Radiotherapy for Pituitary Adenomas: What You Need to Know - - PDF document
Radiotherapy for Pituitary Adenomas: What You Need to Know Pituitary Disorders: Advances in Diagnosis and Management Steve Braunstein, MD, PhD Assistant Professor and Vice Chair SRS Program Co-Director UCSF Department of Radiation Oncology
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 1
1/25/20
Steve Braunstein, MD, PhD Assistant Professor and Vice Chair SRS Program Co-Director UCSF Department of Radiation Oncology
1
I have no relevant disclosures
1/25/20 Radiotherapy approaches to pituitary adenomas 2
2
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 2
Overview of radiotherapy in management of pituitary tumors
1/25/20 Radiotherapy approaches to pituitary adenomas 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 3
Tumors of the pituitary (rare?)
1/25/20 Radiotherapy approaches to pituitary adenomas 4
§10-20% of intracranial tumors §Pituitary incidentaloma ~10-20%
Orija et al. BPRCEM 2012
4
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 3
Sept 1991-1993 n = 328
Gliomas 22% 8%
Mening Schw Pit Other
2012-2016 n = 1627
10%
Mening 16% 9%
Schw Pit AVMs Other
1/25/20 Radiotherapy approaches to pituitary adenomas 5
Fn Fn
5
Tumors of the pituitary
1/25/20 Radiotherapy approaches to pituitary adenomas 6
mone, LH luteinizing hormone, SF steroidogenic factor) 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
6
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 4
Tumors of the pituitary
1/25/20 Radiotherapy approaches to pituitary adenomas 7
§Pituitary adenoma
§Pituitary carcinoma §Metastases (breast and lung) 7
1/25/20 Radiotherapy approaches to pituitary adenomas 8
m analysis refmect 2010 US dollars. specifjcally to assess QOL in patients suffering from ac to rely on nonspecifjc QOL questionnaires. Data obtained either source were quantifjed whenever possible to make cifjc treatments on QOL. Results Effjcacy
However, other data have shown no signifjcant improve so the overall effjcacy of this ly a fjrst-line modality and is usually reserved for treat attributable to variability in the defjnition of “remission”
8
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 5
1/25/20 Radiotherapy approaches to pituitary adenomas 9
Chen et al. Neuro-endocrinology 2012
Non-functioning pituitary adenoma progression-free survival
Tumor recurrence and tumor growth-free survival rates in 15 studies before 2011
Study reference Num- ber of cases Follow-up time months Rate of tumor recurrence Tumor growth-free survival rate at 5 years Tumor growth-free survival rate at 10 years total residual nonresidual total residual nonresidual total residual nonresidual Brochier S. [44] 142 83 56/142 10/42 47/100 75% 82 70 57% 68% 52% O’Sullivan E.P. [41] 126 68 53/126 53/100 0/26 76% 85 or 49%§ 100% 49% 58 or 23%† 100% Losa M. [59] 355 53 NA/355 NA/76 NA/279 NA 39% 87% NA 17% 62% van den Bergh A.C. [57] 43 71 17/43 16/28 1/15 NA 49% 100% NA 22% 67% Dekkers O.M. [39] 91 72 9/91 9/70 0/21 94% 92% 100% 81% 74% 100% Ferrante E. [40] 150 112 59/150 45/77 14/73 NA 55% 93% NA 36% 62% Picozzi P. [60] 68 42 32/68 32/68 NA 51% 51% NA 51% 51% NA Park P. [5] 132 45 26/132 NA NA 85% NA NA 50% NA NA Greenman Y. [11] 108 51 47/108 41/78 6/30 48% 30% 84% NA 29% 63% Soto-Ares G. [58] 51 68 13/51 13/34 0/17 74% 61% 100% NA NA 100% Woollons A.C. [6] 22 58 10/22 8/11 2/11 34% 22% NA 34% 22% NA Turner H.E. [42] 65 76 21/65 12/34 9/31 82% NA NA 56% NA NA Lillehei K.O. [56] 32 66 2/32 NA 2/32 NA NA NA NA NA NA Gittoes N.J. [9] 53 97 14/53 NA NA 82% NA NA 59% NA NA Bradley K.M. [38] 73 NA 8/73 NA 8/73 NA NA NA 90% NA 70%
§ †
9
1/25/20 Radiotherapy approaches to pituitary adenomas 10
Chen et al. Neuro-endocrinology 2012
Non-functioning pituitary adenoma progression-free survival
Tumor recurrence and tumor growth-free survival rates in 15 studies before 2011
Study reference Num- ber of cases Follow-up time months Rate of tumor recurrence Tumor growth-free survival rate at 5 years Tumor growth-free survival rate at 10 years total residual nonresidual total residual nonresidual total residual nonresidual Brochier S. [44] 142 83 56/142 10/42 47/100 75% 82 70 57% 68% 52% O’Sullivan E.P. [41] 126 68 53/126 53/100 0/26 76% 85 or 49%§ 100% 49% 58 or 23%† 100% Losa M. [59] 355 53 NA/355 NA/76 NA/279 NA 39% 87% NA 17% 62% van den Bergh A.C. [57] 43 71 17/43 16/28 1/15 NA 49% 100% NA 22% 67% Dekkers O.M. [39] 91 72 9/91 9/70 0/21 94% 92% 100% 81% 74% 100% Ferrante E. [40] 150 112 59/150 45/77 14/73 NA 55% 93% NA 36% 62% Picozzi P. [60] 68 42 32/68 32/68 NA 51% 51% NA 51% 51% NA Park P. [5] 132 45 26/132 NA NA 85% NA NA 50% NA NA Greenman Y. [11] 108 51 47/108 41/78 6/30 48% 30% 84% NA 29% 63% Soto-Ares G. [58] 51 68 13/51 13/34 0/17 74% 61% 100% NA NA 100% Woollons A.C. [6] 22 58 10/22 8/11 2/11 34% 22% NA 34% 22% NA Turner H.E. [42] 65 76 21/65 12/34 9/31 82% NA NA 56% NA NA Lillehei K.O. [56] 32 66 2/32 NA 2/32 NA NA NA NA NA NA Gittoes N.J. [9] 53 97 14/53 NA NA 82% NA NA 59% NA NA Bradley K.M. [38] 73 NA 8/73 NA 8/73 NA NA NA 90% NA 70%
§ †
10
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 6
1/25/20 Radiotherapy approaches to pituitary adenomas 11
Study reference TVDT P-TVDT 95% CI Hsu C.Y., 2010 [65] 3.0 3.00 [2.10; 4.00] Honegger J., 2008 [66] 3.0 3.00 [2.10; 4.00] Tanaka Y., 2003 [61] 5.0 5.00 [4.00; 6.00] Ekramullah S.M., 1996 [62] 2.5 2.50 [1.70; 3.50] Summary 3.4 3.40 [2.40; 4.50] 2 4 6 8 10
Residual Tumor Volume Doubling Time (~3-4 years)
Chen et al. Neuro-endocrinology 2012
11
Overall local control is 50-80% following resection Recurrence Risk for non-functioning tumors:
1/25/20 Radiotherapy approaches to pituitary adenomas 12
Post-op MRI 5 yr 10 yr GTR 10-20% 30% STR 25-40% >50%
Cortet-Rudelli et al. Annales d’Endocrinologie 2015
12
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 7
Surgical local control 50-80%
1/25/20 Radiotherapy approaches to pituitary adenomas 13
§Medically inoperable (panhypopituitarism) §Subtotal resection (persistent hypersecretion) §Large tumor with extrasellar extension §Recurrence §Pituitary carcinoma (high mitotic index, invasive features)
13
Pre-treatment workup
1/25/20 Radiotherapy approaches to pituitary adenomas 14
§Complete endocrine evaluation §Visual field testing Cessation of suppressive medications §Non-randomized data
14
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 8
Conventionally/classically fractionated (LINAC-based)
1/25/20 Radiotherapy approaches to pituitary adenomas 15
312
.2 .I 0 E
Oncology 0 Biology l Physics Volume 33, Number 2, 1995
Dose response in pituitary adenoma local control after irradiation and surgery
. ..i.
d.
Zierhut
dose in Gray
response in pituitary adenoma: local control after irradiation and surgery. The most serious side effects are ophthalmological com- tions that optic nerve or chiasm injury by radiotherapy of plications in terms of optic neuropathy or injury to the chi- pituitary adenomas, using adequate treatment technique and
dosage, is a rare complication (16, 22, 23). with large daily or total doses (2, 28, 35). ln a recent study, We, therefore, conclude that, if tolerance of the optic Goldsmith and co-workers estimated the tolerance dose of nerve is not suspected to be reduced because of damage the optic nerve concerning development of neuropathy to prior to radiotherapy or underlying vascular disease, doses be beyond 48 Gy with 2.0 Gy single dose, or 54 Gy with between 45 to 48 Gy, using conventional fractionation, 1.8 Gy single dose (19). Our results confirm prior observa- should be given. REFERENCES
B.; Velasco, M.; bromocriptine in the treatment
Manni, A.; Pearson,
microsurgery itary tumours.
24505-5 13; 1986. in the treatment
and gigantism.
J.; Faust, D. S.; Han, S. H.;
Olsen,
chai, S.; Torpie,
J. R.; Asbell, S. 0. Radia-
fractionation factors to complications in the tion therapy in pituitary adenomas. In: Kryston, L. J.; Shaw, treatment
by irradiation.
New York
2:667-673; 1977. Grune & Stratton; 1975:69-78.
K.; Thomer,
Horvath, E.; Hoffmann, J. C., Jr. Clinical and pathologic G.; Dallabonzana, D.; Spelta, B.; Silvestrini, F.; Borghi, effects of bromocriptine
and other G.; Luccarelli, G.; Rainer, E.; Horowski,
reduction pituitary tumors.
60:1-7; 1984.
by bromocriptine
treat-
microsurgical removal of growth hormone-secreting pitu-
in itary adenomas. A review of 137 cases.
the treatment
Oncol. 56:634-641; 1982.
L.; Games, Schulte, H. M.; Lancranjan, I.; Reinwein, D. Parenteral
microsurgery
Zeirhut et al. IJROBP 1995
15
Conventionally/classically fractionated (LINAC-based)
1/25/20 Radiotherapy approaches to pituitary adenomas 16
Snead et al. IJROBP 2008
16
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 9
Conventionally/classically fractionated (LINAC-based)
1/25/20 Radiotherapy approaches to pituitary adenomas 17
§385 patients with pituitary adenoma receiving RT 1974-2003 §Mixed FPA/NFPA §60% underwent resection §RT 35-60 Gy total dose §PFS-10yr 97%, -20yr 96%
Erridge et al. Radiother Oncol 2009
17
Conventionally/classically fractionated (LINAC-based)
1/25/20 Radiotherapy approaches to pituitary adenomas 18
Late toxicities §Optic neuropathy 0.8% at 10 yrs §Stroke risk increased RR 1.5-2.2 §Secondary tumor actuarial risk 1.8% at 20 years
Erridge et al. Radiother Oncol 2009
18
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 10
Conventionally/classically fractionated (LINAC-based)
1/25/20 Radiotherapy approaches to pituitary adenomas 19
§Nonfunctioning: 45- 50 Gy §Functioning: 50.4-54 Gy 19
1/25/20 Radiotherapy approaches to pituitary adenomas 20
Preferred for large pituitary adenomas and/or when lesion is < 2mm from optic chiasm
20
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 11
Single session radiosurgery (Gamma knife, Cyberknife, LINAC)
1/25/20 Radiotherapy approaches to pituitary adenomas 21
21
Single session radiosurgery (Gamma knife, Cyberknife, LINAC)
1/25/20 Radiotherapy approaches to pituitary adenomas 22
§Nonfunctioning: 12-20 Gy §Functioning: 15-30 Gy
Preferred to decrease dose to hypothalamus and cortical brain
22
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 12
Biologic Effective Dose
1/25/20 Radiotherapy approaches to pituitary adenomas 23
Total Dose Number of Fractions Tumor BED (a/b = 10) Normal Tissue BED (a/b = 3)
20 Gy 10 24 33 20 Gy 5 28 47 20 Gy 1 60? 153?
23
Therapeutic Window
1/25/20 Radiotherapy approaches to pituitary adenomas 24
“favorable” “unfavorable”
24
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 13
Multisession radiosurgery (Gamma knife, Cyberknife, LINAC)
1/25/20 Radiotherapy approaches to pituitary adenomas 25
§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
25
Effect of endocrine suppression
1/25/20 Radiotherapy approaches to pituitary adenomas 26
benefjt. tumor growth, new-onset pituitary hormone defjciency, in specifjc smaller cohorts (for example, our institutional diation dose was the only factor that infmuenced control of ated with a trend to statistical signifjcance regarding Our current time for withholding a long- Our time for withholding a dop New onset of pituitary hormone defjciency occurred
vided into 3 tiers, and then best fjts for each tier were plotted as Weibull model predictions. There was a strong trend toward statistical signifj
there was a trend toward statistical signifjcance.
Sheehan et al. JNS 2011 HS No-HS 418 pts 1989-2006 266 pts FPA
26
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 14
Effect of endocrine suppression
1/25/20 Radiotherapy approaches to pituitary adenomas 27
benefjt. tumor growth, new-onset pituitary hormone defjciency, in specifjc smaller cohorts (for example, our institutional diation dose was the only factor that infmuenced control of ated with a trend to statistical signifjcance regarding Our current time for withholding a long- Our time for withholding a dop New onset of pituitary hormone defjciency occurred
vided into 3 tiers, and then best fjts for each tier were plotted as Weibull model predictions. There was a strong trend toward statistical signifj
there was a trend toward statistical signifjcance.
Sheehan et al. JNS 2011 HS No-HS Hormone Normalization 60-80% at 5 yr
27
Single session radiosurgery (Gamma knife, Cyberknife, LINAC)
1/25/20 Radiotherapy approaches to pituitary adenomas 28
subset analysis was conducted specifjcally to determine New Pituitary Hormone Defjciency mone defjciency developed in 102 patients (24.4%). Pi tuitary defjciency was typically observed in the fjrst 2–5 to development of new pituitary hormone defjciency in the time of Gamma Knife treatment (p < 0.001; OR 1.85 [95% CI 1.28–2.58]), prior craniotomy (p = 0.027; OR 0.007; OR 1.10 [95% CI 1.03–1.19]). Prior radiation ther apy was not related in a statistically signifjcant fashion to development of a new pituitary hormone defjciency. defjcits; 1 partial IV cranial nerve defjcit, and 1 partial VI cranial nerve defjcit. Two of these cranial nerve defjcits were permanent. After GKS, new visual acuity or fjeld defj cits were noted in 8 patients. Seventy-fjve percent of these Discussion
fering conclusions about factors that infmuence outcomes. For example, some studies have shown a benefjt to ces
Defjciency signifjcance with either adenoma volume control or time * A p value < 0.05 was deemed statistically signifjcant. Abbreviation: to endocrine remission was plotted, and then best fjts for each group was signifjcantly related to endocrine remission.
Sheehan et al. JNS 2011
28
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 15
Single session radiosurgery (Gamma knife, Cyberknife, LINAC)
1/25/20 Radiotherapy approaches to pituitary adenomas 29
Pollock et al. NS 2008 46 pts 1990-2003 FPA ≥ 18 Gy
29
Single session radiosurgery (Gamma knife, Cyberknife, LINAC)
1/25/20 Radiotherapy approaches to pituitary adenomas 30
Pollock et al. NS 2008
30
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 16
Single Session Radiosurgery
1/25/20 Radiotherapy approaches to pituitary adenomas 31
Triffileti et al. IJROBP 2018
31
Single session radiosurgery:
1/25/20 Radiotherapy approaches to pituitary adenomas 32
Grant et al. WNS 2014 31 pts 1998-2009 FPA 35 Gy
32
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 17
Single session radiosurgery: FPA, SRS dose 35 Gy
1/25/20 Radiotherapy approaches to pituitary adenomas 33
Grant et al. WNS 2014
33
Local Control
1/25/20 Radiotherapy approaches to pituitary adenomas 34
Kotecha et al. Neuro-Oncol 2019
34
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 18
Early vs Late Post-operative Radiosurgery
1/25/20 Radiotherapy approaches to pituitary adenomas 35
Pomeraneic et al. J Neurosurg 2018
35
1/25/20 Radiotherapy approaches to pituitary adenomas 36
Summary
Tumor type Tteatment protocol Disease free survival 10 yr Non-functioning Surgeryàobs vs RT 90% RT alone 80% GH-secreting Surgeryàobs vs RT 70-80% (more rapid) RT alone 60-70% Prolactin secreting Obs vs MM vs Sg vs RT 80-90% ACTH-secreting Surgeryàobs vs RT 50-60% (more rapid) RT alone 50-60% TSH-sectreting SurgeryàRT 40-50%
36
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 19
Functional control
1/25/20 Radiotherapy approaches to pituitary adenomas 37
§ACTH, TSH normalizes < 1yr §Prolactin > 1yr §Growth hormone > 1yr (50% at 2 yr, 70% at 10 yr) 37
Overall survival
1/25/20 Radiotherapy approaches to pituitary adenomas 38
§No difference in OS among:
§Choose therapy based on minimizing side effects 38
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 20
Cost-effectiveness
1/25/20 Radiotherapy approaches to pituitary adenomas 39
m analysis refmect 2010 US dollars. specifjcally to assess QOL in patients suffering from ac to rely on nonspecifjc QOL questionnaires. Data obtained either source were quantifjed whenever possible to make cifjc treatments on QOL. Results Effjcacy
However, other data have shown no signifjcant improve so the overall effjcacy of this ly a fjrst-line modality and is usually reserved for treat attributable to variability in the defjnition of “remission”
39
Cost-effectiveness: GH-secreting FPA
1/25/20 Radiotherapy approaches to pituitary adenomas 40
modality actually has a higher effjcacy than both soma fjcacy data) of the 5 examined treatment regimens was specifjc regimen, however, is more diffjcult in that QOL for specifjc regimens is not feasible at this time, cost, ef fjcacy, and QOL were evaluated for individual treatments, each of the 3 domains (cost, effjcacy, and QOL) equally.
fjrst medical therapy in clinical practice, due in part to need to inject it daily. Its effjcacy, however, ranks above its high cost per dose and lifetime use), its high effjcacy nifjcantly higher QOL than SRS, it can be inferred that a higher than the domains of cost and effjcacy, in the eyes Our study suggests that surgery is the most effjcacious fjrst-line treatment option when treating a GH-secreting
TABLE 10: Effectiveness of treatments for a pituitary microadenoma Treatment Effjcacy (%) Rank Cost (lifetime) Rank QOL Rank Total Rank Score Overall Rank AcroQoL Side Effects surgery 80 1 $39,322 1 >all other therapies rare (meningitis, CSF leak) 1 3 1 peg 80 1 $2,325,423 4 given w/ SA, >SA alone common (elevated liver enzymes) 2 7 2 SAs 60 3 $1,622,597 3 <other therapies common (abdominal pain, lithiasis) 3 9 3 SRS 45 4 $56,356 2 <all other therapies hypopituitarism 4 10 4 TABLE 11: Cost-effectiveness of the newly recommended treatment approach versus previously evaluated modalities
Marko et al. JNS 2013
40
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 21
Cost-effectiveness: GH-secreting FPA
1/25/20 Radiotherapy approaches to pituitary adenomas 41
Marko et al. JNS 2013
modality actually has a higher effjcacy than both soma fjcacy data) of the 5 examined treatment regimens was specifjc regimen, however, is more diffjcult in that QOL for specifjc regimens is not feasible at this time, cost, ef fjcacy, and QOL were evaluated for individual treatments, each of the 3 domains (cost, effjcacy, and QOL) equally.
fjrst medical therapy in clinical practice, due in part to need to inject it daily. Its effjcacy, however, ranks above its high cost per dose and lifetime use), its high effjcacy nifjcantly higher QOL than SRS, it can be inferred that a higher than the domains of cost and effjcacy, in the eyes Our study suggests that surgery is the most effjcacious fjrst-line treatment option when treating a GH-secreting
TABLE 10: Effectiveness of treatments for a pituitary microadenoma Effjcacy TABLE 11: Cost-effectiveness of the newly recommended treatment approach versus previously evaluated modalities Strategy Step 1 Step 2 Step 3 Step 4 Average Cost/Pt ($) Rank 1 surgery SA peg SA + peg 495,156 3 2 surgery SRS SA peg 242,789 1 3 SA surgery SA peg 1,137,506 4 4 SA peg surgery SA + peg 1,866,837 6 5 SA SRS peg SA + peg 1,570,784 5 novel strategy surgery SA peg SA + peg 387,390 2
41
Delayed response and toxicity
1/25/20 Radiotherapy approaches to pituitary adenomas 42
§MRI 3-6 and 12 months, then annually §Endocrine evaluation every 6-12 months §Formal visual field testing annually
42
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 22
Delayed radiographic response
1/25/20 Radiotherapy approaches to pituitary adenomas 43
9 yrs post RT Kopp et al. IJROBP 2012
43
Delayed radiographic response
1/25/20 Radiotherapy approaches to pituitary adenomas 44
Kopp et al. IJROBP 2012
44
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 23
Hypopituitarism
1/25/20 Radiotherapy approaches to pituitary adenomas 45
Xu et al. Neurosurgery 2013 Hormone deficiency 20-50%
45
Hypopituitarism
1/25/20 Radiotherapy approaches to pituitary adenomas 46
Graffeo et al. IJROBP 2018 ≥11 Gy <11 Gy
46
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 24
Radiation Induced Optic Neuropathy
1/25/20 Radiotherapy approaches to pituitary adenomas 47
§EBRT: < 50-54 Gy §SRS: < 8-12 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
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
47
Radiation Induced Optic Neuropathy: (Fractionated) Radiosurgery
1/25/20 Radiotherapy approaches to pituitary adenomas 48
Milano et al. IJROBP 2018
48
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 25
Role of debulking surgery to mitigate potential SRS toxicity
1/25/20 Radiotherapy approaches to pituitary adenomas 49
Forster et al. J Neuro Onc 2018 Pre-op Post-Op
49
Role of debulking surgery to mitigate potential SRS toxicity
1/25/20 Radiotherapy approaches to pituitary adenomas 50
Forster et al. J Neuro Onc 2018
50
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 26
Secondary Malignancy
1/25/20 Radiotherapy approaches to pituitary adenomas 51
Simmons and Laws Neurosurgery 1998 17M GH/Pr-secreting FPA s/p STR f/b RT 50 Gy R temporal lobe GBM 11 yrs
51
Secondary Malignancy
1/25/20 Radiotherapy approaches to pituitary adenomas 52
Tsang et al. Cancer 1993
Glioma after Radiation Therapy/Tsang et al.
2229
Table 1. Characteristics of 305 Patients With Pituitary Adenoma Who Received Radiation Therapy No.
patients (%) Age at radiation (yr) Younger than 20 20-39 40-59 60-79 Tumor type Nonfunctional 12 (4) 106 (35) 145 (47) 42 (14) 160 (52) Prolactinoma 64 (21) Growth hormone-secreting Cushing disease Plurihormonal 48 (16) 29 (10) 4 (1) Treatment Primary radiation therapy 21 (7) Postoperative radiation therapy 237 (78) Radiation therapy for recurrence 47 (15) Requiring glucocorticoid 166 (54) Requiring thyroid hormone 164 (54) Reauirina sex hormone 149 (49) Hypopituitarism at last follow-up
Case 3 Case 2 A 34-year-old woman with acromegaly was referred in Au- gust 1974 after a partial resection of a growth hormone-se- creting pituitary adenoma via a craniotomy. She also had im- pairment of bitemporal visual fields
therapy was administered via 8-cm circular fields (laterally
riod of 4 weeks. Subsequent follow-up revealed persistence
(normal, less than 10 ng/ml). In April 1984, she reported headaches and aphasia. A computed tomography scan showed a contrast-enhancing mass in the left temporal area. She was treated with a temporal lobectomy, with debulking
External hyperfractionated radi- ation therapy was administered postoperatively, with 30 Gy in 30 fractions given four times a day (every 3 hours) in an
a year but died of recurrent glioblastoma in November 1985 at the age of 45 years. A postmortem examination confirmed recurrent glioblastoma lining the walls of the surgical defect (Fig. 3). There was a rim of residual pituitary adenoma in the posterior aspect of the largely empty sella turcica. unit (Fig. 1). The region of the brain stem received approxi- mately 21.4 Gy (Fig. 2). He was followed up regularly, and there was no recurrence of the pituitary adenoma. In July 1982, he experienced vertigo, left facial numbness, and weak-
(nystagmus, absent gag reflex). A computed tomography scan revealed a contrast-enhancing lesion in the pons. Biopsy was deemed too risky, and a clinical diagnosis of pontine glioma was made. Despite additional palliative radiation therapy in August 1982, the patient’s condition deteriorated rapidly, and he died on August 20, 1982, at the age of 36 years. A request for autopsy was refused. A 42-year-old man was found to have an enlarged sella in 1975, when a skull radiograph was taken after a minor injury at work. He had subtle visual impairment, but this was poorly
adenoma was done through a right frontal craniotomy. He received radiation therapy with 6-cm circular portals to a total dose of 50 Gy (25 fractions) during a 5-week period. Follow- up computed tomography scans revealed a residual mass in an enlarged sella with no progression over time. In December 1990, he reported a 2-month history of headache, syncope, dysarthria, and a gadolinium-enhanced magnetic resonance Table 2. Summary of Four Patients Who Had Brain Gliomas Develop After Pituitary Irradiation
Case
1
2 3
4
Diagnosis Age when radiated (yr) Year
XRT dose (Gy)
Second tumor (biopsy) Latency (yr) Treatment Occurrence of death Nonfunc adenoma 26 1972 45 6 (5) Pontine glioma (not done) GH adenoma 34 1974 42.5 2 (8) Left temporal glioblastoma (+) Nonfunc adenoma 42 1975 50 2 (6) Pontine glioblastoma (+) 10 Palliative X R T (to 10 Gy) < I 10 Surg debulking and X R T 19 (30 GY) 15 None
L
Prolactinoma 38 1979 50 2 (8) Left frontoparietal m astrocytoma (+) 8 Sur debulking and
,155 implant
23 (mo) Nonfunc: nonfunctional; GH: growth hormone; X R T radiation; m: malignant; Surg: surgical; +: positive; I iodine.
52
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 27
Secondary Malignancy
1/25/20 Radiotherapy approaches to pituitary adenomas 53
Tsang et al. Cancer 1993
2232
CANCER October 1, 2993, Volume 72, No. 7 12
I
gt
3t
23 103 7
t
201
I
5 10 15 20 Time from completion of radiotherapy (years)
Figure 6. Kaplan-Meier plot of the estimated cumulative risk of a second brain cancer versus time from completion of radiation therapy.
although it is impossible to determine whether their
prior radiation (thus allowing them to receive conven- tional postoperative radiation therapy) because astro- cytic gliomas are rarely eradicated by any form of treat-
stem, but this was the location of the glioma in two of
clusion in the radiation field(s) in most patients treated with radiation therapy. Several sources of bias can potentially affect our risk estimate. Because our patients were followed up regularly in an oncology clinic, they may be more likely to have a secondary problem diagnosed than would the general population. This is unlikely to affect our results because all four patients who had secondary brain tu- mor had gliomas, and the fatality rate (death:incidence ratio) for patients with gliomas is high.18 There is no evidence that gliomas are under-reported in the general
mors of the brain over time also can create bias. Mao et al." showed a marked increase in brain tumor inci- dence rates in the Canadian population from 1959 to 1988, primarily in those 65 years of age or older. We have chosen to use the published age-adjusted rates to minimize the dependence of incidence rates on age. We also have assumed that patients started to be at risk of a second brain tumor once their radiation therapy was
takes time (often measured in years), if there was a latency period
at risk, the real risk would be higher than our estimate. Although it is reasonable to assume that radiation is a causative factor in our observation of second brain tumors, we caution that this cannot be proved from our
increased risk of brain tumor in patients with pituitary adenomas treated by surgery or medical therapy (or in patients with treated hypopituitarism), although there is no reason to believe that it is increased. It was impossi- ble in our study to control for genetic and environmen- tal factors that may have a causative effect on a small proportion of patients with malignant brain tumors. In
radiation field(s) and occurred after a latency of 8-15
tion of radiation-induced malignancies first described by Cahan et a1." Thus, we think that radiation is the most likely causative factor. Brada et al.19 recently re- ported on a similar increased risk of second brain tu- mors in patients with pituitary adenoma who were treated by conservative surgery and radiation therapy, with a relative risk of 9.4. Two of their patients had meningiomas, two had astrocytomas, and one a menin- geal sarcoma. Because most patients with diagnoses of pituitary adenoma can have a normal or near-normal life expec- tancy,14 we believe that our risk estimates of malignant brain tumor developing after radiation therapy, with a substantially increased O/E ratio of 16 and cumulative 15-year actuarial risk of 2.7%, are clinically significant. Thus, before advising postoperative radiation therapy for pituitary adenoma, the risk:benefit ratio should be carefully considered and should take into account the risk of secondary brain tumors. Additional factors, such as patient age and condition, size
ness of surgical removal, availability of medical ther- apy, residual pituitary reserve, and reliability of the pa- tient in a surveillance policy, should be considered be- fore arriving at an individual decision regarding the use
y identifying and selecting patients based on these factors, it may be possible in the future to avoid or delay the use of radiation therapy in a significant pro- portion of patients, without increasing the risks of ade- noma-related morbidity. However, any study protocol
currence or progression of adenoma is detected early and treated appropriately, usually with repeat surgery and postoperative radiation therapy. References
docrinol Metab Clin North Am 1987; 16:667-84.
1.7% at 10yr 2.7% at 15 yr
53
Secondary Malignancy
1/25/20 Radiotherapy approaches to pituitary adenomas 54
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
54
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 28
Secondary Malignancy
1/25/20 Radiotherapy approaches to pituitary adenomas 55
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 Mamlouk et al. Neuroradiol J 2013
Latency
55
Secondary Malignancy Long Latency >20 yrs
1/25/20 Radiotherapy approaches to pituitary adenomas 56
Wu-chen et al. J Neuro-Ophthalmol 2009
TABLE 1. Continued Publication Hormonal Secretion by Initial Tumor Age at Treatment of Initial Tumor (years), Sex Radiation Dose (Gy) Latency (years) Clinical Presentation Secondary Tumor Simmons and Laws, 1998 (22) GH, PRL 17, M 50 11 Seizures Glioblastoma GH 23, F 45 18 Headache, left sided weakness Glioblastoma Alexander et al, 1998 (25) None 22, M 30.5 31 Syncope Ependymoma, meningioma, cavernous malformation Kato et al, 2000 (27) None 34, F 50 20 Aphasia and right hemiparesis Glioblastoma Gnanalingham et al, 2002 (4) None 67, F 52.2 14 Right visual loss and third cranial nerve palsy Osteosarcoma Loeffler et al, 2003 (24) GH 41, M 87 16 Left visual loss Meningioma GH 53, M 104 19 Left hearing loss Vestibular schwannoma Minniti et al, 2004 (20) None 54, M 40–50 6 NA Astrocytoma None 40, F 40–50 9 NA Astrocytoma None 48, F 40–50 7 NA Meningeal sarcoma GH 19, F 40–50 10 NA Meningioma NA 58, F 40–50 21 NA Meningioma None 22, M 40–50 34 NA Meningioma NA 22, F 40–50 22 NA Meningioma None 39, F 40–50 7 NA Astrocytoma None 39, F 40–50 29 NA Meningioma GH 51, M 40–50 6 NA Astrocytoma GH 31, M 40–50 6 NA Primitive neuroectodermal tumor Present study None 9, F NA 28 Left third cranial nerve palsy Sarcoma None 39, M 54 23 Sudden left eye visual loss Anaplastic astrocytoma
56
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 29
Secondary Malignancy Dose-Response Curve
1/25/20 Radiotherapy approaches to pituitary adenomas 57
Newhauser and Durante Nat Rev Ca 2011
a b
5–10% cancer risk
Adaptive response
Dose (Sv)
Low dose extrapolation Bystander effect Sensitive subpopulation High doses The ‘gold standard’: A-bomb survivors 0.01 0.05 0.1 1.0 2.5 10 100
AML incidence (%) Dose (Gy)
1 2 3 4 5 5 10 15 20 Neutrons Fe ions
γ-rays
recommends a linear extrapolation (the linear-no-threshold (LNT) model). However, the non-targeted (bystander) effect or the existence of radiosensitive subpopulations may suggest that the LNT model underestimates the . Conversely, an adaptive response would imply that the LNT is overestimating the risk relevant for the risk of in-field second malignant neoplasms (SMNs), is uncertain. The risk may decrease owing to cell killing SMNs in the CCSS database courtesy of E. J. Hall, Columbia University, USA.
57
Cognitive Function
1/25/20 Radiotherapy approaches to pituitary adenomas 58
Table 3. Neuropsychological test scores at baseline and 3-week and 6-month follow-up Attention Executive Memory Emotional CPT-II* WCSTy WMS-IIIz HVLT-Rx SCL-90-Ry Interval Clinical
Confidence index (%) Perseverative error T score LM-I SS LM-II SS VR-I SS VR-II SS Total Z score Learning Z score General severity index T score Pre Clinical 70.6 45 9 11 5 8 1.05 0.47 56 3 wk Clinical 62.9 50 9 12 7 11 1.74 1.53 44 6 mo Clinical 74.8 53 10 12 9 12 1.74 0.2 33 Pre Clinical 55.6 24 12 12 7 5 1 1.2 74 3 wk Nonclinical 49.9 50 11 13 7 8 1 1.2 74 6 mo N/A N/A 48 9 10 11 8 3.37 0.13 81 Pre Nonclinical 49.9 37 12 11 6 8 1.26 1.47 N/A 3 wk Clinical 60.5 43 12 12 8 9 0.74 1.2 58 6 mos Clinical 63.3 48 11 11 13 12 0.47 0.13 56 Pre Nonclinical 43.6 47 10 11 11 15 0.05 0.53 48 3 wk Nonclinical 42.7 51 9 14 9 12 0.58 2.8 68 6 mos Clinical 55.7 57 12 8 14 11 0.84 0.13 40 Pre Nonclinical 43.7 38 4 8 9 6 2.05 0.53 55 3 wk Clinical 52.6 31 6 9 9 9 3.1 0.13 52 6 mos Clinical 61.8 60 9 10 4 6 2.58 0.8 52 Pre Clinical 56.0 59 11 13 10 12 1.73 0.07 52 3 wk Clinical 88.0 56 12 13 9 11 0.65 0.79 62 6 mo N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A Abbreviations: Pre = baseline; CPT-II = conners continous performance test-II; WCST = wisconsin card sorting test; WMS-III = wechsler memory scale-III; HVLT-R = hopkins verbal learning test–revised; SCL-90-R = symptom checklist-90-R; LM = logical memory; SS = scaled score; VM = visual reproduction; N/A = not applicable.
Hahn et al. IJROBP 2009
58
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 30
Cognitive Function: Decline following whole brain radiotherapy
1/25/20 Radiotherapy approaches to pituitary adenomas 59
Gondi et al. IJROBP 2013
59
Cognitive Function: External Beam Radiotherapy
1/25/20 Radiotherapy approaches to pituitary adenomas 60
Brummelman et al. Eur J Endo 2012
Three fields technique Four fields technique Five fields technique
60
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 31
Cognitive Function: Limited data for pituitary adenoma
1/25/20 Radiotherapy approaches to pituitary adenomas 61
With different RT techniques Three fields Four fields Five fields Without RT P value* n 10 15 5 45 Estimated dosimetric data (RT dose received at 30/50/70% of the volume of:) Left hippocampus (Gy) 23.0/3.2/2.0 21.8/14.9/13.5 19.6/4.1/2.9 Right hippocampus (Gy) 28.5/4.4/2.0 29.8/15.2/14.2 19.0/4.6/2.8 Prefrontal cortex (Gy) 23.0/19.0/3.6 26.5/18.2/17.3 25.6/16.2/4.9 Memory performance (15 Words Test; mean (S.D.)) Short-term memory K0.13 (1.42) K0.65 (0.90) K0.39 (1.23) K0.20 (1.09) 0.536 Total memory K0.46 (1.66) K1.33 (1.07) K0.92 (0.72) K0.62 (1.15) 0.337 Learning score K0.23 (1.17) K0.70 (0.93) K0.16 (0.90) K0.22 (1.04) 0.280 Delayed memory 0.00 (1.39) K0.96 (1.21) K1.26 (0.67) K0.86 (1.19) 0.249 Executive functioning (Ruff Figural Fluency Test; mean (S.D.)) Unique designs K0.52 (1.08) K1.19 (1.08) K0.43 (1.39) K0.56 (1.13) 0.150 Perseverative errors K0.87 (0.73) K0.60 (0.89) K0.61 (0.67) K0.33 (1.46) 0.618 Error ratio K0.80 (0.48) K0.31 (1.40) K0.59 (0.71) K0.09 (1.78) 0.732
Brummelman et al. Eur J Endo 2012
61
RT RT RT RT Mean SD p Population reference Mean Z score SD* p RAND 36 Physical functioning 84 18 74 23 NS 82 23 0.31 0.80† 0.16 1.01 0.024 Social functioning 85 19 77 23 NS 87 21 0.06 0.88 0.40 1.08‡ NS Role limitations due to physical problems 76 38 69 41 NS 79 36 0.03 1.02 0.19 1.07 NS Role limitations due to emotional problems 88 30 78 37 NS 84 32 0.05 1.01 0.24 1.17 NS Mental health 79 14 72 20 NS 77 18 0.13 0.74 0.28 1.10 NS Vitality 66 17 56 25 0.042 67 20 0.03 0.82 0.51 1.18‡ 0.045 Pain 84 19 81 23 NS 80 26 0.27 0.76† 0.13 0.90 NS General health perception 60 19 59 24 NS 73 23 0.31 0.82‡ 0.39 1.05‡ NS HADS Anxiety 3.6 2.9 5.0 4.4 NS 4.7 3.6 0.30 0.81† 0.08 1.22 NS Depression 3.0 2.5 5.0 4.4 0.018 3.5 3.4 0.16 0.73 0.43 1.30‡ 0.018 MFI-20 General fatigue 10.3 4.3 11.6 5.6 NS 9.9 5.2 0.08 0.82 0.33 1.08 NS Physical fatigue 9.2 4.0 11.8 5.4 0.015 8.8 4.9 0.07 0.82 0.62 1.10‡ 0.015 Reduced activity 8.8 4.3 10.6 5.1 NS 8.7 4.6 0.03 0.93 0.42 1.10‡ NS Reduced motivation 8.9 3.7 10.1 5.3 NS 8.2 4.0 0.18 0.94 0.46 1.31‡ NS Mental fatigue 8.4 4.8 10.9 5.3 0.035 8.3 4.8 0.03 1.00 0.53 1.10‡ 0.035 CFQ Memory 28 18 28 22 NS na Distractibility 35 18 36 19 NS na Blunders 30 16 29 20 NS na (Memory for) names 46 23 51 24 NS na Abbreviations: RT radiotherapy; NS nonsignificant; HADS Hospital Anxiety and Depression Scale; MFI-20 Multidimensional
Cognitive Function: Limited data for pituitary adenoma
1/25/20 Radiotherapy approaches to pituitary adenomas 62
Van Beek et al. IJROBP 2007
62
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 32
Vasculopathy: Radiotherapy
1/25/20 Radiotherapy approaches to pituitary adenomas 63
Brada et al. IJROBP 1999 331 patients FPA/NFPA 1962-1986 CVA RR 4.1
63
Vasculopathy: Radiotherapy
1/25/20 Radiotherapy approaches to pituitary adenomas 64
Tolinson et al. Lancet 2001
6 5 4 1 2 3 Standardised mortality ratio Total (all cause)
p=0·015
Respiratory Malignancy
p=0·036
Circulatory Cerebrovascular
p=0·001 Radiotherapy No radiotherapy
1014 patients 57% NFPA All hypopit 1992-2000 Median f/u 11 yrs
64
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 33
Vasculopathy: Radiotherapy
1/25/20 Radiotherapy approaches to pituitary adenomas 65
Brown et al. NOP 2014 RT Sg alone 143 patients FPA/NFPA 1933-2000 Median f/u 15.5 yrs
65
Vasculopathy: Repeat Radiotherapy
1/25/20 Radiotherapy approaches to pituitary adenomas 66
Brown et al. NOP 2014 Re-RT Sg/RT 143 patients FPA/NFPA 1933-2000 Median f/u 15.5 yrs
66
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 34
1/25/20 Radiotherapy approaches to pituitary adenomas 67
67
Surgery, Radiotherapy, Systemic Therapy
1/25/20 Radiotherapy approaches to pituitary adenomas 68
Heaney J Clin Endocrinol Metab 2011
68
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 35
1/25/20 Radiotherapy approaches to pituitary adenomas 69
§Adaptive hybrid radiosurgery §Proton/charged particles §Molecular prognostic markers/indices
69
Adaptive Hybrid Radiosurgery
1/25/20 Radiotherapy approaches to pituitary adenomas 70
RADIOSURGERY SURGERY
70
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 36
1/25/20 Radiotherapy approaches to pituitary adenomas 71
71
1/25/20 Radiotherapy approaches to pituitary adenomas 72
72
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 37
1/25/20 Radiotherapy approaches to pituitary adenomas 73
73
1/25/20 Radiotherapy approaches to pituitary adenomas 74
Radiation Modality: Photons 74
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 38
1/25/20 Radiotherapy approaches to pituitary adenomas 75
Radiation Modality: Protons
commons.wikimedia.org
75
1/25/20 Radiotherapy approaches to pituitary adenomas 76
RTOG 0933: Phase II Hippocampal Sparing Whole Brain RT for BM
Restrict dose to hippocampus improved measures of cognition and QoL
76
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 39
1/25/20 Radiotherapy approaches to pituitary adenomas 77
Proton Therapy
Kennedy et al. App Rad Onc 2015
n
tologically confjrmed prior to RT. Only Of the 16 who received surgery, 15 un tient was classifjed as undergoing a gross in 5 patients, and defjnitive treatment in 1
FIGURE 1. Typical proton therapy beam arrangements and apertures in a (A) “mohawk” configuration and (B) 2-lateral oblique and superior-
A B
77
1/25/20 Radiotherapy approaches to pituitary adenomas 78
Proton Therapy: N=17, 3yr-LC 100%
Kennedy et al. App Rad Onc 2015
n
years). A recent review by Loeffmer et al. Our series reports treatment of 4 patients with functioning tumors—2 Other documented complications of
78
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 40
1/25/20 Radiotherapy approaches to pituitary adenomas 79
Proton Therapy: N=47
Ronson et al. IJROBP 2006
79
Diagnostic Parameters for APAs/TPAs Cut-off Sensitivity Specitifity Youden-Index Accuracy in % AUC 95 % CI
OR 95 % CI
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
[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
1/25/20 Radiotherapy approaches to pituitary adenomas 80
Miermeister et al. Acta Neuropathologica Comm 2015
80
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 41
Diagnostic Parameters for APAs/TPAs Cut-off Sensitivity Specitifity Youden-Index Accuracy in % AUC 95 % CI
OR 95 % CI
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
[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 Early vs Late Adjuvant EBRT/SRS
1/25/20 Radiotherapy approaches to pituitary adenomas 81
Miermeister et al. Acta Neuropathologica Comm 2015
81
§Management is interdisciplinary §Goal is to minimize morbidity §Radiotherapy for refractory/recurrent disease §Excellent control outcomes §Radiotherapy techniques individualized by clinical features
1/25/20 Radiotherapy approaches to pituitary adenomas 82
82
[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1/25/20 42
83