Use of bevacizumab as a first-line treatment for metastatic breast cancer.

OBJECTIVE: During clinical practice, it can be challenging, given the lack of response biomarkers, to identify the patients with metastatic breast cancer (mbca) who would benefit most from the addition of bevacizumab to first-line standard chemotherapy. The aim of the present review was to summarize the relevant scientific evidence and to discuss the experience of a group of experts in using bevacizumab to treat mbca. METHODS: A panel of 17 Spanish oncology experts met to discuss the literature and their experience in the use of bevacizumab as first-line treatment for mbca. During the meeting, discussions focused on three main issues: the profile of the patients who could benefit most from bevacizumab, the optimal bevacizumab treatment duration, and the safety profile of bevacizumab. RESULTS: The subset of mbca patients who would benefit the most from the addition of bevacizumab to first-line standard chemotherapy are those with clinically defined aggressive disease. Treatment with bevacizumab should be maintained until disease progression or the appearance of unacceptable toxicity. In the mbca setting, the toxicity profile of bevacizumab is well known and can be managed in clinical practice after adequate training. CONCLUSIONS: This expert group recommends administering bevacizumab as first-line treatment in patients with clinically aggressive disease.

Evaluation of the antitumor activity of interleukin-12 in an experimental murine model of colorectal cancer induced by 1,2 dimethyl-hydrazine (DMH).

OBJECTIVE: Interleukin 12 (IL-12) is a cytokine that may enhance the proliferation and cytotoxic activity of T lymphocytes and natural killer (NK) cells. A relationship between extensive intratumoral infiltration of NK cells and longer survival rates in colorectal cancer (CRC) patients was previously noted. Preliminary evidence suggests that the combined administration of IL-12 and IL-2 may produce additive immunomodulatory activity. The purpose of this study was to determine whether the systemic administration of IL-12 (+/- IL-2) may induce an immune response against CRC as induced by 1,2-dimethylhydrazine (DMH). METHODS: Sixty-five 6-week-old Wistar rats were treated with weekly subcutaneous injections of DMH for 26 weeks at a dose of 20 mg/kg of body weight. Once tumoral induction was over, the animals were randomly allocated to one of three groups: I, control; II, intraperitoneal injections of IL-12; III, intraperitoneal injections of IL-12 combined with IL-2. At 30 weeks, all surviving animals were sacrificed. We studied the following parameters in each rat--number of tumors, size of tumors, and total tumoral volume. Tumor samples were studied using the monoclonal antibody CD 57 for the detection of NK cells. The extent of NK infiltration was classified as small, less than 50 NK cells/50 high-power field (HPF); moderate, 50 to 150 NK cells/50 HPF, and extensive, more than 150 NK cells/50 HPF. RESULTS: Thirty-five rats died before completion of the carcinogen exposure, and 30 rats were randomized (10 each group). In group II, 2 animals died during treatment. All rats in groups I and III developed tumors, while in group II two rats (25%) were tumor-free. Moreover, only one rat in group II developed multiple neoplasms, in contrast with group I and group III, where six rats (60%) and seven rats (70%), respectively, had more than one tumor. We found statistically significant differences in the mean number of tumors found in group II when compared to group I (p = 0.028) and group III (p = 0.019). Other parameters measured, such as biggest tumor size and total tumoral volume were found to be lower in group II, although no statistical differences were found between groups. Only 10% of rats in group I showed moderated/extensive NK cell infiltration, vs. 60% of rats in group II (p = 0.077) and 70% in group III (p = 0.02). CONCLUSION: The administration of DMH to rodents provides a reliable and consistent means of inducing CRC that may be suitable for the evaluation of anti-cancer therapies. Our findings suggest that IL-12 is effective against the development of experimental CRC. Its antineoplastic effect could be attributed to the stimulus of this cytokine on the intratumoral infiltration of NK cells.

Estudio de la respuesta antitumoral de la interleucina- 12 en cáncer de colon inducido mediante 1, 2-dimetilhidracina (DMH) / Evaluation of the antitumor activity of interleukin-12 in an experimental murine model of colorectal cancer induced by 1, 2 dimethyl-hydrazine (DMH)

Objetivo: la interleucina (IL-12) es una citocina que estimulala proliferación y la actividad citotóxica de los linfocito T y las célulasnatural killer (NK). En trabajos previos se ha observado unarelación entre la infiltración intratumoral de células NK y una mayorsupervivencia en carcinomas colorrectales (CCR). Existen evidenciasde un efecto aditivo en la actividad inmunomoduladora dela asociación de IL-12 con IL-2. Así, nos hemos propuesto el estudiode la capacidad de respuesta inmune antitumoral, tras la administraciónsistémica de IL-12 sola o combinada con IL-2, en unmodelo experimental de CCR inducidos mediante la administraciónde 1,2-dimetilhidracina (DMH).Método: sesenta y cinco ratas Wistar de 6 semanas a las quese administró en inyección subcutánea una dosis semanal deDMH a razón de 20 mg/kg de peso durante 26 semanas. Finalizadoel periodo de inducción, los animales se distribuyeron aleatoriamenteen tres grupos. I: grupo control. Grupo II, se administróIL-12 recombinante murina. Grupo III: se administró IL-12, combinadacon IL-2. Las ratas se sacrificaron en la semana 30, estudiándoselos siguientes parámetros: número y localización de tumores,tamaño y carga tumoral. Se realizó inmunotinción paracélulas NK con anticuerpo monoclonal CD 57. Se establecierontres grupos según la cuantía del infiltrado: leve, menos 50 células/50 campos de gran aumento (CGA), moderado, entre 50 y150/células/50 CGA y elevado, más de 150 células/50 CGA.Resultados: durante la inducción tumoral fallecieron 35 ratas.Las 30 restantes fueron distribuidas aleatoriamente en 3 gruposde 10. Durante las 2 semanas de tratamiento fallecieron 2 ratas,del grupo II. Todas las ratas de los grupos I y III desarrollaronCCR. En el grupo II, dos animales (25%) no desarrollaron tumor.Sólo una rata del grupo II desarrolló neoplasias múltiples en contrastecon el grupo I en el que esto ocurrió en 6 ratas (60%) y siete(70%) en el grupo III. Se hallaron diferencias estadísticamentesignificativas en el número de tumores desarrollados entre el grupoII respecto al I (p = 0,028) y al grupo III (p = 0,019). El mayortamaño tumoral o el volumen tumoral total fueron menores en elgrupo II pero no se obtuvieron diferencias estadísticamente significativascon los restantes grupos. Un 10% de las ratas del grupo Ipresentó moderada o extensa infiltración, frente al 60% del grupoII (p = 0,077) y al 70% del grupo III (p = 0,02). Entre los grupos IIy III no se encontró ninguna diferencia estadística (p = 1).Conclusión: El modelo usado de inducción tumoral es un modeloútil para el estudio de la eficacia de distintos tratamientos antitumorales.Pensamos que la IL-12 tiene un efecto antineoplásicofrente al desarrollo de tumores experimentales, lo que puede seratribuido, al menos en parte, al estímulo ejercido por esta citocinasobre los infiltrados intratumorales de células NK

Objective: interlukin 12 (IL-12) is a cytokine that may enhancethe proliferation and cytotoxic activity of T lymphocytesand natural killer (NK) cells. A relationship between extensive intratumoralinfiltration of NK cells and longer survival rates in colorectalcancer (CRC) patients was previously noted. Preliminaryevidence suggests that the combined administration of IL-12 andIL-2 may produce additive immunomodulatory activity. The purposeof this study was to determine whether the systemic administrationof IL-12 (+/- IL-2) may induce an immune responseagainst CRC as induced by 1,2-dimethylhydrazine (DMH).Methods: sixty-five 6-week-old Wistar rats were treated withweekly subcutaneous injections of DMH for 26 weeks at a dose of20 mg/kg of body weight. Once tumoral induction was over, theanimals were randomly allocated to one of three groups: I, control;II, intraperitoneal injections of IL-12; III, intraperitoneal injectionsof IL-12 combined with IL-2. At 30 weeks, all surviving animalswere sacrificed. We studied the following parameters in eachrat – number of tumors, size of tumors, and total tumoral volume.Tumor samples were studied using the monoclonal antibodyCD 57 for the detection of NK cells. The extent of NK infiltrationwas classified as small, less than 50 NK cells/50 high-power field(HPF); moderate, 50 to 150 NK cells/50 HPF, and extensive,more than 150 NK cells/50 HPF.Results: thirty-five rats died before completion of the carcinogenexposure, and 30 rats were randomized (10 each group). Ingroup II, 2 animals died during treatment. All rats in groups I andIII developed tumors, while in group II two rats (25%) were tumorfree.Moreover, only one rat in group II developed multiple neoplasms,in contrast with group I and group III, where six rats(60%) and seven rats (70%), respectively, had more than one tumor.We found statistically significant differences in the meannumber of tumors found in group II when compared to group I(p=0.028) and group III (p = 0.019). Other parameters measured,such as biggest tumor size and total tumoral volume were found tobe lower in group II, although no statistical differences were foundbetween groups. Only 10% of rats in group I showed moderated/extensive NK cell infiltration, vs. 60% of rats in group II (p =0.077) and 70% in group III (p = 0.02).Conclusion: The administration of DMH to rodents provides areliable and consistent means of inducing CRC that may be suitablefor the evaluation of anti-cancer therapies. Our findings suggest thatIL-12 is effective against the development of experimental CRC. Itsantineoplastic effect could be attributed to the stimulus of this cytokineon the intratumoral infiltration of NK cells