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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.

Discovery and clinical development of monoclonal antibodies with the ability to interfere in the regulation of the immune response have significantly changed the landscape of oncology in recent years. Among the active agents licensed by the regulatory agencies, nivolumab and pembrolizumab are paradigmatic as the most relevant ones according to the magnitude of available data derived from the extensive preclinical and clinical experience. Although in both cases the respective data sheets indicate well-defined dosage regimens, a review of the literature permits to verify the existence of many issues still unresolved about dosing the two agents, so it must be considered an open question of potentially important consequences, in which to work to improve the effectiveness and efficiency of use.

e13000 Background: A small number of breast cancer patients develops long-lasting loco-regional cutaneous recurrent disease with a delayed appearance of systemic disease. We recently have observed a favourable immunological signature in one patient and thereafter we looked back to the institutional series to formulate a possible hypothesis. Methods: Two datasets of resistant and metastatic solid tumors (362 Agilent microarrays and 169 RNA sequencing), have been studied. Three immunological signatures have been applied (T-cell inflamed, Cytolysis and TMM) and patients with at least one positive signature have been identified. Results: Preliminary evidence identified, from our genomic and transcriptomic advanced breast cancer database (73 patients and 80 procedures), three patients (4%) with loco-regional only cutaneous recurrent disease. Two patients (#1 and #2) were Hormone Receptor-negative, HER2 receptor-positive with a long-lasting breast cancer cutaneous recurrence (57 and 42 months, respectively) until bone (#1) or visceral (pleura and liver) (#2) progression. Patient #3 is a Hormone Receptor-positive, HER2-negative breast cancer that has recently developed an ipsilateral cutaneous (breast) recurrence so we do not have a follow up. Patient #1 had 4 transcriptomic tests, patient #2 had 2 tests and #3 one test. Biopsies were obtained from cutaneous lesions. According to our database, 25 out 80 procedures (31.25%) showed at least one favourable immunological signature (Table). In patients #1 and #2 with consecutive genomic testing, the immunological profile got worse with the resistance to therapies before systemic progression. Conclusions: According to our observation, a positive immunological signature was associated with a loco-regional cutaneous breast cancer recurrence and an unusually prolonged course of the disease. This observation should be confirmed in larger trials with more patients. Immunotherapy might play a role in the management of this clinical situation. None of these 3 patients had a triple negative phenotype for which immunotherapy has been found active. Ayers et al. J Clin Oncol 2017; 127 (8):2930-2940. Yang et al. Clin Cancer Res 2020; 26(8):3296-3306. Manzano et al. BMC Cancer 2021: 432.[Table: see text]

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.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.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.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.

Cytokine-induced killer (CIK) cells form under certain stimulation conditions in cultures of peripheral blood mononuclear cells (PBMCs). They are a heterogeneous immune cell population and contain a high percentage of cells with a mixed T-NK phenotype (CD3+CD56+). The ready availability of a lymphocyte source, together with the high proliferative rate and potent anti-tumor activity of CIK cells, has allowed their use as immunotherapy in a wide variety of neoplasms. Cytotoxicity mediated by CD3+CD56+ T cells depends on the major histocompatibility antigen (MHC)-independent recognition of tumor cells and the activation of signaling pathways through the natural killer group 2 member D (NKG2D) cell-surface receptor. Clinical trials have demonstrated the feasibility and efficacy of CIK cell immunotherapy even in advanced stage cancer patients or those that have not responded to first-line treatment. This review summarizes biological and technical aspects of CIK cells, as well as past and current clinical trials and future trends in this form of immunotherapy.

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. 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. 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. MP-guided therapy is feasible and seems to improve the clinical outcome of extensively pretreated patients but prospective and confirmatory trials are needed.

e13509 Background: Personalized multidrug therapies improve outcomes in patients with drug resistant cancer. For 8 years we have been using microarray-based gene expression profiling (360 procedures) to improve drug selection (Rebollo J et al, 2017; Sureda M et al, 2018). Recently, we have adopted Ion Torrent DNA and RNA Next Generation Sequencing (NGS) to improve the target detection ability. Methods: Since March 2018 DNA (95 analyses) and whole trancriptome RNA (78 analyses) NGS have been performed using Ion Torrent GeneStudio S5 System in fresh-frozen (RNA and DNA sequencing) and paraffin-embedded (DNA sequencing) biopsies obtained from tru-cut or surgical excision procedures from patients with metastatic cancer. Favourable chemotherapy drug profile, treatable (available inhibitory drugs) targets and potentially favourable immunologic signature have been investigated. Results: All biopsies were valid for DNA sequencing but in five patients were invalid (less than 30% viable tumor cells required) for RNA sequencing. Combined DNA and RNA sequencing have been studied in sixty patients with advanced cancer biopsies. Histologies have been NSCLC (12 patents), Breast (9), STS (6), NHL (4), NET (4), Pancreas (4), CRC (4), Ovary/Fallopian tube (3), Prostate (2), Cholangiocarcinoma (2), H&N (2), Esophagus, Bladder, Uterus, Melanoma, SCLC, Anal, Kidney and Cervix (1 each). Most of the patients had been previously treated with systemic therapies. Biopsies have been taken from Lymph nodes (18 patients), Liver (16), Soft Tissues (14), Lung (8), Peritoneum (3) and Adrenal Gland (1). RNA sequencing has predicted favourable chemotherapy drug profile (Median 3 drugs, Range 1-9) in 54 (90%) patients. In addition, treatable targets (Median 3 targets, Range 1-6) have been found in 40 (67%) patients. Favourable immunologic signature has been found in 22 (37%) patients. DNA sequencing has shown treatable (drug available) targets in 14 (23%) patients. In 12 (20%) patients, no targets have been found in any of the sequencing protocols (DNA and RNA). Conclusions: Tumor RNA and DNA sequencing provide potential useful information in personalized cancer treatment decision in a vast majority of advanced cancer patients independent of treatment status.

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. Electronic supplementary material The online version of this article (10.1186/s13550-017-0355-3) contains supplementary material, which is available to authorized users.

The present study evaluates the massive study of gene expression in metastatic breast carcinoma (MBC) patients using microarray gene expression profiling (MAGE) complemented with conventional sequencing, immunohistochemistry (IHC) and fluorescent “in situ” hybridization (FISH), seeking to optimize the treatment in a subset of heavily pretreated patients and with limited life expectancy. MBC patients in hormone therapy progression with survival expectancy of at least 3 months (m) have been included. The MAGE contains gene probes representing genes known to potentially interact with available drugs as cited in the literature. Thirty-nine procedures were performed from October 2010 to April 2016. Within the 30 evaluable procedures, considering all hormonal manipulations as a single line, the patients had received a median of 4 treatment lines prior to MAGE (range 1–7). Progression was observed in 6 cases, stable disease (SD) in 7 cases and partial response (PR) in 16 cases, which implies a clinical benefit rate (SD + PR) of 76%. Actuarial median progression-free survival (PFS) was 6 m (95% CI 2.5–9.5) in patients with clinical benefit. The median overall survival (OS) for the entire series was 11 m (95% CI 2.2–19.8). Data presented here indicate that the use of MAGE provides relevant information to establish personalized treatment in frail patients with limited life expectancy in which therapeutic futility is a particularly difficult burden to assume.

e14089 Background: Fixed dose schemes, regardless of body weight, have been accepted by the regulatory agencies for the PD-1 targeting antibodies. Zaho X. and Ratain M. have elucidated that the mean steady state concentrations of nivolumab (N) at flat-doses of 240 mg Q2W or 480 mg Q4W were 57 µg/mL and 47 µg/mL, respectively. These levels are very similar to those observed at the dosage of 3 mg/kg Q2W. Considering the long half-life of N, its mechanism of action and the absence of correlation between exposure and response or toxicity at clinically tested doses, other schemes can be explored. Moreover, therapeutic drug monitoring (TDM) can contribute to individualize and optimize dosage. We determined serum N levels in patients with solid tumors. Methods: The PK profile of N was analyzed in 15 patients with solid tumors who received 3 mg/kg Q2W from May 2017 through January 2019. Eligible patients had non-small-cell lung cancer (n = 7), urothelial cancer (n = 1), gastric cancer (n = 1), breast cancer (n = 1), renal cell cancer (n = 1), colorectal cancer (n = 1), prostate cancer (n = 1), melanoma (n = 1) and sarcoma (n = 1). Free N serum concentrations were determined with a quantitative ELISA capable of detecting ≥ 0.3 µg/mL (Shikari Q-Nivo, Matriks Biotek, Ankara, Turkey). A total of 28 TDM were done after steady state (6th and 26th cycle). Results: For different reasons, 9 patients received N at 3, 4, 5, 6 or 7 week intervals once the steady state was reached. In these patients, a median reduction of 20.8% (6.7% - 43.0%) of the received doses was observed. Mean plasma concentrations of N observed after administration every 2 weeks was 73.5±32.5 µg/mL (n = 9). Once the steady state was reached, mean plasma concentrations at 3, 4, 5, 6 or 7 weeks, were 54.0±1.3 µg/mL (n = 2), 45.1±25.3 µg/mL (n = 7), 42.9±29.5 µg/mL (n = 5) and 24.4±11.7 µg/mL (n = 5), respectively. No statistically significant differences were observed in the serum levels of N between the dosing intervals of 3, 4 and 5 weeks and the standard regimen (Q2W) (p > 0.05). These data are similar to those described by Long G.V. et al. that compared N pharmacokinetic exposure for the 480 mg Q4W schedule simulated in 3817 patients across multiple tumor types with those for the 3 mg/kg Q2W and 240 mg Q2W schedules. Conclusions: The incorporation of the TDM of N in routine clinical practice could help to maintain a therapeutic drug plasma concentration with lower or less frequent doses, adding a financial benefit, without decreasing clinical efficacy. Further randomized trials to explore alternative dosing schemes of N, including personalization through TDM, are warranted

Resumen La inmunoterapia contra el cancer busca obtener un beneficio terapeutico a traves de la movilizacion del sistema immune. Puede hacerse de forma activa, mediante vacunacion. Las celulas dendriticas (CD) ejercen un papel central en la respuesta inmune. El tipo de respuesta inmune generada depende de la regulacion ejercida por las CD. La generacion de CD ex vivo y la carga de las mismas con antigeno ha permitido utilizarlas con exito en la vacunacion para mejorar la inmunidad de pacientes con cancer e infeccion cronica por HIV, dando asi la prueba preliminar de la validez de las vacunas con CD. Nueve preparados para vacunacion antitumoral en pacientes han alcanzado los estudios fase III. De ellos, unicamente el sipuleucel-T, para tratamiento del carcinoma de prostata diseminado independiente de androgenos que utiliza CD, ha recibido la aprobacion preliminar de la Food and Drug Administration (FDA) de los Estados Unidos.

Resumen Las celulas dendriticas (CD) juegan un papel fundamental en la regulacion de la respuesta inmune. Son las principales celulas presentadoras antigenicas, por su capacidad de capturar, procesar y presentar antigenos de forma optima a linfocitos T, y generar respuestas inmunes especificas. Posteriormente al descubrimiento de esta funcion y al aparecer tecnicas metodologicas que permitian su purificacion y maduracion in vitro , se ha comprobado que tambien son capaces de activar otros tipos celulares, como linfocitos B, celulas NK, macrofagos o eosinofilos, e incluso generar tolerancia inmunologica. Este mejor conocimiento de su biologia y funciones ha permitido el desarrollo de ensayos clinicos basados en el uso de CD en el campo de la inmunoterapia antitumoral y antiinfecciosa o para inducir tolerancia postrasplante o en patologias autoinmunes.

INTRODUCTION Epidermal growth factor receptor (EGFR) mutation related to tyrosine kinase inhibitors' (TKIs) responsiveness in non-small cell lung cancer (NSCLC) has become an important issue for therapeutic decision-making in NSCLC patients. MATERIAL AND METHODS Sixty-nine Caucasian NSCLC patients were screened for mutations in the tyrosine kinase (TK) domain of EGFR by direct sequencing from December 2005 to September 2010. RESULTS Activating mutations in the EGFR TK domain were found in 8 of 69 (11.6%) (7 deletions in exon 19 and one L858R mutation in exon 21). Seven of those mutations were found in adenocarcinoma and one mutation in bronchiolo-alveolar carcinoma; five of them in females (one smoker) and three of them in males (one smoker). All patients carrying activating mutations in the TK domain of EGFR were treated with TKIs. Ten patients not carrying an activating mutation in EGFR, who progressed after chemotherapy, were also treated with compassionate use of EGFR-specific TKIs (gefitinib or erlotinib). An objective response (partial response) was observed in all patients carrying an activating mutation in EGFR that received TKIs. Median overall survival for these patients has not been reached, however mean survival has been estimated at 39.5 months (95% CI, 22-57). CONCLUSIONS As previously reported, EGFR TK mutational analysis was a predictive test for response to targeted therapy with EGFR TKIs. The early identification of these patients consistently attains disease response and clearly improves outcomes.

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).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.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.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.

2571Background: TKIs show a high pharmacokinetic variability. So, fixed dosing could result in inadequate exposure with decreased efficacy or increased toxicity. TDM allows individualized posology ...

11573 Background: Proliferating cancer cells consume elevated quantity of glucose, converted into lactate regardless the presence of oxygen (Warburg effect). This effect has been useful for imaging metabolically active tumors with FDG-PET, although its use in early response is controversial. Molecular mechanisms of FDG uptake are not fully understood. We have used MAGE to determine the most relevant genes involved in FDG uptake. Methods: Fresh-frozen tumor biopsies and quantitative basal FDG-PET/CT were obtained from metastatic lesions in cancer patients. Total tumor RNA was hybridized to a whole human genome oligonucleotide microarray. Gene expression signature-based prediction, using the most relevant genes involved in FDG uptake measured by SUV, was finally determined by Partial Least Squares (PLS). The interpretation of biological phenomena (IBP) derived from the selected genes was made by means of different public statistical bioinformatics resources. Results: 71 patients with different histological diagnosis were included in the training cohort and 13 in the validation one. 909 probes correlated significantly with SUV: 333 positively and 576 negatively. A predictive signature based on these 909 probes was built using PLS-3, with an RMSE in the validation set of 0.645 (within the 95% CI of RMSE determined in the training set). In IBP, other biological processes were more relevant than glycolysis in FDG uptake: RNA processing, ribosome biogenesis, protein processing, cell adhesion, cytoskeleton organization, angiogenesis and autophagy. Conclusions: This PLS-3-built signature is the first reported one that can accurately predict SUV. FDG uptake is a complex phenomenon that involves multiple biological processes, confirming the value of PET/CT in early response.

Summary 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.

BACKGROUND. Using a fixed higher-dose schedule, the efficacy and toxicity of suramin plus hydrocortisone were assessed in patients with metastatic hormone-refractory prostate carcinoma (HRPC). METHODS. Fifty consecutive patients with HRPC (including those in whom hormonotherapy was withdrawn) and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited. Treatment was comprised of a bolus intravenous infusion of 200 mg of suramin followed by suramin (500 mg/m 2 intravenously [i.v.] over 24 hours) given daily over 5 days as a loading course, followed by suramin (350 mg/m 2 i.v. over 2 hours) administered weekly for 12 weeks. This 12-week course was repeated at 6-month intervals. All patients received concomitant hydrocortisone. RESULTS. Five hundred fifty weekly doses of therapy were delivered over the course of the entire study. A partial response, based on a > 50% decrease in the prostate specific antigen (PSA) level, was achieved in 27 patients (54%; 95% confidence interval [95% CI], 44.7-65.0%), 16 of whom (32%; 95%CI, 23.9-43.2%) had a > 75% decrease in their PSA levels. The measurable disease objective response rate was 18% (95% CI, 2.3-51.8%). Of the 37 patients with bone pain requiring analgesia, 27 patients (73%; 95% Cl, 55.9-86.2%) reduced their medication consumption to a lower level on the World Health Organization analgesic ladder. The median duration of response was 15.5 weeks (range, 6-70 weeks), the median time to disease progression was 13 weeks, and the median overall survival time was 11 months. Treatment generally was well tolerated. Fatigue and severe lymphopenia were the most commonly reported significant toxicities. In addition, there was 1 septic toxic death reported, and 10% of the patients were found to have NCl Grade 3-4 neurotoxicity. CONCLUSIONS. The results of the current study demonstrated that the fixed-dose suramin regimen administered herein showed high, although short-lived, activity and a good tolerance profile in HRPC patients.

e14028Background: Genomic-based profiling of tumors constitutes an encouraging approach that favors the selection of active regimens minimizing the possibility of futile therapies. Previous experie...

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.

The aim of the study is to evaluate the limb salvage rate achieved by treating locally advanced extremity sarcoma and melanoma by hyperthermic isolated limb perfusion with melphalan and TNF-α (ILP-MT).A retrospective study was conducted on patients suffering from locally advanced soft tissue sarcoma and melanoma of the limb and treated by means of ILP-MT between November 2001 and February 2010. The response rate, toxicity, complications, disease free intervals, overall survival and limb salvage rate were evaluated.A total of 30 patients (19 females and 11 males) with a median age of 60 years (14-82) were treated by this technique. The overall response rate was 93.4% (complete, 46.7%; partial 46.7%); the mean follow-up was 23 months. The median duration of response was 5 months (0-62), The median overall survival was 13.5 months (range 1 - 62). Limb salvage rate was 86.7%. Eleven patients are currently alive (5 without disease, 2 with residual disease on treatment, 2 with local progression and 2 with systemic progression).With the use of ILP-MT we have avoided the amputation of 26 limbs affected by locally advanced sarcoma or melanoma. ILP-MT is feasible and safe in a multidisciplinary environment.

e22071 Background: Genomic-based profiling of tumors constitutes an encouraging approach that favors the selection of active regimens minimizing the possibility of futile therapies. Previous experi...

Background and objective: After oral administration, SIR (mTOR inhibitor) is rapid absorbed with a bioavailability around 14%. SIR is distributed mostly into red blood cells, 92% is bound to proteins and its apparent steady state volume of distribution is higher than 650 L. The apparent clearance has been determined to be 13 L/h. SIR undergoes extensive hepatic and intestinal metabolism via CYP3A4 and CYP3A5, as well as excretion by P-glycoprotein. The purpose of this study was to develop a simple and sensitive HPLC method with UV-Visible detection for SIR blood quantification to allow therapeutic drug monitoring (TDM) in cancer patients. A pilot phase I study in advanced cancer patients was initiated to evaluate the effect of grapefruit juice in SIR pharmacokinetics. Methods: After a liquid-liquid extraction with 1-chlorobutane, SIR and paclitaxel (internal standard, IS) are separated in Ultrabase C18 column using a mobile phase consisting of a mixture of methanol and water in a proportion 77:23 pumped at a constant flow rate of 1 mL/min. The column was maintained at 50°C and the eluent was monitored at a wavelength of 277 nm. Validation experiments were carried out after the guidelines for Bioanalytical Method Validation published by the FDA and the EMA. SIR was administered once weekly as an oral solution in three dose leves (10, 20 or 30 mg). Natural grapefruit juice (250 cc) was administered half an hour before SIR administration, once a week. Results: The calibration curve was linear in the range of 10-700 ng/mL. The limit of quantification was determined to be 10 ng/mL. SIR and IS retention times were 12.2 and 3.4 min, respectively. Inter- and intra-day coefficients of variation were less than 8%. The mean extraction recovery from plasma was higher than 67%. In the first six patients evaluated, SIR blood concentrations were well quantified and showed that the analytical method was capable of measuring the blood concentrations of SIR in advanced cancer patients undergoing SIR therapy. In all patients, SIR concentrations were significantly increased by grapefruit juice at all dose levels because its clearance was reduce around 50% confirming previous results published by Cohen E et al. (Clin Cancer Res, 2012). Conclusion: The simple, rapid and sensitive HPLC-UV method developed and validated for the measurement of SIR in human blood using paclitaxel as IS can be applied easily in routine clinical practice for the TDM of SIR. Co-administration of grapefruit juice and SIR must be evaluated in the context of Phase II and III clinical trials in order to explore alternative and safer treatments. Note: This abstract was not presented at the meeting. Citation Format: Vanesa Escudero-Ortiz, Belen Valenzuela, Joseba Rebollo, Manuel Sureda, Antonio Brugarolas. Development and validation of an HPLC-UV method for Sirolimus (sir) quantification in human blood and application to cancer patients in routine clinical practice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4648. doi:10.1158/1538-7445.AM2014-4648

e22198 Background: Previous studies have postulated the role of IL6, VEGF and srIL2 as indicators of disease activity in different morbid conditions including cancer. Methods: Serum samples from pa...

e22173 Background: MP is potentially useful for the sensitivity and resistance prediction to conventional and targeted drugs, although the wide number of platforms and algorithms used makes validat...

e22120 Background: Genomic-based profiling of tumors is a promising approach that allows the selection of the optimal chemotherapy regimen minimizing the possibility of futile therapies. Preliminary clinical results by our group showing a 23% response rate were presented at ASCO’12 (abstract 3,064). However, RNA isolation is a challenging technical step that requires a high quality specimen and takes 2-4 weeks interval to be finished. For this reason we analyzed the feasibility conditions in our series. Methods: Patients (pts) with R/R solid tumors had immediately frozen biopsies, underwent RNA isolation and quality validation after a pathologic confirmation of viable tumor in more than 30% of the sample. Results: From August 2010 to December 2012, 138 patients accepted the MAGE chemotherapy profiling. The median time from biopsy to MAGE analysis has been 4 weeks (ranging 2 to 6). In 17 (12%) pts the procedure was aborted for technical reasons. In these cases tumor samples were obtained from liver in 7 pts, local recurrence in 3 pts, soft tissues in 3 pts, peritoneum in 2 pts, and nodes in 2 pts. Reasons for canceling the assay were mainly a very low tumor cells rate (less than 30%) in 10 pts (fibrotic changes in 5 pts and predominance of necrosis in 5 pts), 2 pts with no tumor, 1 pt with a non-radiologically identifiable lesion, 1 pt with radiofrequency deterioration of the specimen and 3 pts with poor quality RNA. Among the remaining 121 pts who completed the procedure only 74 (61.2%) were treated according to the selected chemotherapy agents achieving a clinical benefit rate of 60%. The high attrition rate (38.8%) was due to poor clinical condition, refusal of recommendations and/or short life expectancy. Conclusions: MAGE-based chemotherapy profiling of tumors was feasible to guide antitumor therapy in selected patients. We recommend performing the study in untreated patients or earlier in the course of their disease (i.e. after failure to first line chemotherapy) in patients with a life expectancy of more than 3 months.

3074 Background: F. Recchia et al. (Interleukin-2 and 13-cis retinoic acid in the treatment of minimal residual disease: A phase II study. Int J Oncol. 20: 1275-1282, 2002) previously defined the possibility of achieving a chronic immune stimulation through a prolonged low dose sc interleukin 2 (IL2)-based schedule, leading to a prolongation of PFS in advanced cancer patients (pts). A confirmatory phase II study was started. Methods: Pts diagnosed of high risk solid tumors in response to chemotherapy were included. RIS consisted in low dose IL2 (1.8 MU sc per day, 5 days per week, 3 weeks per month) plus oral isotreonin (CRA, 0.5 mg/kg) the same days of IL2 and/or sc PEG-interferon (50 µg per week of treatment). No Chx was allowed with RIS, but concurrent maintenance with TKI or Hx was permitted. Results: Since 08/2007 to 01/2013, 69 pts (39 M/30 F, median age 60 y, range 31-78) were included. 51 pts were treated with stage IV disease. 36 pts entered in complete response (CR), 29 in partial response (PR), 1 with progressive disease, 3 adjuvant. 4/69 grade 3/4 toxicity, (6%): 1 fatal poliserositis resistant to cortisone after 20 months of RIS, 1 stopped RIS for reaction requiring steroids, 1 for multiinfarction dementia, 1 for grade 3 liver toxicity. 3 pts presented other alterations managed along the course of the RIS (1 PVT, 1 ITP, 1 angina resolved after stent placement). Grade 1-2 fever, fatigue and joint pain were commonly observed but usually controlled with NSAIDs. Among the 68 pts evaluable for response, one pt progressed, 26 presented stable disease (median TTP 3 mo, range 2-28), 3 presented PR (1 melanoma, 1 prostatic ca, 1 ovarian ca; 9, 11 and 28 mo respectively), and 38 maintained or presented CR (median TTP 19 mo, range 2-62+). Three pts in PR were converted to a CR during RIS (1 pancreatic ca, 1 ovarian ca, 1 larynx ca). Conclusions: In this study we confirm the previous results reported by F. Recchia et al. RIS represents a good alternative for high risk pts with solid tumors after systemic chemotherapy induced response with acceptable tolerability and offers in selected pts a possibility of obtaining a CR after a PR. Further validation and randomized studies are warranted.

e16000 Background: IAHDP has been employed as a part of the treatment of relapsed or locally advanced H&N tumors with controversial results (RADPLAT protocol). We hypothesize that patients (pts) with relapsed or locally advanced tumors in several locations can be treated with IAHDP, in order to achieve a response, to be followed by a consolidation with radiotherapy, surgery or both. Methods: Pts with relapsed or locally advanced tumors of the H&N were treated with IAHDP (150 mg/m2/wk), after an initial supraselective angiography performed with the goal of mapping adequately the arterial supply. Prevention of toxicity with hyperhydration and simultaneous and delayed thiosulfate was done according to the previous schema of the RADPLAT protocol. Results: From June 2007 to September 2011, 11 patients – 8 M/ 3F; age 37-77 y, median 56 y- were treated (10 H&N epidermoid carcinomas, 1 orbitary mts of adenocarcinoma of unknown origin). A total of 50 cycles were administered (2-9 per pt, median 4). In 4 pts IAHDP was part of the primary treatment; 7 pts were treated in relapse. Three pts were retreated after relapse, one of them two times. Five pts received radiotherapy simultaneously with IAHDP. Toxicity was generally mild and reversible. Mucositis g4 was observed in 3 cycles, facial edema requiring extra dexametasone in 7, pain during infusion in 9, nausea and vomiting in 3, lasting ipsilateral hypoacusia in 1, persistent trismus in 1. No significant alterations of renal function were observed. One pt progressed after the first cycle; 7 pts presented partial response (duration 1-6 m, median 2 m; 2 of them were converted to a complete response with surgery); 2 pts presented complete response with IAHDP simultaneous to radiotherapy. Four pts remained with no evidence of disease at 3+, 15+, 16+ and 38+ m respectively. Conclusions: IAHDP constitutes a feasible and promising therapeutic option for selected pts and a consolidation with surgery and/or radiotherapy after IAHDP is possible. Further development of this approach is warranted.

Background and objective: Lapatinib is a 4-anilinoquinazoline that can reversible and selectively inhibit both human epidermal growth factor receptor (EGFR, HER1) and human epidermal growth factor receptor type 2 (HER2) tyrosine kinases. As others tyrosine kinase inhibitors (TKIs), lapatinib shows a large interindividual variability in its pharmacokinetics (PK). So, the variability in drug exposure to TKIs may contribute to the variation in anti-cancer PD effect. Causes for this PK variability are manifold during the different processes of ADME. Up to date, only mass spectrometry detection is currently available to determine lapatinib in human plasma. The purpose of this study was to develop a simple and sensitive high-performance liquid chromatographic method with UV-Visible detection for quantification of lapatinib concentrations in human plasma to allow therapeutic drug monitoring (TDM) of lapatinib in cancer patients. Methods: After a liquid-liquid extraction with acetonitrile, lapatinib and sorafenib (internal standard, IS) are separated on Ultrabase C18 column using a mobile phase consisting of a mixture of 0.02 M ammonium acetate and acetonitrile in a proportion 47:53 pumped at a constant flow rate of 1.2 mL/min. The column was maintained at 25°C and the eluent was monitored at a wavelength of 260 nm. Results: The calibration curve was linear in the range 200-10000 ng/mL. The limit of quantification was determined to be 200 ng/mL. Lapatinib and IS retention times were 3.2 and 10.6 min, respectively. Inter- and intra-day coefficients of variation were less than 7%. The mean extraction recovery from plasma was higher than 86%. Conclusion: The simple, rapid and sensitive HPLC-UV method developed and validated for the measurement of lapatinib in human plasma using sorafenib as IS can be applied easily in routine clinical practice for the TDM of lapatinib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 757. doi:1538-7445.AM2012-757

Background: Anthracyclines (A) and Taxanes (T) remain amongst the most active drugs in breast cancer chemotherapy. However, significant toxicities are associated when administered at full doses in a number of patients (pts), so careful dose adjustments should be made in order to optimize their clinical effectiveness. A and T have high inter- and intra-patient variability, and a correlation between exposure and efficacy and toxicity has been demonstrated. Therefore, therapeutic drug monitoring (TDM) of these drugs, based on the individual pharmacokinetic (PK) parameters could personalize doses in order to diminish its toxicity and/or to improve the clinical benefit. Methods: A total of 24 pts (92 cycles) were treated with either single drugs, or combinations of two of these agents, usually with four initial cycles of A and 4 subsequent cycles of T. The initial dose was calculated using body-surface algorithm. Pts were monitored since the first cycle and subsequent doses pharmacokinetically adjusted until the target plasma concentration was reached. Bayesian estimates of individual PK parameters were calculated using a population PK models previously published and used for PK-based dose adjustment. Results: The main results are shown in the following table: 43% of pts treated with A had the initial dose increased by an average of 22% without toxicities grade II, except one pt which developed mucositis grade II. For paclitaxel, initial dose was increased in 25% of patients by an average of 22% with only one case of grade 2 asthenia. However, docetaxel initial dose of 60-75 mg/m2 was more toxic than the other drugs evaluated. The doses were reduced by an average of 22% due to toxicities such as grade 3 neutropenia, grade 2 asthenia or grade 2 leucopenia. Conclusion: Standard dosing regimen of A and T in breast cancer pts could be optimized by TDM in order to achieve the target plasma concentration during the chemotherapy treatment and ensure that pts receive the right dose. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 762. doi:1538-7445.AM2012-762

2094 Background: Usual treatment of brain tumors includes surgery, radiotherapy and chemotherapy, but the general prognosis is bad, with local relapse as the main cause of death. PDT is a local ant...

e14104 Background: Therapeutic options for patients (pts) with advanced colorectal cancer (CRC) that have progressed to irinotecan- and oxaliplatin-based combination chemotherapy are few. Raltitrex...

e13015 Background: Therapeutic drug monitoring (TDM) is not routinely used for chemotherapy agents. Nonetheless, TDM has the potential to improve the clinical benefit of chemotherapy agents due to ...

Irinotecan and Anthracyclines (Topoisomerase I and II inhibitors, respectively) are widely used as antitumoral agents in cancer treatment. However, no data have been reported when used in combination. In this study we report the activity of biweekly Irinotecan (150 mg/m2) plus Anthracycline (Doxorrubicin 30 mg/m2 or Pegylated Doxorrubicin 20 mg/m2) - based combination chemotherapy in some previously treated advanced solid tumours. From June ’04 to June ’09, eighteen patients (pt) have been treated. Median age has been 64 y (range 28-84 y). Eight pt had ovarian cancer, 8 pt non-small-cell lung cancer (NSCLC) and 2 pt gastric cancer. Therapy has been administered as a second line treatment in 11 pt and as a third and further treatment in 7 pt. Four pt have received radiotherapy previously. Toxicities have been leucopenia (3 pt grade III-IV, 6 pt grade I-II), mucositis (6 pt grade III-IV, 5 pt grade I-II), diarrhea (2 pt grade III) and hand-foot syndrome (2 pt grade II). One pt died of neutropenic sepsis after the first dose of chemotherapy. Seven out of 16 (44%) pt presented objective response: 4/7 ovarian cancer pt, 2/7 NSCLC pt and 1/2 gastric cancer pt. Two pt are not evaluable for response (one pt without evaluable disease and 1 pt early toxic death). Median Progression Free Survival has been 4 mo (range 1-13 mo). Irinotecan plus Anthracycline - based combination chemotherapy is an active treatment in some solid tumours and it is well tolerated. Most of the toxic events were related to heavily pre-treated pt. It is infrequent to observe objective good quality responses in first line therapy resistant tumours. For this reason, we purpose there is a synergistic effect based on the known mechanisms of both drugs (Topoisomerase I and II inhibition) and an early-use first line therapy is recommended with this combination. This combination should be tested in larger trials to confirm antineoplastic activity. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4677.

13550 Background: 5-FU efficacy and toxicity depends on steady-state 5-FU plasma concentration (ss[5-FU]) and AUC 5-FU concentration-time curve. However a wide interindividual variability of plasma...

4793 Background: Bone metastasis is a major complication for prostate carcinoma patients, and some times the first indication of progressive disease and worsening prognosis. Various bone target rad...