by Howard H. Pai, M.D., FRCPC, and Anne Klibanski, M.D.
NEPTCC Newsletter MGH Neuroendocrine Center Bulletin Vol 6, Issue 1, Winter 2000
The treatment of benign and malignant neoplasms in the head and neck region and the brain represent a special challenge to oncologists due to the close proximity of these tumors to neurovascular structures. Surgical access is limited and complete tumor resection is often not possible due to the risk of damage to neurovascular structures with aggressive surgery. Extensive surgery can also result in significant disfigurement or loss of function. Some examples include malignant neoplasms of the nasopharynx, nasal cavity and paranasal sinuses, benign and malignant tumors of the brain such as meningiomas, gliomas, and neuroectodermal tumors. Neoplasms located in the base of skull region is another example of where surgical resection is limited by the presence of critical structures such as the pituitary gland, hypothalamus, brainstem, cranial nerves and blood vessels. External beam radiation therapy has the advantage of being non-invasive and has an established role in the management of these tumors. The delivery of radiation therapy to this region must be very carefully planned, as these structures are also susceptible to damage by radiation. One clinically relevant aspect of radiation effects on normal tissue in this region is the neuroendocrine effect of radiation to the pituitary gland and hypothalamus, which is the focus of this article
It is well-established that therapeutic doses of radiation can cause damage to the pituitary gland and hypothalamus. For example, patients with secretory pituitary adenomas who are treated with external beam radiation therapy, typically with fractionated doses of at least 45 Gy, have a gradual decline in excess hormone production by the adenoma. However, because the rest of the normal pituitary gland receives the full dose of radiation, a decline in the other hormones secreted by the pituitary gland is frequently observed. One could debate whether the presence of the adenoma itself compromises pituitary gland function thus contributing to hypopituitarism after external beam radiation therapy. However, patients treated with external beam radiation therapy for non-pituitary gland neoplasms also exhibit hypopituitarism following external beam radiation therapy. Evidence supporting hypothalamus and pituitary gland damage following external beam radiation therapy for non-pituitary gland tumors comes from several sources. Children who receive cranial or craniospinal irradiation for leukemia or primary tumors of the brain often develop hypopituitarism. Hypopituitarism is manifested by anterior pituitary gland hormone deficiencies. Clinically apparent growth hormone insufficiency is particularly prevalent in children. Other anterior pituitary gland hormones can also be affected with deficiencies in TSH, LH, FSH, and ACTH. Patients can also develop hyperprolactinemia after external beam radiation therapy. The mechanism involves decreased availability of dopamine from the hypothalamus to the pituitary gland through radiation damage to the hypothalamus or portal system. The inhibitory effect of dopamine on prolactin secretion is diminished, resulting in a rise in prolactin. More than one hormone can be affected. A less common neuroendocrine effect is precocious puberty observed in prepubertal patients. For reasons not well understood, vasopressin insufficiency (an indicator of posterior pituitary gland function) after external beam radiation therapy is rarely seen.
Radiation induced pituitary gland-hypothalamic dysfunction also occurs in adults with high incidence. The same type of anterior hormone deficiencies can occur as with children. The incidence of each hormone defect varies from study to study. Growth hormone deficiency can range from 60 to 100%, hyperprolactinemia from 15% to 85%, hypothyroidism from 15 to 65%, hypoadrenalism from 14 to 55%, and hypogonadism from 30 to 60%. Clinically overt diabetes insipidus is a very uncommon event in adults, similar to children.
Hypopituitarism after external beam radiation therapy is a late effect typically occurring 2-3 years after radiation therapy but as early as 6 months. Patients continue to be at risk many years after completion of external beam radiation therapy with cases documented 10 to 15 years after treatment. Thus, the importance of lifelong monitoring after external beam radiation therapy cannot be over-emphasized. The patho-physiological mechanism of damage is not well elucidated but may reflect damage to the microvasculature of the pituitary gland or portal system or direct damage to the hormone producing cells of the pituitary gland. The hypothalamus is also susceptible to radiation injury resulting in hypopituitarism.
Monitoring of hypothalamic-pituitary gland function following external beam radiation therapy begins with a complete baseline evaluation prior to completion of external beam radiation therapy to detect any pre-existing endocrine deficits. Baseline neuroendocrine evaluation should assess central and end organ endocrine function including thyroid, adrenal, gonadal, prolactin, vasopressin, and growth hormone secretion when appropriate, using history and physical and blood tests. Provocative blood tests can be used to determine a central or primary origin but certain stimulatory tests such as insulin stress test are relatively contraindicated in patients with brain or parasellar tumors due to the risk of hypoglycemia induced seizures especially if prior neurosurgical procedures have been performed. Patients should be routinely monitored for endocrine changes at 6 months after completion of external beam radiation therapy and then at 1 year and yearly thereafter. Our protocol for neuroendocrine follow-up after external beam radiation therapy to the pituitary gland-hypothalamic region consists of a history and physical, blood levels for prolactin, T4, fT4, 8 am cortisol and/or ACTH stimulation test, FSH, LH, free and total testosterone in males and estradiol in non-menstruating pre-menopausal females. Subclinical adrenal insufficiency is important to diagnosis and treat to avoid precipitating acute adrenal insufficiency during periods of stress such as a surgical procedure. Tests for vasopressin or growth hormone insufficiency are only ordered for adults with symptoms or signs suspicious for diabetes insipidus or in whom GH therapy is contemplated, respectively. Hormone replacement should be instituted when an endocrinopathy is found. Controversy exists as to whether GH replacement should be offered for adult patients with neoplasms. Although there are no data supporting tumor proliferation during exogenous GH administration, it has been our policy to avoid growth hormone replacement for adults after radiation therapy for malignant or aggressive neoplasms.
Table 1. Neoplasms which frequently require radiation therapy to the pituitary / hypothalamus region
- Primitive neuroectodermal
tumor of the CNS (e.g.
- Pineal gland tumors
- CNS Germ cell tumors
- Gliomas, ependymomas of
the brainstem or thalamus region
- Pituitary adenomas
- Parasellar meningiomas
- Chordomas, chondrosarcomas,
giant cell tumors of the clivus or parasellar region
- Cancer of the nasopharynx,
nasal cavity or paranasal sinuses
Not all patients who receive radiation to the pituitary gland-hypothalamic region develop pituitary or hypothalamic insufficiency. Several factors may influence the risk of developing hypopituitarism. These include age, gender, daily dose of radiation and total dose of radiation delivered to the pituitary gland and hypothalamus. With respect to gender, women become hyperprolactinemic after radiation more often than men. Patients who are older (e.g. > 40-50 years) tend to have a higher incidence of endocrinopathies after radiation, noted in 3 separate studies. One possible explanation for this may be decreased pituitary reserve with aging. Limited data have suggested that fraction size or the daily dose of radiation delivered may influence the risk of endocrinopathy with larger fraction sizes causing a higher incidence of hypopituitarism . This observation is consistent with the general axiom that larger fraction size is associated with increased late toxicity for neurovascular tissue. The total dose of radiation absorbed by the pituitary gland and hypothalamus is undoubtedly a risk factor for causing hypothalamic-pituitary gland damage resulting in hypopituitarism. In the early 1980’s, the first indication of a dose response was suggested in a report from Australia, albeit from a small series of patients and with only estimations of dose to the pituitary gland and hypothalamus and using fraction sizes not considered standard in the US. In the late 80’s, a large series of patients (n=268) who received cranial irradiation for various neoplasms were analyzed for dose response effect . It was noted that at very low therapeutic doses of radiation of 12 Gy, the incidence of endocrinopathy was negligible. At doses > 20 Gy, the incidence became clinically relevant and a dose response was seen between 20 Gy and 35 Gy or above. This study was performed in United Kingdom where higher dose per fraction (e.g. 2.5 to 3.75 Gy per fraction) was used compared to US standards. A smaller series of patients (n=32) treated at the University of Rochester in NY were analyzed and found to have a dose response such that patients receiving doses greater than 50 Gy had a higher incidence of hypothyroidism and hypoadrenalism . A dose response from 18 Gy to > 24 Gy to > 35 Gy for GH insufficiency exists for children treated with cranial irradiation for acute leukemia or brain tumors. At Massachusetts General Hospital and the Harvard Cyclotron Laboratory, we have treated over 500 patients with moderate to high dose radiation using proton beam radiation therapy to the parasellar region for non-pituitary gland and non-hypothalamus tumors of the base of skull region, most typically chondrosarcomas and chordomas of the clival region. A significant number of these patients have been followed for neuroendocrine outcome prospectively and recent analysis of 107 such adult patients have shown that doses above 50 centigray equivalent (CGE) to the pituitary gland or hypothalamus significantly increases the risk of hypopituitarism . Patients receiving 70 CGE to any portion of the pituitary gland were also at increased risk. A high incidence of hyperprolactinemia was also observed using proton therapy with a 10-year actuarial incidence of over 85%. What was unique to this study was the ability to determine the dose to the pituitary gland and hypothalamus more precisely using 3 dimensional computerized treatment planning algorithms not available in the past at other institutions.
Radiation therapy has a proven role in the treatment of neoplasms arising from the brain and head and neck region where sensitive neurovascular structures preclude aggressive surgical resection. Radiation can also cause damage to these neurovascular structures such as the pituitary gland and hypothalamus resulting in hypopituitarism. Both children and adults can be affected and the incidence of hypopituitarism is very high. Patients often require hormone replacement therapy and life long monitoring is strongly recommended. Patients with neoplasms listed in Table I are recommended to have longitudinal endocrine follow-up after radiation therapy. However, any patient receiving radiation therapy where the pituitary gland and hypothalamic region is at risk for irradiation should be screened as well. Radiation induced hypopituitarism is generally limited to dysfunction of the anterior pituitary gland. The types of endocrinopathies, timing and risk factors have been described. The radiation dose is an important factor with several studies indicating a dose response for hypopituitarism. In the last decade, advancements in computer technology, diagnostic imaging and radiation treatment techniques have enabled radiation oncologists to deliver radiation more precisely to the intended target. This approach limits the dose to surrounding normal tissue thereby improving the therapeutic ratio. Efforts should continue in this direction to reduce the incidence of radiation induced hypopituitarism.
- Littley, M D, Shalet, S M, Beardwell, C G, Robinson, E L, Sutton, M L., Radiation-induced hypopituitarism is dose-dependent. Clinical Endocrinology, 1989. 31: p. 464-373
- Constine, Louis S, Woolf, Paul D, Cann, Donald, Mick, Gail, McCormick, Kenneth, Raubertas, Richard F, Rubin, Philip. Hypothalamic-Pituitary dysfunction after radiation for brain tumors. N Engl J Med, 1993. 328: p. 87-94.
- Pai, Howard H, Katznelson, Laurence, Klibanski, Anne, Finkelstein, Dianne M, Adams, Judith A, Fullerton, Barbara C, Thornton, Allan, Leibsch, Norbert J., Munzenrider, John E. Hypothalamic/Pituitary Gland Dysfunction following High Dose Conformal Mixed Proton-Photon Beam Radiotherapy to the Base of Skull Region: Demonstration of a Dose Effect Relationship using Dose Volume Histogram Analysis. in 41th ASTRO (American Society for Therapeutic Radiology and Oncology) conference. 1999. San Antonio, TX.