Radiotherapy approaches to pituitary tumors Pituitary Disorders: - - PDF document

Radiotherapy approaches to pituitary tumors

Pituitary Disorders: Advances in Diagnosis and Management

10/22/16

Steve Braunstein, MD, PhD UCSF Department of Radiation Oncology CNS and Pediatric Service

Disclosures

No relevant disclosures

10/22/16 Radiotherapy approaches to pituitary tumors 2

Outline

Overview of radiotherapy in management of pituitary tumors

10/22/16 Radiotherapy approaches to pituitary tumors 3

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

Classification

Tumors of the pituitary

10/22/16 Radiotherapy approaches to pituitary tumors 4

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 2006

Classification

Tumors of the pituitary

10/22/16 Radiotherapy approaches to pituitary tumors 5

Pituitary adenoma

• Microadenoma (<1cm)
• Macroadenoma (≥1cm)
• Functional
• Non-functional

Pituitary carcinoma Metastases (breast and lung)

Post surgical outcomes

Overall local control is 50-80% following resection Recurrence Risk for non-functional tumors:

10/22/16 Radiotherapy approaches to pituitary tumors 6

Post-op MRI 5 yr 10 yr GTR 10-20% 30% STR 25-40% >50%

Cortet-Rudelli et al. Annales d’Endocrinologie 2015

Radiotherapy indications

Surgical local control 50-80%

10/22/16 Radiotherapy approaches to pituitary tumors 7

Medically inoperable (panhypopituitarism) Subtotal resection (persistent hypersecretion) Large tumor with extrasellar extension Recurrence Pituitary carcinoma (high mitotic index, invasive features)

Radiotherapy approach

Pre-treatment workup

10/22/16 Radiotherapy approaches to pituitary tumors 8

Complete endocrine evaluation Visual field testing Cessation of suppressive medications Non-randomized data

Radiotherapy approach

Effect of endocrine suppression

10/22/16 Radiotherapy approaches to pituitary tumors 9

Sheehan et al. JNS 2011 HS No-HS

Fractionated external beam radiotherapy

Conventionally/classically fractionated (LINAC-based)

10/22/16 Radiotherapy approaches to pituitary tumors 10

Nonfunctioning: 45- 50 Gy Functioning: 50.4-54 Gy

Fractionated external beam radiotherapy

Conventionally/classically fractionated (LINAC-based)

10/22/16 Radiotherapy approaches to pituitary tumors 11

Zeirhut et al. IJROBP 1995

Fractionated external beam radiotherapy

45 Gy McCoullough WM IJROBP 1991, 95% LC

10/22/16 Radiotherapy approaches to pituitary tumors 12

Preferred when large pituitary adenomas and/or when lesion is < 2mm from optic chiasm

Stereotactic radiosurgery

Single session radiosurgery (Gamma knife, Cyberknife, LINAC)

10/22/16 Radiotherapy approaches to pituitary tumors 13

Nonfunctioning: 12-20 Gy Functioning: 15-30 Gy

Preferred to decrease dose to hypothalamus and cortical brain

Stereotactic radiosurgery

Single session radiosurgery (Gamma knife, Cyberknife, LINAC)

10/22/16 Radiotherapy approaches to pituitary tumors 14

Fractionated stereotactic radiotherapy

Multisession radiosurgery (Gamma knife, Cyberknife, LINAC)

10/22/16 Radiotherapy approaches to pituitary tumors 15

Nonfunctioning: 25-30 Gy in 5 fractions Functioning: 30-35 Gy in 5 fractions

Preferred when pituitary lesion is > 3cm and/or when lesion is < 2mm from optic chiasm

Outcomes

10/22/16 Radiotherapy approaches to pituitary tumors 16

Tumor type Tteatment protocol Disease free survival 10 yr Non-functioning Surgeryobs vs RT 90% RT alone 80% GH-secreting Surgeryobs vs RT 70-80% RT alone 60-70% Prolactin secreting Obs vs MM vs Sg vs RT 80-90% ACTH-secreting Surgeryobs vs RT 50-60% (more rapid) RT alone 50-60% TSH-sectreing SurgeryRT 40-50%

Outcomes

Functional control

10/22/16 Radiotherapy approaches to pituitary tumors 17

ACTH normalizes < 1yr Prolactin > 1yr Growth hormone > 1yr (50% at 2 yr, 70% at 10 yr)

Outcomes

Overall survival

10/22/16 Radiotherapy approaches to pituitary tumors 18

No difference in OS among:

• Surgery
• Surgery + RT
• RT alone

Choose therapy based on minimizing side effects

Follow up

Delayed response and toxicity

10/22/16 Radiotherapy approaches to pituitary tumors 19

MRI 6 and 12 months, then annually Endocrine evaluation every 6-12 months Formal visual field testing annually

Outcomes

Pituitary function

10/22/16 Radiotherapy approaches to pituitary tumors 20

Xu et al. Neurosurgery 2013

Outcomes

Visual function

10/22/16 Radiotherapy approaches to pituitary tumors 21

EBRT: 50-54 Gy SRS: 8 Gy

10 20 30 40 50 60 70 14 12 10 8 6 4 2

Dose per Fraction (Gy)

Total Dose (Gy)

Model: LQ extrapolation from 1.8 Gy/fx, 59.4 Gy with α/β=3.3 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 Model: Iso Optic RET = 8.9 Gy Literature Findings: > 10% Incidence RION Literature Findings: 1-9% Incidence RION Literature Findings: No Incidence RION Only a few detailed publications in SRS region Lack of published data in hypo-fractionation region Majority of published data pre-date planning and treatment delivery technology that allows for steep dose gradients in or near optic

• structures. Effect on partial

volume tolerance needs further exploration. Models and literature indicate better tolerance at lower dose per fraction.

Applicability of models to predict RION from conventional to SRS fractionations

Mayo et al. IJROBP 2010

Outcomes/Toxicity

Secondary Malignancy

10/22/16 Radiotherapy approaches to pituitary tumors 22

Pendulum treatment Two opposed lateral fields Three fields Total Number of patients 38 138 61 237 Median age/years at radiotherapy (range) 54 (24–75) 55 (18–79) 62 (16–82) 56 (16–82) Number of person-years at risk 750 1861 499 3110 Number of second primary tumours within area of radiotherapy 1 4 5 Total number of second primary tumours 5 20 5 30 Number of tumours/103 person-years at risk 6·6 10·7 10·0 9·6

Norberg et al. Clin Endocrinology 2008

Outcomes/Toxicity

Secondary Malignancy

10/22/16 Radiotherapy approaches to pituitary tumors 23

Norberg et al. Clin Endocrinology 2008

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

Pituitary carcinoma

10/22/16 Radiotherapy approaches to pituitary tumors 24

Pituitary carcinoma

10/22/16 Radiotherapy approaches to pituitary tumors 25

Heaney J Clin Endocrinol Metab 2011

Future directions

10/22/16 Radiotherapy approaches to pituitary tumors 26

Proton Heavy particle Adaptive hybrid radiosurgery LGKS Molecular prognostic markers/indices

Future directions

Diagnostic Parameters for APAs/TPAs Cut-off Sensitivity Specitifity Youden-Index Accuracy in % AUC 95 % CI

• f AUC

OR 95 % CI

• f OR

P-value Ki-67 pos. nuclei in % ≥4 0.95 0.97 0.92 96 0.98 [0.96; 1.0] 5.2 [3.43; 7.83] <0.001 P53 pos. nuclei in % ≥2 0.85 0.93 0.78 90 0.94 [0.90; 0.97] 3.1 [2.31; 4.04] <0.001 Mitotic Index in 10 HPF ≥2 0.90 0.74 0.64 79 0.89 [0.84; 0.93] 2.1 [1.70; 2.57] <0.001 Invasiveness Yes 0.88 0.53 0.41 64

• 8.2

[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

Molecular Prognostic indices Ki-67, p53, MI

10/22/16 Presentation Title and/or Sub Brand Name Here 27

Miermeister et al. Acta Neuropathologica Comm 2015