Precision Oncology by Point-of-Care Therapeutic Drug Monitoring and Dosage Adjustment of Conventional Cytotoxic Chemotherapies: A Perspective.

Therapeutic drug monitoring (TDM) of conventional cytotoxic chemotherapies is strongly supported yet poorly implemented in daily practice in hospitals. Analytical methods for the quantification of cytotoxic drugs are instead widely presented in the scientific literature, while the use of these therapeutics is expected to keep going for longer. There are two main issues hindering the implementation of TDM: turnaround time, which is incompatible with the dosage profiles of these drugs, and exposure surrogate marker, namely total area under the curve (AUC). Therefore, this perspective article aims to define the adjustment needed from current to efficient TDM practice for cytotoxics, namely point-of-care (POC) TDM. For real-time dose adjustment, which is required for chemotherapies, such POC TDM is only achievable with analytical methods that match the sensitivity and selectivity of current methods, such as chromatography, as well as model-informed precision dosing platforms to assist the oncologist with dose fine-tuning based on quantification results and targeted intervals.

Are cytostatic drugs in surface waters a potential threat?

Cytostatic drugs are pharmaceuticals administered to cancer patients under chemotherapy. Their occurrence in surface waters has been reported worldwide, increasing environmental and human health concerns. This work addresses a question of worldwide interest: are these hazardous pharmaceuticals in surface waters a potential threat? For the first time, this study brings information on the presence of cytostatic drugs in Portuguese rivers. Furthermore, cutting-edge data on the occurrence of two cytostatic drugs is provided; up to the authors' best knowledge, flutamide and mycophenolate mofetil have never been monitored in worldwide surface waters. Nine out of thirteen cytostatic drugs were detected in Portuguese rivers. Despite bicalutamide being the cytostatic most frequently detected, the highest concentration was recorded for cyproterone (19 ± 3 ng/L). Three different scenarios were considered to estimate the risks from the exposure of humans to cytostatic drugs via surface waters. Two scenarios are associated with bathing practices in rivers, particularly in the spring and summer seasons (river beaches): (i) the exposure to cytostatic drugs by dermal contact with contaminated water and (ii) the exposure by accidental ingestion of contaminated water, which is less likely but also occurs. The third exposure scenario is related to (iii) the long-life consumption of drinking water produced from river water capture, under worst-case conditions, i.e. negligible degradation of cytostatic drugs at drinking water treatment plants. It was concluded that the third exposure context to cytostatics could represent a risk to children, if the highest concentration ever reported in the literature for cyclophosphamide in surface waters is considered. Still, attending to the carcinogenicity of some of these compounds (e.g., cyclophosphamide, chlorambucil, etoposide and tamoxifen), health risks might always be expected, regardless of the contamination level. Furthermore, health risks associated with synergic effects and/or long-term exposures cannot be ruled out, even for the remaining cytostatics/exposure contexts.

Wipe-sampling procedure optimisation for the determination of 23 antineoplastic drugs used in the hospital pharmacy.

PURPOSE: Optimise a wipe sampling procedure to evaluate the surface contamination for 23 antineoplastic drugs used in the hospital pharmacy. METHODS: The influence of various parameters (ie, sampling device, sampling solution, desorption modes) was evaluated using a validated liquid chromatography-mass spectrometry (LC-MS/MS) method able to quantify 23 antineoplastic drugs widely used in the hospital pharmacy: 5-fluorouracil, busulfan, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, etoposide phosphate, fludarabine phosphate, ganciclovir, gemcitabine, idarubicin, ifosfamide, irinotecan, methotrexate, paclitaxel, pemetrexed, raltitrexed, topotecan and vincristine. Best conditions were tested with real samples from a hospital pharmacy chemotherapy compounding unit. RESULTS: Polyester swabs (TX714 and TX716) gave satisfactory results for the desorption step for all compounds with mean recoveries of 90% and 95%, respectively. For the wiping step, higher recoveries were obtained using TX716 and isopropanol 75% as wiping solution. As anticipated, most intense contaminations were found close to the chemotherapy production site, on surfaces the most frequently in contact with operators' hands. CONCLUSION: Wipe sampling method was successfully developed and applied to real samples to determine surface contamination with 23 antineoplastic agents in trace amounts.

Proposal of a simple and rapid method for the chemotherapy preparations analytical control by spectrophotometry UV-Vis method.

INTRODUCTION: The preparation of anticancer chemotherapy in a hospital must meet several objectives; the first main is the quality, which can be provided by setting up a surveillance system and a quality control of each preparations. The aim of this work is to present a simple, fast and accurate spectrophotometric method for the routine control of cytotoxic preparations. MATERIALS AND METHODS: This is a study carried out in the cytotoxic preparation unit of the university center of Rabat-Sale children's hospital in Morocco. All samples of preparations were collected and analyzed daily on the site. After validation of the analytical method with respect to many parameters such as: linearity, accuracy and precision according to ICH Q2 guidelines, samples of cytotoxic preparations collected were assayed. RESULTS: The results are satisfactory with good level of exactitude, and high precision. CONCLUSION: Compared to other techniques, this method can be considered as a useful alternative in the routine quality control of preparations. It can quickly obtain qualitative and quantitative information with instrumentation and inexpensive reagents.

Assessment of efficacy of postinfusion tubing flushing in reducing risk of cytotoxic contamination.

PURPOSE: Infusion of cytotoxic drugs carries the risk of occupational exposure of healthcare workers. Since disconnecting an infusion line is a source of contamination, flushing of tubing after infusion of cytotoxic agents is recommended, but the optimal volume of rinsing solution is unknown. The objective of this study was to assess whether postinfusion line flushing completely eliminates cytotoxics. METHODS: Infusions were simulated with 3 cytotoxics (gemcitabine, cytarabine, and paclitaxel) diluted in 5% dextrose injection or 0.9% sodium chloride injection in 250-mL infusion bags. Infusion lines were flushed using 5% dextrose injection or 0.9% sodium chloride solution at 2 different flow rates. The remaining concentration of cytotoxics in the infusion line was measured by a validated high-performance liquid chromatography (HPLC) method after passage of every 10 mL of flushing volume until a total of 100 mL had been flushed through. RESULTS: All cytotoxics remained detectable even after line flushing with 80 mL of flushing solution (a volume 3-fold greater than the dead space volume within the infusion set). Gemcitabine and cytarabine were still quantifiable via HPLC even after flushing with 100 mL of solution. Efficacy of flushing was influenced by the lipophilicity of drugs but not by either the flushing solvent used or the flushing flow rate. After 2-fold dead space volume flushing, the estimated amount of drug remaining in the infusion set was within 0.19% to 0.56% of the prescribed dose for all 3 cytotoxics evaluated. CONCLUSION: Complete elimination of cytotoxics from an infusion line is an unrealistic objective. Two-fold dead space volume flushing could be considered optimal in terms of administered dose but not from an environmental contamination point of view. Even when flushed, the infusion set should still be considered a source of cytotoxic contamination.

Like a Rolling Stone: Sting-Cgas Pathway and Cell-Free DNA as Biomarkers for Combinatorial Immunotherapy.

Combining immune checkpoint inhibitors with other treatments likely to harness tumor immunity is a rising strategy in oncology. The exact modalities of such a combinatorial regimen are yet to be defined, and most attempts have relied so far on concomitant dosing, rather than sequential or phased administration. Because immunomodulating features are likely to be time-, dose-, and-schedule dependent, the need for biomarkers providing real-time information is critical to better define the optimal time-window to combine immune checkpoint inhibitors with other drugs. In this review, we present the various putative markers that have been investigated as predictive tools with immune checkpoint inhibitors and could be used to help further combining treatments. Whereas none of the current biomarkers, such as the PDL1 expression of a tumor mutational burden, is suitable to identify the best way to combine treatments, monitoring circulating tumor DNA is a promising strategy, in particular to check whether the STING-cGAS pathway has been activated by cytotoxics. As such, circulating tumor DNA could help defining the best time-window to administrate immune checkpoint inhibitors after that cytotoxics have been given.

Cytotoxic-induced heart failure among breast cancer patients in Nigeria: A call to prevent today's cancer patients from being tomorrow's cardiac patients.

We report three cases of heart failure (HF) associated with the use of cytotoxic drugs such as anthracycline, cyclophosphamide, and 5-fluorouracil in the treatment of breast cancer in Nigerians. The patients had systolic and diastolic HF: HF with reduced ejection fraction and preserved ejection fraction. The prevalence of breast cancer is increasing across Africa, and cytotoxics are some of the most common and best drugs used during management. The cardiotoxicity caused by these drugs limits their use as chemotherapeutic agents. Cytotoxic-induced HF is a preventable and manageable cause of cardiovascular disease (CVD) in Nigeria and Africa. This article discusses the pathophysiology of cytotoxic-induced HF and presents the risk factors that impair cardiovascular function. The importance of proper assessment and the prophylactic and therapeutic measures in the management of cytotoxic-induced HF are emphasized. The peculiar challenges in the management of cytotoxic-induced HF in Nigeria were also discussed. The need for early involvement of cardiologists by oncologists to improve on the chemotherapeutic and cardiovascular outcome in the management of patients with breast cancer was stressed. Perhaps, it is time to birth a new discipline of cardiooncology in Nigeria.

Résumé Nous rapportons trois cas d'insuffisance cardiaque (IC) associés à l'utilisation de médicaments cytotoxiques tels que l'anthracycline, le cyclophosphamide et le 5-fluorouracile dans le traitement du cancer du sein chez les Nigérians. Les patients avaient une HF systolique et diastolique: HF avec une fraction d'éjection réduite et une fraction d'éjection préservée. La prévalence du cancer du sein augmente à travers l'Afrique et les cytotoxiques sont parmi les médicaments les plus courants et les meilleurs utilisés pendant la prise en charge. La cardiotoxicité causée par ces médicaments limite leur utilisation comme agents chimiothérapeutiques. L'IC induite par les cytotoxiques est une cause évitable et gérable de maladies cardiovasculaires (MCV) au Nigéria et en Afrique. Cet article traite de la physiopathologie de l'IC induite par cytotoxique et présente les facteurs de risque qui altèrent la fonction cardiovasculaire. L'importance d'une évaluation appropriée et des mesures prophylactiques et thérapeutiques dans la gestion de l'IC induite par les cytotoxiques est soulignée. Les défis particuliers de la gestion de l'IC induit par des cytotoxiques au Nigeria ont également été discutés. La nécessité d'une implication précoce des cardiologues par les oncologues pour améliorer les résultats chimiothérapeutiques et cardiovasculaires dans la prise en charge des patientes atteintes d'un cancer du sein a été soulignée. Peut-être est-il temps de donner naissance à une nouvelle discipline de cardiooncologie au Nigeria.

Pharmacodynamics of current and emerging treatments for cervical cancer.

Introduction: Beyond early stages of cervical cancer (1A1, IA2, IB1, IIA1,), locally advanced disease (IB2, IIA2, IIA2, IIB, IIIA, IIIB, IIIC, IVA) and advanced (metastatic, recurrent or persistent disease) patients require drug therapy either as radiosensitizer, adjuvant or as palliative systemic chemotherapy. Areas covered: This review briefly discusses the achievements in treating cervical cancer. Expert opinion: Two studies are ongoing to optimize treatment after radical hysterectomy. These studies compare chemoradiation versus radiation in intermediate-risk patients or increasing treatment intensity (chemoradiation plus adjuvant chemotherapy versus chemoradiation) for high-risk and locally advanced cervical cancer. Concerning advanced disease, bevacizumab increased median survival for only 3.5 months when added to a cisplatin-doublet. Although this increase is slightly superior to the 2.9 months gained with cisplatin topotecan versus cisplatin, (0.6 months of difference), the doublet plus bevacizumab is considered the standard of care. Recently, pembrolizumab became an alternative for advanced disease that progresses to first-line treatment. Beyond that, the number of phase II and phase III trials in advanced disease is limited but on the increase. HPV E6/E7 oncoproteins are the Achilles Heel of cervical cancer, and there is cautious optimism that antagonists of these oncoproteins will be further developed.

Calcium signaling and the therapeutic targeting of cancer cells.

The calcium signal is implicated in a variety of processes important in tumor progression (e.g. proliferation and invasiveness). The calcium signal has also been shown to be important in other processes important in cancer progression including the development of resistance to current cancer therapies. In this review, we discuss how Ca2+ channels, pumps and exchangers may be drug targets in some cancer types. We consider what factors should be taken into account when considering an optimal Ca2+ channel, pump or exchanger as a candidate for further assessment as a novel drug target in cancer. We also present and summarize how some therapies for the treatment of cancer intersect with Ca2+ signaling and how pharmacological manipulation of the machinery of Ca2+ signaling could promote the effectiveness of some therapies. We also review new therapeutic opportunities for Ca2+ signal modulators in the context of the tumor microenvironment.

A comprehensive survey of the mutagenic impact of common cancer cytotoxics.

BACKGROUND: Genomic mutations caused by cytotoxic agents used in cancer chemotherapy may cause secondary malignancies as well as contribute to the evolution of treatment-resistant tumour cells. The stable diploid genome of the chicken DT40 lymphoblast cell line, an established DNA repair model system, is well suited to accurately assay genomic mutations. RESULTS: We use whole genome sequencing of multiple DT40 clones to determine the mutagenic effect of eight common cytotoxics used for the treatment of millions of patients worldwide. We determine the spontaneous mutagenesis rate at 2.3 × 10(-10) per base per cell division and find that cisplatin, cyclophosphamide and etoposide induce extra base substitutions with distinct spectra. After four cycles of exposure, cisplatin induces 0.8 mutations per Mb, equivalent to the median mutational burden in common leukaemias. Cisplatin-induced mutations, including short insertions and deletions, are mainly located at sites of putative intrastrand crosslinks. We find two of the newly defined cisplatin-specific mutation types as causes of the reversion of BRCA2 mutations in emerging cisplatin-resistant tumours or cell clones. Gemcitabine, 5-fluorouracil, hydroxyurea, doxorubicin and paclitaxel have no measurable mutagenic effect. The cisplatin-induced mutation spectrum shows good correlation with cancer mutation signatures attributed to smoking and other sources of guanine-directed base damage. CONCLUSION: This study provides support for the use of cell line mutagenesis assays to validate or predict the mutagenic effect of environmental and iatrogenic exposures. Our results suggest genetic reversion due to cisplatin-induced mutations as a distinct mechanism for developing resistance.

An update on PARP inhibitors for the treatment of cancer.

The development of poly (adenosine diphosphate [ADP]) ribose polymerase (PARP) inhibitors (PARPi) has progressed greatly over the last few years and has shown encouraging results in the BRCA1/2 mutation-related cancers. This article attempts to summarize the rationale and theory behind PARPi, the clinical trials already reported, as well as ongoing studies designed to determine the role of PARPi in patients with and without germline mutations of BRCA genes. Future plans for PARPi both as monotherapy and in combination with standard cytotoxics, other biological agents, and as radiosensitizers are also covered. The widening scope of PARPi adds another important targeted agent to the growing list of molecular inhibitors; future and ongoing trials will identify the most effective role for PARPi, including for patients other than BRCA germline mutation carriers.

Emerging drugs for the treatment of cervical cancer.

INTRODUCTION: Worldwide, most cervical cancer (CC) patients require the use of drug therapy either adjuvant, concurrent with radiation or palliative. AREAS COVERED: This review briefly discusses the current achievements in treating CC with an emphasis in emerging agents. EXPERT OPINION: Concurrent cisplatin with radiation and lately, gemcitabine-cisplatin chemoradiation has resulted in small but significant improvements in the treatment of locally advanced and high-risk early-stage patients. So far, only antiangiogenic therapy with bevacizumab added to cisplatin chemoradiation has demonstrated safety and encouraging results in a Phase II study. In advanced disease, cisplatin doublets yield median survival rates not exceeding 14 months. The first Phase III study of bevacizumab, added to standard chemotherapy cisplatin- or non-cisplatin-containing doublet, has shown significant increase in both overall survival and progression-free survival. Further studies are needed before bevacizumab plus chemotherapy can be considered the standard of care for advanced disease. The characterization of the mutational landscape of CC and developments of novel targeted therapies may result in more effective and individualized treatments for CC. The potential efficacy of knocking down the key alterations in CC, E6 and E7 human papilloma virus oncoproteins must not be overlooked.

Review of therapeutic drug monitoring of anticancer drugs part 1--cytotoxics.

Most anticancer drugs are characterised by a steep dose-response relationship and narrow therapeutic window. Inter-individual pharmacokinetic (PK) variability is often substantial. The most relevant PK parameter for cytotoxic drugs is the area under the plasma concentration versus time curve (AUC). Thus it is somewhat surprising that therapeutic drug monitoring (TDM) is still uncommon for the majority of agents. Goals of the review were to assess the rationale for more widely used TDM of cytotoxics in oncology. There are several reasons why TDM has never been fully implemented into daily oncology practice. These include difficulties in establishing appropriate concentration target ranges, common use of combination chemotherapies for many tumour types, analytical challenges with prodrugs, intracellular compounds, the paucity of published data from pharmacological trials and 'Day1 = Day21' administration schedules. There are some specific situations for which these limitations are overcome, including high dose methotrexate, 5-fluorouracil infusion, mitotane and some high dose chemotherapy regimens. TDM in paediatric oncology represents an important challenge. Established TDM approaches includes the widely used anticancer agents carboplatin, busulfan and methotrexate, with 13-cis-retinoic acid also recently of interest. Considerable effort should be made to better define concentration-effect relationships and to utilise tools such as population PK/PD models and comparative randomised trials of classic dosing versus pharmacokinetically guided adaptive dosing. There is an important heterogeneity among clinical practices and a strong need to promote TDM guidelines among the oncological community.

Therapeutic drug monitoring in cancer--are we missing a trick?

Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individualise treatment by adapting drug dose to improve efficacy and/or reduce toxicity. The cytotoxic drugs are characterised by steep dose-response relationships and narrow therapeutic windows. Inter-individual pharmacokinetic (PK) variability is often substantial. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies and the paucity of published data from pharmacological trials. The situation is different with targeted therapies. The large interindividual PK variability is influenced by the pharmacogenetic background of the patient (e.g. cytochrome P450 and ABC transporters polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure correlates with treatment response in various cancers. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and concerns over adherence treatment. There are still few data with monoclonal antibodies (mAbs) in favour of TDM approaches, even if data showed encouraging results with rituximab and cetuximab. TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.

Antiemetic therapy options for chemotherapy-induced nausea and vomiting in breast cancer patients.

Chemotherapy-induced nausea and vomiting (CINV) continues to be one of the most distressing side effects of chemotherapy in breast cancer patients, which can result in poor compliance to therapy that may, in turn, affect overall survival. The extent of CINV is dependent on the emetogenic potential of the individual cytotoxic agents or regimens employed as well as certain patient factors. Advances in our understanding in the pathophysiology of CINV and the identification of risk factors have enabled the utilization of appropriate antiemetic regimens to improve the control of CINV. Most of the chemotherapy regimens used in this patient population are considered to be moderately emetogenic; 60%-90% of chemotherapeutic regimens used in breast cancer patients cause nausea and vomiting, amongst which regimens doxorubicin-cyclophosphamide (AC) combination is commonly regarded as of relatively higher emetogenicity. Currently, corticosteroids, 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, and neurokinin 1 (NK-1) receptor antagonists are the three classes of antiemetic agents with the highest therapeutic index, which have been supported by data from large-scale randomized clinical trials. Treatment guidelines enable physicians to integrate the latest research data into their clinical practices. This review focuses on the three classes of antiemetic therapy options for CINV in breast cancer patients, as well as their safety and tolerability profiles. Recommendations from major guidelines/consensus including from the Multinational Association for Supportive Care in Cancer/European Society of Medical Oncology (MASCC/ESMO), the American Society of Clinical Oncology (ASCO), and the US National Comprehensive Cancer Network (NCCN), are also discussed. With the correct use of antiemetic regimens, chemotherapy-induced vomiting could be prevented in the majority of patients. However, chemotherapy-induced nausea remains an important symptom and a challenge for physicians to manage.