Efficacy and safety of radiosurgery in acromegaly.

Stereotactic radiosurgery (SRS) more and more frequently plays a crucial role in the treatment of acromegaly. We provide a systematic review of the literature and meta-analysis, according to PRISMA, on SRS for the management of growth hormone (GH)-secreting pituitary adenomas, including several radiosurgical techniques, with the aim of describing efficacy and safety of this treatment. A weighted random effects model was used to calculate pooled outcome estimates. From 346 abstract reviews, 27 retrospective studies were included. Despite the variability in hormonal remission criteria and the heterogeneity between treatment guidelines among included studies, most of them reported an endocrine remission rate between 40% and 60%. Random effects meta-analysis for overall endocrine remission and 5-year probability of remission estimate after SRS were 46% (95% CI: 39-53%) and of 48% (95% CI: 38-57%), respectively. Random effects meta-analysis for new hypopituitarism estimate after SRS was 23% (95% CI: 17-29%). Furthermore, incidence of radiation induced optic neuropathy after SRS ranged between 0% and 6% This meta-analysis confirms and quantifies safety and effectiveness of SRS to achieve endocrine remission after surgical management in acromegaly.

Single Versus Fractionated Gamma Knife Radiosurgery for Nonfunctioning Pituitary Adenomas Close to the Optic Pathway: A Multicenter Propensity Score Matched Study.

BACKGROUND AND OBJECTIVES: Gamma Knife radiosurgery (GKRS), typically administered in a single session (S-GKRS), is an effective treatment for nonfunctioning pituitary adenoma (NFPA). For lesions close to the optic pathway, the use of hypofractionated radiosurgery is growing. This study seeks to compare the results of S-GKRS vs fractionated-GKRS (F-GKRS) for NFPAs adjacent to the optic pathway. METHODS: Two cohorts of patients with residual or recurrent NFPAs in contact to the optic pathway were retrospectively included in this study: (1) a group of patients who underwent a 3-day course of F-GKRS in Europe and (2) a group of patients treated with S-GKRS in the United States. A propensity score matching (ratio 1:1) was carried out to obtain and compare 2 homogeneous groups of patients with NFPA. RESULTS: A total of 84 patients were included for analysis (42 in the S-GKRS cohort and 42 in the F-GKRS group). The 2 cohorts did not differ for age, sex, number of previous surgical procedure, tumor volume, and follow-up. The mean follow-up was 60.2 ± 37.0 months and 62.4 ± 37.4 months for F-GKRS and S-GKRS cohort, respectively ( P = .38). The overall tumor control at last follow-up was achieved in 95.2% and 92.9% of patients in F-GKRS and S-GKRS, respectively ( P = .64). The 1-year, 3-year, 5-year, and 7-year progression-free survival rate after F-GKRS was 100%, 97.1%, 97.1%, and 91%, respectively. In the S-GKRS sample, progression-free survival rates were 100%, 100%, 92.5%, and 92.5% at 1, 3, 5, and 7 years after treatment, respectively. Two patients (4.7%) from the F-GKRS cohort and 2 (4.7%) from the S-GKRS cohort sustained visual worsening after radiosurgery ( P = 1.0). CONCLUSION: In the management of NFPAs adjacent to the optic pathway both F-GKRS and S-GKRS had comparable outcomes and risks at 7 years. Future prospective studies including larger cohorts with longer follow-up are needed to confirm our results.

Adenomas no funcionantes: análisis retrospectivo de 202 pacientes / Non-functional adenomas: retrospective analysis of 202 patients

RESUMEN Los pacientes con adenomas hipofisarios constituyen una población heterogénea y requieren un enfoque individualizado. El objetivo de nuestro trabajo fue analizar nuestra población con adenomas hipofisarios no funcionantes (ACNF) y evaluar factores pronóstico de crecimiento (como el Ki-67) que ayuden en la toma de decisiones. Se realizó un análisis retrospectivo de 202 pacientes, incluyendo evaluación basal, enfoque terapéutico y evolución tumoral en 2 grupos: pacientes con conducta expectante (n = 69) y pacientes con cirugía (n = 133). La serie tuvo 55% de pacientes mujeres y la edad media al diagnóstico fue de 49 años. Los motivos de consulta más frecuentes fueron incidentaloma hipofisario y alteraciones visuales. Radiológicamente, 83% fueron macroadenomas, 77% invasivos y 55% mostraron compromiso visual. Entre los adenomas invasores, el 53% tenían disfunción hipofisaria, siendo el hipogonadismo el hallazgo más frecuente. El tratamiento inicial fue la cirugía en el 65,8% realizándose por vía transnasal en el 79% de los casos. Las complicaciones más frecuentes fueron diabetes insípida transitoria e hiponatremia, con mayor incidencia de diabetes insípida permanente en la cirugía transcraneal. La inmunohistoquímica mostró gonatropinomas en el 43,4% de los casos y fue negativa en el 37,7%. Doce adenomas tuvieron índice de proliferación Ki-67 ≥3%. Luego de la cirugía 56,8% de los pacientes mejoraron el campo visual, 22,6% recuperó alguna función endocrina y 18,8% agregó un nuevo déficit. En pacientes no operados, se observó crecimiento tumoral en 5,6% de los adenomas Hardy 1-2 y en el 21% de los Hardy 3-4. Entre los adenomas operados, aquellos sin resto tumoral postoperatorio no presentaron recurrencia. De los tumores con remanente postoperatorio (78,6%) no irradiados, el 41,5% mostró recrecimiento lesional al seguimiento. Este porcentaje se eleva a 66,6% en aquellos con Ki-67 ≥3% y disminuye a 12% en los que recibieron radioterapia.

ABSTRACT Patients with pituitary adenomas are a heterogeneous population and require an individualized approach. The aim of our study was to analyze our population of patients with nonfunctioning pituitary adenomas (NFA) and to evaluate prognostic growth factors (such as Ki-67) that help in decision making. A retrospective analysis of 202 patients, including baseline assessment, therapeutic approach and tumor evolution was performed in 2 groups: expectant management (n = 69) and surgery (n = 133). The mean age at diagnosis was 49 years, 55% women. The most frequent reasons for consultation were pituitary incidentaloma and visual impairment. Eighty three percent were macroadenomas, 77% invasive, and 55% with visual impairment. Among the invasive adenomas, 53% had pituitary dysfunction, with hypogonadism being the most frequent finding. The initial treatment was surgery in 65.8%, 79% of them through transnasal approach. The most frequent complications were transient diabetes insipidus and hyponatremia, with a higher incidence of permanent diabetes insipidus in transcranial surgery. The immunohistochemistry showed: 43.4% gonadotropinomas, 37.7% negative. Twelve adenomas had proliferation index Ki-67 ≥3%. After surgery, 56.8% improved the visual fields, 22.6% recovered some endocrine function and 18.8% added a new deficit. In non-operated patients, tumor growth was observed in 5.6% of the Hardy 1-2 adenomas and 21% of the Hardy 3-4 adenomas. Among the operated adenomas, those without postoperative tumor residue did not present recurrence. In tumors with non-irradiated postoperative remnant (78.6%), 41.5% increased. This percentage rises to 66.6% in those with Ki-67 ≥3%, and decreases to 12% in those who received radiotherapy.

Radioterapia como indicación post operatoria en macroadenomas hipofisiarios no funcionantes: a propósito de un caso / Surgical treatment of a non functioning pituitary macroadenoma without postoperative radiotherapy: report of one case

We report a 45 years old female that consulted for amenorrhea and galactorrhea after discontinuing oral contraceptives, that she used for several years. The patient had hyperprolactinemia, a hypogonadotrophic hypogonadism and a primary hypothyroidism. Sella turcica magnetic resonance showed a pituitary macroadenoma with a diameter of 23 mm and supraselar extension. The patient was subjected to a transsphenoidal excision of the tumor with good clinical and surgical results. Therefore radiotherapy was not used for the treatment of the tumor.

Avaliação do perfil e resposta ao tratamento de pacientes portadores de adenoma hipofisário submetidos a radioterapia / Clinical profile and response to treatment of patients with pituitary

OBJETIVO: Avaliar o perfil de pacientes portadores de adenoma hipofisário e a resposta à radioterapia externa. MATERIAL E MÉTODO: Foi realizado estudo retrospectivo com 22 pacientes portadores de adenoma hipofisário, os quais foram submetidos à radioterapia entre março de 2004 e dezembrode 2008. Foram analisadas características dos pacientes, como sexo, idade e quadro clínico, tipo de cirurgia, perfil imuno-histoquímico, dose de radioterapia, resposta à terapia com dosagens hormonais e exames de imagem. RESULTADOS: Observou-se idade mediana de 51 anos, com distribuição semelhante em ambos os sexos. De acordo com a classificação de Hardy para tumores hipofisários, 27,5% apresentavam grau II, 27,5% eram grau III e 45%, grau IV. O principal sintoma apresentado pelos pacientes na ocasião do diagnóstico foi deficiência visual em 77% dos casos, seguido de cefaleia em 68%, acromegalia em 27%, amenorreia em 18% e galactorreia em 4,5%. A abordagem cirúrgica por via transesfenoidal ocorreu em 21 pacientes e em somente um por viatranscraniana, sendo realizadas ressecções parciais em 91% dos casos. Quanto à imuno-histoquímica, a expressão de ACTH foi a mais frequente, estando presente em 41% dos casos. Os pacientes foram tratados em aparelhos de megavoltagem, em sua grande maioria com acelerador linear de 6 MV, com dose total de 45 Gy em 68% e dose de 50,4 Gy em 13% dos casos. O planejamento tridimensional foi utilizado em 20 pacientes. O seguimento mediano foi de 41 meses, sendo observado, no seguimento laboratorial e de imagem, melhora em 73% dos pacientes, estabilidade do quadro em 22,5% e piora em 4,5%. CONCLUSÃO: Os resultados encontrados mostram bons índices de resposta e controle dos tumores de hipófise após radioterapia adjuvante à cirurgia, e por ser uma doença de resposta lenta ao tratamento é grande a probabilidade de melhora ainda maior dos resultados a médio prazo.

OBJECTIVE: To evaluate the clinical profile of patients with pituitaryadenoma and their response to radiotherapy. MATERIAL AND METHOD: Retrospective study with 22 patients with diagnosis of pituitary adenoma which were submitted to radiotherapy between March 2004 and December 2008. Patients' characteristics such as gender, age, clinical presentation, surgical approach, immunohistochemistry profile, dose of radiation and the response to therapy were analyzed using hormonal dosages and imaging exams. RESULTS: The median age was 51 years and equally distributed in both genders. The tumors were divided according to the Hardy's classification: 27.5% had grade II, 27.5% had grade III and 45% had grade IV. The main symptoms presented by patients at diagnosis were visual impairment in 77% of cases, headache in68%, amenorrhea and acromegaly in 27% and galactorrhea in 4.5%. Transphenoidal surgery was performed in 21 patients and only 1 patient was submitted to transcranial approach; 91% of cases had partial resection. Concerning to immunohistochemistry, the expression of ACTH was the most frequent, being present in 41% of cases.The patients were treated in megavoltage equipment mostly with6 MV linear accelerator. The total radiation dose was 45 Gy in 68%of patients and a dose of 50.4 Gy in 13% of cases. Three-dimensionalplanning was used in 20 patients. The median follow-up was 41 months. Laboratory and imaging improvement were observed in 73% of patients, stability in 22.5%, and worsening in 4.5%. CONCLUSION: The results show good rates of response and control of pituitary adenomas by radiation in the first four years after treatment. Considering it has a slow response to treatment, there is a high chance of improvement in results later during the follow-up. Keywords: Radiotherapy; Pituitary; Adenoma.

Radiotherapy and radiosurgery for Cushing's disease

Patients with residual or recurrent Cushing's disease receive external beam radiotherapy (RT) with the aim of achieving long-term tumour control and normalization of elevated hormone levels. Treatment is given either as conventional radiotherapy using conformal techniques or as stereotactic radiotherapy, which is either used as fractionated treatment (SCRT) or as single fraction radiosurgery (SRS). We describe the technical aspects of treatment and report a systematic review of the published literature on the efficacy and toxicity of conventional RT, SCRT and SRS. There are no studies directly comparing the different radiation techniques and the reported results are inevitably of selected patients by investigators with interest in the treatment tested. Nevertheless the review of the published literature suggests better hormone and tumour control rates after fractionated irradiation compared to single fraction radiosurgery. Hypopituitarism represents the most commonly reported late complication of radiotherapy seen after all treatments. Although the incidence of other late effects is low, the risk of radiation injury to normal neural structures is higher with single fraction compared to fractionated treatment. Stereotactic techniques offer more localized irradiation compared with conventional radiotherapy, however longer follow-up is necessary to confirm the potential reduction of long-term radiation toxicity of fractionated SCRT compared to conventional RT. On the basis of the available literature, fractionated conventional and stereotactic radiotherapy offer effective treatment for Cushing's disease not controlled with surgery alone. The lower efficacy and higher toxicity of single fraction treatment suggest that SRS is not the appropriate therapy for the majority of patients with Cushing's disease.

Pacientes com doença de Cushing residual ou recorrente recebem radioterapia externa em feixe (RT) com o objetivo de alcançar um controle tumoral prolongado e a normalização dos níveis hormonais elevados. O tratamento é realizado tanto com RT convencional, usando técnicas conformacionais, ou com RT estereotáxica, que é usada tanto como tratamento fracionado (RTF) ou como radiocirurgia em procedimento único (RCU). Descreveremos os aspectos técnicos do tratamento e mostraremos uma revisão sistemática da literatura sobre a eficácia e toxicidade da RT convencional, da RTF e da RCU. Não existem estudos comparando diretamente as diferentes técnicas de radiação, e os resultados reportados são inevitavelmente os de pacientes selecionados pelos investigadores com interesse no tratamento testado. De qualquer maneira, a revisão dos dados publicados sugere que há melhores taxas de controle hormonal e tumoral após RTF em comparação com RCU. O hipopituitarismo representa a complicação tardia mais comumente relatada da RT, vista após todos os tipos de tratamento. Embora a incidência de outros efeitos tardios seja baixa, o risco de a radiação comprometer estruturas neurais normais é mais elevado com RCU do que com RTF. Técnicas estereotáxicas oferecem irradiação mais localizada se comparadas com a RT convencional, embora um acompanhamento prolongado seja necessário para confirmar a possível redução da toxicidade continuada da radiação na RTF em comparação com a RT convencional. Com base na literatura disponível, a RT fracionada convencional e a estereotáxica oferecem tratamento efetivo para a doença de Cushing não controlada isoladamente pela cirurgia. A baixa eficácia e alta toxicidade do tratamento em dose única sugere que a RCU não seja a terapia mais apropriada para a maioria dos pacientes com doença de Cushing.

Radioterapia estereotáxica fraccionada en adenomas de hipófisis: resultados y factores pronósticos / Fractionated stereotactic-guided radiotherapy in the treatment of pituitary adenomas

Introducción. Se analizan retrospectivamente la supervivencia global (SG), control local, factores pronóstico y toxicidad, de pacientes con adenoma de hipófisis tratados con radioterapia estereotáxica fraccionada (REF). Material y métodos. Entre mayo de 1994 y junio de 2001 se trataron 56 pacientes con adenomas de hipófisis, 23 (41,1%) primarios y 33 recidivas. Veinticuatro (42,9%) casos fueron adenomas no funcionantes, y 32 (57,1%) funcionantes. La mediana de dosis administrada fue 54 Gy (rango 24-56 Gy), 2 Gy/día, 5 días/semana. Resultados. Con un seguimiento de 51 meses (9-102 meses), al cierre del estudio, 49 pacientes están vivos sin evidencia de enfermedad, una paciente viva, con pérdida de visión y progresión hormonal, 2 pacientes han fallecido con progresión y uno falleció por otra causa. La supervivencia global fue de 94% (50/53), con una supervivencia libre de fallo del 92% (49/53). En análisis univariado sólo el tipo de hormona secretada (ACTH) y la irradiación previa resultaron de mal pronóstico. Catorce pacientes (25%) presentaron síntomas leves de toxicidad aguda durante la radioterapia estereotáxica fraccionada y 3 (5,4%) desarrollaron toxicidad tardía, neuropatía óptica (2 pacientes, multipatología asociada) y radionecrosis (1 paciente, reirradiación). Conclusiones. La radioterapia estereotáxica fraccionada es eficaz para adenomas de hipófisis, aunque es preciso valorar individualmente a aquellos pacientes con patologías concomitantes, o con tratamientos de radioterapia previa, con objeto de minimizar la aparición de efectos adversos a largo plazo

Aims. To evaluate the survival rates, prognostic factors and adverse events in patients with pituitary adenomas following fractionated stereotactic-guided radiotherapy (FSRT). Material and methods. Fifty-six patients with pituitary adenomas were treated with FSRT; 23 patients (41.1%) had primary adenomas, 33 had recurrent disease; 24 (42.9%) with non-functional and 32 (57.1%) with functional adenomas. Using conventional fractionation, median total dose administered was 54 Gy (range: 24-56 Gy). Results. The median follow-up was 51 months (range: 9-102) and, at the time of analysis, 49 patients were alive and disease-free, 1 patient was alive with reduced visual acuity and biochemical indications of recurrence, 2 patients had died from the disease and 1 patient had died from unrelated causes. Overall survival was 94% (50/53) and overall local tumour control was 92% (49/53). Univariate analysis indicated hormonal secretion (ACTH) and previous radiotherapy as being statistically significant. Fourteen patients (25%) had minor side-effects during treatment and 3 patients (5.4%) had late-onset events; 2 with optical neuropathy (both patients had other relevant co-existing diseases) and 1 patient had brain necrosis (re-irradiation). Conclusion. Fractionated stereotactic-guided radiotherapy is an effective modality for the treatment of pituitary adenomas. Care is required in patients with co-morbidities and/or previously-irradiated recurrent tumour so as to minimise late-onset secondary effects

Tratamiento quirúrgico: técnicas, indicaciones, resultados y complicaciones / Surgical treatment: techniques, indications, results and complications

En el momento actual, el tratamiento electivo de la acromegalia consiste en la resección quirúrgica del adenoma productor de hormona del crecimiento con conservación de la función hipofisaria. La mayoría de los casos son intervenidos mediante un abordaje transesfenoidal, que puede ser sublabial o intranasal. El endoscopio puede mejorar la visión de algunos aspectos de la resección quirúrgica realizada con un microscopio y es útil como adyuvante de la microcirugía. La resección quirúrgica de un adenoma con técnica endoscópica exclusiva puede presentar serias limitaciones en los campos quirúrgicos con hemorragia, lo que añade riesgo y en ningún caso mejora los resultados endocrinológicos que ofrece la microcirugía. Estos resultados guardan relación con el tamaño del tumor y los criterios de curación utilizados, así como con el tiempo de evolución postoperatoria. En general se puede esperar una remisión de la enfermedad en más del 90% de los casos intervenidos por tumores < 1 cm de diámetro, pero también se puede obtener la remisión de la enfermedad en al menos un 15% de los casos con adenomas invasivos. El porcentaje de complicaciones es bajo, con insuficiencia de la función hipofisara secundaria al acto quirúrgico en alrededor del 1% de los casos (AU)

Transsphenoidal microsurgery remains the most valid and widely used method of treating acromegaly. This procedure that has been proved relatively safe, achieves selective adenomectomy in a great number of cases and a successful outcome in about 90% of patients with microadenomas. Pituitary insuficiency surgically realated in less than 1% of the cases. 90% of all pituitary adenomas can be treated via the transphenoidal approach using different entry sites: sublabial, pernasal, endonasal. The use of endoscopes is very helpful for better visualization within the sphenoid sinus, especially within the sella, but does not seem to improve the final endocrinological results. Acurate endocrinological diagnosis and early surgical treatment lead to prevent tumor growth and possible focal or general invasion. An other surgical point, is the the prevention of the possibility of pituitary apoplexy rare but life threatening (AU)

Radioterapia en el tratamiento de la acromegalia: técnicas, indicaciones, resultados y complicaciones / Radiotherapy in the treatment of acromegaly: techniques, indications, results and complications

El tratamiento de la acromegalia incluye cirugía, medicación y radioterapia. El objetivo común es normalizar la hipersecreción hormonal, reducir los síntomas y controlar el tamaño tumoral. Esto debería cumplirse manteniendo, además, la función hipofisaria normal y con la menor morbilidad posible. La radioterapia esta indicada en los casos de rechazo a la cirugía y/o fracaso del tratamiento médico o quirúrgico. Una radioterapia convencional con dosis de al menos 45 Gy pueden normalizar las concentraciones de hormona del crecimiento y factor de crecimiento similar a la insulina tipo I, pero se requiere un tiempo prolongado, de 6 a 10 años para conseguirlo. La complicación más frecuente es el hipopituitarismo. Nuevas técnicas de alta precisión en las que se utilizan varias fracciones (radioterapia estereotáxica) o altas dosis en una única fracción (radiocirugía) son efectivas, con el beneficio potencial de reducir el volumen de tejido sano irradiado. La comparación de resultados en la probabilidad de normalización bioquímica entre radiocirugía y radioterapia es muy compleja por los diferentes valores utilizados en las diversas series. Con radiocirugía, los porcentajes de curación son muy dispares (20-80%), pero en los trabajos en los cuales los datos son examinados por los mismos autores, la respuesta es significativamente más rápida con radiocirugía. El momento adecuado para administrar el tratamiento médico en relación con la fecha y la irradiación debe ser definido debido al efecto negativo que ejerce con la radioterapia. Para conocer la verdadera ventaja de estas nuevas modalidades en la curación y la reducción de los efectos secundarios es necesario que se empleen los criterios de curación correctos y que se realicen estudios amplios, prospectivos y con seguimientos prolongados (AU)

Currently available therapies for acromegaly are surgery, medical therapy and radiotherapy. The goals of these therapies are normalize excessive hormone secretion, to reduce the clinical signs and symptoms and to control tumour size. These goals should be accomplished while preserving pituitary function and with a few side effects as possible. Indications for radiotherapy include patients refusing surgery or in whom medical and surgical therapies failed. Conventionally fractionated radiotherapy at least 45 Gy can lower GH levels and normalize IGF-I, but there is a long lag time 5-10 years, before this effect is achieved. The most common complications are the development of new hipopituitarism. New high precision techniques using several fractions (stereotactic radiotherapy) or high doses in single fraction (radiosurgery) are an effective procedure in acromegaly with the potential benefit in reducing the volume of normal brain irradiated. Comparison of results of hormone normalization in radiosurgery series to radiotherapy series is made difficult by the different values used by investigators, and endocrine cure rates whit radiosurgery fairly wide variations (20-80%) but in reports in which the data are examined by the same authors, the response is significantly faster with radiosurgery. The optimal timing of administration of antisecretory medications with respect to the date of radiation needs to be clarified for the negative effect in radiation response. To know the real advantages of new techniques in endocrine cure rate and toxicity level is necessary to use correct cure criteria and long-term prospective studies (AU)

Radiocirugía: indicaciones y resultados. Perspectivas frente a la asociación farmacológica

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