SEOM clinical guideline for treatment of kidney cancer (2017)

The goal of this article is to provide recommendations about the management of kidney cancer. Based on pathologic and molecular features, several kidney cancer variants were described. Nephron-sparing techniques are the gold standard of localized disease. After a randomized trial, sunitinib could be considered in adjuvant treatment in high-risk patients. Patients with advanced disease constitute a heterogeneous population. Prognostic classification should be considered. Both sunitinib and pazopanib are the standard options for first-line systemic therapy in advanced renal cell carcinoma. Based on the results of two randomized trials, both nivolumab and cabozantinib should be considered the standard for second and further lines of therapy. Response evaluation for present therapies is a challenge (AU)

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Stereotactic body radiation therapy (SBRT) delays the emergence of castration resistance in patients with oligometastatic prostate cancer

Purpose: To investigate whether bone metastases-directed stereotactic body radiation therapy (SBRT) delays the emergence of castration resistance in patients with oligometastatic prostate cancer (OPC). Methods and material: OPC is usually managed with androgen deprivation therapy (ADT). Migration to castration-resistant prostate cancer will inevitably occur in the majority of these patients. There are several strategies aimed to delay the emergence of castration resistance including intermittent ADT, second generation antiandrogens (abiraterone, enzalutamide) or metastases-directed SBRT. The present report describes two cases of patients with OPC that received SBRT 24 Gy/3Rx to the solitary bony lesion after ADT failure. Results: Both cases showed complete and durable biochemical response for 13 and 17 months, respectively. Conclusions: SBRT can be used to delay the emergence of castration resistance and the need for systemic therapy when used after ADT failure (AU)

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Tratamiento del cáncer de próstata en función de la esperanza de vida, la comorbilidad y las guías de práctica clínica / Treatment of prostate cancer according to life expectancy, comorbidity and clinical practice guidelines

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Cost analysis of skeletal-related events in Spanish patients with bone metastases from solid tumours

PURPOSE: To estimate the cost per skeletal-related event (SRE) in patients with bone metastases secondary to solid tumours in the Spanish healthcare setting. METHODS: Patients diagnosed with bone metastases secondary to breast, prostate or lung cancer were included in this multicentre, observational study. SREs are defined as pathologic fracture (vertebral and non-vertebral fracture), radiation to bone, spinal cord compression or surgery to bone. Health resource utilisation associated with these events (inpatient stays, outpatient, emergency room and home health visits, nursing home stays and procedures) were collected retrospectively for all SREs that occurred in the 97 days prior to enrolment and prospectively during follow-up. Unit costs were obtained from the 2010 eSalud healthcare costs database. RESULTS: A total of 93 Spanish patients with solid tumours were included (31 had breast cancer, 21 prostate cancer and 41 lung cancer), contributing a total of 143 SREs to this cost analysis. Inpatient stays (between 9.0 and 29.9 days of mean length of stay per inpatient stay by SRE type) and outpatient visits (between 1.7 and 6.4 mean visits per SRE type) were the most frequently reported types of health resources utilised. The mean cost per SRE was between 2,377.79 (radiation to bone) and 7,902.62 (spinal cord compression). CONCLUSION: SREs are associated with a significant consumption of healthcare resources that generate a substantial economic burden for the Spanish healthcare system (AU)

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Células dendríticas especializadas en presentación de antígenos exógenos a linfocitos T citotóxicos / Specialized dendritic cells in cross-presentation of exogenous antigens to cytotoxic T lymphocytes

Las células dendríticas son células de origen hematopoiético, que expresan constitutivamente moléculas presentadoras de antígeno MHC de clase I y II, y son funcionalmente las inductoras más potentes de la activación y proliferación de linfocitos Ta los que presentan antígenos. Los linfocitos T CD8+ proliferan y adquieren capacidad citotóxica cuando reconocen su antígeno específico presentado en la superficie de una o varias células dendríticas con las que interactúan. Sin embargo, solamente algunas subpoblaciones de células dendríticas pueden presentar antígenos internalizados desde el exterior celular a través de procesos de pinocitosis y fagocitosis a precursores de linfocitos T citotóxicos. Esta función se denomina presentación cruzada o presentación subrogada (en inglés, cross presentation) y requiere mecanismos de translocación de los antígenos que se encuentran internalizados en fagosomas al citosol para su procesamiento. Se ha establecido que la diferenciación de subpoblaciones de células dendríticas con capacidad de efectuar este tipo de presentación cruzada a linfocitos T CD8+ son dependientes del factor de crecimiento FLT-3L y del factor de transcripción BATF3. Presentan peculiaridades tanto funcionales como de marcadores de membrana que nos permiten identificarlas. En ratones se distinguen por la expresión de CD8α y en humanos por la de CD141 (BDCA-3). Esta población en ambas especies es capaz de internalizar selectivamente restos de células necróticas mediante su receptorCLEC9A que se une a actina polimerizada extracelular. Disponen del receptor de quimioquinas XCR1 que asegura su encuentro con linfocitos T CD8+. La vacunación terapéutica con antígenos tumorales utilizando células dendríticas es una estrategia en desarrollo para el tratamiento del cáncer. La utilización de subpoblaciones de células dendríticas con mayor capacidad de realizar presentación cruzada o subrogada remeda los mecanismos naturales de inmunización para inducir linfocitos T citotóxicos. La dianización in vivo de antígenos a estas subpoblaciones celulares mediante anticuerpos monoclonales anti-DEC-205 o anti-CLEC9A consigue respuestas inmunitarias muy intensas y se están probando en ensayos clínicos frente a viriasis crónicas y enfermedades malignas (AU)

Dendritic cells (DC) are cells of hematopoietic origin, which constitutively express MHC class I and II, and are functionally the most potent inducers of T-lymphocyte activation and proliferation. CD8+ T lymphocytes proliferate and acquire cytotoxic functions upon recognition of their cognate antigen on the surface of one or various dendritic cells with which they interact. However, only some DC subsets are able to present antigen to cytotoxic T cell precursors as taken up from extracellular sources. This function is termed cross-presentation (in Spanish, presentacion cruzada or presentacion subrogada) and requires shuttle mechanisms from phagosomes to the cytosol for antigen processing. It has been demonstrated that the differentiation of DC with these capabilities is dependent on FLT-3Land the transcription factor BATF3. They express peculiar functions and differentiation markers. These cells are distinguished in mice by surface CD8 α features, while CD141 (BDCA-3) marks these cells in the human. These subpopulations are capable of selective internalization of necrotic cell debris by means of their CLEC9A lectin which is a receptor for extracellular polymerized actin. Expression of the chemokine receptor XCR1 favours contact with CD8+ T cells. Therapeutic vaccination with tumour antigens using DC is a strategy under development for the treatment of cancer. The use of DC subsets with more prominent capabilities for cross-presentation would mimic the natural mechanisms of immunization to induce cytolitic T lymphocytes. In vivo targeting of antigens with monoclonal antibodies against DEC-205 or CLEC9A attains very robust immune responses and is a strategy undergoing clinical trials for chronic viral diseases and malignancies (AU)

Phase II trial of sequential subcutaneous interleukin-2 plus interferon alpha followed by sorafenib in renal cell carcinoma (RCC)

PURPOSE: Immunotherapy (IL-2 and INF-α) was the treatment of choice for advanced renal cell carcinoma (RCC) until antiangiogenic therapy with tyrosin kinase inhibitors was developed in the early 2000s. This clinical trial explored the efficacy and toxicity of sequential treatment of IL-2 plus INF-α followed by sorafenib. METHODS: Eligibility criteria included measurable, non-resectable, histologically confirmed predominantly clear cell RCC, no prior systemic treatment, and ECOG PS 0-2. The treatment regimen was a 6-week cycle of subcutaneous IL-2 at 9 × 10(6) IU on days 1-6 of weeks 1, 2, 4 and 5 plus s.c. INF-α at 6 × 10(6) IU on days 1, 3 and 5 of weeks 1-6. Responders received 6 additional weeks of this regimen. All patients received oral sorafenib (400 mg bid) after immunotherapy until disease progression. The primary endpoint was progression-free survival. RESULTS: Forty-one patients were enrolled, median age 57 years. ECOG was 0/1 in 17/20 patients, 35 patients had prior nephrectomy and 18 patients pure clear cell cancer. Median PFS was 7.4 months (95 % CI 6.5-13.1) and OS was 16.6 months (95 % CI not reached). In 36 patients evaluable for response, ORR was 44.4 % and control rate was 94.4 %. Most adverse events (AEs) were Grade 1 or 2 toxicities (84.7 %). During immunotherapy the most common AEs were pyrexia (82.9 %), asthenia (56.1 %) and anorexia (46.3 %), whereas during sorafenib were diarrhoea (48.8 %) and hand-foot syndrome (46.3 %). CONCLUSIONS: A sequential regimen of IL-2 and INF-α followed by sorafenib showed effectiveness and manageable toxicity in patients with advanced RCC (AU)

The multimodal management of locally advanced N2-non-small cell lung cancer: is there a role for surgical resection? A single institution's experience

BACKGROUND: The management of operable locally advanced N2 non-small cell lung cancer (NSCLC) is a controversial topic. Concurrent chemoradiation (CT-RT) is considered the standard of care for inoperable or unresectable patients, but the role of trimodality treatment remains controversial. We present our institution's experience with the management of stage III (N2) NSCLC patients, analyzing whether the addition of surgery improves survival when compared with definitive CT-RT alone. METHODS: From 1996 to 2006, 72 N2 NSCLC patients were treated. Thirty-four patients received cisplatin-based induction chemotherapy, followed by paclitaxel-cisplatin CT-RT, and 38 patients underwent surgery preceded by induction and/or followed by adjuvant therapy. Survival curves were estimated by Kaplan-Meier analysis, and the differences were assessed with the log-rank test. RESULTS: Most of the patients (87 %) were men. The median age was 59 years. A statistically significant association between T3-T4c and definitive CT-RT as well as between T1-T2c and surgery was noted (p < 0.0001). After a median follow-up period of 35 months, the median overall survival (OS) was 42 months for the surgery group versus 41 months for the CT-RT patients (p = 0.590). The median progression-free survival (PFS) was 14 months after surgery and 25 months after CT-RT (p = 0.933). Responders to radical CT-RT had a better OS than non-responders (43 vs. 17 months, respectively, p = 0.011). No significant differences were found in the OS or PFS between the pN0 [14 (37.8 %) patients] and non-pN0 patients at thoracotomy. Three treatment-related deaths (7.8 %) were observed in the surgical cohort and none in the CT-RT group. CONCLUSIONS: The addition of surgery did not render a median OS or PFS benefit when compared with CT-RT alone in our series of stage III-N2 NSCLC patients, in accordance with previously published data. However, responses to CT-RT had a greater impact in terms of OS and PFS. Although the patients selected for management including surgery showed a favorable T clinical staging in comparison to patients exclusively treated with definitive CT-RT, similar survival outcomes were found (AU)

Novel antiangiogenic therapies against advanced hepatocellular carcinoma (HCC)

Angiogenesis is a cornerstone in the process of hepatocarcinogenesis. In the sorafenib era, other antiangiogenic targeted drugs, such as monoclonal antibodies and a new generation of tyrosine kinase inhibitors, have been shown in phase II trials to be safe and effective in the treatment of advanced hepatocellular carcinoma. Several currently active phase III trials are testing these drugs, both in first- and second-line settings. Strategies to overcome primary and acquired resistance to antiangiogenic therapy are urgently needed. Novel biomarkers may help in improving the efficacy of drugs targeting angiogenesis (AU)

SEOM clinical guidelines for using molecular markers in clinical practice

Nowadays, treatment selection for most types of cancers is based on anatomical, histological and clinical criteria, which are defi ned by the selection criteria used in registration phase III trials. However, different cancers present distinct molecular features, so the current approach results in a lack of specificity of cancer therapy, which is associated with decreased efficacy and unnecessary toxicities and costs. Molecular diagnostics has proved able to predict the efficacy of selected targeted therapies. This allows the selection of specific treatments for different types of cancer, increasing their efficiency. Even though the number of treatments for solid tumours that can be selected based on molecular diagnostic tools is limited, much effort is being put into the identification of new biomarkers. This guideline reviews molecular diagnostic biomarkers that allow selection of specific therapies that have obtained regulatory approval as treatment of solid tumours (AU)

Selection of extreme phenotypes: the role of clinical observation in translational research

Systematic collection of phenotypes and their correlation with molecular data has been proposed as a useful method to advance in the study of disease. Although some databases for animal species are being developed, progress in humans is slow, probably due to the multifactorial origin of many human diseases and to the intricacy of accurately classifying phenotypes, among other factors. An alternative approach has been to identify and to study individuals or families with very characteristic, clinically relevant phenotypes. This strategy has shown increased efficiency to identify the molecular features underlying such phenotypes. While on most occasions the subjects selected for these studies presented harmful phenotypes, a few studies have been performed in individuals with very favourable phenotypes. The consistent results achieved suggest that it seems logical to further develop this strategy as a methodology to study human disease, including cancer. The identification and the study with high-throughput techniques of individuals showing a markedly decreased risk of developing cancer or of cancer patients presenting either an unusually favourable prognosis or striking responses following a specific treatment, might be promising ways to maximize the yield of this approach and to reveal the molecular causes that explain those phenotypes and thus highlight useful therapeutic targets. This manuscript reviews the current status of selection of extreme phenotypes in cancer research and provides directions for future development of this methodology (AU)

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Oxaliplatin plus gemcitabine as a salvage schedule for hormone-refractory prostate adenocarcinoma

We report a case of hormone-refractory prostate cancer (HRPC) treated with oxaliplatin plus gemcitabine in a third-line schedule after liver progression, with an excellent clinical, biochemical and radiological response and with an acceptable tolerance. Prior chemotherapy regimens included docetaxel plus estramustine and oral etoposide. To our knowledge, this is the first report that shows this approach in an HRPC patient (AU)

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Nuevos tratamientos para el carcinoma renal / New treatments for renal carcinoma

El cáncer renal presenta varias características que lo diferencian de otros tumores. El aumento de supervivencia observado en pacientes con carcinoma renal metastásico tras la realización de nefrectomía, rompe un concepto clásico de la oncología según el cual la extirpación del tumor primario en tumores avanzados carece de sentido. Junto con el melanoma, es el único tumor en el que tratamientos inmunomoduladores, como interleukina- 2 producen un beneficio clínico al paciente. El tratamiento del cáncer renal metastásico con interleukina-2 intravenosa a dosis altas ha confirmado en estudios aleatorios que puede producir respuestas completas de muy larga duración, en la práctica equivalentes a la curación. Por último, el cáncer renal está siendo empleado como modelo clínico para demostrar la eficacia de múltiples tratamientos dirigidos frente a nuevas dianas. En la actualidad se están estudiando más de 30 nuevos fármacos como tratamiento del cáncer renal, habiendo sido el primer tumor en el que se ha demostrado el beneficio clínico del tratamiento con inhibidores de la angiogénesis. En este artículo se revisan los aspectos más relevantes sobre el cáncer renal, incluyendo epidemiología, factores pronósticos, presentación clínica; bases moleculares y el estado actual de desarrollo de varios de los múltiples fármacos que se están estudiando en esta enfermedad

Renal cell carcinoma presents several unique features, which distinguish it from other tumours. The increase in survival that has been described in patients with renal cell carcinoma following nephrectomy breaks a classical rule of oncology, which states that surgery of the primary tumour has no role in the treatment of patients with advanced disease. Together with melanoma, it is the only tumour in which immunomodulatory treatments with drugs such as interleukin-2 produces a clinical benefit to patients. In randomized trials treatment of metastatic renal cell carcinoma with high dose interleukin-2 has confirmed its ability to induce long-term complete responses, which in practice can be considered equivalent to cure. Lastly, renal cell carcinoma is being used as a clinical model to demonstrate the role of several targeted treatments, with over 30 novel agents under development. It has been the first tumour type in which treatment with angiogenesis inhibitors has shown a clinical benefit. This article reviews the most relevant aspects of renal cell carcinoma, including epidemiology, prognostic factors, clinical presentation, molecular bases and the current status of development of the most relevant novel treatments for this disease

Carcinoma microcítico de pulmón / No disponible

El cáncer microcítico de pulmón es uno de los tumores sólidos más agresivos, por su rápido crecimiento y por su tendencia a metastatizar desde fases tempranas. Sin embargo, también es uno de los tumores más sensibles a los tratamientos de quimioterapia y radioterapia, con los cuales algunos pacientes con enfermedad limitada pueden sobrevivir a largo plazo. Estas características han hecho de este tumor un modelo clínico sobre el cual se han probado múltiples estrategias de tratamiento, incluyendo tratamientos concomitantes con quimioterapia y radioterapia, esquemas de quimioterapia alternante o de altas dosis con soporte hematológico o la utilización de radioterapia holocraneal profi láctica. Además en los últimos años el cáncer microcítico de pulmón también se ha empleado como plataforma de desarrollo de tratamientos dirigidos contra dianas específi cas o de inmunoterapia

Small cell lung cancer is one of the most aggressive solid tumors because of its rapid growth and early tendency to spread to distant organs. Nonetheless, it is also one of the most sensitive tumors to chemotherapy and radiotherapy, which can give patients with limited disease a chance to become long-term survivors. These characteristics have made this tumor a clinical model to explore various treatment strategies, including concomitant chemotherapy and radiotherapy, alternant chemotherapy, high-dose chemotherapy with hematologic support, or use of wholebrain prophylactic radiotherapy. In addition, in recent years, small cell lung cancer has been used as a platform to develop some new targeted therapy agents or immunotherapeutic approaches

El potencial de la inmunomodulación con anticuerpos monoclonales anti-CD137 (4-1BB) para terapia de enfermedades malignas e infecciones virales crónicas / The immunotherapy potential of agonistic anti-CD137 (4-1BB) monoclonal antibodies for malignancies and chronic viral diseases

La manipulación farmacológica del sistema inmunitario para conseguir respuestas linfocitarias de mayor intensidad tiene aplicación potencial en inmunoterapia tumoral y en el tratamiento de enfermedades virales crónicas. Los anticuerpos monoclonales inmunoestimuladores se definen como una familia de fármacos que aumentan la respuesta inmunitaria al interaccionar como ligandos artificiales con proteínas funcionales del sistema inmunitario, activando o inhibiendo su función. Hay anticuerpos monoclonales humanizados dirigidos frente al receptor inhibidor linfocitario CD152 (CTLA-4) que se están probando en ensayos clínicos con evidencia de actividad antitumoral, aunque con la contrapartida de producir reacciones autoinmunitarias severas. Los anticuerpos anti-CD137 tienen la capacidad de inducir potentes respuestas inmunitarias, mediadas principalmente por linfocitos T citotóxicos, con el resultado de erradicar tumores transplantables de ratón de forma comparativamente superior a los anticuerpos frente a CD152. CD137 (4-1BB) es un antígeno de diferenciación expresado selectivamente en la superficie de linfocitos T y NK activados y sobre células dendríticas. Los anticuerpos monoclonales que actúan como ligandos artificiales estimuladores de este receptor (anticuerpos monoclonales agonistas anti-CD137) potencian la inmunidad celular antitumoral y antiviral en modelos experimentales murinos. Paradójicamente, estos mismos anticuerpos previenen o mejoran el curso de enfermedades autoinmunitarias establecidas en ratones como modelo. A la luz de estos datos experimentales, varios grupos de investigación han procedido a la humanización de anticuerpos dirigidos frente a CD137 humano y se plantea la inminente realización de los primeros ensayos clínicos

Pharmacological intervention on the immune system to achieve more intense lymphocyte responses has potential application in tumour immunology and in the treatment of chronic viral diseases. Immunostimulating monoclonal antibodies are defined as a new family of drugs that augment cellular immune responses. They interact as artificial ligands with functional proteins of the immune system, either activating or inhibiting their functions. There are humanized monoclonal antibodies directed to the inhibitory receptor CD152 (CTLA-4) that are being tested in clinical trials with evidence of antitumoural activity. As a drawback, anti-CTLA-4 monoclonal antibodies induce severe autoimmunity reactions in a fraction of the patients. Anti-CD137 monoclonal antibodies have the ability to induce potent immune responses mainly mediated by cytotoxic lymphocytes with the result of frequent complete tumour eradications in mice. Comparative studies in experimental models indicate that the antitumour activity of anti-CD137 monoclonal antibodies is superior to that of anti-CD152. CD137 (4-1BB) is a leukocyte differentiation antigen selectively expressed on the surface of activated T and NK lymphocytes, as well as on dendritic cells. Monoclonal antibodies acting as artificial stimulatory ligands of this receptor (anti-CD137 agonist antibodies) enhance cellular antitumoural and antiviral immunity in a variety of mouse models. Paradoxically, anti-CD137 monoclonal antibodies are therapeutic or preventive in the course of model autoimmune diseases in mice. In light of these experimental results, a number of research groups have humanized antibodies against human CD137 and early clinical trials are about to start