Metronomic chemotherapy: bridging theory to clinical application in canine and feline oncology.

Veterinary oncology has experienced significant evolution over the last few decades, with chemotherapy being currently applied to several neoplasms with therapeutic success. Traditionally, chemotherapy protocols are based on classic cytostatic drugs under the concept of maximum tolerated dose (MTD), which has been associated with a greater risk of toxicity and resistance. Thus, new therapeutic alternatives have emerged, such as metronomic chemotherapy (MC), introducing a new paradigm in cancer treatment. MC consists of administering low doses of chemotherapy drugs continuously over a long period of time, modulating the tumour microenvironment (TME) due to the combination of cytotoxic, antiangiogenic and immunomodulatory effects. This multi-targeted therapy has been described as a treatment option in several canine and feline cancers since 2007, with positive results already published in the literature, particularly in mammary carcinomas and soft tissue sarcomas in dogs. The aim of this review article is to describe the current knowledge about the use of MC in small animal oncology, with emphasis on its mechanisms of action, the most commonly used drugs and clinical outcome.

Bilateral Visual Impairment following Combination Chemotherapy with Carboplatin in Patients with Small Cell Lung Cancer: A Case Report.

Background: Platinum-based combination chemotherapy, including cisplatin and carboplatin, are important cytotoxic anti-cancer agents that are widely used to treat various solid tumors. Carboplatin has a similar effect on survival in small cell lung cancer, but generally has a milder toxicity profile when compared with cisplatin. Both may cause moderate or severe neurotoxicity, but ocular neurotoxicity from carboplatin is rarely reported. Case presentation: A 79-year-old man underwent intravenous polychemotherapy (atezolizumab, etoposide, and carboplatin) for small cell lung cancer. One week after the second cycle of chemotherapy, he reported bilateral visual loss as hand motion in both eyes. Dilated fundus examination showed retinal arterial narrowing without hemorrhage, and diffuse choroidal and retinal thinning was observed in an optical coherence tomography scan. Fluorescein angiography revealed significantly delayed circulation without evidence of obstructive lesions. 30-Flicker electroretinogram testing showed a complete absence of cone response in both eyes. The patient's visual acuity aggravated to no light perception in both eyes, even after the cessation of chemotherapy. Conclusions: Carboplatin combination chemotherapy administered at therapeutic doses can result in irreversible visual loss, a side effect that is not widely acknowledged. When using carboplatin, physicians should be aware of its potential ocular toxicity.

Development and validation of a quantitative wipe sampling method to determine platinum contamination from antineoplastic drugs on surfaces in workplaces at Swedish hospitals.

INTRODUCTION: Antineoplastic drugs (ADs) are frequently used pharmaceuticals in the healthcare, and healthcare workers can be occupationally exposed to ADs. Monitoring of surface contamination is a common way to assess occupational exposure to ADs. The objective was to develop and validate a sensitive and quantitative monitoring method to determine surface contaminations of Pt as a marker for Pt-containing ADs. The surface contaminations of Pt-containing ADs were monitored at four Swedish hospital workplaces. METHODS: An analytical method was developed based on inductively coupled plasma mass spectrometry. The wipe sampling procedure was validated regarding different surface materials. The stability of collected wipe samples was investigated. Workplace surfaces were monitored by wipe sampling to determine contaminations of Pt-containing ADs. RESULTS: A wipe sampling and analytical method with a limit of detection of 0.1 pg Pt/cm2 was developed. Pt was detected in 67% of the wipe samples collected from four workplaces, and the concentrations ranged from <0.10 to 21100 pg/cm2. In 4% of samples, the detected surface contaminations of Pt in three hospital wards were above proposed hygienic guidance value (HGV) of Pt. In the hospital pharmacy, 9% of the detected surface contaminations of Pt were above lowest proposed HGV. CONCLUSIONS: A user-friendly, specific, and sensitive method for determination of surface contaminations of Pt from ADs in work environments was developed and validated. A large variation of contaminations was observed between detected surface contaminations of Pt in samples collected in wards, and it likely reflects differences in amounts handled and work practices between the wards.

5-Fluorouracil-Related Pneumatosis Intestinalis: A Case Report and Review of the Literature.

Pneumatosis intestinalis (PI) refers to the presence of air within the bowel wall. It can be associated with many causes including chemotherapy. We report a case of a 70-year-old male with metastatic tongue squamous cell carcinoma (SCC), whose hospital course was complicated by diarrhea and the development of PI, which was attributed to 5-fluorouracil (5-FU) chemotherapy after a comprehensive diagnostic workup and reassuring physical examination. The patient was treated conservatively with antibiotics and a bowel rest. A repeat imaging done before discharge showed stable findings. The patient was discharged afterward without complications. We highlight the importance of recognizing 5-FU as a cause for PI among patients with reassuring physical examination and diagnostic workup. Furthermore, we highlight that it may still be successfully managed with conservative measures.

Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) methods for the therapeutic drug monitoring of cytotoxic anticancer drugs: An update.

In the era of precision medicine, there is increasing evidence that conventional cytotoxic agents may be suitable candidates for therapeutic drug monitoring (TDM)- guided drug dosage adjustments and patient's tailored personalization of non-selective chemotherapies. To that end, many liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) assays have been developed for the quantification of conventional cytotoxic anticancer chemotherapies, that have been comprehensively and critically reviewed. The use of stable isotopically labelled internal standards (IS) of cytotoxic drugs was strikingly uncommon, accounting for only 48 % of the methods found, although their use could possible to suitably circumvent patients' samples matrix effects variability. Furthermore, this approach would increase the reliability of cytotoxic drug quantification in highly multi-mediated cancer patients with complex fluctuating pathophysiological and clinical conditions. LC-MS/MS assays can accommodate multiplexed analyses of cytotoxic drugs with optimal selectivity and specificity as well as short analytical times and, when using stable-isotopically labelled IS for quantification, provide concentrations measurements with a high degree of certainty. However, there are still organisational, pharmacological, and medical constraints to tackle before TDM of cytotoxic drugs can be more largely adopted in the clinics for contributing to our ever-lasting quest to improve cancer treatment outcomes.

A simple and inexpensive method to monitor and minimize exposure from manipulation of cytotoxic drugs.

Pharmacy personnel that manipulate cytotoxic drugs are under continuous exposure risk. Therefore, training and strict adherence to recommended practices should always be promoted. The main objective of this study was to develop and apply a safe, effective and low-cost method for the training and assessment of the safe handling of cytotoxic drugs, using commercially available tonic water. To evaluate the potential of tonic water as a replacement marker for quinine hydrochloride, deliberate spills of 1 mL of four different tonic waters (one coloured and three non-coloured) were analysed under ultraviolet light (300-400 nm). The pigmented sample did not produce fluorescence under ultraviolet (UV) light. The three commercially available tonic waters that exhibited fluorescence were further analysed by UV/Vis spectrophotometry (300-500 nm). Afterwards, a protocol of simulated manipulation of cytotoxic drugs was developed and applied to 12 pharmacy technicians, that prepared 24 intravenous bags according to recommended routine procedures using tonic water. Participants responded to a brief questionnaire to evaluate the adequacy and applicability of the activity. Seven of the participants had spillages during manipulation, the majority of which recorded during manipulation with needles. All participants scored the tonic water manipulation simulation with 4 or 5 points for simplicity, efficiency and feasibility. The obtained results suggest that tonic water can be used to simulate the manipulation of cytotoxic drugs in training and assessment programs. By using this replacement marker for quinine hydrochloride, it is possible to perform a more cost-effective, yet equally effective, assessment.

Testicular function after non-cytotoxic and immunotherapy drug treatment.

BACKGROUND: The effects of novel non-cytotoxic and immunotherapy drugs for cancer treatment on human testicular function have not been studied systematically. OBJECTIVES: The present study aimed to characterize effects of non-cytotoxic and immunotherapy drugs in patients with cancers who had not been previously treated with gonadotoxic chemo- or radiotherapy. MATERIALS AND METHODS: This study involved 34 men, not previously treated with gonadotoxic regimens, in a mixed longitudinal (Cohort 1: 19 men about to start and approximately 1 year on non-cytotoxic and immunotherapy treatment) and cross-sectional (Cohort 2: 15 men already on non-cytotoxic and immunotherapy treatment) study using data modeling to estimate within-person time-course changes in testicular exocrine and endocrine functions. Cohort 1 provided 45 paired semen and blood samples (34 prior to and nine during treatment) and Cohort 2 provided 45 sets of samples (15 pre-treatment, 30 on treatment), including six men in Cohort 2 who had pre-treatment spermatozoa cryostorage prior to the study. Men on non-cytotoxic and immunotherapy treatment had undergone a median of 33.5 months long-term treatment. RESULTS: Spermatozoa output and concentration were reduced by about 50%, with corresponding increases in serum follicle-stimulating hormone and decreases in serum inhibin B. Serum testosterone, luteinizing hormone, and sex hormone-binding globulin were unaffected by non-cytotoxic and immunotherapy treatment. CONCLUSION: Within limits of the present study of sample size and duration of on-non-cytotoxic and immunotherapy treatment, non-cytotoxic and immunotherapy drugs have a modest effects on testicular exocrine function (sperm production) or its hormonal correlates (follicle-stimulating hormone, inhibin B), with minimal impact on testicular endocrine (testosterone, luteinizing hormone) function.

A review of FDA approved drugs and their formulations for the treatment of breast cancer.

Breast cancer is one of the most diagnosed solid cancers globally. Extensive research has been going on for decades to meet the challenges of treating solid tumors with selective compounds. This article aims to summarize the therapeutic agents which are either being used or are currently under approval for use in the treatment or mitigation of breast cancer by the US FDA, to date. A structured search of bibliographic databases for previously published peer-reviewed research papers on registered molecules was explored and data was sorted in terms of various categories of drugs used in first line/adjuvant therapy for different stages of breast cancer. We included more than 300 peer-reviewed papers, including both research and reviews articles, in order to provide readers an useful comprehensive information. A list of 39 drugs are discussed along with their current status, dose protocols, mechanism of action, pharmacokinetics, possible side effects, and marketed formulations. Another interesting aspect of the article included focusing on novel formulations of these drugs which are currently in clinical trials or in the process of approval. This exhaustive review thus shall be a one-stop solution for researchers who are working in the areas of formulation development for these drugs.

Nanomedicine and Hyperthermia for the Treatment of Gastrointestinal Cancer: A Systematic Review.

The incidence of gastrointestinal cancers has increased in recent years. Current treatments present numerous challenges, including drug resistance, non-specificity, and severe side effects, needing the exploration of new therapeutic strategies. One promising avenue is the use of magnetic nanoparticles, which have gained considerable interest due to their ability to generate heat in tumor regions upon the application of an external alternating magnetic field, a process known as hyperthermia. This review conducted a systematic search of in vitro and in vivo studies published in the last decade that employ hyperthermia therapy mediated by magnetic nanoparticles for treating gastrointestinal cancers. After applying various inclusion and exclusion criteria (studies in the last 10 years where hyperthermia using alternative magnetic field is applied), a total of 40 articles were analyzed. The results revealed that iron oxide is the preferred material for magnetism generation in the nanoparticles, and colorectal cancer is the most studied gastrointestinal cancer. Interestingly, novel therapies employing nanoparticles loaded with chemotherapeutic drugs in combination with magnetic hyperthermia demonstrated an excellent antitumor effect. In conclusion, hyperthermia treatments mediated by magnetic nanoparticles appear to be an effective approach for the treatment of gastrointestinal cancers, offering advantages over traditional therapies.

An Integrated Methodology to Quantify the Glycolytic Stress in Plasma Cell Myeloma in Response to Cytotoxic Drugs.

Multiple myeloma (MM) is an incurable plasma cell malignancy primarily localized within the bone marrow (BM). Myeloma plasma cells, like many other cancer cells, change their metabolism in response to internal and external stimuli. The main metabolic alterations of MM cells include deregulated glycolysis (commonly associated with enhanced uptake and utilization of glucose), lipid metabolism dysregulation, as well as deregulated mitochondrial respiration (commonly associated with the deregulated formation of reactive oxygen species). Over the past decade, the discovery of novel methodologies and the commercialization of sophisticated instrumentation and reagents have facilitated the detection of real-time changes in cellular bioenergetics. Of those, the Seahorse™ extracellular flux (XF) analyzer has been widely used to evaluate the glycolytic flux and mitochondrial respiration in many cell types. While adherent cell lines are easy to use with this technology, non-adherent suspension cells are more difficult to handle especially when their metabolic activities are being investigated in response to drug treatment. Here, we provide an integrated protocol that allows the detection of extracellular acidification rate (ECAR) of live myeloma plasma cells in response to chemotherapeutic drugs. Our optimized protocol consists of treating myeloma cells with cytotoxic drug of interest in a standard culture plate prior to the real-time analysis in the XF analyzer. Furthermore, we provide results of experiments in which the metabolic activities of myeloma cells in response to cytotoxic treatment were compared between the manufacturer's basic procedure and our optimized protocol. Our observations suggest that our integrated protocol can be used to achieve consistent, well-standardized results and thus it may have broad applications in studies focusing on the characterization of metabolic events in non-adherent suspension cells.

Pillararenes as Promising Carriers for Drug Delivery.

Since their discovery in 2008 by N. Ogoshi and co-authors, pillararenes (PAs) have become popular hosts for molecular recognition and supramolecular chemistry, as well as other practical applications. The most useful property of these fascinating macrocycles is their ability to accommodate reversibly guest molecules of various kinds, including drugs or drug-like molecules, in their highly ordered rigid cavity. The last two features of pillararenes are widely used in various pillararene-based molecular devices and machines, stimuli-responsive supramolecular/host-guest systems, porous/nonporous materials, organic-inorganic hybrid systems, catalysis, and, finally, drug delivery systems. In this review, the most representative and important results on using pillararenes for drug delivery systems for the last decade are presented.

Evaluation of Robotic Systems on Cytotoxic Drug Preparation: A Systematic Review and Meta-Analysis.

Background and Objectives: With the increased prevalence of patients with cancer, the demand for preparing cytotoxic drugs was increased by health-system pharmacists. To reduce the workload and contamination of work areas in pharmacies, compounding robots preparing cytotoxic drugs have been introduced, and the use of the robots has been expanded in recent years. As reports on the comprehensive and quantitative evaluation of compounding robots remain lacking, a systematic review and meta-analysis were conducted to provide descriptive and quantitative evaluations of the accuracy of preparing injectable cytotoxic drugs. Materials and Methods: A systematic review and meta-analysis were conducted using published studies up to 2020. To identify eligible studies, PubMed, EMBASE, and Cochrane Library were used. All studies reporting the outcomes relevant to drug-compounding robots such as accuracy, safety, and drug contamination were included. Outcomes from included studies were descriptively summarized. Drug contamination by the robot was quantitatively analyzed using the odds ratio (OR) with a 95% confidence interval (CI). The risk of bias was assessed using the Risk of Bias Assessment tool for Non-randomized Studies (RoBANS). Results: A total of 14 compounding robot studies were eligible for review and 4 studies were included in the meta-analysis. Robotic compounding showed failure rates of 0.9-16.75%, while the accuracy range was set at 5%. Two studies reported that robotic compounding needed more time than manual compounding, two reported that robotic compounding needed less time, and one just reported preparation time without a control group. In a meta-analysis regarding the contamination of the compounding area, manual compounding was associated with lower contamination, although the result was not statistically significant (OR 4.251, 95% CI 0.439-51.772). For the contamination of infusion bags, the robot was associated with lower contamination (OR 0.176, 95% CI 0.084-0.365). Conclusions: Robotic compounding showed better accuracy than manual compounding and, without control groups, showed a high accuracy rate and also reduced the risk of drug contamination and compounding workload. The preparation time of the robot was not consistent because the type of robot and introduced system were different. In conclusion, robotic compounding showed mixed results compared to the manual compounding of drugs, so the system should be introduced considering the risks and benefits of robots.

Occupational Exposure to Antineoplastic Drugs in Twelve French Health Care Setting: Biological Monitoring and Surface Contamination.

Antineoplastic drugs used in the treatment of cancers have an intrinsic toxicity, because of their genotoxic, teratogenic, and carcinogenic properties. Their use is recognized as an occupational hazard for healthcare workers (HCWs) who may be exposed. The purpose of this article is to present biological- and environmental-monitoring data collected in twelve French hospitals over eight years. Urine samples were collected from a wide range of HCWs (250 participants) from pharmacy and oncology units, including physicians, pharmacists, pharmacy technicians, nurses, auxiliary nurses, and cleaners. The investigated drugs were cyclophosphamide, ifosfamide, methotrexate, and α-fluoro-ß-alanine, the main urinary metabolite of 5-fluorouracil. Wipe samples were collected from various locations in pharmacy and oncology units. More than 50% of participants, from all exposure groups, were contaminated with either drug, depending on the unit, the day, or the task performed. However, workers from oncology units were more frequently exposed than workers from pharmacy units. Significant contamination was detected on various surfaces in pharmacy and oncology units, highlighting potential sources of exposure. Risk-management measures should be implemented to reduce and maintain exposures at lowest-possible levels. In addition, regular exposure assessment, including biological and environmental monitoring, is recommended to ensure the long-term efficiency of the prevention measures.

PD-1/PD-L1 and DNA Damage Response in Cancer.

The application of immunotherapy for cancer treatment is rapidly becoming more widespread. Immunotherapeutic agents are frequently combined with various types of treatments to obtain a more durable antitumor clinical response in patients who have developed resistance to monotherapy. Chemotherapeutic drugs that induce DNA damage and trigger DNA damage response (DDR) frequently induce an increase in the expression of the programmed death ligand-1 (PD-L1) that can be employed by cancer cells to avoid immune surveillance. PD-L1 exposed on cancer cells can in turn be targeted to re-establish the immune-reactive tumor microenvironment, which ultimately increases the tumor's susceptibility to combined therapies. Here we review the recent advances in how the DDR regulates PD-L1 expression and point out the effect of etoposide, irinotecan, and platinum compounds on the anti-tumor immune response.

Development and Evaluation of an e-Learning Module for Low- and Middle-Income Countries on the Safe Handling of Chemotherapy Drugs.

Despite the growing use of chemotherapy drugs in resource-constrained settings, training opportunities on safe handling practices are lacking. This study's objectives were to develop and evaluate an e-learning training module on the safe handling of chemotherapy drugs to strengthen knowledge and practices in low- and middle-income countries (LMICs). The module's curriculum was developed using the Six-Step Approach for Curriculum Development for Medical Education. Asynchronous, self-paced, e-learning lessons within the module were created and uploaded onto a free online platform, Pharm-Ed. The study ran online from January to April 2021. Participant recruitment was done using convenience sampling through various channels (social media, communities of practice). Training module effectiveness was evaluated using knowledge assessments (a pre-test and post-test study design) and participant satisfaction. We developed a comprehensive e-learning module on the safe handling of chemotherapy drugs comprising 11 asynchronous, self-paced, e-learning lessons. Eighty-two participants (68% pharmacists and 17% pharmacy students) from 17 countries completed at least one lesson, with a total of 259 lessons completed. Evaluation of the different lessons showed significant improvements in theoretical knowledge (p < 0.01) in all except one lesson and a high degree of participant satisfaction. As the use of anti-cancer drugs in LMICs will continue to increase, this e-learning module is an effective means to address the lack of training opportunities on the safe handling of chemotherapies for healthcare workers in these countries. The module could be integrated into a multi-modal approach aimed at reducing occupational exposure and increasing patient safety in cancer care centers.

Onco-pharmacist led evaluation of knowledge, attitude & practice (KAP) of safe handling cytotoxic drugs among health care professional's (HCP's) in tertiary care hospital: A hospital based interventional Study.

BACKGROUND: Cytotoxic drugs (CDs) are hazardous in nature. But it is necessary for the treatment in cancer patients. The healthcare professionals (HCPs) act as a facilitator through which the manufactured CDs reach the patient. However, safe handling of CDs becomes a primary concern not only for the recipients but also for the HCPs. METHODS: On Ethics committee approval, a prospective- interventional study was conducted among HCPs who are involved in handling of CDs in Oncology department of tertiary care hospital. The participants were screened for their eligibility criteria & 73 HCPs were recruited. The initial data was collected from the HCPs through interview & questionnaires. Later the participants were trained by oncology-pharmacist (7-8 months) for safe handling of CDs. After the training the participants were tested again through interview & questionnaires. RESULTS: 73 participants, (75%) nurses & (25%) physicians were included in the study. Among these participants, only 32.87% underwent training on reconstitution whereas 67.12% of the participants didn't undergo any training. The increase in mean score of KAP after the training was observed to be 3.44 ± 4.32, 1.23 ± 1.51 and 1.3 ± 1.01 respectively. CONCLUSION: The study concludes that mandatory requirement of training for HCPs using SOP's by qualified oncology-pharmacist to minimize the hazardous effects of CDs. It also highlights the improvisation techniques for handling of CDs will enhance the safety profile of HCPs & the patients, which helps in refining the quality of pharmaceutical and health care services provided in the cancer care settings.

Health professionals' practice to care cytotoxic drug handling and associated factors: The case of university of gondar specialized hospital.

BACKGROUND: Health care professionals are potential to be in contact with cytotoxic drugs during their daily work activ-ities. The study aimed to assess the practice of health professionals to care for cytotoxic drugs and associated factors in the University of Gondar Specialized Hospital. METHODS: Cross-sectional study design was employed. EPI Info 7 was used for data entry and then exported into SPSS 20 for statistical analysis. Frequencies and mean with standard deviation were computed. Logistic regression had been performed to find out associated factors. Crude' and adjusted Odds' ratio with 95% uncertainty interval was done. Variables with a p < 0.05 were declared as significant factors for practice of cytotoxic drug handling. RESULTS: The study used four-hundred and twelve health professionals took part in the study with 97.4% response rate. The mean age of study participants was 29.9 years ranging from 20-60 years and twenty (53.4%) participants were males. One hundred and fifty-five (37.6%) health professionals had good cytotoxic drug handling practice. Attending an average of 4-9 patients per day (AOR = 2.12, 95% CI: 1.05, 4.22), Medium work stress (AOR = 2.01, 95% CI: 1.04, 3.90), availability of cytotoxic drug handling manual (AOR = 2.51: 95% CI: 1.22, 5.12), and good knowledge (AOR = 4.09, 95% CI: 2.35, 7.11) were significantly associated with cytotoxic drug handling practice. CONCLUSION: The practice of cytotoxic drug handling care was low. It demands the engagement of the health sector to avert such inadequate practice and has to focus on delivering knowledge and logistics for the practice of cytotoxic drug handling.

Comparison of permeabilities of eight different types of cytotoxic drugs to five gloves with different materials by LC-MS/MS methods to reduce occupational exposure of medical personnel.

PURPOSE: Occupational exposure is a long-standing public health concern, which has drawn more and more attention in recent years to the problem of how to carry out occupational protection effectively. Gloves are regarded as the most critical protective equipment for cytotoxic medications. However, there is still little research conducted on the protective performance of gloves made of different materials and the optimal glove combination for cytotoxic agents. METHODS: In this research, a specific instrument intended for glove permeation experiment was designed, with various methods of liquid chromatography-tandem mass spectrometry (LC-MS/MS) developed and validated. By using the specific instrument and LC-MS/MS methods, a study was conducted on the permeation ability of eight selected cytotoxic drugs (fluorouracil, epirubicin (EPI), docetaxel (DCT), methotrexate (MTX), cyclophosphamide (CTX), etoposide (ETP), vincristine sulfate (VCR), and cisplatin derivatives Pt-(DDTC)3) into five kinds of gloves (rubber (RB), nitrile (NT), chlorinated polyethylene (CPE), low-density polyethylene, and polyvinylchloride (PVC) resin) given different contact times. Then, the experimental data were analyzed through a generalized estimation equation and Pearson correlation analysis. RESULTS: The results show that within a short period of time (less than five minutes), ETP, CTX, fluorouracil, DCT, and cisplatin passed through five types of gloves but the level of MTX, VCR, and EPI permeation was minimal, despite the duration of contact between the three drugs and the gloves reaching as long as three hours. Furthermore, the permeation of DCT and ETP was found to be positively correlated with time. CONCLUSIONS: Chlorinated polyethylene and PVC resin perform well in protecting against most cytotoxic drugs and are recommendable for clinical practice. Due to the poor protective ability, RB gloves are not recommended for this purpose. Based on the performance of various gloves in offering protection, the protection grade of two gloves can be deduced. Chlorinated polyethylene + PVC resin, CPE + NT glove combination shows good protective performance against most target drugs and can be recommended for clinical practice.

Therapeutic drug monitoring for cytotoxic anticancer drugs: Principles and evidence-based practices.

Cytotoxic drugs are highly efficacious and also have low therapeutic index. A great degree of caution needs to be exercised in their usage. To optimize the efficacy these drugs need to be given at maximum tolerated dose which leads to significant amount of toxicity to the patient. The fine balance between efficacy and safety is the key to the success of cytotoxic chemotherapeutics. However, it is possibly more rewarding to obtain that balance for this class drugs as the frequency of drug related toxicities are higher compared to the other therapeutic class and are potentially life threatening and may cause prolonged morbidity. Significant efforts have been invested in last three to four decades in therapeutic drug monitoring (TDM) research to understand the relationship between the drug concentration and the response achieved for therapeutic efficacy as well as drug toxicity for cytotoxic drugs. TDM evolved over this period and the evidence gathered favored its routine use for certain drugs. Since, TDM is an expensive endeavor both from economic and logistic point of view, to justify its use it is necessary to demonstrate that the implementation leads to perceivable improvement in the patient outcomes. It is indeed challenging to prove the utility of TDM in randomized controlled trials and at times may be nearly impossible to generate such data in view of the obvious findings and concern of compromising patient safety. Therefore, good quality data from well-designed observational study do add immense value to the scientific knowledge base, when they are examined in totality, despite the heterogeneity amongst them. This article compiles the summary of the evidence and the best practices for TDM for the three cytotoxic drug, busulfan, 5-FU and methotrexate. Traditional use of TDM or drug concentration data for dose modification has been witnessing a sea change and model informed precision dosing is the future of cytotoxic drug therapeutic management.

Complications of Totally Implantable Central Venous Catheters (Ports) Inserted via the Internal Jugular Vein Under Ultrasound and Fluoroscopy Guidance in Adult Oncology Patients: A Single-Center Experience.

Introduction In this retrospective study, the safety and complication rates of port implantations via the internal jugular vein under ultrasound and fluoroscopy guidance in adult oncology patients were analyzed. Material and methods Eight hundred seven ports implanted in 799 adult oncology patients at a tertiary Oncology-Anticancer Hospital during a 36-month period from January 1, 2017 to December 31, 2019 were retrospectively reviewed. Data acquisition was obtained until December 31, 2020. All procedures were performed by two specialized interventional radiologists under ultrasound and fluoroscopy guidance. The vein access was via the internal jugular vein. Catheter days (the total number of days of maintenance of the port by all of the patients until removal, death, or December 31, 2020), technical success rates, and complication rates were evaluated based on the interventional radiological reports and patient medical records. Multivariate analysis regarding patients such as age, sex, body mass index (BMI), marital status, educational level, cancer type, side of insertion, diameter of internal jugular vein, diabetes, anticoagulants/antiplatelets, purpose of implantation, and catheter material as to the risk of complications was conducted. Results A total of 369,329 catheter maintenance days were observed (457.7±345.0). The technical success rate was 99.9%, and a total of 85 (10.5%) complications occurred, of which 24 (28.2%) occurred early (<30 days) and the remaining 61 (71.8%) were late (>30 days) complications. Specifically, 28 (3.5%) were catheter-related thrombosis (CRT), 27 (3.4%) related to infection, 17 (2.1%) were mechanical complications (16 fibrin sheath formation and one catheter occlusion), six (0.7%) related to catheter migration, four (0.5%) related to incision healing problems, and the remaining three (0.4%) related to ischemic skin necrosis. Forty-seven (5.8%) ports were removed due to complications. On multivariate analysis, cancer type was found as a risk factor for the development of a complication. Additionally, there was an indication that hematologic malignancy is related to infection. Conclusion Placement of ports via the internal jugular vein under ultrasound and fluoroscopy guidance is a safe procedure, with low rates of early and late complications.