management of pituitary adenoma

1. Current Management of Pituitary
Adenoma: Role of Radiotherapy
Presenter: Dr Rashmi Sarawagi
Moderator: Dr Subhash Gupta

2. Anatomy
• Also known as hypophysis cerebri
• Endocrine organ, size:1.3x1.0x0.5cm , weighs 0.55 to 0.6gm
• Situated in the hypophysial fossa of sphenoid bone
• Relation: Above- optic chiasma
Below- intercavernous venous sinus and sphenoid air sinus
• Divided into two main parts: adenohypophysis and neurohypophysis
• Adenohypophysis comprises pars infundibularis, pars intermedia and pars
distalis
• Neurohypophysis comprises median eminence, infundibular stem and
infundibular process or neural lobe

3. • Adenohypophysis constitute
about 80% of total volume of
pituitary gland and it is an
embryologic diverticulum from
buccopharyngeal region
• Adenohypophysis secretes GH,
PRL,FSH, LH, TSH, ACTH, MSH,
Endorphins
• Neurohypophysis develops as a
diverticulum from floor of third
ventricle

5. Pituitary Adenoma
Functioning Adenoma
Non-functioning
Adenoma

6. Epidemiology
• Accounts for 10-15% of CNS neoplasms with 10,000 cases diagnosed/year
• Age:30-50yrs
• M:F: 1:1, but females more frequently symptomatic and have higher
incidence rate until 30 yrs when pattern reverses
• Incidence higher in African Americans
• 75% are secretory

7. Classification Systems

9. Specific types of pituitary adenoma

10. Prolactinoma
• Most common
• Normal PRL level: <25ng/ml
- >100ng/ml for macroadenoma, 30-100ng/ml for
microadenoma
Clinical feature:- amenorrhea, galactorrhea, loss of libido, infertility.
At older age, clinical manifestation can be subtle and present with mass
effect as primary symptom such as headache, visual deficit.

11. • Only pituitary tumor for which medical therapy has a proven primary
role
• Dopamine Agonist: Bromocriptine, Cabergoline

12. Growth Hormone secreting tumor
• Second most common
• Clinical Feature: Gigantism in children before fusion of epiphyses
Acromegaly in young adults after fusion of epiphyses
(enlarged hands and feet, increased bone density, enlarged thyroid,
heart, liver, adrenals, broadening of lower face with jaw protrusion that
can develop into prognathism)

13. • First line treatment is surgical removal via transphenoid approach.
• For patients failing surgery, 50-60% shows reduced GH/IGF-1 level
with somatostatin analogues(octreotide)
• GH receptor antagonist (pegvisomant) reduced IGF-1 level but not GH
if other treatment fails

14. ACTH secreting pituitary adenomas
• Corticotrophin cell adenomas usually present as microadenoma
• Excess secretion leads to Cushing Syndrome, with a chronic
hypersecretion of cortisol from adrenal stimulation
• More common in women and younger patients
• ACTH precursor molecules can also stimulate melanocytes, thus
producing hyperpigmentation

15. Clinical feature

16. • First line treatment is surgery i.e. transsphenoidal surgical resection
• Remission rate after surgery : 89% for microadenomas, 63% for
macroadenomas and 81% for macroadenomas where GTR anticipated
• RT is preferred second line treatment over medical management

17. TSHoma(hyperthyroidism)
• Rare, found in about 1% of patients
• 90% macroadenomas
• Mixed hormonal secretion-30%
-GH, PRL, Gonadotropins
• Mean duration of presentation 9 yrs
• C/F: goitre, warm skin, heat intolerance, cardiac arrhythmias and other
hyperthyroid features

18. • First line treatment is surgery
• Consider post-op RT to higher dose of 54Gy as TSHoma are locally
aggressive and less responsive to RT
• Somatostatin analogues: > 90% respond
• Dopamine agonists: Bromocriptine- 20% respond

19. Gonadotropinomas
• Luteinizing or follicle stimulating producing tumor of middle age men
and women
• Clinical features of mass effect: visual symptoms, hypogonadism,
amenorrhea, chronic fatigue

20. Nonsecretory/functioning adenoma
• 25-30% of patients do not have classical hypersecretory syndromes
• May grow to a large size before they are detected
• Present due to mass effect- Visual deficits, Hormonal deficiency
• First line treatment is surgery to relieve compression

21. RADIOTHERAPY
-Transsphenoidal surgery is recommended first-line treatment for
pituitary adenoma.
- External beam radiation therapy (RT) should be offered to patients
with residual, recurrent, or progressive disease uncured by surgery
and/or medical therapy.
- RT is associated with excellent long-term local tumor control but
somewhat lower and variable rates of biochemical remission

22. INDICATION
Patients with non-functioning adenomas
 at the time of progression
 If there are concern of significant threat to function( vision) with tumor progression
 Histology with concern of earlier recurrence risk, e.g atypical features, silent corticotroph
adenoma
 Residual disease
Patients with functioning adenomas
 when surgery and medical treatment is insufficient to normalize hormone level.
 Medically inoperable
 Upfront adjuvant RT should be considered in patients with adverse features such as high
proliferative index, atypical histology or invasion, that may be associated with higher risk of
recurrence after surgery alone

24. Immobilization device
• custom-made closely fitting lightweight thermoplastic mask- most
commonly used system for immobilization
• Repositioning accuracy of this system is 3-5mm, can be improved to
2-3mm, by using tighter fitting but less comfortable mask

26. 3D CT SIMULATION
• CONTRAST CT BRAIN (3-7min)
• 3mm or less slice thickness
• Planning CT coregistered with MRI

33. Tumor volume delineation
• For NFPA, any grossly visible tumor is delineated as gross tumor
volume (GTV).
• No specific need for defining a clinical target volume (CTV) in NFPA to
encompass microscopic extension of disease given its benign nature,
well-defined margins, and lack of infiltration/invasion.
• In view of potential uncertainties in GTV delineation, errors in
multimodality fusion, and particularly in the presence of cavernous
sinus invasion- use an isotropic margin of 3–5 mm around the GTV, to
be edited away from natural anatomic barriers to create the CTV.

34. • Patients with functional pituitary adenoma, gross tumor may or may
not be visible on imaging, with microscopic tumor cell rests being
responsible for persistently elevated hormonal levels in the absence
of visible tumor
• Entire sella should be included in the CTV to encompass any residual cell
rests.
• An isometric expansion of the CTV by 3–5 mm defines the planning
target volume (PTV) to account for geometric uncertainties and set-
up errors

35. RADIOTHERAPY TECHNIQUES

36. Stereotactic Radiosurgery (SRS)
• Reserved for small adenomas (typically <2–3 cm) which are well
defined and are located away from the optic chiasm (≥3 mm)
• Leksell GammaKnife-
• dedicated SRS system
• 180–201 miniaturized radio-active cobalt (60 Co) sources in a hemispherical
array
• emitted ionizing radiation is focused via means of primary and secondary
collimation to achieve extreme degree of conformality for small intracranial
targets
• excellent sparing of surrounding normal critical structures

37. • CyberKnife
• robotic radiosurgery system
• linear accelerator mounted on a robotic arm
• extreme degree of conformality due to the potential of few hundred
noncoplanar beam trajectories in conjunction with a robotic couch
(integrating all six degrees of freedom) and stereoscopic image-guidance
during delivery
• Linear accelerator-based SRS
• incident beam is conformally shaped by either fixed or removable variable
apertures (microMLCs, collimators, or cones)
• allow a high degree of conformality for efficient delivery of radiosurgical
treatments

38. Dose Fractionation Schemes
• Conventional fractionated RT are given to total dose of 45 to 50.4 Gy
at 1.8 Gy per fractionation, once a day, five days per week
• The recommended dose of SRS in pituitary adenoma ranges from 12–
20Gy given in a single fraction, with higher doses (16–20Gy) being
preferred in functioning/secretory adenomas, while keeping the dose
to optic chiasma constrained to a maximum dose (Dmax) of <8–10Gy.
• In recent times, hypofractionated SRS delivering 5–8Gy per fraction in
3–5 fractions over 1–2 weeks has emerged as an alternative
radiosurgery schedule in pituitary adenoma.

39. Role of particles(protons and heavy ions)
• Attractive option due to the inherent physical characteristics of such
beams whereby dose deposition in normal tissues both proximal and
distal to the target is negligible on account of the Bragg peak, hence
reducing RT-induced late effects, particularly second malignancies.
• Proton therapy has been used to treat patients in single institutional
series with high rates of local control.
• Longer and mature follow-up on the available proton literature with
regards to the incremental benefit of neurocognitive preservation and
mitigation of long-term toxicities is likely to clarify its role in the
future.

40. Efficacy of treatment
TUMOR CONTROL
- actuarial PFS is in the region of 80%-90% at 10 years and 75%-90%
at 20 years
- Single largest series of patients with pituitary adenomas treated
with conventional fractionated radiotherapy is that from The Royal
Marsden Hospital which reported a 10-year PFS of 92% and a 20-year
PFS of 88%

41. BIOCHEMICAL CONTROL
-For acromegaly, RT achieves normalization of GH/IGF-I levels in
30-50% of patients at 5-10 years, and in 75% of patients at 15 years,
after treatment
-For Cushing’s disease, urinary free cortisol (UFC) is reduced to
50% of the pre-treatment levels after an interval of 6-12 months, and
plasma cortisol after around 12 months
The overall tumor and hormone control rates in the reported
studies, at median follow up of 8 years, are 97% and 74% respectively
-For prolactinoma, the reported 10-year tumor and hormone
control rates are 90% and 50% respectively

45. • Local control (>90%) and biochemical remission rates (50%–80%) with
SRS are also similar to fractionated RT in Cushing's disease,
acromegaly, and prolactinoma.
• Some reports has demonstrated that reduction of hormonal
hypersecretion, particularly cortisol and less commonly for GH/IGF-1
starts earlier leading to faster biochemical remission with SRS
compared to fractionated RT.
• Hormonal response to SRS is diminished in patients on medical
management of hormonal hypersecretion, leading to the
recommendation of temporary discontinuation of suppressive
medications 6–8 weeks prior to planned SRS.

46. • More recently, biochemical recurrence after initial remission have
been reported in patients receiving and continued on cabergoline for
ACTH-secreting pituitary adenoma during fractionated high-precision
RT.
• It is therefore recommended that medical management be withheld
temporarily prior to SRS/RT in functioning/secretory adenomas.

49. TOXICITY
• Hypopituitarism- most common complication, occur in 30-60% of
patients by 10 years after treatment
- sequence of Hormones affected:
GH > gonadotrophins > ACTH> TSH
• Visual Pathway Deficit and other structural CNS damage
- incidence of optic neuropathy is 1-3%

50. • Cerebrovascular Disease
- In a retrospective cohort study of 342 patients treated with
pituitary surgery and post-operative RT, 31 patients died from stroke
after a median follow-up interval of 21 years
• Second brain tumor: 2% at 20 years
• Neurocognitive Deficit

51. SUMMARY
• Radiation therapy should not be considered as a first-line alternative
to surgery or medical management in pituitary adenomas
• RT should be offered to patients with residual, recurrent, progressive,
or high-risk tumors with careful assessment of the benefit-risk ratio
• RT is an effective treatment modality providing excellent (>90%) local
control, but, somewhat lower and variable (50%–80%) rates of
biochemical remission in functional/secretory tumors

52. Thank You