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BACKGROUND: 6-mercaptopurine is a cornerstone of maintenance therapy for pediatric ALL. Response to 6MP is typically determined by the ANC. Therapeutic ANC range while receiving 6MP is between 500 and 1500/µL. In addition to desired myelosuppression, 6MP is associated with multiple adverse drug effects. Increased doses of 6MP can lead to therapeutic ANC values; however, patients may experience adverse effects before obtaining therapeutic myelosuppression, often deemed "skewed metabolism." Allopurinol may potentially correct skewed 6MP metabolism. PROCEDURE: Pediatric patients with ALL with 6MMP and 6TGN metabolites drawn during maintenance therapy were analyzed for allopurinol use. The primary outcome evaluated the percentage of time spent in therapeutic ANC range before and after allopurinol initiation. In addition, the difference in 6MMP:6TGN ratios before and after allopurinol initiation, incidence of hepatotoxicity, and rates of relapse, were analyzed. RESULTS: Ninety-five patients were included for analysis. Thirty-two (34%) patients received allopurinol. There were no significant differences in baseline demographics between the patients who received allopurinol and those who did not. When comparing ANC values pre- and post-allopurinol initiation, a statistically significant increase in the percentage of time spent in therapeutic range was observed (27% vs. 43%; p = .03). In addition, when comparing metabolite ratios pre- and post-allopurinol initiation, a statistically significant decrease in 6MMP:6TGN metabolite ratio values was observed (86.7 vs. 3.6; p < .0001). CONCLUSIONS: Allopurinol significantly increased the percent time in therapeutic ANC range and can be safely utilized to significantly lower the ratio of 6MMP:6TGN metabolites, alleviating the undesirable side effects of 6MMP, and optimizing the anti-leukemic effects associated with 6TGN.
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INTRODUCTION: Palbociclib is a small-molecule cyclin-dependent kinase 4/6 inhibitor used to treat hormone receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer. Patient-specific factors impacting dose reductions or discontinuations are unknown. METHODS: The primary objective was to evaluate the association of age (<60 vs. ≥60 years) with palbociclib dose reductions or discontinuations secondary to neutropenia. This single-center, retrospective chart review included hormone receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer patients ≥18 years treated with palbociclib between April 2015 and May 2020. Patients <60 years at the time of palbociclib initiation were in the younger group and patients ≥60 years were in the older group. RESULTS: Among the 107 patients included, younger patients were less likely than older patients to have a palbociclib starting dose <125â mg (0% vs. 11.9%, p = 0.02). Differences in palbociclib dose reductions or treatment discontinuations secondary to neutropenia were not detected (35.4% vs. 42.4%, p = 0.55). Neither the total number of palbociclib dose reductions (none: 54.2% vs. 49.1%, one: 33.3% vs. 42.4%, two: 12.5% vs. 8.5%, p = 0.61), nor the final dose of palbociclib (125 mg: 54.2% vs. 40.7%, 100 mg: 29.2% vs. 27.1%, 75 mg: 16.7% vs. 32.2%, p = 0.17) differed between younger and older patients. CONCLUSIONS: Age (<60 vs. ≥60 years) was not associated with the rate of palbociclib dose reductions or discontinuations secondary to neutropenia. Older (≥60 years) patients were more likely to start palbociclib at lower doses which may impact neutropenia and non-neutropenic intolerance.
Subject(s)
Breast Neoplasms , Neutropenia , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Retrospective Studies , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Neutropenia/drug therapyABSTRACT
No biomarkers are available to predict patients at risk of developing hypertension induced by VEGF-pathway inhibitors. This study aimed to identify predictive biomarkers of hypertension induced by these drugs using a discovery-replication approach. The discovery set included 140 sorafenib-treated patients (TARGET study) genotyped for 973 SNPs in 56 genes. The most statistically significant SNPs associated with grade ≥2 hypertension were tested for association with grade ≥2 hypertension in the replication set of a GWAS of 1039 bevacizumab-treated patients from four clinical trials (CALGB/Alliance). In the discovery set, rs444904 (G > A) in PIK3R5 was associated with an increased risk of sorafenib-induced hypertension (p = 0.006, OR = 3.88 95% CI 1.54-9.81). In the replication set, rs427554 (G > A) in PIK3R5 (in complete linkage disequilibrium with rs444904) was associated with an increased risk of bevacizumab-induced hypertension (p = 0.008, OR = 1.39, 95% CI 1.09-1.78). This study identified a predictive marker of drug-induced hypertension that should be evaluated for other VEGF-pathway inhibitors.ClinicalTrials.gov Identifier:NCT00073307 (TARGET).
Subject(s)
Hypertension/chemically induced , Hypertension/genetics , Phosphatidylinositol 3-Kinase/genetics , Signal Transduction/drug effects , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Aged , Bevacizumab/adverse effects , Biomarkers , Double-Blind Method , Female , Genetic Testing , Humans , Linkage Disequilibrium , Male , Middle Aged , Polymorphism, Single Nucleotide , Predictive Value of Tests , Risk Assessment , Signal Transduction/genetics , Vascular Endothelial Growth Factor A/geneticsABSTRACT
No biomarkers are available to predict toxicities induced by VEGFR TKIs. This study aimed to identify markers of toxicities induced by these drugs using a discovery-validation approach. The discovery set included 140 sorafenib-treated cancer patients (TARGET study) genotyped for SNPs in 56 genes. The most significant SNPs associated with grade ≥2 hypertension, diarrhea, dermatologic toxicities, and composite toxicity (any one of the toxicities) were tested for association with grade ≥2 toxicity in a validation set of 201 sorafenib-treated patients (Alliance/CALGB 80802). The validated SNP was tested for association with grade ≥2 toxicity in 107 (LCCC 1029) and 82 (Italian cohort) regorafenib-treated patients. SNP-toxicity associations were evaluated using logistic regression, and a meta-analysis between the studies was performed by inverse variance. Variant rs4864950 in KDR increased the risk of grade ≥2 composite toxicity in TARGET, Alliance/CALGB 80802, and the Italian cohort (meta-analysis p = 6.79 × 10-4, OR = 2.01, 95% CI 1.34-3.01). We identified a predictor of toxicities induced by VEGFR TKIs. CLINICALTRIALS.GOV IDENTIFIER: NCT00073307 (TARGET), NCT01015833 (Alliance/CALGB 80802), and NCT01298570 (LCCC 1029).
Subject(s)
Neoplasms , Phenylurea Compounds , Humans , Sorafenib/adverse effects , Phenylurea Compounds/adverse effects , Pyridines/adverse effects , Neoplasms/drug therapy , Vascular Endothelial Growth Factor Receptor-2/therapeutic useABSTRACT
BACKGROUND: Tyrosine kinase inhibitors (TKIs) are the front-line therapy for chronic myeloid leukemia (CML), where phase 3 clinical trials have demonstrated their safety and efficacy. However, trial patients may not be representative of real-world patients (RWPs). OBJECTIVE: To evaluate RWP clinical factors associated with effectiveness and safety in CML patients treated with TKIs. METHODS: Patients with CML treated with at least 30 days of imatinib, dasatinib, nilotinib, or bosutinib between 2014 and 2018 were included. Patients were stratified into categories based on the number of factors that would have precluded enrollment into pivotal TKI phase 3 trials (0, 1, ≥2). End points included complete hematologic response (CHR), early molecular response (EMR), major molecular response (MMR), adverse event (AE)-induced dose decreases, treatment interruptions, and treatment discontinuations. RESULTS: Final analyses included 174 patients. Patients with ≥2 factors had a higher risk of dose decreases (relative risk = 1.54; 95% CI = 1.02-2.34; P = 0.02) and a shorter time to dose decrease (hazard ratio = 2.43; 95% CI = 1.23-4.97; P = 0.006) compared with patients with 0 factors. Significant differences were observed in CHR at 1 month and MMR at 3 months between patients with 0 and ≥2 factors (P = 0.03 and P = 0.04, respectively). CONCLUSION AND RELEVANCE: Approximately 60% of our RWPs would have been excluded from the pivotal phase 3 TKI trials. These data suggest that RWPs require more precise dosing to achieve CML clinical milestones and to mitigate AEs, but findings should be validated prospectively.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Protein Kinase Inhibitors , Dasatinib/adverse effects , Humans , Imatinib Mesylate/adverse effects , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/chemically induced , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/adverse effects , Treatment OutcomeABSTRACT
Background: Pharmacogenetics may explain a substantial proportion of the variation seen in the efficacy and risk profile of analgesosedative drugs and the incidence of delirium in critically ill adults. Objectives: Conduct a feasibility study to demonstrate the reliability of collecting and analyzing pharmacogenetic information from critically ill patients and to assess the impact of pharmacogenetics on intensive care unit (ICU) outcomes. Methods: We prospectively enrolled subjects from the Medical ICU at the University of North Carolina (UNC). DNA was obtained via a buccal swab and evaluated using the DNA2Rx assay. We collected data on demographics, daily cumulative psychoactive medication exposure, and severity of illness. We performed daily delirium assessments via the CAM-ICU. We analyzed associations between select single nucleotide polymorphisms (SNPs) and delirium. Results: From June, 2018 through January, 2019, we screened 244 patients and enrolled 50. The median age was 62.0 years old (range: 28-82 years old), and 27 (54%) of the subjects were female. In all, 49 (98%) samples were both high quality and sufficient quantity. In secondary analyses, we found that 80% (12/15) of patients with two 2 copies of a G allele at rs4680 on COMT experienced delirium, whereas 44% (4/9) of patients with 2 copies of an A allele at this location had delirium. In all, 44% (4/9) of patients with 2 T allele copies at rs7439366 on UGT2B7 experienced delirium compared to 73% (11/15) of patients with 2 C allele copies at this location. Conclusions: We can feasibly collect genetic information from critically ill adults. We were able to efficiently collect high quality DNA of sufficient quantity to conduct pharmacogenetic analysis in this critically ill population. Although the sample size of our current study is too small to conduct robust inferential analyses, it suggests potential SNP targets for a future larger study.
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INTRODUCTION: Haemophilia A patients require perioperative clotting factor replacement to limit excessive bleeding. Weight-based dosing of Factor VIII (FVIII) does not account for inter-individual pharmacokinetic (PK) variability, and may lead to suboptimal FVIII exposure. AIM: To perform an external validation of a previously developed population PK (popPK) model of perioperative FVIII in haemophilia A patients. METHODS: A retrospective chart review identified perioperative haemophilia A patients at the University of North Carolina (UNC) between April 2014 and November 2019. Patient data was used to externally validate a previously published popPK model proposed by Hazendonk. Based on these validation results, a modified popPK model was developed to characterize FVIII PK in our patients. Dosing simulations were performed using this model to compare FVIII target attainment between intermittent bolus (IB) and continuous infusion (CI) administration methods. RESULTS: A total of 521 FVIII concentrations, drawn from 34 patients, were analysed. Validation analyses revealed that the Hazendonk model did not fully capture FVIII PK in the UNC cohort. Therefore, a modified one-compartment model, with weight and age as covariates on clearance (CL), was developed. Dosing simulations revealed that CI resulted in improved target attainment by 16%, with reduced overall FVIII usage by 58 IU/kg, compared to IB. CONCLUSION: External validation revealed a previously published popPK model of FVIII did not adequately characterize UNC patients, likely due to differences in patient populations. Future prospective studies are needed to evaluate our model prior to implementation into clinical practice.
Subject(s)
Hemophilia A , Hemostatics , Adult , Factor VIII , Hemophilia A/drug therapy , Hemorrhage , Humans , Retrospective StudiesABSTRACT
Heteroatom rich 1,2,3-dithiazoles are relatively underexplored in medicinal chemistry. We now report screening data on a series of structurally diverse 1,2,3-dithiazoles and electronically related 1,2,4-dithiazines with the aim of identifying interesting starting points for potential future optimisation. The 1,2,3-dithiazoles, were obtained via a number of different syntheses and screened on a series of cancer cell lines. These included breast, bladder, prostate, pancreatic, chordoma and lung cancer cell lines with an additional skin fibroblast cell line as a toxicity control. Several low single digit micromolar compounds with promising therapeutic windows were identified for breast, bladder and prostate cancer. Furthermore, key structural features of 1,2,3-dithiazoles are discussed, that show encouraging scope for future refinement.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Thiazoles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
A focused series of substituted 4H-1,2,6-thiadiazin-4-ones was designed and synthesized to probe the anti-cancer properties of this scaffold. Insights from previous kinase inhibitor programs were used to carefully select several different substitution patterns. Compounds were tested on bladder, prostate, pancreatic, breast, chordoma, and lung cancer cell lines with an additional skin fibroblast cell line as a toxicity control. This resulted in the identification of several low single digit micro molar compounds with promising therapeutic windows, particularly for bladder and prostate cancer. A number of key structural features of the 4H-1,2,6-thiadiazin-4-one scaffold are discussed that show promising scope for future improvement.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Thiadiazines/chemistry , Cell Proliferation , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Cytochrome P-450 CYP3A/genetics , Hematopoietic Stem Cell Transplantation , Immunosuppressive Agents/pharmacokinetics , Tacrolimus/pharmacokinetics , Adult , Aged , Databases, Genetic , Female , Genotype , Germ-Line Mutation , Graft vs Host Disease/genetics , Graft vs Host Disease/prevention & control , Humans , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/therapeutic use , Logistic Models , Male , Middle Aged , Odds Ratio , Polymorphism, Single Nucleotide , Tacrolimus/pharmacology , Tacrolimus/therapeutic use , Transplantation, Homologous , Young AdultABSTRACT
OBJECTIVES: One of the standard of care regimens for advanced pancreatic cancer is gemcitabine-based chemotherapy. The efficacy of gemcitabine is limited by dose-limiting hematologic toxicities especially neutropenia. Uncovering the variability of these toxicities attributed to germline DNA variation is of great importance. PATIENTS AND METHODS: CALGB 80303 was a randomized study in advanced pancreatic cancer patients treated with gemcitabine with or without bevacizumab. The study protocol included genotyping of genes of gemcitabine disposition (CDA, DCTD, SLC29A1, SLC28A1, and SLC29A2), as well as a genome-wide analysis. The clinical phenotype was time to early high-grade neutropenia event accounting for progression or death or other treatment-terminating adverse events as competing for informative events. The inference was carried out on the basis of the association between genotype and cause-specific hazard of a neutropenic event. RESULTS: The primary analyses were carried out on the basis of 294 genetically estimated European pancreatic cancer patients. For CDA rs2072671 (A>C), AC and CC patients had a lower risk of neutropenia than AA patients (P=0.01, hazard ratio: 0.61, 95% confidence interval: 0.41-0.89). For SLC28A1 rs3825876 (G>A), AA patients have a higher risk of neutropenia than GA and GG patients (P=0.02, hazard ratio: 1.51, 95% confidence interval: 1.06-2.16). CDA rs2072671 was associated with increased mRNA expression in whole blood in three studies (P=2.7e-14, 6.61e-62, and 9.70e-65). In the genome-wide analysis, variants in TGFB2 were among the top hits (lowest P=1.62e-06) but had no effect in luciferase assays. CONCLUSION: This is the first genetic analysis of gemcitabine-induced neutropenia using a competing risk model in a prospective randomized clinical study has proposed a potentially novel mechanism of the protective effect of the CDA rs2072671 variant. Further confirmation is needed.
Subject(s)
Cytidine Deaminase/genetics , Deoxycytidine/analogs & derivatives , Neutropenia/genetics , Pancreatic Neoplasms/drug therapy , Polymorphism, Single Nucleotide , Administration, Intravenous , Aged , Deoxycytidine/adverse effects , Deoxycytidine/therapeutic use , Double-Blind Method , Female , Humans , Male , Middle Aged , Neutropenia/chemically induced , Pancreatic Neoplasms/genetics , Prospective Studies , GemcitabineABSTRACT
PURPOSE: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers. METHODS: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned. RESULTS: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability. CONCLUSION: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.
Subject(s)
Cytochrome P-450 CYP2D6/genetics , Genetic Testing/methods , Pharmacogenetics/methods , Cytochrome P-450 CYP2D6/pharmacology , Decision Support Systems, Clinical , Drug Prescriptions/standards , Genotype , Humans , Pharmacogenomic Testing/methods , Pharmacogenomic Testing/trends , PhenotypeABSTRACT
We screened a series of 4-anilinoquinolines and 4-anilinoquinazolines and identified novel inhibitors of Mycobacterium tuberculosis (Mtb). The focused 4-anilinoquinoline/quinazoline scaffold arrays yielded compounds with high potency and the identification of 6,7-dimethoxy-N-(4-((4-methylbenzyl)oxy)phenyl)quinolin-4-amine (34) with an MIC90 value of 0.63-1.25⯵M. We also defined a series of key structural features, including the benzyloxy aniline and the 6,7-dimethoxy quinoline ring, that are important for Mtb inhibition. Importantly the compounds showed very limited toxicity and scope for further improvement by iterative medicinal chemistry.
Subject(s)
Aniline Compounds/pharmacology , Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Quinazolines/pharmacology , Quinolines/pharmacology , Aniline Compounds/chemical synthesis , Aniline Compounds/chemistry , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Quinazolines/chemical synthesis , Quinazolines/chemistry , Quinolines/chemical synthesis , Quinolines/chemistry , Structure-Activity RelationshipABSTRACT
In 2017, due to a fluid shortage secondary to Hurricane Maria's devastation of Puerto Rico, hospitals and health-systems began to substitute rolapitant for fosaprepitant as part of chemotherapy-induced nausea and vomiting prevention and treatment strategies. However, despite advantageous pharmacologic and formulation (e.g. long half-life, quicker time to onset, and lack of first-pass hepatic metabolism) profiles, there seems to be significant risk of infusion-related hypersensitivity reactions associated with the administration of intravenous rolapitant. In January 2018, the U.S. FDA issued a Health Care Provider Letter stating that anaphylaxis, anaphylactic shock, and other serious hypersensitivity reactions have been reported in the postmarketing setting. Importantly, these reactions were observed at a higher rate than initially reported in the phase 1 bioequivalence study that led to FDA approval of intravenous rolapitant (2.8%), with many resulting in hospitalizations. At our institution, rolapitant-induced infusion-related reactions also occurred in more patients than expected (8.7%). Described herein are six cases of infusion-related hypersensitivity reactions with intravenous rolapitant at the North Carolina Cancer Hospital. Due to the quick onset of the infusion-related hypersensitivity reactions with intravenous rolapitant, interpatient differences in pharmacokinetics or pharmacodynamics are unlikely to be the cause. An objective assessment utilizing the Naranjo Causality Scale rates these infusion-related hypersensitivity reactions as definite adverse drug reactions.
Subject(s)
Neurokinin-1 Receptor Antagonists/administration & dosage , Spiro Compounds/administration & dosage , Academic Medical Centers , Administration, Intravenous , Adult , Aged , Cancer Care Facilities , Female , Humans , Male , Nausea/chemically induced , Nausea/prevention & control , Neurokinin-1 Receptor Antagonists/adverse effects , North Carolina , Spiro Compounds/adverse effects , Vomiting/chemically induced , Vomiting/prevention & control , Young AdultABSTRACT
Cabozantinib is a multikinase inhibitor approved for the treatment of metastatic medullary thyroid cancer and advanced renal cell carcinoma (RCC) in patients who have received prior anti-angiogenic therapy. While associations between serum creatine kinase (CK) elevations and other tyrosine kinase inhibitors used for the treatment of solid malignancies have been previously reported, we report a case of cabozantinib-associated CK elevation that was associated with musculoskeletal complaints by an RCC patient. Nine days following initiation of cabozantinib, the patient reported muscle cramps and serum CK had increased from levels 12 months earlier that were within normal limits to a grade 1 elevation of 244 units/L. Despite a dose reduction, her CK continued to rise over the next 2 months, leading to a peak CK of 914 units/L. Due to this grade 3 elevation, cabozantinib was permanently discontinued, and her CK subsequently returned to a grade 1 elevation within one week and then to baseline within 3 weeks. The temporal relationship between drug exposure and CK increase strongly suggests causality. To the authors' knowledge, this is the first reported case of CK elevation attributed to cabozantinib, but cabozantinib-induced CK elevations could be under-reported, and providers should monitor for musculoskeletal complaints during cabozantinib therapy.
Subject(s)
Anilides/adverse effects , Creatine Kinase/blood , Musculoskeletal Diseases/blood , Musculoskeletal Diseases/chemically induced , Pyridines/adverse effects , Female , Humans , Middle Aged , Muscle Cramp/chemically induced , Musculoskeletal Diseases/enzymologyABSTRACT
INTRODUCTION: Cisplatin, a platinum-based antineoplastic agent, is the cornerstone for the treatment of many malignancies. Nephrotoxicity is the primary dose-limiting toxicity, and various hydration regimens and supplementation strategies are used to prevent cisplatin-induced kidney injury. However, evidence-based recommendations on specific hydration regimens are limited. A systematic review was performed to evaluate clinical studies that have examined hydration and supplementation strategies to prevent cisplatin-induced nephrotoxicity. MATERIALS AND METHODS: PubMed and Excerpta Medica databases were searched from 1966 through October 2015 for clinical trials and other studies focused on hydration regimens to prevent nephrotoxicity in cancer patients treated with cisplatin. The University of Oxford Centre for Evidence-Based Medicine criteria were used to grade level of evidence. RESULTS: Among the 1,407 identified studies, 24 were included in this systematic review. All studies differed on type, volume, and duration of hydration. Among the 24 studies, 5 evaluated short-duration hydration, 4 evaluated low-volume hydration, 4 investigated magnesium supplementation, and 7 reviewed forced diuresis with hydration. Short-duration and lower-volume hydration regimens are effective in preventing cisplatin-induced nephrotoxicity. Magnesium supplementation may have a role as a nephroprotectant, and forced diuresis may be appropriate in some patients receiving cisplatin. CONCLUSION: Hydration is essential for all patients to prevent cisplatin-induced nephrotoxicity. Specifically, short-duration, low-volume, outpatient hydration with magnesium supplementation and mannitol forced diuresis (in select patients) represent best practice principles for the safe use of cisplatin. The Oncologist 2017;22:609-619 IMPLICATIONS FOR PRACTICE: The findings contained within this systematic review show that (a) hydration is essential for all patients to prevent cisplatin-induced nephrotoxicity, (b) short-duration, low-volume, outpatient hydration regimens appear to be safe and feasible, even in patients receiving intermediate- to high-dose cisplatin, (c) magnesium supplementation (8-16 milliequivalents) may limit cisplatin-induced nephrotoxicity, and (d) mannitol may be considered for high-dose cisplatin and/or patients with preexisting hypertension. These findings have broad implications for clinical practice and represent best practice principles for the prevention of cisplatin-induced nephrotoxicity.
Subject(s)
Antineoplastic Agents/therapeutic use , Cisplatin/therapeutic use , Drug-Related Side Effects and Adverse Reactions/pathology , Neoplasms/drug therapy , Antineoplastic Agents/adverse effects , Cisplatin/adverse effects , Dose-Response Relationship, Drug , Evidence-Based Medicine , Female , Humans , Kidney/drug effects , Male , Neoplasms/complications , Neoplasms/pathologyABSTRACT
Posterior reversible encephalopathy syndrome (PRES) is a clinical/radiological syndrome characterized by symptoms that can include seizure, headache, impaired vision and hypertension, and can be confirmed by magnetic resonance imaging. Numerous reports have emerged that describe PRES in cancer patients. The list of medications linked to PRES can include traditional cytotoxic chemotherapeutics (e.g., cisplatin, cyclophosphamide, and high-dose corticosteroids), newer agents that target the vascular endothelial growth factor pathway (e.g., bevacizumab, sunitinib, and pazopanib), and supportive care mediations (e.g., granulocyte colony stimulating factors and erythropoietin). We report, for the first time, a case of PRES that is secondary to treatment with enzalutamide, a potent androgen receptor antagonist used in the treatment of metastatic castration-resistant prostate cancer. Enzalutamide is approved for the treatment of both docetaxel-pretreated and chemotherapy-naïve metastatic castration-resistant prostate cancer. Enzalutamide has been previously linked to the increased risk of seizures. Clinicians should be aware that, in rare cases, patients treated with enzalutamide could potentially be at risk for PRES. If symptoms suggestive of PRES arise in patients receiving enzalutamide, the drug should be discontinued immediately and the diagnostic process should be initiated.
Subject(s)
Phenylthiohydantoin/analogs & derivatives , Posterior Leukoencephalopathy Syndrome/chemically induced , Prostatic Neoplasms, Castration-Resistant/drug therapy , Aged , Benzamides , Humans , Magnetic Resonance Imaging , Male , Nitriles , Phenylthiohydantoin/adverse effects , Phenylthiohydantoin/therapeutic useABSTRACT
OBJECTIVE: To review currently available literature on the oral multikinase inhibitor regorafenib and its role in the treatment of metastatic colorectal cancer (mCRC), and imatinib- and sunitinib-resistant gastrointestinal stromal tumors (GISTs). DATA SOURCES: A comprehensive literature search was performed of PubMed/MEDLINE and American Society of Clinical Oncology (ASCO) abstracts (through August 2013). STUDY SELECTION/DATA EXTRACTION: Preclinical pharmacological and phase I to III trials data analyzing regorafenib efficacy and safety in mCRC or imatinib- and sunitinib-resistant GIST patients were evaluated. All available English-language, peer-reviewed articles and ASCO abstracts with relevant information were reviewed. DATA SYNTHESIS: Regorafenib was approved for mCRC in September 2012 and for imatinib- and sunitinib-resistant GISTs in February 2013. Regorafenib is an inhibitor of stromal, angiogenic, and oncogenic receptor tyrosine kinases, as well as the RAF/MEK/ERK signaling pathway. Phase III CORRECT (Regorafenib Monotherapy for Previously Treated Metastatic Colorectal Cancer) trial data demonstrated an overall survival benefit for mCRC patients treated with regorafenib (6.4 vs 5.0 months; P = .0052). Phase III GRID (Gastrointestinal Stromal Tumors After Failure of Imatinib and Sunitinib) trial data revealed a progression-free survival benefit in imatinib- and sunitinib-resistant GIST patients (4.8 vs 0.9 months; P < .0001). Its adverse event (AE) profile is comparable to that of other multikinase inhibitors. The most commonly observed grade ≥3 AEs included hypertension, hand-foot skin reaction, rash, diarrhea, and fatigue. CONCLUSIONS: Regorafenib is a novel oral multikinase inhibitor that has shown promising results for patients with advanced, unresectable or metastatic treatment-refractory CRCs or imatinib- and sunitinib-resistant GISTs.