Estudio piloto de monitorización terapéutica de nivolumab en la práctica clínica habitual / Therapeutic drug monitoring of nivolumab in routine clinical practice. A pilot study

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

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 perso-nalization 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 bet-ween 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

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.

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.

Células dendríticas II: utilización clínica en vacunación antitumoral / Dendritic Cells II: Clinical use for antitumor vaccination

La inmunoterapia contra el cáncer busca obtener un beneficio terapéutico a través de la movilización del sistema immune. Puede hacerse de forma activa, mediante vacunación. Las células dendríticas (CD) ejercen un papel central en la respuesta inmune. El tipo de respuesta inmune generada depende de la regulación ejercida por las CD. La generación de CD ex vivo y la carga de las mismas con antígeno ha permitido utilizarlas con éxito en la vacunación para mejorar la inmunidad de pacientes con cáncer e infección crónica por HIV, dando así la prueba preliminar de la validez de las vacunas con CD. Nueve preparados para vacunación antitumoral en pacientes han alcanzado los estudios fase III. De ellos, únicamente el sipuleucel-T, para tratamiento del carcinoma de próstata diseminado independiente de andrógenos que utiliza CD, ha recibido la aprobación preliminar de la Foodand Drug Administration (FDA) de los Estados Unidos (AU)

Cancer immunotherapy seeks to mobilize the patient's immune system for therapeutic benefit. It can be active, as in vaccination. Dendritic cells play a central role in immuneresponse. The type of immune response obtained depends on the regulation by the DC. Exvivo generated and antigen-loaded DC have been used as vaccines to improve immunity in patients with cancer and chronic HIV infection, thus providing a "proof-of-principle" that DC vaccines can work. Nine preparations for antitumoral vaccination in patients have achieved phase III studies. Between them, only sipuleucel-T, for the treatment of metastatic hormonerefractory prostate cancer, using DC, has received a preliminary approval of the FDA of the United States (AU)

Células dendríticas I: aspectos básicos de su biologíay funciones / Dendritic cells I: Basic biology and functions

Las células dendríticas (CD) juegan un papel fundamental en la regulación de la respuesta inmune. Son las principales células presentadoras antigénicas, por su capacidad de capturar, procesar y presentar antígenos de forma óptima a linfocitos T, y generar respuestas inmunes específicas. Posteriormente al descubrimiento de esta función y al aparecer técnicas metodológicas que permitían su purificación y maduración in vitro, se ha comprobado que también son capaces de activar otros tipos celulares, como linfocitos B, células NK, macró-fagos o eosinófilos, e incluso generar tolerancia inmunológica. Este mejor conocimiento de su biología y funciones ha permitido el desarrollo de ensayos clínicos basados en el uso de CD en el campo de la inmunoterapia antitumoral y antiinfecciosa o para inducir tolerancia postrasplante o en patologías autoinmunes (AU)

Dendritic cells (DC) play a critical role in the regulation of the immune response. They are the main antigen presenting cells, due to their ability to capture, process and present antigens to T lymphocytes in an optimal way, and to generate specific immune responses. Subsequently ,when methodological techniques allowed their in vitro purification and maturation, it was verified that they were able to activate several other immune cell subsets, like B lymphocytes, NK cells, macrophages or eosinophils, and even to induce immune tolerance. A deeper knowledge of their biology and functions has allowed the development of clinical trials in anti-tumour and anti-infective DC-based therapies, and also to induce post-transplant tolerance and to treat autoimmunity (AU)

Irinotecan, oxaliplatin, and 5-fluorouracil/leucovorin combination chemotherapy in advanced colorectal carcinoma: a phase II study.

The purpose of this study was to evaluate the efficacy and tolerance of a combination of irinotecan, oxaliplatin, and 5-fluorouracil (5-FU)/leucovorin in advanced colorectal cancer (ACC). Twenty-six consecutive patients with ACC and an Eastern Cooperative Oncology Group performance status of 0-2 were treated with a combination of oxaliplatin (120 mg/m2 intravenously [i.v.] for 2 hours) on day 1, irinotecan (250 mg/m2 i.v. for 90 minutes) on day 1, and 5-FU (2600 mg/m2 plus leucovorin 500 mg/m2 i.v. in a 24-hour infusion) on day 1 and 15, every 4 weeks. Five of the patients (19.2%) had shown previous chemoresistance. One hundred sixty-two cycles were administered (median, 6; range, 3-13 cycles). All patients were evaluated for toxicity; 23 were evaluable for response. According to intention-to-treat, the overall response rate was 69.2% (18 patients; 95% CI: 48.2%-85.7%), including 3 complete remissions (11.5%). Four additional patients (15.3%) had stable disease, and only 1 (3.8%) progressed. Major toxicities were neutropenia and diarrhea. Grade 3 neutropenia occurred in 9 patients (34.6%), and grade 4 occurred in 1 patient (3.8%). Grade 3 diarrhea occurred in 8 patients (30.7%) and grade 4 in 1 patient (3.8%). Other toxicities were mild. After a median follow-up of 15.5 months, the median progression-free survival was 14 months. Seventeen patients (65.4%) are still alive, and the median overall survival has not been reached yet. This combination of irinotecan, oxaliplatin, and 5-FU/leucovorin is fairly well tolerated and shows promising activity in ACC. This treatment merits further comparison with other combination regimens.

Radiation therapy after high-dose chemotherapy with peripheral blood stem cell support for high-risk breast cancer.

Multidisciplinary treatment in high-risk breast cancer improves survival and local control. The feasibility and patterns of failure after several induction and high-dose consolidation regimens of chemotherapy were evaluated in this study. Between November 1990 and January 1997, 65 patients with histologically proven breast cancer American Joint Committee on Cancer stages II-III with four or more axillary lymph nodes positive or locally advanced breast cancer underwent high-dose chemotherapy (HDC) with peripheral stem cell support after surgery and induction chemotherapy. All patients were subsequently treated with radiotherapy (up to total doses of 50-60 Gy), which included the ipsilateral axilla and supraclavicular fossa and the chest wall or breast. A minimum follow-up period of 2 years from the completion of radiotherapy was required for analysis. Local control (LC), disease-free survival (DFS), overall survival (OS), and toxicity were evaluated. With a median follow-up of 62 months (range: 32-107 months), LC was 89%, and 5-year OS and DFS were 78% and 63%, respectively. Symptomatic pneumonitis developed in six patients (9%); only one patient had her radiotherapy interrupted because of hematologic toxicity. No treatment-related mortality was observed. Radiation therapy after HDC provides excellent local control rates without excessive toxicity. Delaying the start of irradiation until recovery from HDC does not seem to increase local failure rates.