Modelos de impacto presupuestario. una nueva herramienta de evaluación para drogas de alto costo en oncología / Models budgetary impact. a new evaluation tool for high-cost drugs in oncology

Dentro de las evaluaciones fármaco-económicas habituales de nuevas drogas, se ha generalizado el uso del análisis de impacto presupuestario, que es un complemento de las evaluaciones más conocidas de costo-efectividad y costo-utilidad y tiene una importancia fundamental al momento de decidir la incorporación de una nueva molécula (o intervención terapéutica) al formulario terapéutico de una organización o subsistema de salud. Varios factores, no utilizados habitualmente en evaluaciones de costo-efectividad, son necesarios para los análisis de impacto presupuestario, incluyendo el tamaño de la población pasible de recibir tratamiento y las tasas de difusión en el mercado de la nueva intervención, entre otros. Se presenta en este artículo un prototipo básico de modelo de impacto presupuestario (MIP) y se discute la relevancia de los datos que se obtienen de ellos y su utilidad para quien toma las decisiones dentro de las organizaciones de salud.

In recent years, budget impact analysis have become morecommon among pharmaco-economic evaluations, this typeof analysis is complementary to the more traditional healthtechnology assessments like cost effectiveness analysisand cost utility analysis, and have an important role toplay when making decisions regarding the incorporationof a new drug (or technology) to the therapeutic formularyof a health organization. Several factors not usedin standard cost effectiveness analysis are needed whenperforming a budget impact analysis, including the sizeof the whole population able to be treated with the newdrug and the penetration rates of the new technology inthe target population. In this paper, a basic prototype of abudget impact model is presented, and the relevance forthe decision makers of the data obtained by the budgetimpact models is discussed.

Resultados de la integración de las distintas subespecialidades en un centro mamario. Experiencia inicial del Centro Mamario del Hospital Universitario Austral / Multidisciplinary approach in a breast center. Initial experience in the Hospital Universitario Austral

Luego del desarrollo de los centros o unidades de mama a nivel mundial, en octubre de 2006 el Hospital Universitario Austral crea el Centro Mamario. El objetivo de este trabajo es comunicar los resultados que se obtuvieron en los primeros 5 años de trabajo multidisciplinario integrado. Se evaluaron en forma retrospectiva los cinco primeros años de funcionamiento del Centro Mamario del HUA. Para analizar el funcionamiento y resultados de los distintos procesos diagnósticos y terapéuticos se tuvieron como referencia los indicadores de calidad propuestos por EUSOMA, pudiendo cumplirlos en casi todos los ítems analizados, excepto en lo referente a la información pronóstica y de predicción completa (83,1% y 81,4%, para un mínimo del 95,0%) y en la indicación de radioterapia posmastectomía(79,4% para un mínimo de 90,0%). Como conclusión, nuestros resultados iniciales comprueban que la coordinación e integración de los distintos servicios involucrados en forma de unidad o centro mamario, permitió la optimización de la calidad de atención de las pacientes con cáncer de mama.

Resultados de la integración de las distintas subespecialidades en un centro mamario. Experiencia inicial del Centro Mamario del Hospital Universitario Austral / Multidisciplinary approach in a breast center. Initial experience in the Hospital Universitario Austral

Luego del desarrollo de los centros o unidades de mama a nivel mundial, en octubre de 2006 el Hospital Universitario Austral crea el Centro Mamario. El objetivo de este trabajo es comunicar los resultados que se obtuvieron en los primeros 5 años de trabajo multidisciplinario integrado. Se evaluaron en forma retrospectiva los cinco primeros años de funcionamiento del Centro Mamario del HUA. Para analizar el funcionamiento y resultados de los distintos procesos diagnósticos y terapéuticos se tuvieron como referencia los indicadores de calidad propuestos por EUSOMA, pudiendo cumplirlos en casi todos los ítems analizados, excepto en lo referente a la información pronóstica y de predicción completa (83,1% y 81,4%, para un mínimo del 95,0%) y en la indicación de radioterapia posmastectomía(79,4% para un mínimo de 90,0%). Como conclusión, nuestros resultados iniciales comprueban que la coordinación e integración de los distintos servicios involucrados en forma de unidad o centro mamario, permitió la optimización de la calidad de atención de las pacientes con cáncer de mama.(AU)

Leucemia mieloide crónica: mecanismos genéticos de resistencia al mesilato de Imatinib (STI571) / Chronic myeloid leukemia genetic mechanisms of Imatinib resistance

La resistencia al tratamiento con Imatinib resulta de mecanismos dependientes del BCR/ABL tales como la sobreexpresión y la adquisición de mutaciones de punto en sitios críticos del dominio kinasa de ABL o de diferentes mecanismos independientes, como la evolución clonal. El propósito de este estudio fue identificar las mutaciones del dominio kinasa del gen ABL y la amplificación del reordenamiento genómico BCR/ABL en pacientes con LMC con falta o pérdida de respuesta hematológica y/o citogenética al tratamiento con Imatinib. Se incluyeron 71 pacientes, de los cuales 56 fueron evaluables. En trece pacientes (24 por ciento) se identificó algún mecanismo de resistencia: 10 (18 por ciento) presentaron mutaciones de punto en el dominio kinasa, 3 (5 por ciento) duplicación del cromosoma Ph' y sólo 1 (1 por ciento) mostró amplificación del BCR/ABL. La mutación T315I se observó en 1 caso. La mediana de edad fue significativamente menor [39 años (20-53)] en los pacientes en los que se encontraron mutaciones que en los casos sin ellas [51 años (24-75)] p=0.047. Se detectaron mutaciones en 1 de 29 (3 por ciento) pacientes en fase crónica, 8 de 20 (40 por ciento) pacientes en fase acelerada y en 1 de 8 (12 por ciento) pacientes en crisis blástica (p=0.001). La mediana de aparición de las mismas fue de 45 meses desde el diagnóstico de LMC (12-158) y 28.5 meses (1-56) desde el inicio de la terapia con Imatinib (p=0.591 y p=0.762 respectivamente). Las mutaciones en la región p-loop fueron las más frecuentes. El análisis univariado demostró que edad y fase de la enfermedad se asociaron significativamente con presencia de mutaciones. Las mutaciones en el dominio kinasa se reconocen como el principal mecanismo de resistencia al tratamiento con Imatinib y su detección puede determinar un cambio en la estrategia terapéutica.

Cellular and humoral immune response to N-Glycolyl-GM3 elicited by prolonged immunotherapy with an anti-idiotypic vaccine in high-risk and metastatic breast cancer patients.

In this study, the immunogenicity and toxicity profile of 1E10, an anti-idiotypic vaccine mimicking the N-glycolyl-GM3 ganglioside, was investigated with an extended vaccination protocol. The year-long vaccination scheme consisted of 6 biweekly intradermal injections (induction phase), followed by 10 monthly boosters (maintenance). Nineteen patients with high-risk (stage III) or metastatic breast cancer were vaccinated with different dose levels of 1E10 (0.5, 1, and 2 mg). The humoral and cellular responses to 1E10 and the targeted ganglioside were assessed at baseline and throughout the treatment. Local skin reactions represented the most common adverse event (National Cancer Institute Toxicity Criteria (NCIC) grades I and II), followed by mild flu-like symptoms lasting for 1 to 2 days. Two patients were removed from the study because of vaccine-related hypersensitivity reactions. A third patient was removed from the study after a transient loss of consciousness with uncertain relation to the vaccine. All patients showed a strong antibody response to the targeted ganglioside. In addition, ganglioside-specific T-cell responses were recorded in 5 of 13 evaluable patients. Vaccination with 1E10 was immunogenic and relatively well tolerated. Because similar results were observed with the 3 tested dose levels, the 0.5-mg dose level was selected for future trials.

Active specific immunotherapy of melanoma with a GM3 ganglioside-based vaccine: a report on safety and immunogenicity.

A novel cancer vaccine was obtained by combining GM3 ganglioside with Neisseria meningitidis outer membrane protein complex to obtain very-small-size proteoliposomes (GM3/VSSP). The authors report the results of a phase 1 study of intramuscular administration of GM3/VSSP/Montanide ISA 51 to patients with metastatic melanoma. Twenty-six patients were included in three dose-level cohorts of 120, 240, and 360 mug. The first five doses (induction phase) were given at 2-week intervals, and the remaining four doses were given monthly. Patients were evaluated for dose-related toxicities and antitumor effects. In addition, serum and peripheral blood mononuclear cells were obtained at baseline and throughout treatment to evaluate humoral and cellular immune responses. One episode of severe hypotension and fever was observed in a patient included at the highest dose level. Other toxicities consisted of local reactions at the site of injection and mild fever and chills. Five doses of GM3/VSSP induced an anti-GM3 IgM response in 44% of patients. Serum reactivity was also observed against melanoma cell lines and tumor biopsies. GM3/VSSP was shown to induce very strong in vitro IFNgamma secretion in all evaluated melanoma patients. Furthermore, in one patient IFNgamma secretion was shown to be GM3-specific. A 62% reduction of a mediastinal mass was documented in one patient (partial response), while a second patient benefited from initial disease stabilization followed by tumor reduction in nonmeasurable soft tissue lesions accompanied by vitiligo.

Cancer vaccines: a critical review on clinical impact.

Developing cancer vaccines to treat solid tumors is not an easy task. As solid tumors develop, the immune system places cancer cells under selective pressure; it detects those that are more 'antigenically different', selecting those cells that are not recognized by the immune system and are therefore resistant to immune surveillance. Resistant cells survive, and in turn their clones will spread to distant sites. This phenomenon, called 'immune editing', is not novel, but is quite similar in principle to the selective pressure induced by chemotherapy and hormone therapy, and is molecularly based on the clonal heterogeneity and molecular instability present in most solid tumors. This explains, at least in part, why many cancer vaccines work in animal models but not in a clinical setting. The aim of this article is to review the most commonly used cancer vaccine strategies and to evaluate the evidence supporting their efficacy. This is not as easy at it may sound, as each research group involved in cancer vaccine development uses different technologies, targets different antigens, combines different carriers and adjuvants to obtain an immune response, and immunizes patients with different administration schedules. The final picture is somewhat confusing, and comparison of different vaccine strategies is almost impossible. Most of the vaccines are still experimental, far from being approved by regulatory authorities, and their clinical utility is almost negligible.

An anti-idiotype vaccine elicits a specific response to N-glycolyl sialic acid residues of glycoconjugates in melanoma patients.

We generated the 1E10 gamma-type anti-idiotype mAb (Ab2) specific to an Ab1 mAb able to react specifically with N-glycolyl-containing gangliosides and with Ags expressed on human melanoma and breast carcinoma cells. This Ab2 mAb induced an Ab response in animal models sharing immunochemically defined idiotopes with the Ab1. The treatment of tumor-bearing mice with 1E10 mAb induced a strong antitumor activity. A clinical trial was conducted in 20 patients with advanced malignant melanoma. Patients were treated with six intradermal injections of aluminum hydroxide-precipitated 1E10 anti-Id mAb given at 2-wk intervals. Sixteen of the 17 patients who received at least four doses of the anti-Id vaccine develop Ab3 Abs capable of inhibiting Ab2 binding to Ab1 (Ab3Id+). In contrast to the incapacity of 1E10 mAb to generate Ab3 Abs with the same antigenic specificity as the Ab1 mAb in mice, a very specific and strong Ab3 response against N-glycolyl-containing gangliosides was induced in 16 patients (Ab3Ag+). No evidence of serious or unexpected adverse effects has been observed in this clinical trial. 1E10 anti-Id vaccine was safe, well tolerated, and immunologically effective, with most patients being able to generate a specific immune response against 1E10 and Neu-glycolyl-GM(3) ganglioside.

Cancer vaccines: an update with special focus on ganglioside antigens.

Vaccine development is one of the most promising and exciting fields in cancer research; numerous approaches are being studied to developed effective cancer vaccines. The aim of this form of therapy is to teach the patient's immune system to recognize the antigens expressed in tumor cells, but not in normal tissue, to be able to destroy these abnormal cells leaving the normal cells intact. In other words, is an attempt to teach the immune system to recognize antigens that escaped the immunologic surveillance and are by it, therefore able to survive and, in time, disseminate. However each research group developing a cancer vaccine, uses a different technology, targeting different antigens, combining different carriers and adjuvants, and using different immunization schedules. Most of the vaccines are still experimental and not approved by the US or European Regulatory Agencies. In this work, we will offer an update in the knowledge in cancer immunology and all the anticancer vaccine approaches, with special emphasis in ganglioside based vaccines. It has been demonstrated that quantitative and qualitative changes occur in ganglioside expression during the oncogenic transformation. Malignant transformation appears to activate enzymes associated with ganglioside glycosylation, resulting in altered patterns of ganglioside expression in tumors. Direct evidence of the importance of gangliosides as potential targets for active immunotherapy has been suggested by the observation that human monoclonal antibodies against these glycolipids induce shrinkage of human cutaneous melanoma metastasis. Thus, the cellular over-expression and shedding of gangliosides into the interstitial space may play a central role in cell growth regulation, immune tolerance and tumor-angiogenesis, therefore representing a new target for anticancer therapy. Since 1993 researchers at the University of Buenos Aires and the University of Quilmes (Argentina), have taken part in a project carried out by the (CIM) from La Havana, Cuba, to developed new strategies for specific active immunotherapy. The project included two ganglioside based vaccines and one anti-idiotypic vaccine. We focused on two antigens: first GM3, an ubiquitous antigen which is over-expressed in several epithelial tumor types; and a second one, N-Glycolyl-GM3 a more molecule, not being expressed in normal tissues and recently found in several neoplastic cells, in particular breast, melanoma and neuroectodermal cancer cells. We developed two vaccines, one with each antigen, both using proteins derived from the outer membrane proteins (OMP) of Neisseria Meningitidis B, as carriers. We developed also the 1E10 vaccine; an anti-idiotype vaccine designed to mimic the N-Glycolyl-GM3 gangliosides. This monoclonal antibody is an Ab2-type-antibody which recognizes the Ab1 antibody called P3, the latter is a monoclonal antibody that specifically recognizes gangliosides as antigens. Since 1998 we initiated a clinical development program for these three compounds. Results of the phase I clinical trials proved that the three vaccines were safe and able to elicit specific antibody responses. In addition we were able to demonstrate the activation of the cellular arm of the immune response in patients treated with the GM3 vaccine. Although phase I trials are not designed to evaluate antitumor efficacy, it was encouraging to observe tumor shrinkage in some patients treated both with the GM3 and N-Glycolyl-GM3 vaccines. We have already begun a phase II program in several neoplastic diseases, with all three vaccines.