Therapeutic Drug Monitoring of Erlotinib in Non-Small Cell Lung Carcinoma: A Case Study.

ABSTRACT: We describe a clinical case of an 84-year-old man diagnosed with non-small cell lung carcinoma and epidermal growth factor receptor mutation, who was treated with erlotinib, with doses adjusted by therapeutic drug monitoring. This case involved a clearance fluctuation leading to over-therapeutic drug concentrations of erlotinib and toxicity. The intrapatient and interpatient variability of erlotinib, in addition to other factors such as age or variations in liver clearance, create situations that are challenging in clinical practice. During treatment, erlotinib serum concentrations were measured, and the dose was accordingly adjusted. The erlotinib dose required to reduce toxicity (rash grade III) and maintain effective plasma concentrations, as well as clinical and radiological responses, was 50% of the initial dose, underscoring the relevance of therapeutic drug monitoring for tyrosine kinase inhibitors in routine clinical practice.

Relevance of Therapeutic Drug Monitoring of Tyrosine Kinase Inhibitors in Routine Clinical Practice: A Pilot Study.

INTRODUCTION: The main goal of treatment in cancer patients is to achieve the highest therapeutic effectiveness with the least iatrogenic toxicity. Tyrosine kinase inhibitors (TKIs) are anticancer oral agents, usually administered at fixed doses, which present high inter- and intra-individual variability due to their pharmacokinetic characteristics. Therapeutic drug monitoring (TDM) can be used to optimize the use of several types of medication. OBJECTIVE: We evaluated the use of TDM of TKIs in routine clinical practice through studying the variability in exposure to erlotinib, imatinib, lapatinib, and sorafenib and dose adjustment. MATERIALS AND METHODS: We conducted a retrospective analytical study involving patients who received treatment with TKIs, guided by TDM and with subsequent recommendation of dose adjustment. The quantification of the plasma levels of the different drugs was performed using high-performance liquid chromatography (HPLC). The Clinical Research Ethics Committee of the Hospital Quirónsalud Torrevieja approved this study. RESULTS: The inter-individual variability in the first cycle and in the last monitored cycle was 46.2% and 44.0% for erlotinib, 48.9 and 50.8% for imatinib, 60.7% and 56.0% for lapatinib and 89.7% and 72.5% for sorafenib. Relationships between exposure and baseline characteristics for erlotinib, imatinib, lapatinib and sorafenib were not statistically significant for any of the variables evaluated (weight, height, body surface area (BSA), age and sex). Relationships between height (p = 0.021) and BSA (p = 0.022) were statistically significant for sorafenib. No significant relationships were observed between Ctrough and progression-free survival (PFS) or overall survival (OS) for any drug, except in the case of sunitinib (correlation between Ctrough and PFS p = 0.023) in the exposure-efficacy analysis. CONCLUSIONS: Erlotinib, imatinib, lapatinib and sorafenib show large inter-individual variability in exposure. TDM entails a significant improvement in exposure and enables more effective and safe use of TKIs in routine clinical practice.

Psycho-Oncological Intervention Through Counseling in Patients With Differentiated Thyroid Cancer in Treatment With Radioiodine (COUNTHY, NCT05054634): A Non-randomized Controlled Study.

Background: Diagnosis and treatment of differentiated thyroid carcinomas (DTC) cause anxiety and depression. Additionally, these patients suffer hormonal alterations that are associated with psychological symptoms (e.g., changes in mood, emotional instability, and memory loss). This study aims to evaluate the effectiveness of a psycho-oncological intervention based on counseling to reduce anxiety and depression related to the treatment in patients with DTC. Methods: A non-randomized controlled study, with two groups [experimental group (EG), n = 37, and control group (CG), n = 38] and baseline and posttreatment measures, was designed. Patients in the EG received a psycho-oncological intervention based on counseling in addition to the standard treatment. The independent variable was the assigned group and the dependent one was the evolution of anxiety and depression, which were analyzed separately, and both were evaluated using the Hospital Anxiety and Depression Scale. Other relevant covariables related to the quality of life (QoL) were also analyzed using Short Form-36 Health Survey and Psychological General Wellbeing Index scales. Results: The difference of the posttreatment-baseline variation showed a statistically significant reduction in anxiety and depression in the EG in relation to the CG (p < 0.001). The mean of the Psychological General Wellbeing Index scales score increased significantly in the EG (p < 0.001) and decreased significantly in the CG (p < 0.001). All the baseline and the posttreatment scores of the variables evaluated showed a statistically significant improvement in the EG vs. the CG. Conclusion: This study demonstrates significant benefits of psycho-oncological intervention based on counseling in anxiety, depression, QoL, and wellbeing of the patient with differentiated thyroid carcinomas.

Relevance of Fc Gamma Receptor Polymorphisms in Cancer Therapy With Monoclonal Antibodies.

Therapeutic monoclonal antibodies (mAbs), including immune checkpoint inhibitors (ICIs), are an important breakthrough for the treatment of cancer and have dramatically changed clinical outcomes in a wide variety of tumours. However, clinical response varies among patients receiving mAb-based treatment, so it is necessary to search for predictive biomarkers of response to identify the patients who will derive the greatest therapeutic benefit. The interaction of mAbs with Fc gamma receptors (FcγR) expressed by innate immune cells is essential for antibody-dependent cellular cytotoxicity (ADCC) and this binding is often critical for their in vivo efficacy. FcγRIIa (H131R) and FcγRIIIa (V158F) polymorphisms have been reported to correlate with response to therapeutic mAbs. These polymorphisms play a major role in the affinity of mAb receptors and, therefore, can exert a profound impact on antitumor response in these therapies. Furthermore, recent reports have revealed potential mechanisms of ICIs to modulate myeloid subset composition within the tumour microenvironment through FcγR-binding, optimizing their anti-tumour activity. The purpose of this review is to highlight the clinical contribution of FcγR polymorphisms to predict response to mAbs in cancer patients.

Therapeutic drug monitoring of nivolumab in routine clinical practice. A pilot study.

OBJECTIVE: A review of the literature about the anti-programmed death 1 monoclonal antibody nivolumab permits to verify the existence  of several issues still unresolved about their dosing schedule. The aim of the present work was to explore possibilities of nivolumab treatment  personalization through therapeutic drug monitoring, in order to  improve their effectiveness and efficiency. METHOD: Observational, prospective study carried out from May 2017  through June 2019 in patients with different tumor diagnoses treated with nivolumab. Blood samples were obtained in the routine  clinical practice, once nivolumab steady state was reached. Serum  nivolumab levels were determined by means of quantitative ELISA. The  standard schedule of 3 mg/kg every two weeks (Q2W) was modified in  some patients due to different circumstances, and resulting serum  concentrations were compared with those from the non-modified  patients and the published data. RESULTS: Blood samples from 19 patients in treatment with nivolumab were analyzed. A total of 39 samples of nivolumab were  analyzed between 6th and 27th cycles. The standard schedule of 3  mg/kg every two weeks was modified in 12/19 (60%) patients, with  intervals of 3, 4, 5, 6 or 7 weeks, once the steady state was reached.  No statistically significant differences were detected when comparing  every two weeks and every four week intervals. When the intervals  were six or seven weeks, mean plasma concentration showed a  statistically significant difference compared with every two weeks. CONCLUSIONS: Current data contribute to confirm former suspects about the possibilities of exploring new scenarios to improve and  personalize nivolumab dosage. Additional studies to confirm it in bigger  series and correlate it with clinical results, and to better define the role  of therapeutic drug monitoring in the treatment, are warranted, not only by financial concerns but also for improving quality of life of patients  and clinical management aspects.

Objetivo: Una revisión de la literatura sobre nivolumab permite  verificar la existencia de diversos aspectos sin resolver sobre su  intervalo de dosificación. El objetivo del presente estudio ha sido  explorar las posibilidades de personalización del tratamiento con  nivolumab mediante la monitorización terapéutica de sus  concentraciones séricas para mejorar su efectividad y eficiencia.Método: Estudio observacional, prospectivo, realizado entre mayo de 2017 y junio de 2019 en pacientes tratados con nivolumab que  estaban diagnosticados de diferentes tumores. Se obtuvieron muestras  de sangre en la práctica clínica habitual, una vez alcanzado el estado de  equilibrio de nivolumab. Las concentraciones séricas de nivolumab  fueron determinadas mediante ELISA cuantitativo. La pauta posológica  habitual de 3 mg/kg cada dos semanas tuvo que ser modificada en  algunos pacientes debido a diferentes circunstancias, y las  concentraciones séricas resultantes se compararon con las  correspondientes a los pacientes en los que no se modificó y con datos  publicados.Resultados: Se analizaron muestras de 19 pacientes que recibieron inicialmente 3 mg/kg de nivolumab cada dos semanas. Se  analizó un total de 39 muestras, entre los ciclos 6 y 27. La pauta  habitual se modificó, una vez alcanzado el estado de equilibrio, en  12/19 (60%) pacientes, en los que se amplió el intervalo a 3, 4, 5, 6 o 7 semanas. No se encontraron diferencias estadísticamente significativas  al comparar la administración cada dos semanas y cada cuatro  semanas. Cuando los intervalos fueron de seis o siete semanas, la  concentración sérica media mostró una diferencia estadísticamente  significativa en comparación con la administración cada dos semanas.Conclusiones: La información recogida parece confirmar la necesidad de explorar nuevos escenarios para personalizar la  dosificación de nivolumab. Se necesitan estudios adicionales en series  de mayor tamaño para confirmar esta información, correlacionarla con  los resultados clínicos y definir mejor el papel de la monitorización  terapéutica, no solo por motivos económicos, sino también para mejorar  la calidad de vida de los pacientes y facilitar la administración  clínica del tratamiento.

A novel genomic signature predicting FDG uptake in diverse metastatic tumors.

BACKGROUND: Building a universal genomic signature predicting the intensity of FDG uptake in diverse metastatic tumors may allow us to understand better the biological processes underlying this phenomenon and their requirements of glucose uptake. METHODS: A balanced training set (n = 71) of metastatic tumors including some of the most frequent histologies, with matched PET/CT quantification measurements and whole human genome gene expression microarrays, was used to build the signature. Selection of microarray features was carried out exclusively on the basis of their strong association with FDG uptake (as measured by SUVmean35) by means of univariate linear regression. A thorough bioinformatics study of these genes was performed, and multivariable models were built by fitting several state of the art regression techniques to the training set for comparison. RESULTS: The 909 probes with the strongest association with the SUVmean35 (comprising 742 identifiable genes and 62 probes not matched to a symbol) were used to build the signature. Partial least squares using three components (PLS-3) was the best performing model in the training dataset cross-validation (root mean square error, RMSE = 0.443) and was validated further in an independent validation dataset (n = 13) obtaining a performance within the 95% CI of that obtained in the training dataset (RMSE = 0.645). Significantly overrepresented biological processes correlating with the SUVmean35 were identified beyond glycolysis, such as ribosome biogenesis and DNA replication (correlating with a higher SUVmean35) and cytoskeleton reorganization and autophagy (correlating with a lower SUVmean35). CONCLUSIONS: PLS-3 is a signature predicting accurately the intensity of FDG uptake in diverse metastatic tumors. FDG-PET might help in the design of specific targeted therapies directed to counteract the identified malignant biological processes more likely activated in a tumor as inferred from the SUVmean35 and also from its variations in response to antineoplastic treatments.

Gene Expression Profiling of Tumors From Heavily Pretreated Patients With Metastatic Cancer for the Selection of Therapy: A Pilot Study.

BACKGROUND: Recently, it has been shown that it is possible to identify tumor profiles of sensitivity for potentially useful drugs, both conventional and experimental, based on whole oligonucleotide microarray gene expression studies in heavily pretreated patients with metastatic solid tumors. METHODS: Fresh-frozen tumor biopsies for molecular profiling (MP) were obtained from patients with advanced and refractory cancer. Total tumor and control tissue RNA was hybridized to a whole human genome oligonucleotide microarray. Differentially expressed genes interacting with potential therapeutic targets were identified. Results were complemented with DNA sequencing of selected driver genes and with immunohistochemistry and fluorescent "in situ" hybridization. The results were used to guide experimental treatment. RESULTS: MP assays led to a potentially active available drug in 91.2% of the patients. The median number of available active drugs per tumor was 5 (range, 1 to 9). Nine treated patients were not evaluable for response. Partial response was observed in 18 patients (33%), stable disease in 22 patients (40%) (clinical benefit rate of 73%), and progression in 15 (27%). Overall median progression-free survival and overall survival were 8 and 13 months, respectively. CONCLUSION: MP-guided therapy is feasible and seems to improve the clinical outcome of extensively pretreated patients but prospective and confirmatory trials are needed.

Photodynamic therapy in the treatment of brain tumours. A feasibility study.

BACKGROUND: Photodynamic therapy (PDT) constitutes a treatment modality that combines a photosensitizing agent with exposure to laser light in order to elicit phototoxic reactions that selectively destroy tumor cells and spare normal cells. PDT is a local treatment modality without long-term systemic effects. Its application can be repeated more than once to the same area without accumulative effects. METHODS: Patients diagnosed with primary brain tumors were treated with PDT. Treatment consisted in administration of the photosensitizer followed by craniotomy, surgical resection and laser illumination of the surgical bed. Primary brain tumors received also temozolomide-based chemotherapy and radiotherapy (RT). RESULTS: From May 2000 to December 2010, 41 patients (27 male, 14 female) with a median age of 49 years (range 13-70) diagnosed of primary brain tumors were included in the study. In 7 patients PDT was repeated at the time of the relapse. In 22 episodes PDT was part of the initial treatment of primary brain tumors and in 26 episodes was part of the treatment at relapse. Median PFS observed was 10 months for GBM (95% confidence interval 5.7-14.3), 26 months for AA (95% CI 4.5-47.5), and 43 months for OD (95% CI 4.5-47.5). Median OS was 9 months for GBM (95% CI 2.3-15.7), 20 months for AA (95% CI 0.0-59) and 50 months for OD (95% CI 32.5-67.5). The apparent discrepancy between PFS and OS data is due to patients not censored for PFS because they die from causes other than tumor progression. Median OS since first diagnosis was 17 months for GBM (95% CI 15.2-17.8), 66 months for AA (95% CI 2.9-129.1) and 122 months for OD (95% CI 116.1-127.8). Side effects were mild and manageable. CONCLUSIONS: This study confirms that PDT can be considered as an adjunctive to surgery and/or RT and chemotherapy in the treatment of brain tumors, excluding those patients with thalamic or brain stem locations. It adds therapeutic effect without adding significant toxicity. In order to improve its contribution, it is essential to find new drugs with more penetration in order to destroy tumor cells more deeply at resection margins.

Pharmacokinetic and pharmacodynamic analysis of hyperthermic intraperitoneal oxaliplatin-induced neutropenia in subjects with peritoneal carcinomatosis.

The objective of this study was to characterize the pharmacokinetics and the time course of the neutropenia-induced by hyperthermic intraperitoneal oxaliplatin (HIO) after cytoreductive surgery in cancer patients with peritoneal carcinomatosis. Data from 30 patients who received 360 mg/m(2) of HIO following cytoreductive surgery were used for pharmacokinetic-pharmacodynamic (PK/PD) analysis. The oxaliplatin plasma concentrations were characterized by an open two-compartment pharmacokinetic model after first-order absorption from peritoneum to plasma. An oxaliplatin-sensitive progenitor cell compartment was used to describe the absolute neutrophil counts in blood. The reduction of the proliferation rate of the progenitor cells was modeled by a linear function of the oxaliplatin plasma concentrations. The typical values of oxaliplatin absorption and terminal half-lives were estimated to be 2.2 and 40 h, with moderate interindividual variability. Oxaliplatin reduced the proliferation rate of the progenitor cells by 18.2% per mg/L. No patient's covariates were related to oxaliplatin PK/PD parameters. Bootstrap and visual predictive check evidenced the model was deemed appropriate to describe oxaliplatin pharmacokinetics and the incidence and severity of neutropenia. A peritoneum oxaliplatin exposure of 65 and 120 mg·L/h was associated with a 20% and 33% incidence of neutropenia grade 4. The time course of neutropenia following HIO administration was well described by the semiphysiological PK/PD model. The maximum tolerated peritoneum oxaliplatin exposure is 120 mg L/h and higher exposures should be avoided in future studies. We suggest the prophylactic use of granulocyte colony stimulating factor for patients treated with HIO exposure higher than 65 mg L/h.

Cytoreductive surgery and perioperative intraperitoneal chemotherapy in patients with peritoneal carcinomatosis of colonic origin: outcomes after 7 years' experience of a new centre for peritoneal surface malignancies.

INTRODUCTION: Peritoneal carcinomatosis is a relatively frequent situation in the natural history of colorectal cancer and is associated with a dismal prognosis. Promising results have been shown after radical cytoreduction followed by intraperitoneal chemohyperthermic perfusion. The aim our study was to assess the outcomes after treating patients with peritoneal carcinomatosis of colonic origin by means of cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) followed by early postoperative intraperitoneal chemotherapy (EPIC). METHODS: Tumour resection was performed in accordance with the guidelines for oncologic surgery. Selective peritonectomies and remnant nodule electroevaporation were performed with the aim of achieving a complete cytoreduction. Peritoneal perfusion was carried out according to the Coliseum technique at 0.5-1 L/min, and chemotherapy was administered at 42oC for 40-90 min. Mitomycin C 10-12.5 mg/m(2) or oxaliplatin 360 mg/m(2) was used. Postoperative intraperitoneally administered 5-fluorouracil (5-FU) (650 mg/m(2) per day) was given for 5 consecutive days. RESULTS: Twenty patients were treated from 2001 to 2008. The mean peritoneal cancer index was 11 (range 2-39). Fifteen patients had undergone complete cytoreductive surgery. The morbidity was 40%. There was one case of death due to bone marrow aplasia. Ten patients had recurrence; five of them underwent salvage surgery. Two patients were treated with a second HIPEC. Actuarial overall survival and progression-free survival were 36% and 30% at 5 years, respectively, with a median follow-up of 18 (range 8-28) months. CONCLUSIONS: Cytoreductive surgery combined with HIPEC is a feasible technique that might increase patient survival. It represents a potential cure for selected patients who have no other alternatives.