Radiotherapy approaches to pituitary tumors

Transcription

1 Disclosures No relevant disclosures Radiotherapy approaches to pituitary tumors Pituitary Disorders: Advances in Diagnosis and Management Steve Braunstein, MD, PhD UCSF Department of Radiation Oncology CNS and Pediatric Service 2 Outline Classification Overview of radiotherapy in management of pituitary tumors Indication/decision algorithm Conventional/fractionated external beam radiotherapy (EBRT) Stereotactic radiosurgery (SRS) Fractionated stereotactic radiotherapy (FSRT/SBRT) Disease outcomes Follow up protocol Toxicity Future directions Tumors of the pituitary Tumor type Transcription factors Hormones, others The Pit-1 family Somatotroph adenoma Densely granulated somatotroph adenoma Pit-1 GH, a-subunit Sparsely granulated somatotroph adenoma Pit-1 GH, keratin whorls (fibrous bodies) Mammosomatotroph/mixed adenoma Pit-1, ER GH, PRL, a-subunit Lactotroph adenoma Sparsely granulated lactotroph adenoma Pit-1, ER,?GH-repressor PRL, Golgi pattern Densely granulated lactotroph adenoma Pit-1, ER,?GH-repressor PRL diffuse cytoplasmic Acidophil stem cell adenoma Pit-1, ER PRL, (GH), keratin whorls (fibrous bodies) Thyrotroph adenoma Pit-1, TEF, GATA-2 b-tsh, a-subunit Plurihormonal adenoma Pit-1, ER, TEF, GATA-2 GH, PRL, b-tsh, a-subunit ACTH family Corticotroph adenoma Tpit ACTH, keratins Gonadotropin family Gonadotroph adenoma SF-1, ER, GATA-2 b-fsh, b-lh, a-subunit Unclassified adenoma Hormone-negative/ null cell adenoma None None Unusual plurihormonal adenoma?multiple Multiple Al-Shraim et al. Acta Neuropath

2 Classification Post surgical outcomes Tumors of the pituitary Pituitary adenoma Microadenoma (<1cm) Macroadenoma ( 1cm) Overall local control is 50-80% following resection Recurrence Risk for non-functional tumors: Post-op MRI 5 yr 10 yr GTR 10-20% 30% STR 25-40% >50% Functional Non-functional Pituitary carcinoma Metastases (breast and lung) Cortet-Rudelli et al. Annales d Endocrinologie Radiotherapy indications Radiotherapy approach Surgical local control 50-80% Medically inoperable (panhypopituitarism) Subtotal resection (persistent hypersecretion) Large tumor with extrasellar extension Recurrence Pituitary carcinoma (high mitotic index, invasive features) Pre-treatment workup Complete endocrine evaluation Visual field testing Cessation of suppressive medications Non-randomized data 7 8

3 Radiotherapy approach Fractionated external beam radiotherapy Effect of endocrine suppression Conventionally/classically fractionated (LINAC-based) Nonfunctioning: Gy Functioning: Gy HS No-HS Sheehan et al. JNS Fractionated external beam radiotherapy Fractionated external beam radiotherapy Conventionally/classically fractionated (LINAC-based) 45 Gy McCoullough WM IJROBP 1991, 95% LC Zeirhut et al. IJROBP 1995 Preferred when large pituitary adenomas and/or when lesion is < 2mm from optic chiasm 11 12

4 Stereotactic radiosurgery Stereotactic radiosurgery Single session radiosurgery (Gamma knife, Cyberknife, LINAC) Nonfunctioning: Gy Functioning: Gy Single session radiosurgery (Gamma knife, Cyberknife, LINAC) Preferred to decrease dose to hypothalamus and cortical brain Fractionated stereotactic radiotherapy Outcomes Multisession radiosurgery (Gamma knife, Cyberknife, LINAC) Nonfunctioning: Gy in 5 fractions Functioning: Gy in 5 fractions Preferred when pituitary lesion is > 3cm and/or when lesion is < 2mm from optic chiasm Tumor type Tteatment protocol Disease free survival 10 yr Non-functioning Surgery obs vs RT 90% RT alone 80% GH-secreting Surgery obs vs RT 70-80% RT alone 60-70% Prolactin secreting Obs vs MM vs Sg vs RT 80-90% ACTH-secreting Surgery obs vs RT 50-60% (more rapid) RT alone 50-60% TSH-sectreing Surgery RT 40-50% 15 16

5 Outcomes Outcomes Functional control ACTH normalizes < 1yr Prolactin > 1yr Growth hormone > 1yr (50% at 2 yr, 70% at 10 yr) Overall survival No difference in OS among: Surgery Surgery + RT RT alone Choose therapy based on minimizing side effects Follow up Outcomes Delayed response and toxicity Pituitary function MRI 6 and 12 months, then annually Endocrine evaluation every 6-12 months Formal visual field testing annually Xu et al. Neurosurgery

6 Outcomes Visual function EBRT: Gy SRS: 8 Gy Total Dose (Gy) 70 Applicability of models to predict RION from conventional to SRS fractionations Models and literature indicate 60 Model: LQ extrapolation from 1.8 Gy/fx, 59.4 Gy with α/β=3.3 better tolerance at lower dose per fraction. Model: LQ extrapolation from 1.8 Gy/fx, 59.4 Gy with α/β=1.6 Model: Iso Neuret(NSD) = 60 Gy, 1.8 Gy/fx 50 Model: Iso Optic RET = 8.9 Gy Literature Findings: > 10% Incidence RION 40 Literature Findings: 1-9% Incidence RION Literature Findings: No Incidence RION 30 Majority of published data pre-date planning and 20 treatment delivery technology that allows for steep dose gradients in or near optic 10 structures. Effect on partial volume tolerance needs Lack of published data in further exploration. hypo-fractionation region Only a few detailed publications in SRS region Dose per Fraction (Gy) Mayo et al. IJROBP 2010 Outcomes/Toxicity Secondary Malignancy Pendulum treatment Two opposed lateral fields Three fields Total Number of patients Median age/years at radiotherapy (range) 54 (24 75) 55 (18 79) 62 (16 82) 56 (16 82) Number of person-years at risk Number of second primary tumours within area of radiotherapy Total number of second primary tumours Number of tumours/10 3 person-years at risk Norberg et al. Clin Endocrinology Outcomes/Toxicity Pituitary carcinoma Secondary Malignancy Type of tumour Sex/age (in years) at radiotherapy for pituitary adenoma Years between radiotherapy and the diagnosis of a second primary tumour Number of fields used and radiation dose received (in Gy) Glioma (astrocytoma grade III) Male/55 7 Two opposed lateral fields, 40 Meningioma Male/46 9 Two opposed lateral fields, 45 Meningioma Male/54 First treatment 24 First treatment: pendulum, 41 Second treatment 1 Second treatment: two opposed lateral fields, 31 Cancer in the parotid gland Female/73 8 Two opposed lateral fields, 42 Squamous cell carcinoma in the external ear Male/51 9 Two opposed lateral fields, 42 Norberg et al. Clin Endocrinology

7 Pituitary carcinoma Future directions Proton Heavy particle Adaptive hybrid radiosurgery LGKS Molecular prognostic markers/indices Heaney J Clin Endocrinol Metab Future directions Molecular Prognostic indices Ki-67, p53, MI Diagnostic Parameters for APAs/TPAs Cut-off Sensitivity Specitifity Youden-Index Accuracy in % AUC 95 % CI of AUC OR 95 % CI of OR Ki-67 pos. nuclei in % [0.96; 1.0] 5.2 [3.43; 7.83] <0.001 P53 pos. nuclei in % [0.90; 0.97] 3.1 [2.31; 4.04] <0.001 Mitotic Index in 10 HPF [0.84; 0.93] 2.1 [1.70; 2.57] <0.001 Invasiveness Yes [3.66; 18.42] <0.001 The proposed threshold values for Ki-67, p53, number of mitotic figures in 10 HPF (high power fields) and the status of invasive tumor growth, to distinguish APA and TPA are shown with their respective statistical values OR odds ratio, AUC area under curve, CI confidence interval P-value Miermeister et al. Acta Neuropathologica Comm Presentation Title and/or Sub Brand Name Here