlinear mixed-effects modeling with stepwise covariate modeling is frequently used to build structural covariate models, and the most commonly used software—NONMEM—provides estimations for the fixed-effect parameters (e.g., drug clearance), interindividual and residual unidentified random effects. The aim of covariate modeling is not only to find covariates that significantly influence the population PK parameters, but also to provide dosing recommendations for a certain drug under different conditions, e.g., organ dysfunction, combination chemotherapy. A true covariate is usually seen as one that carries unique information on a structural model parameter. Covariate models have improved our understanding of the pharmacology of many anticancer drugs, including busulfan or melphalan that are part of high-dose pretransplant treatments, the antifolate methotrexate whose elimination is strongly dependent on GFR and comedication, the taxanes and tyrosine kinase inhibitors, the latter being subject of cytochrome p450 3A4 (CYP3A4) associated metabolism. The purpose of this review article is to provide a tool to help understand population covariate analysis and their potential implications for the clinic. Accordingly, several population covariate models are listed, and their clinical relevance is discussed. The target audience of this article are clinical oncologists with a special interest in clinical and mathematical pharmacology.

Methotrexate at doses ≥1 g/m2remains the most efficient anticancer drug against primary central nervous system lymphoma, and is the most widely used drug in prospective cli­nical trials. Methotrexate is a folate analogue that inhibits dihydrofolate reductase, thereby blocking de novo purine synthesis. After intracellular uptake by the reduced folate carrier and the folate receptor-α, methotrexate undergoes intracellular polyglutamation by folypolyglutamate synthase on the γ-position of the parent glutamate moiety, resulting in the active polyglutamate moieties. Methotrexate as well as 7-hydroxy-methotrexate, its main metabolite in serum, are both eliminated by the kidneys. Accordingly, the elimination of methotrexate is prolonged in patients with renal impairment or third space fluid collections, due to a slow redistribution of methotrexate from this extravascular compartment. Main unwanted adverse events with high-dose methotrexate include severe myelosuppression, renal dysfunction and mucositis with diarrhea or stomatitis. Therefore, supportive measures such as rigorous hydration, urine alkalinization and careful drug monitoring with supplemental leucovorin rescue are used to avoid significant drug-related adverse events. A recent randomized clinical study has established a new treatment standard by showing an improved clinical outcome with the addition of high-dose cytarabine 2 g/m2twice daily on days 2 and 3 to high-dose methotrexate 3.5 g/m2on day 1, repeated every 3 weeks, and followed by consolidating radiotherapy if necessary.

Preclinical models that illuminate the bone metastasis cascade.- The role of bone microenvironment, vitamin D and calcium.- Bisphosphonates: Prevention of bone metastases in breast cancer.- Bisphosphonates: Prevention of bone metastases in lung cancer.- Bisphosphonates: Prevention of bone metastases in prostate cancer.- Bisphosphonates: Prevention of disease progression in patients with multiple myeloma.- Combinations of bisphosphonates and classical anticancer drugs - a preclinical perspective.- Special issues in the elderly patient.- Denosumab: First data and ongoing studies on the prevention of bone metastases.- Diagnostic and prognostic use of bone turnover markers.- Osteolytic and osteoblastic bone metastases: Two extremes of the same spectrum?.

The use of bone turnover markers in oncology includes monitoring of anticancer treatment in patients with malignant disease metastatic to the bones (therapeutic monitoring), predicting the risk of bone relapse in patients with a first diagnosis of potentially curative, early-stage malignant tumors (prognostic use), and making an early diagnosis of (microscopic) malignant bone disease in patients with a known malignant tumor to start early bone-targeted treatment and avoid skeletal-related events (diagnostic use). Concerning prognostic use, there is limited evidence for bone turnover markers to predict the occurrence of metachronous bone metastases in patients with early-stage malignant tumors, with serum PINP (N-terminal propeptide of procollagen type 1), ICTP (Carboxyterminal cross-linked telopeptide of type I collagen), bone sialoprotein (BSP), and tumor immunoexpression of BSP being the most promising candidates. Concerning diagnostic use, serum bone-specific alkaline phosphatise (BSAP), PINP and osteoprotegerin (OPG) were repeatedly shown to be associated with synchronous bone metastases in patients with breast or lung cancer, but sensitivity of these markers was too low to suggest that they might be preferred over conventional bone scans for the diagnosis of bone metastases. A somewhat higher sensitivity for the diagnosis of bone metastases was found for urinary NTx (N-terminal cross-linked telopeptide of type I collagen) and serum ICTP in solid tumor patients, serum TRAcP-5b (Tartrate-resistant acid phosphatase type 5b) in patients with breast cancer and serum BSAP, PINP and OPG in prostate cancer patients. Both prognostic and diagnostic use of bone turnover markers are reviewed in this chapter.

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.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.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.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.

There is no consensus regarding optimal dosing of high dose methotrexate (HDMTX) in patients with primary CNS lymphoma. Our aim was to develop a convenient dosing algorithm to target AUC(MTX) in the range between 1000 and 1100 µmol l(-1) h.A population covariate model from a pooled dataset of 131 patients receiving HDMTX was used to simulate concentration-time curves of 10,000 patients and test the efficacy of a dosing algorithm based on 24 h MTX plasma concentrations to target the prespecified AUC(MTX) . These data simulations included interindividual, interoccasion and residual unidentified variability. Patients received a total of four simulated cycles of HDMTX and adjusted MTX dosages were given for cycles two to four.The dosing algorithm proposes MTX dose adaptations ranging from +75% in patients with MTX C(24)0.5 µmol l(-1) up to -35% in patients with MTX C(24)12 µmol l(-1). The proposed dosing algorithm resulted in a marked improvement of the proportion of patients within the AUC(MTX) target between 1000 and 1100 µmol l(-1) h (11% with standard MTX dose, 35% with the adjusted dose) and a marked reduction of the interindividual variability of MTX exposure.A simple and practical dosing algorithm for HDMTX has been developed based on MTX 24 h plasma concentrations, and its potential efficacy in improving the proportion of patients within a prespecified target AUC(MTX) and reducing the interindividual variability of MTX exposure has been shown by data simulations. The clinical benefit of this dosing algorithm should be assessed in patients with primary central nervous system lymphoma (PCNSL).

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.

Department of Oncology and Hematology, Cantonal Hospital, St. Gallen, Switzerland, Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands, Department of Hematology and Oncology, University Medical Center, Freiburg, Germany, and Unit of Lymphoid Malignancies, Department of Onco-Hematology, San Raffaele Scientific Institute, Milan, Italy

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.