Open-label phase II clinical trial of ketoconazole as CYP17 inhibitor in metastatic or advanced non-resectable granulosa cell ovarian tumors: the GREKO (GRanulosa Et KetOconazole) trial, GETHI 2011-03.

BACKGROUND: Granulosa cell ovarian tumor (GCT) is characterized by a pathognomonic mutation in the FOXL2 gene (402 C > G) that leads to an overactivation of steroidogenesis. CYP17 is a key enzyme in such process and can be inhibited by ketoconazole. METHODS: We designed a phase II clinical trial to assess the efficacy of ketoconazole in advanced GCT and conducted several in vitro studies to support the clinical findings. RESULTS: From October 1st 2012 to January 31st 2014, six evaluable patients were recruited in ten hospitals of the Spanish Group for Transversal Oncology and Research in Orphan and Infrequent Tumors" (GETTHI). FOXL2 (402C > G) mutation was confirmed in three; two cases were wild type and it could not be assessed in one. No objective response by RECIST was observed, but five cases achieved stable disease longer than 12 months. Median progression-free survival was 14.06 months (CI 95% 5.43-22.69) for the whole study population (3.38 and 13.47 months for wild-type cases and 14.06, 20.67 and 26.51 for those with confirmed FOXL2 mutation). Median overall survival was 22·99 months (CI 95% 8.99-36.99). In vitro assays confirmed the activity of ketoconazole in this tumor and suggested potential synergisms with other hormone therapies. CONCLUSION: Ketoconazole has shown activity in advanced GCT in clinical and in vitro studies. Based on these data, an orphan designation was granted by the European Medicines Agency for ketoconazole in GCT (EU/3/17/1857). GOV IDENTIFIER: NCT01584297.

Dos casos de metástasis hipofisarias como forma de presentación de un carcinoma microcítico de pulmón / Two cases of pituitary metastases as initial presentation form of small cell lung cancer

Las metástasis en la silla turca son raras y se encuentran en muchas ocasiones incidentalmente o en necropsias. Solo un 7% de los casos son sintomáticos. Las manifestaciones clínicas más frecuentes son la diabetes insípida, la clínica compresiva y los síntomas derivados de déficit hormonales de la adenohipófisis. Se presentan los casos de 2 varones con un carcinoma microcítico de pulmón cuya manifestación clínica inicial correspondía a afectación metastásica de la silla turca. Un caso debutó con invasión del seno cavernoso y panhipopituitarismo, y el otro con una diabetes insípida. Ambos casos presentaron una rápida progresión de su enfermedad neoplásica, con escasa respuesta al tratamiento sistémico en uno de los casos y fueron éxitus a los pocos meses. Las metástasis hipofisarias se presentan con mayor frecuencia en mujeres con cáncer de mama y hombres con neoplasias de pulmón. La presencia de poliuria y polidipsia en un paciente oncológico debe hacer sospechar una diabetes insípida, siendo necesario un estudio de imagen de la silla turca. El tratamiento de estos tumores incluye la cirugía, la radioterapia, la quimioterapia y el tratamiento hormonal sustitutivo. A pesar que el tratamiento quirúrgico no se ha asociado a un aumento de la supervivencia, algunos pacientes pueden mejorar su calidad de vida.

Metastases in the sellar region are rare and are frequently found incidentally or in necropsies. Only 7% are reported to be symptomatic. Diabetes insipidus, anterior pituitary dysfunction, visual field defects, headache/pain and ophthalmoplegia are the most commonly reported symptoms. We present the cases of two male patients with a small-cell lung carcinoma whose first clinical symptoms were due to pituitary metastasis. One case presented with symptoms of cavernous sinus invasion and panhypopituitarism and the other case with diabetes insipidus. Both patients had a rapid progression of their disease despite chemotherapy and died after a few months. Pituitary metastases occur most commonly with breast cancer in women and lung cancer in men. The presence of polyuria and polydipsia in an oncologic patient should alert the physician for diabetes insipidus and, if confirmed, an imaging procedure of the pituitary gland is mandatory. Treatment for these tumors is often multimodal and includes surgery, radiation therapy, chemotherapy and hormone replacement. Although surgical series have not shown any significant survival benefits given by tumor resection, the patient’s quality of life may be improved.

[Two cases of pituitary metastases as initial presentation form of small cell lung cancer]. / Dos casos de metástasis hipofisarias como forma de presentación de un carcinoma microcítico de pulmón.

Metastases in the sellar region are rare and are frequently found incidentally or in necropsies. Only 7% are reported to be symptomatic. Diabetes insipidus, anterior pituitary dysfunction, visual field defects, headache/pain and ophthalmoplegia are the most commonly reported symptoms. We present the cases of two male patients with a small-cell lung carcinoma whose first clinical symptoms were due to pituitary metastasis. One case presented with symptoms of cavernous sinus invasion and panhypopituitarism and the other case with diabetes insipidus. Both patients had a rapid progression of their disease despite chemotherapy and died after a few months. Pituitary metastases occur most commonly with breast cancer in women and lung cancer in men. The presence of polyuria and polydipsia in an oncologic patient should alert the physician for diabetes insipidus and, if confirmed, an imaging procedure of the pituitary gland is mandatory. Treatment for these tumors is often multimodal and includes surgery, radiation therapy, chemotherapy and hormone replacement. Although surgical series have not shown any significant survival benefits given by tumor resection, the patient's quality of life may be improved.