Clinical Cancer Drugs - Volume 4, Issue 2, 2017

Background: 5-Fluoro-Uracil (5-FU) ranks among the most widely prescribed anticancer agents worldwide. Fluoropyrimidines are a mainstay in the treatment of numerous solid tumors, mostly used in combination with other cytotoxics, targeted therapies or biologics. Because most of the administered 5-FU dose will undergo extensive catabolism driven by dihydropyrimidine dehydrogenase (DPD), a liver enzyme that converts 5-FU into inactive metabolite, drug dosing is particularly high in some settings such as digestive or head-and-neck cancers. Variations in fluoropyrimidine disposition are a major cause for the erratic pharmacokinetics profile observed in cancer patients. Because of the elevated doses administered, DPD-deficient patients are likely to experience lifethreatening toxicities and those are now a rising issue regarding pre-emptive strategies to be undertaken to improve safety. Numerous clinical reports and meta-analysis have investigated on possible strategies to forecast DPD deficiency, thus opening the way to preventive adaptive dosing strategies with 5-FU or oral capecitabine. Objective: This Part-1 aims at covering the achievements, limits and perspectives of current strategies to detect DPD deficiency at the bedside. Method: A Pubmed research was performed regarding genotyping and phenotyping DPD deficiency, as well as their cost-effectiveness studies, in order to discuss and compare their performance. Results and Conclusion: To date, defining the best upfront method to sort patients on their DPD status remains a challenging issue because genotyping approaches show a low sensitivity with respect to the actual number of 5-FU-related toxicity reported cases, and that phenotyping approaches have several technical limitations.

Background: Fluoropyrimidines remain the cornerstone of several regimens for solid malignancies, despite their administration may result in severe or fatal toxicities. Objective: To review pharmacokinetic markers predictive of fluoropyrimidine- associated toxicities. Shifting from i.v. boluses to both continuous infusions of 5-fluorouracil (5-FU) and oral prodrugs, as well as capecitabine, significantly increased the treatment tolerability. However, a variable percentage of patients still suffer from toxic effects that require the delay of next chemotherapeutic cycles, their definitive discontinuation, or urgent life support because of life-threatening adverse reactions. Methods: Appropriate and pertinent articles were retrieved through PubMed search. Results: Fluoropyrimidine-associated toxicities are mainly due to a dihydropyrimidine dehydrogenase enzymatic deficiency, leading to a reduced excretion of the drug, its increased activation and increased toxic effects against healthy tissues. Among the pharmacokinetic tests, test doses of 5-FU, uracil and thymine have been evaluated in clinical trials, as well as the measurement of uracil (U) and dihydrouracil (UH2) plasma concentrations. The therapeutic monitoring of 5-FU concentrations during i.v. infusions is another tool to optimize drug dosage before the occurrence of toxicities. Advances in technical platforms, as well as chromatography coupled with mass spectrometry, have simplified the implementation of those tests in clinical routine. Conclusion: Several studies have demonstrated that it is possible to predict the occurrence of severe toxicities from fluoropyrimidines, and the review will discuss all those pharmacokinetic approaches.

Background: Fluoropyrimidines (FPs) have been used for a long time as first-line treatment for colorectal cancer and continue to represent the backbone of combination chemotherapy in both the adjuvant and metastatic disease settings. In a consistent percentage of patients (10-40%) FPs induce severe to life-threatening toxicity. On this basis, markers of tolerance to treatment need to be found. Dihydropyrimidine dehydrogenase (DPYD) pharmacogenetic screening is a useful tool to identify individuals at high risk of FPs severe toxicity. However, constitutional DPYD mutations only partially explain polymorphic DPD activity and toxic response. Recent advances in research have suggested that epigenetic mechanisms may provide a new source of explanations in the context of drugassociated toxicities. Objective and Methods: A systematic literature search of MEDLINE and EMBASE databases was performed in order to review the current state of knowledge about epigenetic aspects related to fluoropyrimidine- associated toxicities. Results: Various genes and pathways involved in FPs metabolism and mechanism of action have been shown to be regulated by promoter methylation and specific miRNA expression at the transcriptional level, responsible for an intrinsic or acquired chemoresistance. Also, preclinical evidences are accumulating that epigenetic drugs may increase cell chemosensitivity. Conclusion: Associations between epigenetic patterns and effects of FPs have been outlined and some critical issues on the translation to clinical practice discussed.

Background: Fluoropyrimidines are anticancer drugs used for the treatment of solid tumours. Apart from general side effects common to other anticancer drugs, the intravenously administered 5-fluorouracil (5-FU) and the recently developed oral prodrugs can induce toxicity at cardiovascular, neurologic and dermatologic level, which is reversed by treatment interruption, discontinuation, dose reduction and supportive therapies. Objective: To examine, from the morphohistopathological point of view, the main toxic effects induced by fluoropyrimidines. Methods: Pertinent articles were retrieved through PubMed search. Results: Unlike dermatologic toxicity, with evident histopathological observations because of the easy approach to skin examination, cardio- and neurotoxicity are scarcely documented, with most imaging and functional data poorly altered. Animal models are useful to corroborate data obtained in humans. Fluoropyrimidines can associate with specific cutaneous side effects, including the hand-foot syndrome (HFS), with symmetrical erythema, dysaesthesia, dryness, rash, swelling and desquamation on palms and soles. Cardiotoxicity includes angina pectoris, arrhythmias, palpitation, hypotension, hypertension, malaise and dyspnea, until life-threatening damages, with myocardial infarction and sudden death. Neurotoxicity is an uncommon but potentially severe side effect, consisting of rare cases of cerebellar alterations with ataxia, as well as multifocal cerebral leukoencephalopathy, with or without seizures, announcing with dizziness, memory deficits, trismus, headache, vertigo, gait disturbances and confusion, until coma. These adverse events are likely due to direct chemotoxic effects of fluoropyrimidine metabolites and most of them can be regarded as allergic reactions triggered by the hapten-like properties of these molecules. Conclusion: Fluoropyrimidines are able to induce specific morphohistopathological changes in tissues.

Background and Objective: The extensive clinical use of capecitabine may be associated with important adverse drug reactions. The aim of this study was to prevent the risk of toxicities in patients who are candidates to capecitabine treatment. Methods: Pharmacokinetic parameters of 5-fluorouracil (5-FU)/ 5-fluoro-5,6-dihydrouracil (5-FDHU) were examined in 133 cancer patients given a test dose of 5-FU (250 mg/m2) 2 weeks before starting capecitabine treatment. 5-FU and 5-FDHU plasma levels were measured, and related pharmacokinetic parameters were calculated. Toxicities were graded according to Common Toxicity Criteria (CTC) criteria. Results: Some significant relationships between 5-FU and 5-FDHU pharmacokinetic parameters and capecitabine toxicities were found. Higher values of 5-FU AUC0-∞ and t½β were found in patients who experienced grade ≥2 dermatitis, stomatitis and nausea during capecitabine chemotherapy. Moreover tmax higher than the threshold limit of 15 minutes was predictive for the risk of developing severe diarrhea after the first cycle of capecitabine therapy. Conclusion: This study suggests a successful approach for preventing moderate/severe toxicities in cancer patients who are candidates to capecitabine treatment by analyzing the 5-FU and 5-FDHU pharmacokinetic parameters after the administration of a reduced 5-FU test dose.

Background: Upfront screening for dihydropyrimidine dehydrogenase (DPD) deficiency in patients scheduled for 5-FU should help to reduce the risk of toxicities by preventive adaptive dosing. Our group has developed a simple functional testing categorizing patients upon their DPD status, i.e. extensive metabolizer (EM) or poor metabolizer (PM) patients, using UH2/U ratio measurement in plasma as a surrogate for DPD activity. 5-FU dosing can be next tailored according to DPD deficiency status. Objectives: We present here an observational study of this strategy implemented in routine clinical practice when treating head-and-neck cancer patients. Results: A total of 218 evaluable adult patients were treated with a 5-FU-regimen, with DPD-based adaptive dosing. Among them, 20 (9%) were identified as PM and received subsequently a 20-50% reduced dosing of 5-FU as compared with EM patients (2102 ±254 mg VS. 2577 ±353mg, p<0.001 ttest). Gender (Female) was associated with higher risk for being PM (p=0.01, Pearson's Chi squared test). Overall, early severe toxicities were seen only in 5% of patients, all being EM with standard dosing. Similarly, overall severe toxicities were observed in 12.8% of patients only, both figures being markedly lower than usually reported with standard 5-FU. Despite the average -20% reduction in 5- FU dosing between PM and EM patients, clinical efficacy was not statistically different between the two groups (p = 0.2774, chi-square test). Conclusion: This study shows that 5-FU-related toxicities can be greatly reduced in routine clinical practice by the upfront detection of DPD deficient patients with simple adaptive dosing strategy.

Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. HCC patients have a poor prognosis due to shortage of effective therapies though a small proportion of patients are eligible for curative treatments. Precision medicine, a recently emerging medicinal model, has provided more avenues in the management of HCC. Methods: Published literatures related to HCC and precision medicine were reviewed. The article aims to discuss the recent progress of HCC therapy under the guidance of precision medicine, and the major obstacles for its application. Results: Sorafenib remains the only first-line drug proved for treating advanced HCC, though it displays limited beneficial effects. Advances have been achieved in the technologies of new generation sequencing and molecular biology, bioinformatics, big data and cloud computing frame. Recent progresses in seeking tumor biomarkers and oncogenic addiction loops, re-analyses of failed clinical trials, techniques of circulating tumor cells and liquid biopsy, new clinical designs based on molecular information have offered a glimmer of hope in combating HCC. However, there are many obstacles, such as high heterogeneity, unpredictable driver genes, oncogenetic addiction loops and actionable events and drug resistance. Conclusion: The future progress in interdisciplinary application of computing, mathematics and information in medicine may further promote the development of precision medicine in the prevention, diagnosis, treatment and monitoring of HCC. We hope this article can provide some new clues for clinicians and scientists engaged in the clinical and basic research of HCC.

Background: The blood-brain barrier (BBB) is a major obstacle in the treatment of brain tumors. Intra-arterial (IA) administration with osmotic BBB disruption (BBBD) allows greater drug delivery to the central nervous system (CNS). Its use with temozolomide (TMZ), the first-line agent in the treatment of glioblastoma, has never been reported in an animal glioma model. Objective: This study was designed to investigate whether increased TMZ delivery would improve survival in the Fischer-F98 glioma model. Methods: Alternative methods of administration for TMZ (200 mg/m2) were tested, comparing intravenous infusions (IV, n=13) to IA (n=13) or BBBD with IA (n=13). IA normal saline (NS) was used as a control group (n=13). Five rats per group also underwent radiotherapy. Survival and adverse effects were measured. TMZ was quantified in plasma, CSF and brain at three time-points post-TMZ infusion (IV, IA or IA+BBBD) by LC-MS\MS. Results: Compared to IV, higher peak TMZ concentrations were observed in brain tumor (BT) tissues with IA and IA+BBBD infusions (4-fold and 5-fold, respectively). No difference in survival was observed between the IA with/without BBBD vs. IV/control groups. Radiotherapy increased survival independently of the method of TMZ delivery. Conclusion: We show that the enhanced delivery of TMZ by IA infusion (with/without BBBD) does not improve survival in this resistant model. However, the method of TMZ administration has a significant impact on CNS delivery. Bypassing the BBB with judicious use of local delivery approaches and appropriate therapeutic agents has potential for the treatment of glioblastomas.

Background: After the detection of recurrent high-grade glioma, there are no standard approaches; salvage surgery, chemotherapy and radiotherapy are often used despite the fact that no real clinical benefit has been confirmed and the combination of these approaches has not yet been fully investigated. Objective: In the present retrospective study, we reported the results of a mono-institutional experience studying the association of salvage hypofractionated stereotactic radiotherapy in combination with bevacizumab in patients with recurrent glioblastoma after standard up-front therapy with the Stupp protocol. Method: From May 2010 to December 2016, eight patients with recurrent glioblastoma were treated with hypofractionated radiotherapy 25 Gy in 5 fractions in combination with bevacizumab at the University Hospital of Pisa. Results: All patients showed appreciable improvements in Karnofsky Performance Status and median survival following the beginning of radiotherapy treatment to 7 months (range 3–15 months). Severe toxicity has not been recorded. Conclusion: Hypofractionated radiotherapy associated with bevacizumab may represent a valid therapeutic option in selected patients with recurrent high-grade glioma.