Radiation Oncology/CNS/Pituitary adenoma

Pituitary Adenoma

Epidemiology

 * Comprise ~10% of intracranial tumors
 * On autopsy found in 5-25%
 * Male:female 1:1
 * Majority present between 30 and 50 years old
 * Genetic predisposition in MEN-1
 * Benign histologically
 * Nonsecretory ~25%
 * Secretory (hormonally active) ~75%
 * Typically slow growth with insidious onset of symptoms

Anatomy

 * Pituitary gland is confined within the sella turcica, part of the sphenoid bone.
 * It measures ~1.5 cm
 * Divisions
 * Anterior pituitary (from Rathke's pouch): prolactin, growth hormone, ACTH, TSH, FSH, LH, and beta endorphin
 * Intermediate lobe (from Rathke's pouch): MSH
 * Posterior pituitary (from 3rd ventricle): oxytocin, ADH
 * Due to the bony sella enclosure, growth of pituitary tumors is upward

Clinical presentation

 * Incidental imaging finding
 * Local compression
 * Pituitary stalk: disruption of prolactin suppression from hypothalamus, leading to PRL overproduction
 * Optic chiasm: visual symptoms, including bitemporal hemianopsia and loss of color discrimination
 * Cavernous sinus: cranial nerve palsies, particularly ocular palsies
 * 3rd ventricle: hydrocephalus
 * Headaches
 * Functional secretory symptoms
 * Prolactin (~50%)
 * Women: galactorrhea and hypoestrogenism, including decreased menstruation, anovulatory infertility, loss of libido, vaginal dryness
 * Men: loss of libido, erectile dysfunction, infertility
 * Growth hormone (~25%)
 * Acromegaly: bone enlargement in hand/feet/skull, prominent jaw, cardiomegaly, heat intolerance, weight gain
 * ACTH (~20%)
 * Cushing's disease: central obesity (moon facies, buffalo hump), thin skin with striae, hirsutism
 * Nelson's syndrome: hyperpigmentation and muscle weakness
 * TSH (<1%)
 * hyperthyroid symptoms
 * Other hormonal tumors are rare

Diagnosis

 * MRI
 * Endocrine evaluation
 * Prolactin level (>100 ng/ml)
 * Basal GH level (>10 ng/ml), IGF-1 level, glucose suppression
 * Serum ACTH, free cortisol, dexamethasone suppression (>10 ug/ml after 8 hours)
 * TSH, T3, T4
 * FSH, LH, plasma estradiol, testosterone
 * Skeletal survey in acromegaly

Staging

 * By tumor size
 * Microadenoma (<1 cm)
 * Macroadenoma (>1 cm)
 * By expansion or erosion of the sella (PMID 945663), not uniformly accepted
 * Grade 0: Intrapituitary microadenoma with normal sellar appearance
 * Grade I: Normal-sized sella (15 × 12 mm) with asymmetry of the floor
 * Grade II: Enlarged sella with an intact floor
 * Grade III: Localized erosion or destruction of the sellar floor
 * Grade IV: Diffusely eroded or destroyed floor

Treatment Overview

 * Observation for select nonsecreting microadenomas and small prolactinomas
 * Microadenoma, not secreting prolactin: surgery
 * Microadenoma, secreting prolactin: bromocriptine
 * Macroadenoma: multimodality approach, typically surgery, if failed to suppress biochemically, then adjuvant/salvage RT

Medical Management

 * Primary approach for prolactinomas
 * Dopamine agonists - bromocriptine, cabergoline
 * Salvage approach for acromegaly, if inadequate control after surgery
 * Somatostatin analogues - octreotide, lanreotide
 * Symptomatic management for Cushing's disease
 * Ketoconazole to suppress cortisol secretion in adrenal glands

Surgery

 * Goal:
 * Decompress local symptoms
 * Normalize endocrine function for secreting tumors
 * Standard surgical approach is a transsphenoidal resection, either microsurgical or transsphenoidal
 * For localized secretory tumors, surgical cure rate is 80-90%
 * With biochemical failure, on second surgery tumor often found extending through dura into cavernous sinus. Success rate on reoperation tends to be lower
 * Mortality 0.5%, significant morbidity ~1.5%

Conventional External Beam

 * Control of hypersecretion (Perez & Brady)
 * Acromegaly ~80%
 * Cushing's disease 50-80%
 * Hyperprolactinemia ~30%

Stereotactic Radiosurgery (SRS)

 * Multi-Institutional; 2005 PMID 15871511 -- "Stereotactic radiosurgery for pituitary adenomas: an intermediate review of its safety, efficacy, and role in the neurosurgical treatment armamentarium." (Sheehan JP, J Neurosurg. 2005 Apr;102(4):678-91.)
 * Systematic literature review. 35 studies, 1621 patients treated with SRS.
 * Outcome: Tumor size control ~90%; wide variability in endocrine control
 * Toxicity: Risk of hypopituitarism, 2nd tumors, and cerebral vasculopathy appeared less than fractionated RT
 * Conclusion: SRS offeres both safe and effective treatment for recurrent or residual pituitary adenomas; in rare instances it may be the best initial treatment

Proton Therapy

 * Harvard
 * GH; 1968 (1963–1967) PMID 4966299 -- "Proton-beam therapy in acromegaly." (Kjellberg RN, N Engl J Med. 1968 Mar 28;278(13):689-95.)
 * Retrospective. 14/22 patients with acromegaly. Median time from onset to treatment 11.8 years. 5 prior RT therapy (36-40 rads). Proton dose typically 100-120 Gy (60-140 Gy), given 12 portals.
 * Outcome: 7/12 improved clinically, 3/12 unchanged, 2/12 worse.
 * Complications: Transient diplopia, H/A, anterior pituitary insufficiency
 * GH; 2007 (1992–2003) PMID 18194929 -- "Proton stereotactic radiosurgery in management of persistent acromegaly." (Petit JH, Endocr Pract. 2007 Nov-Dec;13(7):726-34.)
 * Retrospective. 22 patients, persistent acromegaly, at least 1 transsphenoidal surgery without biochemical cure. Median dose 20/1 CGE (15-24). Median F/U 6.3 years
 * Outcome: CR (≥ 3 month normalization of IGF-1 without medical suppression) in 59%; median time to CR 3.5 years.
 * Toxicity: New pituitary deficits 38%; no visual complications, seizures, brain injury or secondary tumors
 * Conclusion: Proton SRS effective for persistent acromegaly, with low morbidity
 * ACTH; 2008 (1992–2005) PMID 18029460 -- "Proton stereotactic radiotherapy for persistent adrenocorticotropin-producing adenomas." (Petit JH, J Clin Endocrinol Metab. 2008 Feb;93(2):393-9. Epub 2007 Nov 20.)
 * Retrospective. 38 patients (33 Cushing's disease and 5 Nelson's syndrome), all with prior transsphenoidal surgery without biochemical cure, treated with proton SRS. Patients with NS underwent bilateral adrenalectomy median 40 months before SRS. Median F/U 5.2 years
 * Outcome: CR (≥ 3 month normalization of urinary free cortisol without medical therapy) in Cushing's 52% and Nelson's 100%. Median time to CR 1.5 years
 * Toxicity: New pituitary deficits 52%; no optic nerve damage, seizure or brain injury
 * Conclusion: Proton SRS effective for persistent ACTH-secreting adenomas, with low morbidity
 * Loma Linda; 2006 (1991–2001) PMID 16257131 -- "Fractionated proton beam irradiation of pituitary adenomas." (Ronson BB, Int J Radiat Oncol Biol Phys. 2006 Feb 1;64(2):425-34. Epub 2005 Oct 27.)
 * Retrospective. 47 patients with pituitary adenomas. 42 prior resection, 5 primary RT. Functional 49% (n=23). Median dose 54 CGE in 30 fractions, mean target volume 8 cm3
 * Outcome: Stabilization in 100% with visible tumor, resolution 24%, regression 29%, stabilization 46%. If functional, biochemical control 86%, normalization 38%. OS 89%, due to disease progression 2 patients (Cushings)
 * Toxicity: Temporal lobe necrosis with headaches 1 patient (2%), new visual deficits 3 patients (23%), hypopituitarism 11 patients (30%), panhypopituarism 2 patients (5%)
 * Conclusion: Fractionated proton RT achieved effective radiologic, endocrinological, and symptomatic control; significant morbidity uncommon
 * Saint Petersburg, Russia
 * 1988 PMID 2848234 -- "[Effect of proton irradiation of the hypophysis on its gonadotropic and thyrotropic functions in patients with prolactinoma][Article in Russian]" (Isakov AV, Probl Endokrinol (Mosk). 1988 Jul-Aug;34(4):28-32.)
 * Retrospective. 16 women, prolactin-secreting adenoma. Narrow beam proton therapy (1000 MeV) 40-120 Gy. Tested 2 month-2 years with IV TRH and LH-RH
 * Outcome: Low reproductive function recover, lower functional reserves of hypophyseal thyrotrophs and gonadotrophs
 * Conclusion: Refractivity to radiation exposure, and hypothalamic level of disorder of ovarian function regulation
 * 1993 PMID 7801584 -- "[Results of proton therapy in the treatment of pituitary prolactin-secreting adenomas][Article in Russian]" (Konnov BA, Vestn Rentgenol Radiol. 1993 Sep-Oct;(5):46-9.)
 * Retrospective. 75 female patients, prolactin-secreting pituitary adenomas. Narrow beam proton therapy (1000 MeV)
 * Outcome: Response rate 96% in adenoma stage I-IIIa
 * Conclusion: Outcomes superior to other treatment modalities
 * Lawrence Berkeley Laboratory
 * 1991 PMID 1808652 -- "Heavy-charged-particle radiosurgery of the pituitary gland: clinical results of 840 patients." (Levy RP, Stereotact Funct Neurosurg. 1991;57(1-2):22-35.)
 * Retrospective. 840 patients, 30 treated with protones, and 810 with helium ion. Pituitary tumors n=475 (59%), systemic disease treatment by inducing hypopituitarism n=365 (41%).
 * Outcome: Great majority marked and sustained biochemical and clinical improvement
 * Toxicity: Hypopituitarism in ~30%, focal temporal lobe necrosis ~1%
 * 1980 (1957–1978) PMID 7415170 Full paper -- "Treatment of acromegaly, Cushing disease and Nelson syndrome." (Lawrence JH, West J Med. 1980 Sep;133(3):197-202.)
 * Retrospective. 429 patients (acromegaly 72%, Cushing's disease 13%, chromophobe adenoma 8%, prolactin-secreting adenoma 4%, Nelson's syndrome 4%). Treated with alpha particles or protons. Dose ~60 Gy
 * Outcomes reported
 * ITEP, Russia; 1983 PMID 6314085 -- "[Proton therapy of pituitary adenomas][Article in Russian]" (Minakova EI, Med Radiol (Mosk). 1983 Oct;28(10):7-14.)
 * Retrospective. 59 patients. Beam energy 200 MeV, beam diameter 7-15mm
 * Outcome: Results reported. Least favorable results in prolactinomas
 * Toxicity: No marked radiation reactions, neurological complications, or hypopituitarism

Radiotherapy vs Observation

 * Netherlands (1979–98) PMID 17197121 -- "Immediate postoperative radiotherapy in residual nonfunctioning pituitary adenoma: beneficial effect on local control without additional negative impact on pituitary function and life expectancy." (van den Bergh AC, Int J Radiat Oncol Biol Phys. 2007 Mar 1;67(3):863-9.)
 * Cohort study. 122 pts with nonfunctioning adenomas. 1) Group 1 (Radiotherapy) / residual disease - 76 pts (62%), immediate postoperative radiotherapy at a median of 5.8 months. 2) Group 2 (Observation) / residual disease - 28 pts (23%). 3) Group 3 (No Residual) - 18 pts (15%). 3 pts in group 3 received immediate post-op RT.
 * Median f/u 93 months (Group 1), 71 months (Group 2).
 * Group 1 (RT): progression in 3 of 76 pts (4%). Local control rate 95% at 5 and 10 years.
 * Group 2 (Obs): progression in 16 of 28 pts (57%). Local control rate 49% and 22% at 5 and 10 years. 14 of the 16 pts received RT for salvage (6 RT only, 8 RT + surgery). Control rate after salvage RT 95%.
 * Group 3 (No Residual): progression in 1 of 18 pts (6%).
 * Endocrine function: no difference between Groups 1 and 2.
 * Conclusion: "Immediate postoperative radiotherapy provides a marked improvement of local control among patients with residual NFA compared with surgery alone, without an additional deleterious effect on pituitary function and life expectancy."