Target concentration intervention in oncology: where are we at?

Therapeutic drug monitoring (TDM) and more recently target concentration intervention (TCI) have been widely used in clinical practice for the optimization of drug treatment. TDM and TCI have been applied most frequently in the cardiovascular, respiratory, neurology, and infectious disease areas because the medications used here have both narrow therapeutic indices and a clear relationship between concentration and effect. However, apart from drugs such as methotrexate and 5-fluorouracil, the clinical application of TDM/TCI in oncology is minimal. An important reason for this is that a therapeutic index for most anticancer agents has not been established. However, in the last 20 years, relationships between plasma drug concentrations and clinical outcome have been defined for various chemotherapeutic agents. Defining concentration-effect relationships is also complicated by the fact that cancer is almost always treated with multiple drugs given in combination making the precise definition of the pharmacodynamics of individual agents difficult. The increase in patients with obesity and also those underweight adds to the complexity of effective oncology treatment. This review describes some of the evidence that supports the use of TDM/TCI in oncology. It is proposed that as more patients previously ineligible for chemotherapy become eligible, TDM/TCI may play a critical role in optimizing chemotherapy outcomes. However, pharmacokinetic-pharmacodynamic research to investigate both therapeutic benefit and feasibility in daily clinical practice is required.     

Individualised cancer chemotherapy: strategies and performance of prospective studies on therapeutic drug monitoring with dose adaptation: a review

Therapeutic drug monitoring (TDM) is increasingly used in clinical practice for the optimisation of drug treatment. Although pharmacokinetic variability is an established factor involved in the variation of therapeutic outcome of many chemotherapeutic agents, the use of TDM in the field of oncology has been limited thus far. An important reason for this is that a therapeutic index for most anticancer agents has not been established; however, in the last 20 years, relationships between plasma drug concentrations and clinical outcome have been defined for various chemotherapeutic agents. Several attempts have been made to use these relationships for optimising the administration of chemotherapeutics by applying pharmacokinetically guided dosage. These prospective studies, individualising chemotherapy dose during therapy based on measured drug concentrations, are discussed in this review. We focus on the way a target value is defined, the methodologies used for dose adaptation and the way the performance of the dose-adaptation approach is evaluated. Furthermore, attention is paid to the results of the studies and the applicability of the strategies in clinical practice. It can be concluded that TDM may contribute to improving cancer chemotherapy in terms of patient outcome and survival and should therefore be further investigated.     

Clinical pharmacokinetics of commonly used anticancer drugs

The quantitative aspects of drug disposition in man of the commonly used antineoplastic agents, including cyclophosphamide, the nitrosoureas, cisplatin, methotrexate, cytarabine, 5-fluorouracil, doxorubicin, daunorubicin, bleomycin, vincristine, vinblastine, and vindesine are reviewed. Although the pharmacokinetic behaviour of these drugs has been adequately described in man, the chemical reactivity, the complexity of metabolism and disposition, the lack of simple, rapid and sensitive assays to measure plasma concentration, and the lack of defined therapeutic and toxic plasma concentrations have limited the application of routine drug monitoring in clinical oncology. With the exception of high dose methotrexate, drug doses and administration schedules remain empirical with a standard starting dose and subsequent dosage modifications determined by ensuing drug toxicities. However, many of the pharmacological characteristics of the drugs, such as their low therapeutic index, potentially life-threatening toxicities and wide individual variability in drug disposition, necessitate pharmacological monitoring. Comprehensive pharmacokinetic analysis of new and established antineoplastic agents does play a role in defining dosage, administration schedule, route of administration, and dosage modification in the presence of organ dysfunction. Consideration of the kinetics of these drugs in planning treatment regimens could lead to more rational, safer and possibly more efficacious use.     

Drug treatment of colorectal cancer. Current status.

Drug therapy is most often used in colorectal cancer for palliation of metastatic disease. Current data also support the use of adjuvant chemotherapy following complete surgical resection in patients with locoregional lymph node metastases. The agent most widely used in the treatment of colorectal cancer is the antimetabolite fluorouracil (5-fluorouracil; 5-FU). This fluoridated pyrimidine has been available for over 30 years, yet to date no other single agent has proven to be more efficacious. Controversy exists about the most desirable schedule for administration of fluorouracil. Efforts have been made to improve upon its therapeutic index and efficacy by using the concept of biomodulation, in which chemicals which are not themselves active antineoplastic agents against colorectal cancer are administered with fluorouracil in an attempt to enhance the sensitivity of the cancer cell to fluorouracil. Biomodulation agents currently in use in clinical practice include leucovorin (calcium folinate), methotrexate, and interferon-alpha. Other biomodulation strategies are currently under investigation. Adding putatively active antineoplastic agents to fluorouracil to form combination chemotherapy regimens has not yielded convincingly superior results to treatment with fluorouracil alone, and the toxicities of many of these combination regimens have been formidable. Secondary therapies following failure of fluorouracil-based regimens have been similarly disappointing. Current areas of investigation into the chemotherapy of colorectal cancer include development of new agents, locoregional administration of chemotherapy, and manipulation of intrinsic drug resistance mechanisms of the cancer cells.     

Pharmacist management of antiemetic therapy under protocol in an oncology clinic

The development of a program for pharmacist prescribing of antiemetic agents for nausea and vomiting induced by antineoplastic agents given to ambulatory patients is described. The oncologist and the pharmacists developed a protocol and submitted it to the Washington State Board of Pharmacy, which can authorize a pharmacist to initiate or modify drug therapy in accordance with written guidelines or protocols. The protocol was approved and the pharmacists developed algorithms for antiemetic therapy, based on the emetic potential of the various antineoplastic agents. The oncologist writes an order for the pharmacist to prescribe antiemetic therapy for an individual patient, and the pharmacists selects an algorithm for each patient based on the antineoplastic agent that has the highest potential for causing emesis. The pharmacist writes orders for antiemetic agents to be administered in the clinic and at home, phones the patient 24 hours after antineoplastic drug therapy, and, if necessary, modifies the antiemetic therapy. Pharmacists have managed antiemetic therapy for more than 1200 patient visits and were able to use the first-line therapy in the selected algorithm in 78% of the cases without serious adverse effects. Pharmacist management of antiemetic therapy for nausea and vomiting associated with antineoplastic drug treatment has been well accepted by patients and professionals in this oncology clinic.     

Development and applications of photo-triggered theranostic agents

Theranostics, the fusion of therapy and diagnostics for optimizing efficacy and safety of therapeutic regimes, is a growing field that is paving the way towards the goal of personalized medicine for the benefit of patients. The use of light as a remote-activation mechanism for drug delivery has received increased attention due to its advantages in highly specific spatial and temporal control of compound release. Photo-triggered theranostic constructs could facilitate an entirely new category of clinical solutions which permit early recognition of the disease by enhancing contrast in various imaging modalities followed by the tailored guidance of therapy. Finally, such theranostic agents could aid imaging modalities in monitoring response to therapy. This article reviews recent developments in the use of light-triggered theranostic agents for simultaneous imaging and photoactivation of therapeutic agents. Specifically, we discuss recent developments in the use of theranostic agents for photodynamic-, photothermal- or photo-triggered chemotherapy for several diseases.     

Pharmacovigilance in oncology

Background Side effects of cancer therapy are one of the most important issues faced by cancer patients during their illness. Pharmacovigilance, namely the science and activities aimed at monitoring the safety of drugs, is particularly important in oncology, due to the intrinsic biologic toxicity of antineoplastic agents, their narrow therapeutic windows, and the high doses and rigid timing of treatment regimens. Aim of the review To identify the main issues in carrying out an effective pharmacovigilance activity in oncology. Method We searched PubMed for articles about pharmacovigilance in relation to chemotherapy, radiotherapy and targeted therapy for cancer, using MeSH terms and text words. We also searched Embase, CINAHL, Scopus, Micromedex, the Cochrane Library, two pharmacovigilance databases and the gray literature for articles published in 2012–2018. Overall, 137 articles were considered potentially relevant and were critically appraised independently by two authors, leading to the inclusion of 44 relevant studies, guidelines and reviews. Another 10 important research reports were included in the review. Results Eight critical issues of pharmacovigilance in oncology were identified. These issues pertain to: terminology; range of side effects; targeted therapy and immunotherapy; chemoradiotherapy; generic drugs and biosimilars; drug interactions, pharmacogenetics and polypharmacy; special patient categories; and under-reporting of ADRs. Conclusion The importance of pharmacovigilance in oncology must be highlighted with every effort, to improve safety and offer cancer patients every possible help to improve their quality of life during such a critical period of their lives.     

Novel platinum agents and mesenchymal stromal cells for thoracic malignancies: state of the art and future perspectives

ABSTRACT

Introduction: Non-small cell lung cancer and malignant pleural mesothelioma represent two of the most intriguing and scrutinized thoracic malignancies, presenting interesting perspectives of experimental development and clinical applications.

Areas covered: In advanced non-small cell lung cancer, molecular targeted therapy is the standard first-line treatment for patients with identified driver mutations; on the other hand, chemotherapy is the standard treatment for patients without EGFR mutations or ALK rearrangement or those with unknown mutation status. Once considered an ineffective therapy in pulmonary neoplasms, immunotherapy has been now established as one of the most promising therapeutic options.

Mesenchymal stromal cells are able to migrate specifically toward solid neoplasms and their metastatic localizations when injected intravenously. This peculiar cancer tropism has opened up an emerging field to use them as vectors to deliver antineoplastic drugs for targeted therapies.

Expert opinion: Molecular targeted therapy and immunotherapy are the new alternatives to standard chemotherapy. Mesenchymal stromal cells are a new promising tool in oncology and—although not yet utilized in the clinical practice, we think they will represent another main tool for cancer therapy and will probably play a leading role in the field of nanovectors and molecular medicine.     

Obatoclax mesylate : pharmacology and potential for therapy of hematological neoplasms

INTRODUCTION: Augmentation and acceleration of apoptosis for cancer therapy are logical therapeutic strategies given the increasing body of data suggesting the dysregulation of control of cell death in many neoplasms. Apoptosis is particularly well studied in hematological neoplasms, thus these varied diseases present opportunities for pro-apoptotic drug development both as single agents and in combination with established therapies. Accordingly, several agents targeting function of anti-apoptotic Bcl-2 family members have entered clinical trials in the last decade and are discussed. AREAS COVERED: The pan Bcl-2 family member BH3 domain mimetic obatoclax (GX15-070) is currently under clinical evaluation in solid tumors and hematological neoplasms. This agent offers the attractive property of uniformly inhibiting all of the anti-apoptotic members of the Bcl-2 protein family. Its chemistry and preclinical development and activity are reviewed. Pharmacology, pharmacodynamics, drug resistance and clinical use of this agent in leukemias and lymphomas are discussed. The prospects for obatoclax in changing clinical practice are addressed. EXPERT OPINION: Obatoclax may not prove to have dramatic single agent activity for hematological neoplasms. It seems more likely that its activity will be manifest in combination therapy with other agents, particularly cytotoxic chemotherapies. Results of ongoing studies are awaited.     

Local drug delivery to the brain

The controlled local delivery of antineoplastic agents by biodegradable polymers is a technique that allows for exposure of tumor cells to therapeutic doses of an active agent for prolonged periods of time while avoiding high systemic doses associated with debilitating toxicities. The use of polymers for chemotherapy delivery expands the spectrum of available treatment of neoplasms in the central nervous system, and facilitates new approaches for the treatment of malignant gliomas. In this article, we discuss the rationale and history of the development and use of these polymers, and review the various agents that have used this technology to treat malignant brain tumors.     

Cancer chemotherapy and drug metabolism.

Drug-metabolizing enzymes and drug transporters are key determinants of the pharmacokinetics and pharmacodynamics of many antineoplastic agents. Metabolism and transport influence the cytotoxic effects of antineoplastic agents in target tumor cells and normal host tissues. This article summarizes several state-of-the-art approaches to enhancing the effectiveness and safety of cancer therapy based on recent developments in our understanding of antineoplastic drug metabolism and transport. Advances in four interrelated research areas presented at a recent symposium sponsored by the Division for Drug Metabolism of the American Society for Pharmacology and Experimental Therapeutics (Experimental Biology 2004; Washington D.C., April 17-21, 2004) are discussed: 1) interactions of anthracyclines with drug-metabolizing enzymes; 2) use of hypoxia-selective gene-directed enzyme prodrug therapy (GDEPT) in combination with bioreductive prodrugs; 3) synergy between glutathione conjugation and conjugate efflux in conferring resistance to electrophilic toxins; and 4) use of cytochromes P450 as prodrug-activating enzymes in GDEPT strategies. A clear theme emerged from this symposium: drug metabolism and transport processes can be modulated and exploited in ways that may offer distinct therapeutic advantages in the management of patients with cancer.     

卵巢肿瘤联合化疗合理用药调查分析

目的对卵巢恶性肿瘤联合化疗病例进行合理用药调查、分析。方法医、药共同参与,共调查114份卵巢肿瘤联合化疗归档病历,分析联合化疗及辅助治疗用药过程,进行合理用药评价,分科室比较调查结果并分析原因。结果卵巢肿瘤联合化疗用药过程中,在化疗方案选择、化疗给药剂量、溶媒选择、辅助用药等环节存在较多的不合理用药现象,非肿瘤科室开展的联合化疗存在更多的用药问题。结论卵巢肿瘤联合化疗的多个用药环节可出现不合理用药问题,提醒化疗医生重视合理用药。深入评价用药过程可以促进卵巢肿瘤联合化疗合理用药水平的提高。     

Therapeutic drug monitoring in cancer chemotherapy

For a select number of drugs, proper management of patients includes monitoring serum or plasma concentrations of the drugs and adjusting the doses accordingly - this practice is referred to as therapeutic drug monitoring (TDM). The need for TDM arises when pharmacokinetic variability of drugs is not easily accounted for by common clinical parameters. Many chemotherapeutic drugs have large interindividual variability, yet TDM is not commonplace in chemotherapy management. This review will discuss pharmacokinetics in the context of chemotherapeutic drugs, examine the few instances where TDM is currently used in the field of oncology and propose other drugs where TDM might be useful for dose adjustments in the management of chemotherapy.     

Extemporaneous compounding of oral liquid dosage formulations and alternative drug delivery methods for anticancer drugs

Oncology pharmacists face a constant challenge with patients who cannot swallow oral anticancer drugs, making extemporaneous oral liquid preparation a requirement. Improper extemporaneous preparation of these agents, especially with the traditional chemotherapy with a narrow therapeutic index, may increase the risk of over- or underdosing. In community pharmacies, multiple barriers exist that prevent these pharmacies from preparing extemporaneous oral anticancer drug formulations for a patient's use at home. In a home setting, patients or caregivers without proper counseling and education on how to safely handle chemotherapy are at increased risk for exposure to these drugs. Based on a review of the literature, compounding recipes are available for 46% of oral anticancer agents. A paucity of data exists on dose uniformity, bioequivalence, and stability of extemporaneous oral liquid formulations of anticancer drugs. Pharmacists must have an understanding of the basic scientific principles that are an essential foundation for the proper preparation of extemporaneous oral anticancer liquid formulations. The collaborative effort of a multidisciplinary team can also help identify different barriers in the community setting, especially in areas where community pharmacies may lack resources for the extemporaneous compounding of oral chemotherapy, and to find ways to coordinate better pharmaceutical care. There are great opportunities for oncology pharmacists, as well as community pharmacists, as a resource for educating and monitoring patients receiving oral chemotherapy to ensure dosing accuracy, safe administration, and proper disposal of hazardous drugs. Development of national guidelines to promote standards of practice in the community and/or home setting is urgently needed to help improve the safety of dispensing and handling oral chemotherapeutic agents, including extemporaneously compounded oral liquid formulations of these drugs.     

Advances in image-guided intratumoral drug delivery techniques

Image-guided drug delivery provides a means for treating a variety of diseases with minimal systemic involvement while concurrently monitoring treatment efficacy. These therapies are particularly useful to the field of interventional oncology, where elevation of tumor drug levels, reduction of systemic side effects and post-therapy assessment are essential. This review highlights three such image-guided procedures: transarterial chemoembolization, drug-eluting implants and convection-enhanced delivery. Advancements in medical imaging technology have resulted in a growing number of new applications, including image-guided drug delivery. This minimally invasive approach provides a comprehensive answer to many challenges with local drug delivery. Future evolution of imaging devices, image-acquisition techniques and multifunctional delivery agents will lead to a paradigm shift in patient care.     

Developmental antiangiogenic agents for the treatment of Non-Small Cell Lung Cancer (NSCLC)

Standard therapy for advanced or metastatic non-small cell lung cancer (NSCLC) has primarily consisted of traditional cytotoxic chemotherapy, although use of targeted therapies has been approved in specific settings. Antiangiogenic agents represent a promising therapeutic strategy for treatment of advanced NSCLC. Bevacizumab is currently approved when given in combination with first-line platinum-based therapy in selected patients with nonsquamous NSCLC. Bevacizumab may also provide benefit in other clinical settings, as a part of a combination or maintenance strategy. Other antiangiogenic agents under development, including multi-targeted kinase inhibitors (MTKIs) and antibody-based agents, have exhibited mixed results in the NSCLC population. Published efficacy and safety data from clinical trials for antiangiogenic agents are reviewed, with an emphasis on novel agents and novel settings for established agents. Identification of biomarkers associated with improved efficacy may help select patients likely to receive the most benefit from these agents and may improve outcomes through development of personalized therapeutic strategies.     

Recombinant antibodies in infectious disease

Antibody-based therapies have a proven record of efficacy against many diseases. However, passive immunotherapy is presently underdeveloped in the field of infectious diseases. The emergence of new recombinant technologies for the generation of therapeutic antibodies provides significant opportunities for the development of effective antibody-based drugs. Obstacles to the broader use of antibodies as anti-infectives include a continuous emphasis in the field on the use of microbicidal chemotherapy, the fact that antibodies are usually pathogen-specific drugs with relatively small markets, expense of production, the necessity for early and accurate diagnosis prior to use and the complex logistics necessary for therapeutic use. Nevertheless, many opportunities for developing antibody-based drugs now exist in areas where the available antimicrobial therapies are inadequate. As reflected in patents published in the years 2000 – 2003, activity in this field is increasingly focused on novel antibody drug candidates and it is likely that, in the near future, several antibody reagents will be developed for clinical anti-infective use.     

The role of estrogen and estrogen receptors in chemoresistance

Drug resistance is one of the major obstacles limiting the success of cancer chemotherapy. Biological mechanisms contributing to drug resistance may be present de novo and related to inherent features or may be raised after exposure to anticancer drugs. In recent years, both clinical observations and experimental studies suggested that steroid hormones and their receptors might also affect the therapeutic efficacy of antineoplastic drugs. Estrogens and estrogen receptors (ER) are well-known for their critical roles in the development and progression of breast tumors. It has long been known that breast tumors expressing ERα protein (ERα+) behave in a fundamentally different fashion than ERα-negative (ERα-) tumors with regard to their responses to hormonal therapy. Data obtained from both laboratory and clinical investigations suggested that some chemotherapeutic agents are clearly less effective in ERα+ tumors than ERα- tumors, although the mechanisms of ERα-mediated chemoresistance are not entirely clear. Moreover, recent studies from our laboratory and others demonstrated that the combination of antiestrogenic agents with chemotherapeutic drugs is of significant therapeutic benefit in ERα+ breast cancer over chemotherapy alone. In addition, the ERα-derived peptides, microRNAs specifically targeting ERα, as well as agents targeting estrogen-related receptors (ERRs) may hold promise to sensitize ERα+ breast tumors to chemotherapy. Considering that ERs are expressed in ? 65% of human breast cancer, the ERα-mediated chemoresistance has become a big challenge for clinical treatment. The hope to overcome this drug resistance relies on further clarification of specific pathways or molecules contributing to the resistance. More exhaustive and systematic studies are essential to reach deeper understandings on the underlying mechanisms and to develop novel approaches to sensitize ERα+ breast tumors to chemotherapy.     

The therapeutic monitoring of antimicrobial agents

Aims  To review the basis and optimal use of therapeutic drug monitoring of antimicrobial agents.
Methods  Antimicrobial agents for which a reasonable case exists for therapeutic drug monitoring are reviewed under the following headings: pharmacokinetics, why monitor, therapeutic range, individualization of therapy, sampling times, methods of analysis, interpretative problems and cost-effectiveness of monitoring.
Results  There is a strong historical case for monitoring aminoglycosides. The recent move to once-daily dosing means that criteria for therapeutic drug monitoring need to be redefined. Vancomycin has been monitored routinely but many questions remain about the most appropriate approach to this. A case can be made for monitoring teicoplanin, flucytosine and itraconazole in certain circumstances.
Conclusions  The approach to monitoring aminoglycosides is being redefined in the light of once daily dosing. It may be that less stringent monitoring is required in some circumstances but toxicity, especially ototoxicity, remains a problem with these drugs. Monitoring to avoid high AUCs (areas under the concentration-time curve) is recommended. The ideal method for monitoring vancomycin remains to be defined although a reasonable case exists for measuring trough concentrations, mainly to ensure efficacy. Teicoplanin is sometimes monitored to ensure efficacy while flucytosine may be monitored to avoid high concentrations associated with toxicity. Itraconazole has various pharmacokinetic problems and monitoring has been suggested to ensure that adequate concentrations are achieved.