Pharmacokinetics Of Chemotherapy Research Articles

Nanoparticle drug delivery systems responsive to tumor microenvironment: Promising alternatives in the treatment of triple-negative breast cancer.

The conventional therapeutic treatment of triple-negative breast cancer (TNBC) is negatively influenced by the development of tumor cell drug resistant, and systemic toxicity of therapeutic agents due to off-target activity. In accordance with research findings, nanoparticles (NPs) responsive to the tumor microenvironment (TME) have been discovered for providing opportunities to selectively target tumor cells via active targeting or Enhanced Permeability and Retention (EPR) effect. The combination of the TME control and therapeutic NPs offers promising solutions for improving the prognosis of the TNBC because the TME actively participates in tumor growth, metastasis, and drug resistance. The NP-based systems leverage stimulus-responsive mechanisms, such as low pH value, hypoxic, excessive secretion enzyme, concentration of glutathione (GSH)/reactive oxygen species (ROS), and high concentration of Adenosine triphosphate (ATP) to combat TNBC progression. Concurrently, NP-based stimulus-responsive introduces a novel approach for drug dosage design, administration, and modification of the pharmacokinetics of conventional chemotherapy and immunotherapy drugs. This review provides a comprehensive examination of the strengths, limitations, applications, perspectives, and future expectations of both novel and traditional stimulus-responsive NP-based drug delivery systems for improving outcomes in the medical practice of TNBC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Mechanistic Modeling of Intrathecal Chemotherapy Pharmacokinetics in the Human Central Nervous System.

The pharmacokinetics of intrathecally administered antibody or small-molecule drugs in the human central nervous system (CNS) remains poorly understood. This study aimed to provide mechanistic and quantitative perspectives on the CNS pharmacokinetics of intrathecal chemotherapy, by using a physiologically based pharmacokinetic (PBPK) modeling approach. A novel CNS PBPK model platform was developed and verified, which accounted for the human CNS general anatomy and physiologic processes governing drug distribution and disposition. The model was used to predict CNS pharmacokinetics of antibody (trastuzumab) and small-molecule drugs (methotrexate, abemaciclib, tucatinib) following intraventricular injection or intraventricular 24-hour infusion, and to assess the key determinants of drug penetration into the deep brain parenchyma. Intraventricularly administered antibody and small-molecule drugs exhibited distinct temporal and spatial distribution and disposition in human CNS. Both antibody and small-molecule drugs achieved supratherapeutic or therapeutic concentrations in the cerebrospinal fluid (CSF) compartments and adjacent brain tissue. While intrathecal small-molecule drugs penetrated the deep brain parenchyma to a negligible extent, intrathecal antibodies may achieve therapeutic concentrations in the deep brain parenchyma. Intraventricular 24-hour infusion enabled prolonged CNS exposure to therapeutically relevant concentrations while avoiding excessively high and potentially neurotoxic drug concentrations. CNS PBPK modeling, in line with available clinical efficacy data, confirms the therapeutic value of intrathecal chemotherapy with antibody or small-molecule drugs for treating neoplastic meningitis and warrants further clinical investigation of intrathecal antibody drugs to treat brain parenchyma tumors. Compared with intraventricular injection, intraventricular 24-hour infusion may mitigate neurotoxicity while retaining potential efficacy.

Pharmacokinetic evaluation of oxaliplatin combined with S-1 (SOX) chemotherapy in a rat model of colorectal cancer with acute kidney injury: predictive renal biomarkers for dose optimisation

Dose adjustment based on renal function is essential in S-1, which contains the 5‑fluorouracil prodrug tegafur, and platinum-based agent oxaliplatin (SOX) combination chemotherapy for colorectal cancer in patients with chronic kidney disease. However, limited evidence on dose adjustment in acute kidney injury (AKI) and challenges in determining dosing strategies. This study investigated the pharmacokinetics of SOX chemotherapy and renal biomarkers in rats. AKI was prepared by renal ischaemia-reperfusion injury in 1,2-dimethylhydrazine-induced colorectal cancer model rats. Serum creatinine (sCr) levels were determined as a renal biomarker. After administration of S-1 (2 mg/kg tegafur) and oxaliplatin (5 mg/kg), drug concentrations of tegafur, 5-FU, and platinum were measured in the plasma and tumours. No alterations in the area under the plasma concentration–time curve (AUC0-24h ) values of 5-fluorouracil were observed between control and AKI model rats. The tumour concentrations of 5-fluorouracil in the mild and severe AKI groups were significantly lower than control group. The AUC0-24h for platinum increased with AKI severity. Notably, population pharmacokinetic analysis identified sCr as a covariate in platinum distribution after SOX chemotherapy. To optimise dose adjustment of SOX chemotherapy in patients with AKI, sCr may be a key factor in determining the appropriate dose.

Multicenter Phase 1b/2a Clinical Trial of Radioprotectant BIO 300 Oral Suspension for Patients With Non-Small Cell Lung Cancer Receiving Concurrent Chemoradiotherapy

Radiation therapy is part of the standard treatment regimen for non-small cell lung cancer (NSCLC). Although radiation therapy is an effective tool to manage NSCLC, it can be associated with significant dose-limiting toxicities. These toxicities can lead to treatment interruption or early termination and worsening clinical outcomes in addition to reductions in patient quality of life. Based on preclinical efficacy for radioprotection of normal tissues, we evaluated the clinical utility of BIO 300 Oral Suspension (BIO 300; synthetic genistein nanosuspension) in patients with NSCLC. In this multicenter, open-label, single-arm, ascending dose phase 1b/2a study, patients were enrolled with newly diagnosed stage II-IV NSCLC planned for 60 to 70/1.8-2.0 Gy radiation therapy and concurrent weekly paclitaxel/carboplatin. Oral BIO 300 (cohort 1, 500 mg/d; cohort 2, 1000 mg/d; cohort 3, 1500 mg/d) was self-administered once daily starting 2 to 7 days before initiating concurrent chemoradiotherapy and continued until the end of radiation therapy. The primary endpoint was acute dose-limiting toxicities attributable to BIO 300. Secondary outcomes included pharmacokinetics, pharmacodynamics, overall toxicity profile, quality of life, local response rate, and survival. Twenty-one participants were enrolled. No dose-limiting toxicities were reported. BIO 300 dosing did not alter chemotherapy pharmacokinetics. Adverse events were not dose-dependent, and those attributable to BIO 300 (n=11) were all mild to moderate in severity (grade 1, n=9; grade 2, n=2) and predominantly gastrointestinal (n=7). A dose-dependent decrease in serum transforming growth factor β1 levels was observed across cohorts. Based on safety analysis, the maximum tolerated dose of BIO 300 was not met. Patient-reported quality of life and weight were largely stable throughout the study period. No patient had progression as their best overall response, and a 65% tumor response rate was achieved (20% complete response rate). The low toxicity rates, along with the pharmacodynamic results and tumor response rates, support further investigation of BIO 300 as an effective radioprotector.

Impact of undernutrition on the pharmacokinetics of chemotherapy in children with cancer: A systematic review.

This systematic review provides an overview of the effect of undernutrition on the pharmacokinetics of chemotherapy in children with cancer. PubMed, Embase, and Cochrane were searched to identify eligible studies. This study uses the definition for undernutrition from the World Health Organization and the Gomez classification. Four studies with a total of 668 children with cancer were included and n=121 (18%) were undernourished. Significant decreased clearance rates were found for vincristine in undernourished children compared to children with a normal nutritional status. Presenting outcomes only show significant changes in the pharmacokinetics of vincristine in undernourished children with cancer. However, data are scarce, groups were small, and none of the studies included severely undernourished children. In order to improve outcomes for (severely) undernourished children with cancer, more pharmacokinetic research is needed. The ultimate goal would be to develop subgroups, and ultimately individualized drug dosing in order to improve outcomes for children with cancer worldwide.

A prospective study of dysgeusia and related symptoms in patients with multiple myeloma after autologous hematopoietic cell transplantation.

Dysgeusia is a common but understudied complication in patients undergoing autologous hematopoietic cell transplantation (auto-HCT). We assessed the feasibility of using chemical gustometry (CG) to measure dysgeusia and explored its associations with symptom burden, nutrition, chemotherapy pharmacokinetics (PK), and the oral microbiome. We conducted a single-center, prospective feasibility study (NCT03276481) of patients with multiple myeloma undergoing auto-HCT. CG was performed longitudinally testing five flavors (sweet, sour, salty, bitter, umami) to calculate a total taste score (maximum score, 30). We measured caloric intake and patient-reported symptoms, assessing their correlation with oral microbiota composition and salivary and blood melphalan PK exposure. Among all 45 patients, 39 (87%) completed at least four (>60%) and 22 (49%) completed all six CG assessments. Median total CG scores remained stable over time but were lowest at day +7 (27, range 24-30) with recovery by day +100. Symptom burden was highest by day +10 (area under the curve, 2.9; range, 1.0-4.6) corresponding with the lowest median overall caloric intake (1624 kcal; range, 1345-2267). Higher serum/salivary melphalan levels correlated with higher patient-reported dysgeusia and lower caloric intake. Oral microbiota α-diversity was stable early and increased slightly by day +100. Assessment of dysgeusia by CG is feasible after auto-HCT. Most dysgeusia, symptom burden, and lowest caloric intake occurred during the blood count nadir. Higher melphalan concentrations correlated with more dysgeusia and poorer caloric intake. Future studies will aim to modulate melphalan exposure by PK-targeted dosing and characterize patient taste preferences to personalize diets for improved nutritional intake. Taste changes after cancer treatments are very common. We used chemical gustometry (taste testing) to study taste changes and to better understand why patients with multiple myeloma experience this symptom after autologous hematopoietic cell transplantation. We found that taste testing was feasible, taste changes peaked when blood counts were lowest, and most patients recovered their taste by 100 days after transplantation. Taste changes correlated with lower food intake and with higher levels of chemotherapy in the body. Future work will focus on using personalized chemotherapy doses to reduce taste changes and to match patients' individual taste preferences with their diets.

Effect of Scalp Cooling on the Pharmacokinetics of Paclitaxel.

Simple SummaryThis study investigated the correlation between scalp cooling used to prevent chemotherapy-induced alopecia and the pharmacokinetics of paclitaxel in female cancer patients with a solid tumor. In a prospective cohort study, 14 patients who were treated with weekly paclitaxel and scalp cooling were able to undergo pharmacokinetic sampling of paclitaxel during one cycle of treatment. In comparison to a control cohort of 24 patients treated with weekly paclitaxel without scalp cooling, our data showed that scalp cooling used concomitantly with one course of paclitaxel did not reduce or increase the clearance of paclitaxel. Therefore, it is unlikely that scalp cooling influences paclitaxel efficacy or toxicity. Finally, despite scalp cooling, half of the patients in our study developed a form of hair loss. Importantly, neither an association with difference in paclitaxel clearance nor change in hair loss was found.Chemotherapy-induced alopecia (CIA), a side effect with high impact, can be prevented by cooling the scalp during the administration of some cytotoxic drugs. However, the effects of this prolonged scalp cooling on the pharmacokinetics of chemotherapy have never been investigated. In this study, we compared the pharmacokinetics of the widely used chemotherapeutic agent paclitaxel (weekly dose of 80–100 mg/m2) in female patients with solid tumors using concomitant scalp cooling (n = 14) or not (n = 24). Blood samples were collected in all patients for pharmacokinetic analyses up to 6 h after one course of paclitaxel administration. The primary endpoint was the clearance (L/h) of paclitaxel. Paclitaxel clearance—expressed as relative difference in geometric means—was 6.8% (90% CI: −16.7% to 4.4%) lower when paclitaxel was administered with concomitant scalp cooling versus paclitaxel infusions without scalp cooling. Within the subgroup of patients using scalp cooling, paclitaxel clearance was not statistically significantly different between patients with CIA (alopecia grade 1 or 2) and those without CIA. Hence, scalp cooling did not negatively influence the clearance of paclitaxel treatment.

Abstract 2256: A population-based mouse model for an experimental basal-like mammary cancer

Abstract The prevalence of obesity, an established risk and prognostic factor for basal-like breast cancer (BLBC), has risen dramatically in the US and many other countries over the past 4 decades. Obesity is also associated with increased resistance to several classes of cancer chemotherapeutic agents used for advanced BLBC. Unfortunately the mechanisms underlying chemotherapy resistance, and the inter-individual differences driving resistance, are poorly understood. Population-based experimental mouse models for determining inter-individual genetic differences in chemotherapy pharmacokinetics and treatment-related efficacy or resistance in mammary gland cancer are not well-defined. Our aim is to develop a population-based experimental model based on outcrosses between 30 different Collaborative Cross line females and hemizygous male B6.FVB-Tg(C3-1-TAg) (greater than N15) congenic mice to produce 30 Collaborative Cross (CC) recombinant inbred line intercross (CC RIX) mouse lines to investigate the interactive effects between diet-induced obesity (DIO) and genetic susceptibility to chemotherapy in a genetically heterogeneous mouse model of BLBC. We report here that thirty genetically-different CCRIL X hemizygous B6.FVB-Tg(C3-1-TAg) congenic female and male CC RIX mice observed longitudinally for occurrence of basal-like mammary tumors showed significant differences in both age at first mammary tumor observation and the fraction of females and males in each RIX bearing tumors. Litter size and the number of females and males of each RIX varied across the 30 CC RIX line. The study was well-powered, with at least X males and Y females for each CC RIX line evaluated longitudinally. We observed that 25 of 30 female CC RIX lines presented with BLMC, with distinct times-to-tumor with each CC RIX. The penetrance of the fraction of each CC RIX line (birth cohort) presenting with BLMC varied greatly in females (25-100%). Surprisingly, 11 of 30 male CC RIX lines presented with BLMC, with penetrance of BLMC varying in males between 10-75%. In conclusion, we present preliminary data to support development of an experimental mouse model for BLBC based on the random mating of 8 genetically-diverse homozygous inbred founder lines followed by in-breeding to greater than 95% homozygosity carrying 45 million single-nucleotide and structural variants. Studies are underway using these CC RIX lines to evaluate the genetic underpinnings of obesity-associated resistance to carboplatin in C3-TAg-driven mammary tumors. Citation Format: John Edgar French, William Pressel, Jody Albright, Melissa VerHague, Stephen D. Hursting. A population-based mouse model for an experimental basal-like mammary cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2256.

Effect of ethnicity and chemotherapy (mFOLFOX6) on zolbetuximab pharmacokinetics in patients with claudin 18.2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ).

e16078 Background: Zolbetuximab is a chimeric IgG1 monoclonal antibody that targets Claudin 18.2 (CLDN18.2), a tight junction protein that is normally confined to gastric mucosa but is retained in G/GEJ. A phase 2 (NCT01630083, FAST) trial demonstrated significantly prolonged survival with zolbetuximab + EOX (epirubicin, oxaliplatin, capecitabine) vs EOX in G/GEJ. Two global phase 3 studies are ongoing, comparing zolbetuximab + chemotherapy vs chemotherapy as first-line treatment in CLDN18.2-positive G/GEJ. This study assessed the influence of ethnic differences and chemotherapy on the pharmacokinetics (PK) of zolbetuximab in patients (pts) with G/GEJ and the potential effect of zolbetuximab on chemotherapy PK. Methods: In the Japanese phase 1 and global phase 2 studies, adult pts with CLDN18.2-postitive G/GEJ received zolbetuximab 800 mg/m2 IV on Cycle 1 Day 1 (Cycle 1 Day 3 in Cohort 2 of phase 2) then 600 mg/m2 Q3W. Phase 1 and Cohort 1A of the phase 2 study assessed zolbetuximab monotherapy in 21-day cycles. Cohort 2 of the phase 2 study assessed zolbetuximab + mFOLFOX (5-FU, folinic acid, oxaliplatin; 4 cycles) in 42-day cycles (Q2W from Cycle 1 Day 1). Blood samples for zolbetuximab PK following single and multiple doses, and for chemotherapy (5-FU and oxaliplatin) PK alone or with zolbetuximab were collected. Maximum serum drug concentration (Cmax) and area under the concentration-time curve from 0-21 days (AUC0-21) were assessed. Potential ethnic differences in zolbetuximab exposures across Japanese, other Asian (Korean and Taiwanese), and Western pts, and the potential drug-drug interaction between zolbetuximab and chemotherapy were evaluated. Results: Zolbetuximab concentration profiles and PK parameters were generally comparable across Japanese, other Asian, and Western populations (Table). Zolbetuximab PK properties were similar between monotherapy and combination therapy cohorts (Table). Chemotherapy PK was comparable with and without zolbetuximab. Conclusions: The analyses suggest no apparent ethnic differences in zolbetuximab PK across Japanese/Asian and Western pts and no PK interactions between zolbetuximab and mFOLFOX6. These results support the use of zolbetuximab and mFOLFOX without the need for dose adjustment in global phase 3 trials. Clinical trial information: NCT03505320, NCT03528629. [Table: see text]

Pharmacokinetics of Antimicrobial Chemotherapy Based on Maturation in Children

Pharmacokinetics of Antimicrobial Chemotherapy Based on Maturation in Children

The Potential Predictors in Chemotherapy Sensitivity.

Monitoring of patient and tumor during chemotherapy is important to determine whether the chemotherapy is effective to the patient. Variants affect drug enzyme activities and altered enzyme activities can be potential predictors for chemotherapeutic agents including cyclophosphamide and paclitaxel. Response to chemotherapy is primarily based on somatic mutations but germline variants may predict cancer cell sensitivity to chemotherapeutic agents. Furthermore, patient's genetic variation of immune system was reported to be associated with drug response and toxicity. Recently, the somaric and germilne genomic variation influences the pharmacokinetics of chemotherapy and these variation can be biomarkers for chemotherapy.

Preclinical and clinical investigation of intratumoral chemotherapy pharmacokinetics in DIPG using gemcitabine.

BackgroundHundreds of systemic chemotherapy trials in diffuse intrinsic pontine glioma (DIPG) have not improved survival, potentially due to lack of intratumoral penetration, which has not previously been assessed in humans.MethodsWe used gemcitabine as a model agent to assess DIPG intratumoral pharmacokinetics (PK) using mass spectrometry.ResultsIn a phase 0 clinical trial of i.v. gemcitabine prior to biopsy in children newly diagnosed with DIPG by MRI, mean concentration in 4 biopsy cores in patient 1 (H3K27M diffuse midline glioma) was 7.65 µM. These compare favorably to levels for patient 2 (mean 3.85 µM, found to have an H3K27-wildtype low-grade glioma on histology), and from a similar study in adult glioblastoma (adjusted mean 3.48 µM). In orthotopic patient-derived xenograft (PDX) models of DIPG and H3K27M-wildtype pediatric glioblastoma, gemcitabine levels and clearance were similar in tumor, pons, and cortex and did not depend on H3K27 mutation status or tumor location. Normalized gemcitabine levels were similar in patient 1 and the DIPG PDX.ConclusionsThese findings, while limited to one agent, provide preliminary evidence for the hypotheses that lack of intratumoral penetration is not why systemic chemotherapy has failed in DIPG, and orthotopic PDX models can adequately model intratumoral PK in human DIPG.

Optimizing pharmacokinetics of intravesical chemotherapy for bladder cancer.

Non-muscle-invasive bladder cancer (NMIBC) remains one of the most common malignancies and is associated with considerable treatment costs. Patients with intermediate-risk or high-risk disease can be treated with intravesical BCG, but many of these patients will experience tumour recurrence, despite adequate treatment. Standard of care in these patients is radical cystectomy with urinary diversion, but this approach is associated with considerable morbidity and lifestyle modification. As an alternative, perioperative intravesical chemotherapy is recommended for low-risk papillary NMIBC, and induction intravesical chemotherapy is an option for patients with intermediate-risk NMIBC and BCG-unresponsive NMIBC. However, poor pharmaceutical absorption and drug washout during normal voiding can limit sustained drug concentrations in the urothelium, which reduces efficacy, and small-molecule chemotherapeutic agents can be absorbed through the urothelium into the bloodstream, leading to systemic adverse effects. Several novel drug delivery methods - including hyperthermia, mechanical sustained released devices and nanoparticle drug conjugation - have been developed to overcome these limitations. These novel methods have the potential to be combined with established chemotherapeutic agents to change the paradigm of NMIBC treatment.

Pharmacokinetic and exploratory exposure\u2013response analysis of pertuzumab in patients with operable HER2-positive early breast cancer in the APHINITY study

PurposeTo characterize the pharmacokinetics (PK) of, and perform an exploratory exposure–response (E–R) analysis for, pertuzumab in patients with HER2-positive early breast cancer (EBC) within the APHINITY study (NCT01358877, BIG 4–11/BO25126/TOC4939G).MethodsA previously developed pertuzumab two-compartment linear population pharmacokinetic (popPK) model was subjected to external validation to examine appropriateness for describing pertuzumab concentrations from the APHINITY study. Pharmacokinetic drug–drug interactions (DDIs) between pertuzumab, trastuzumab, and chemotherapy were assessed by comparing observed serum or plasma Cmax, Cmin, and AUClast geometric mean ratios with 90% CIs. Predictions of pertuzumab Cmax,ss, Cmin,ss, and AUCss were derived from individual parameter estimates and used in an exploratory E–R analysis.ResultsUsing data from 72 patients, based on goodness-of-fit, the popPK model was deemed appropriate for predictions of individual exposures for subsequent comparisons to historical data, assessment of DDIs, and E–R analyses. No evidence of DDIs for pertuzumab on trastuzumab, trastuzumab on pertuzumab, or pertuzumab on chemotherapy PK was observed. Analyses of differences in exposure between patients with and without invasive disease-free survival events did not indicate improved efficacy with increased exposure. Overall Grade ≥ 3 diarrhea prevalence was higher with pertuzumab versus placebo, but was not greater with increasing pertuzumab exposure. No apparent E–R relationship was suggested with respect to other grade ≥ 3 AEs.ConclusionOverall, the limited available data from this exploratory study suggest that no dose adjustments are needed for pertuzumab when administered in combination with trastuzumab and an EBC chemotherapy regimen.

The impact of skeletal muscle on the pharmacokinetics and toxicity of 5-fluorouracil in colorectal cancer.

Great heterogeneity exists in the ability of adults with cancer to tolerate chemotherapy. Variability in body composition may affect rates of metabolism of cytotoxic agents and contribute to the variable chemotherapy toxicity observed. The objective of this exploratory study was to examine the association of low skeletal muscle, commonly known as sarcopenia, on the pharmacokinetics (PKs) of 5-fluorouracil (5FU) in patients receiving FOLFOX for colorectal cancer. We performed a secondary analysis of a completed multicenter trial that investigated PK-guided 5FU dosing in patients receiving mFOLFOX6 +/- bevacizumab for colorectal cancer. Cycle 1 PK samples were obtained 2-44h after the start of the 5FU infusion (steady state). No significant differences in first cycle 5FU area-under-the-concentration-time-curve (AUC) were found between sarcopenic and non-sarcopenic patients (17.3 vs. 19.3 AUC, p = 0.43). Patients with grade 3/4 toxicity had a higher dose of 5FU per kg lean body mass (LBM) (105 vs. 93mg/kg, p = 0.06), most notably for hematological toxicities (110 vs. 94mg/kg, p = 0.002); however, no correlation between the dose/LBM and 5FU AUC was found. Although our results did not confirm the impact of low skeletal muscle on PKs of 5FU, further research exploring the impact of body composition on chemotherapy PKs and related toxicities is warranted with the potential for alternative dosing strategies in sarcopenic patients to reduce unnecessary toxicities while maintaining efficacy.

PDCT-01. TOXICITY AND OUTCOME IN ADOLESCENT AND YOUNG ADULTS TREATED FOR MEDULLOBLASTOMA AND PRIMITIVE NEUROECTODERMAL TUMORS ON STUDIES COG-A9961 AND CCG-99701: A REPORT FROM THE CHILDREN’S ONCOLOGY GROUP (COG)

Adolescent and young adults (AYA) with cancer have inferior outcomes compared with younger patients. We explored whether treatment-related toxicity and survival were associated with age in patients with medulloblastoma (MB) and primitive neuroectodermal tumor (PNET) enrolled on children’s oncology group (COG) studies COG-A9961 and CCG-99701. A retrospective analysis was conducted to compare the outcomes between AYA (15-21 years) vs. younger patients (3-14 years). On CCG-99701, 161 patients (16 AYA) with high-risk MB/PNET were treated with chemoradiotherapy followed by six cycles of maintenance chemotherapy cyclophosphamide/cisplatin/vincristine). On A9961 study, 379 patients with standard-risk MB (25 AYA) received chemoradiotherapy followed by eight cycles of maintenance chemotherapy (cisplatin/CCNU/vincristine). On CCG-99701, estimated 5-year event-free survival (EFS) and overall survival (OS) rates were lower for AYA patients (EFS: 37.5% versus 60.3%, p=0.05; OS: 50.0% versus 70.8%, p=0.005). On multivariate analysis, the observed difference in EFS was not statistically significant (p=0.12) but was still consistent with poorer outcome in older patients (HR 1.75, 95% CI 0.89-3.45) after adjustment for extent of resection and pathology. This difference was mainly due to poorer survival for AYA patients with PNET compared to patients 3-14 years of age (55.7% versus 9.1%; p=.002) as there was no significant difference in survival for high-risk medulloblastoma patients (p=0.26). Peripheral neuropathy was higher among AYA as well. On A9961, there was no difference in EFS or OS between AYA and younger patients. Interestingly, the AYA group experienced less hearing loss. Future studies examining the age-related differences in pharmacokinetics of chemotherapy and differences in tumor molecular biology are necessary.

Pharmacokinetics of metronomic chemotherapy: a neglected but crucial aspect.

Metronomic chemotherapy describes the close, regular administration of chemotherapy drugs at less-toxic doses over prolonged periods of time. In 2015, the results of randomized phase III clinical trials demonstrated encouraging, albeit limited, efficacy benefits of metronomic chemotherapy regimens administered as adjuvant maintenance therapy for the treatment of breast cancer, or as maintenance therapy in combination with an antiangiogenic agent for metastatic colorectal cancer. Owing to the investigational nature of this approach, metronomic chemotherapy regimens are highly empirical in terms of the optimal dose and schedule for the drugs administered; therefore, greater knowledge of the pharmacokinetics of metronomic chemotherapy is critical to the future success of this treatment strategy. Unfortunately, such preclinical and clinical pharmacokinetic studies are rare. Herein, we present situations in which active drug concentrations have been achieved with metronomic schedules, and discuss their associated pharmacokinetic parameters. We summarize examples from the limited number of clinical studies in order to illustrate the importance of assessing such pharmacokinetic parameters, and discuss the influence this information can have on improving efficacy and reducing toxicity.

Outcomes of 50 Patients With Ewing Sarcoma Family of Tumors Treated at a Single Institution in Taiwan.

To identify the prognostic factors and long-term outcome of the Ewing sarcoma family of tumors (ESFT), data on 50 patients with ESFT treated at Taipei Veterans General Hospital between February 1991 and March 2014 were retrospectively considered. The influence of patient demographics, tumor features, and clinical and therapeutic parameters on overall survival (OS) and progression-free survival (PFS) rates were assessed. The results revealed that 21 of the 50 patients (42%) were metastatic at diagnosis. The median follow-up time was 1.8 years. The 5-year OS and PFS for patients who were nonmetastatic were 61.6% and 55.5%, respectively, and 18.8% and 15.4% for patients who were metastatic, respectively. The key adverse prognostic factor was metastasis at diagnosis. Radiotherapy for local control was associated with improved PFS. The high rate of primary metastasis and poorer outcomes of nonmetastatic ESFT compared with results from Western studies, along with previously reported low rates of ESFT in Taiwanese people, suggest that genetic factors play a role in the pathogenesis of ESFT and chemotherapy pharmacokinetics and pharmacodynamics. Radiotherapy in local treatment should be considered more aggressively in Taiwanese patients with ESFT.

Germline TYMS genotype is highly predictive in patients with metastatic gastrointestinal malignancies receiving capecitabine-based chemotherapy.

This work was initiated to extend data on the effect of pharmacogenetics and chemotherapy pharmacokinetics (PK) on clinical outcome in patients with gastrointestinal malignancies. We assessed 44 gene polymorphisms in 16 genes (TYMS, MTHFR, GSTP1, GSTM1, GSTT1, DPYD, XRCC1, XRCC3, XPD, ERCC1, RECQ1, RAD54L, ABCB1, ABCC2, ABCG2 and UGT2B7) in 64 patients with metastatic colorectal cancer (CRC) receiving capecitabine/oxaliplatin and 76 patients with advanced gastroesophageal cancer (GEC) receiving epirubicin/cisplatin/capecitabine, respectively. Plasma concentrations of anticancer drugs were measured for up to 24h, and results were submitted to population PK analysis. We calculated the association between gene polymorphisms, chemotherapy exposure, tumor response, progression-free survival (PFS), overall survival (OS) and chemotherapy-related toxicity using appropriate statistical tests. Patients with a low clearance of 5FU were at increased risk of neutropenia (P<0.05) and hand-foot syndrome (P=0.002). DPYD T85C, T1896C and A2846T mutant variants were associated with diarrhea (P<0.05) and HFS (P<0.02), and IVS14+1G>A additionally with diarrhea (P<0.001). The TYMS 2R/3G, 3C/3G or 3G/3G promoter variants were associated with worse PFS in the CRC (HR=2.0, P<0.01) and GEC group (HR=5.4, P<0.001) and worse OS in the GEC group (HR=4.7, P<0.001). The GSTP1 A313G mutant variant was associated with a higher PFS (HR=0.55, P=0.001) and OS (HR=0.60, P=0.002) in the CRC group. Germline polymorphisms of DPYD, TYMS and GSTP1 have a significant effect on toxicity and clinical outcome in patients receiving capecitabine-based chemotherapy for advanced colorectal or gastroesophageal cancer. These data should further be validated in prospective clinical studies.

A Conversation with Richard A. Olshen

Richard Olshen was born in Portland, Oregon, on May 17, 1942. Richard spent his early years in Chevy Chase, Maryland, but has lived most of his life in California. He received an A.B. in Statistics at the University of California, Berkeley, in 1963, and a Ph.D. in Statistics from Yale University in 1966, writing his dissertation under the direction of Jimmie Savage and Frank Anscombe. He served as Research Staff Statistician and Lecturer at Yale in 1966–1967. Richard accepted a faculty appointment at Stanford University in 1967, and has held tenured faculty positions at the University of Michigan (1972–1975), the University of California, San Diego (1975–1989), and Stanford University (since 1989). At Stanford, he is Professor of Health Research and Policy (Biostatistics), Chief of the Division of Biostatistics (since 1998) and Professor (by courtesy) of Electrical Engineering and of Statistics. At various times, he has had visiting faculty positions at Columbia, Harvard, MIT, Stanford and the Hebrew University. Richard’s research interests are in statistics and mathematics and their applications to medicine and biology. Much of his work has concerned binary tree-structured algorithms for classification, regression, survival analysis and clustering. Those for classification and survival analysis have been used with success in computer-aided diagnosis and prognosis, especially in cardiology, oncology and toxicology. He coauthored the 1984 book Classification and Regression Trees (with Leo Brieman, Jerome Friedman and Charles Stone) which gives motivation, algorithms, various examples and mathematical theory for what have come to be known as CART algorithms. The approaches to tree-structured clustering have been applied to problems in digital radiography (with Stanford EE Professor Robert Gray) and to HIV genetics, the latter work including studies on single nucleotide polymorphisms, which has helped to shed light on the presence of hypertension in certain subpopulations of women. Richard also has a long-standing interest in the analyses of longitudinal data. This includes a detailed study of the pharmacokinetics of intracavitary chemotherapy with systemic rescue (with Stephen Howell and John Rice). Related efforts have focused on “mature walking,” concomitants of high cholesterol, and aspects of glomerular filtration in patients with nephrotic disorders (with Bryan Myers). With the late David Sutherland, Edmund Biden and Marilynn Wyatt, he coauthored the monograph The Development of Mature Walking. Richard’s other stochastic-statistical interests include exchangeability, conditional significance levels of particular test statistics, CART-like estimators in regression and successive standardization of rectangular arrays of numbers. Richard is an elected Fellow of the IMS, the AAAS, the ASA and the IEEE. He is a former Guggenheim Fellow and has been a Research Scholar in Cancer of the American Cancer Society.