Radiation therapy of pituitary adenomas

INTRODUCTION — Pituitary adenomas are benign tumors that arise from the cells of the anterior pituitary gland. Primary treatment is usually surgery or pharmacologic treatment. When initial treatment with these interventions fails, or when there is a recurrence, radiation therapy should be considered.

Current radiation therapy employs more sophisticated imaging and targeting techniques than were previously available, but most published papers, which are based on retrospective series, report results using older techniques. The newer techniques offer the promise of reducing the incidence and severity of side effects. The relatively long time required for control of hormonal hypersecretion and the subsequent development of hypopituitarism have limited more widespread use of radiation therapy.

The common forms of radiation therapy for pituitary adenomas and their efficacy and side effects will be discussed here. More detailed discussions of pituitary adenoma treatment are found separately.

●(See "Treatment of gonadotroph and other clinically nonfunctioning adenomas".)

●(See "Overview of the treatment of Cushing syndrome".)

●(See "Management of hyperprolactinemia".)

●(See "Treatment of acromegaly".)

TYPES OF RADIATION THERAPY

Stereotactic radiosurgery (SRS) — SRS is the delivery of a single high dose of radiation therapy using a high-precision localization system to treat a small target. It is most effective and safe when treating small sizes and when able to aim very accurately so that safety margins can be minimized and the total target size is as small as possible.

Fractionated radiation therapy — Fractionated radiation therapy is the delivery of radiation therapy in multiple, small, daily doses, usually five days a week for five to six weeks. This is the most common way radiation therapy is delivered for most other indications of radiation treatment.

In deciding which form of radiation therapy should be employed for a particular pituitary adenoma, we consider these factors:

Treatment considerations — Treatment schedule considerations for pituitary adenomas include:

●Convenience – SRS can be delivered as a single treatment, whereas fractionated radiation therapy requires 25 to 30 treatments.

●Safety – Adenomas that are too close, 3 to 5 mm, to radiation-sensitive tissues, such as the optic chiasm or other parts of the optic pathway, are more safely treated with fractionated radiation therapy since a large, single dose of radiation to these tissues can cause blindness. Large adenomas, eg, 3 cm or greater in diameter, are also more safely treated with fractionated radiation because of the large volume of tissue receiving radiation. (See 'Other damage' below.)

●Therapeutic response – Some studies report that SRS results in a more rapid reduction in elevated hormone concentrations than fractionated radiation treatment. However, these were not randomized trials, and there were differences between the populations receiving the two types of radiation [1,2]. Because SRS can cause damage to the optic pathways, the patients treated by a single large dose had smaller adenomas than those treated by fractionated doses [1,2].

RADIATION DELIVERY SYSTEMS

Gamma Knife — Gamma Knife is a stereotactic radiosurgery (SRS) treatment unit that uses radioactive isotope cobalt-60 to deliver radiation. Much of the radiation treatment for pituitary adenomas was pioneered using Gamma Knife. The radioactive cobalt-60 is housed within the machine, which controls how the small beams of gamma rays, also known as photons, are directed. Patients are positioned within the unit with their head held in place by a metal frame. The machinery aims multiple tiny beams of radiation at the desired intracranial target. The greatest experience of SRS (single treatments) in the management of pituitary adenomas has been with Gamma Knife.

Treatments are typically limited to one visit because the head frame is attached with pins to the scalp that are minimally invasive but pierce the skin to fix on the skull. This localized trauma would not be considered appropriate to perform repeatedly, as it leaves a small wound mark at each pin site with each application. Dose delivery with a low energy source such as cobalt-60 requires a large dose gradient such that the dose delivered to the periphery of a target is approximately half the dose delivered to the geometric center of the target. There are over 200 angles arranged around the patient's head from which these small beams can be directed to the adenoma target. Not all beam sources are used. The choice of beams per target creates the conformal radiation treatment. Doses for each type of pituitary adenoma are described below and refer to the margin dose delivered to the target since this is the expected minimum therapeutic dose. The latest generation of this unit employs a noninvasive immobilization head frame, such that multiple fraction treatments are now feasible. (See 'Efficacy and suggested approach' below.)

Linear accelerator — The linear accelerator is the most common device used to deliver radiation treatments, ie, it is the basic radiation therapy machine. It accelerates electrons to high speeds and then converts this energy to high-energy x-rays, also known as photons. Many technological modifications are used to deliver the radiation to the desired location and dose. Complex shapes can be treated, and the dose can be varied across the target. Terms that are sometimes used to denote types of fractionated radiation delivery using a linear accelerator include three-dimensional conformal therapy, intensity modulated radiation therapy, and fractionated stereotactic radiotherapy. A term describing a single large dose delivered from a linear accelerator can be called single fraction SRS. Both fractionated radiation therapy and single fraction SRS are common uses of the linear accelerator.

CyberKnife — CyberKnife can deliver either a single large dose or fractionated therapy. It is a small linear accelerator mounted on a robotic arm. The arm has more freedom to move around patients than the radiation source in other delivery systems and, therefore, allows patients to be in less confining positions as the unit is able to more easily compensate for variations in the patient's daily position. Numerous small radiation beams are used to deliver the radiation to the desired location. The overall length of time of treatment on a CyberKnife is typically longer than with other radiation therapy modalities.

Proton therapy — Proton therapy is delivery of high-energy proton particles most commonly generated by a cyclotron or synchrotron. Proton therapy results in less exposure of the surrounding normal tissue to an excess dose than do photon-based modalities. The decrease in the collateral unintended radiation exposure of normal tissues may decrease side effects from treatment. The number of proton therapy facilities has been scarce because of the complexity and capital cost of these centers but is increasing, with approximately 40 centers open in 2021 as compared with 2 centers in 2000.

EFFICACY AND SUGGESTED APPROACH — The relatively slow response of hypersecretion to radiation therapy, compared with surgery and even with pharmacologic treatment, is a disadvantage of this technique. Control of adenoma growth, however, is very high using all of the techniques.

There has been extensive experience with use of all forms of radiation therapy for pituitary adenomas, but individual published reports generally describe retrospective experiences using a single technique. As a consequence, it is difficult to compare the results of the various techniques, especially in controlling excessive secretion of pituitary hormones. The difficulty is compounded by the use of different radiation doses and different biochemical criteria for cure of hypersecretion [3].

The effect of adenoma size and concomitant pharmacologic treatment for hormonal hypersecretion on the response to Gamma Knife treatment has been reported in 418 patients with mixed types of pituitary adenomas [4], 40 patients with Cushing's disease [5], and 46 patients with acromegaly [6]:

●Adenoma size – Larger adenoma volume was associated with a lower rate of hormonal control in one study [5] and greater rate of new hormonal deficiencies in another [4] but was not associated with a differential effect on adenoma size in two studies [4,6].

●Concomitant pharmacologic treatment – Pharmacologic treatment (somatostatin analogs for acromegaly and dopamine agonists for lactotroph adenomas) at the time of irradiation was associated with lower rates of hormonal control [4] and a higher incidence of hypopituitarism [4] but no difference in control of adenoma size [4].

These associations are difficult to interpret, however, because concomitant pharmacologic treatment of patients with Cushing's disease with ketoconazole, which blocks cortisol synthesis in the adrenal glands, ie, does not affect the pituitary gland, also reduces the hormonal efficacy of Gamma Knife treatment [5]. This observation suggests that the more favorable effect of radiation when pharmacologic treatment has been withheld is related to another factor, eg, selection bias, and not to a direct effect of the drug on the pituitary adenoma.

Clinically nonfunctioning pituitary adenomas — Radiation therapy is considered for clinically nonfunctioning adenomas:

●When residual adenoma remains after surgery. The rationale is that continued growth is approximately 30 to 60 percent at five years when obvious adenoma tissue, as detected by magnetic resonance imaging (MRI), remains after surgery [7-9]. Residual tumor outside the sella is associated with a higher rate of progression than residual adenoma limited to within the sella [7,10,11]. Alternatively, the residual adenoma can be monitored, and the potential side effects of radiation therapy can be avoided entirely in those patients in which the residual adenoma never progresses or at least postponed. (See "Treatment of gonadotroph and other clinically nonfunctioning adenomas", section on 'Residual adenoma'.)

●When residual adenoma regrows following surgery. In this setting, radiation therapy is an alternative to repeat surgery. (See "Treatment of gonadotroph and other clinically nonfunctioning adenomas".)

●Recurrence of the adenoma when no residual adenoma is seen by MRI is as low as <5 percent at five years or up to 10 to 25 percent at 10 years [7,8,11-13]. When no or little adenoma tissue is apparent after surgery, radiation is not recommended, only observation. (See "Treatment of gonadotroph and other clinically nonfunctioning adenomas".)

The goal of radiation therapy in this setting is to stop adenoma growth. Shrinkage, partly or completely, may occur but is not necessary to consider the treatment a success [14,15].

The type of radiation depends on the proximity of the residual adenoma tissue to the optic pathway and its size.

●Stereotactic radiosurgery (SRS) can be considered if the adenoma tissue is not within 3 to 5 mm of the optic pathway and is less than 3 cm in diameter. A common SRS dose is 18 to 20 Gy [4,16].

●Fractionated radiation therapy is generally chosen for adenoma tissue that is larger and/or closer to the optic pathway. The usual dose is 45 to 50.4 Gy at 1.8 Gy daily fractions [17].

Either form of radiation controls adenoma size in 90 percent of patients at 5 to 10 years [4,16-18]. (See "Treatment of gonadotroph and other clinically nonfunctioning adenomas".)

Clinically functioning pituitary adenomas — The goal of therapy with nonfunctioning pituitary adenomas is tumor growth control; in contrast, the goal of radiation for functioning pituitary adenomas is both tumor growth and biochemical control, which typically require higher radiation doses.

Corticotroph adenomas (Cushing's disease) — Radiation treatment is considered for corticotroph adenomas causing Cushing's disease when surgery has been unsuccessful. The principal goal is to lower corticotropin (ACTH) secretion and thereby lower cortisol secretion to normal. (See "Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation", section on 'Pituitary irradiation'.)

●Type of radiation – SRS (20 to 25 Gy) is considered the first choice if the adenoma is not close to the optic pathway; fractionated radiation (50.4 to 54 Gy) is used for those that are [4,19-23].

●Efficacy – Reduction of cortisol to normal occurs in approximately 50 percent of subjects by two to five years and higher is projected with longer follow-up [4,19,20,22,24]. Normalization of cortisol may occur somewhat faster after SRS than fractionated therapy, a median of 7.5 to 33 months versus 18 to 42 months [1]. Efficacy appears similar among all forms of SRS: Gamma Knife [20], linear accelerator [19], and protons [23]. (See "Overview of the treatment of Cushing syndrome".)

●Control of adenoma growth – This is especially important in corticotroph macroadenomas. All modalities of radiation therapy control adenoma growth in 90 to 100 percent of patients [4,19,20,22], similar to nonfunctioning adenomas. (See 'Clinically nonfunctioning pituitary adenomas' above.)

Corticotroph adenomas associated with Nelson syndrome may be less responsive to radiation than other corticotroph adenomas, but the data are limited [4]. (See "Persistent or recurrent Cushing disease: Surgical adrenalectomy", section on 'Nelson syndrome'.)

Somatotroph adenomas (acromegaly) — Radiation therapy is considered for treatment of acromegaly when surgery and pharmacologic therapy have been unsuccessful in controlling growth hormone secretion or, less commonly, adenoma growth. (See "Treatment of acromegaly", section on 'Radiation therapy'.)

●SRS and fractionated radiation appear to be equivalent for treatment of somatotroph adenomas. The usual doses of radiation are 20 to 25 Gy for SRS and 50.4 to 54 Gy for fractionated radiation therapy [4,12,25-28]. (See "Treatment of acromegaly", section on 'Radiation therapy'.)

●All forms of SRS appear to be equivalent for efficacy. Most experience has been with Gamma Knife [4,12,26], but the results are similar with linear accelerator [25], CyberKnife [29], and proton therapy [23]. With all forms, reduction of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels to normal occurs relatively slowly: 50 to 60 percent response at 5 to 10 years and 65 to 87 percent at 15 years [4,12,25-28]. Patients with lower serum GH concentrations prior to radiation therapy appear to be more responsive to treatment [27,30]. Local control of tumor is high at 95 to 100 percent [12,25,26,28].

Lactotroph adenomas (prolactin-secreting adenomas) — Because 90 percent of lactotroph adenomas respond to dopamine agonists and most of the rest can be treated successfully by surgery, the usual goal of radiation treatment is to control growth of a large adenoma when dopamine agonist treatment and surgery have not. Single-dose and multiple fraction radiation appear to be equally effective.

●Radiation therapy, either single dose [25,31-33] or multiple fractions [17,18], appears to be effective in controlling growth in up to 89 to 100 percent of patients in reported series. These reports, however, do not specifically describe the effect on the aggressive lactotroph adenoma that does not respond to dopamine agonist treatment and cannot be entirely resected surgically, which is the kind of adenoma for which radiation is needed most.

●Radiation therapy results in highly variable effects on hyperprolactinemia, but overall up to 50 percent of patients have a return to normal prolactin level with radiation therapy alone though they generally require more years to respond than other types of functioning adenomas, and a majority are managed with the addition of a dopamine agonist [4,17,34,35]. Hyperprolactinemia, however, does not require correction if it is not causing hypogonadism and, if it is, can be managed by administration of gonadal steroids.

RISKS/ADVERSE EFFECTS — The risks of radiation therapy are development of new hypopituitarism, which is common, and neurologic damage and others, which are not.

Hypopituitarism — Hypopituitarism occurs following both fractionated and single-dose radiation therapy.

●In two series of 385 and 884 patients treated with fractionated radiation therapy, new deficiencies of corticotropin (ACTH), thyroid-stimulating hormone (TSH), and gonadotropins occurred in approximately 20 percent of patients at five years and up to 30 percent at 10 years [17,27].

●In two studies that included a total of 494 patients, 418 and 76 with mixed types of pituitary adenomas treated by single-dose radiation therapy (Gamma Knife), 21 to 24 percent developed one or more pituitary hormone deficiencies, mostly two to four years after radiation (the frequency of individual deficiencies was not described) [4,32]. The risk of hormonal deficiencies increases to as high as 80 percent by 10 to 15 years [13,22]. All patients undergoing sellar radiation therapy should be counseled on the high risk of hypopituitarism and the importance of neuroendocrine function surveillance.

The risk of hypopituitarism can sometimes be reduced with minimization of normal pituitary collateral irradiation, which may be possible with well-lateralized adenomas. Limiting the radiation to the hypothalamus may also reduce radiation-associated hypopituitarism [36,37]. The management of hypopituitarism is reviewed separately. (See "Treatment of hypopituitarism".)

Other damage — Other side effects of sellar irradiation are far less common:

●Optic pathway injury – In two series of 796 patients treated by fractionated radiation therapy, injury to the optic pathway was reported in 0.8 to 1.3 percent at 10 years and 1.5 percent at 20 years [17,38]. Risk is minimized if the dose is kept to 54 Gy or slightly less if there is preexisting injury to vision [39-41]. For single-dose radiation therapy, the risk of optic pathway injury is minimal if the dose to these structures is kept below 8 to 10 Gy but is approximately 1 percent at 12 Gy [39,40].

●Cranial nerve injury – This is uncommon but more likely to occur following re-irradiation [42].

●Secondary tumors – The incidence was 1.9 percent at 20 years in two large studies [17,38], but the radiation delivery technique in those studies exposed a much larger volume of tissue to radiation than do current techniques.

●Strokes – An increased risk of stroke has been observed in pituitary adenoma patients who have received radiation therapy. However, the risk appears to be due to their preexisting cardiovascular risk factors such as coronary disease and peripheral vascular disease and not the radiation therapy [43].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of Cushing syndrome" and "Society guideline links: Diagnosis and treatment of acromegaly" and "Society guideline links: Pituitary tumors and hypopituitarism".)

SUMMARY AND RECOMMENDATIONS

●Radiation therapy can be delivered using x-rays from a linear accelerator or CyberKnife, gamma radiation (Gamma Knife), or protons. Radiation can be delivered in a single large dose (stereotactic radiosurgery [SRS]) or multiple fractions (fractionated radiation therapy). (See 'Types of radiation therapy' above.)

●Radiation therapy of any kind controls adenoma volume in 90 to 100 percent of patients. Radiation therapy may also reduce hormonal hypersecretion, but the effect is variable and slow; complete normalization occurs in approximately 50 percent of patients after 10 years. (See 'Efficacy and suggested approach' above.)

●Radiation therapy causes hypopituitarism in up to 80 percent of patients after 10 years but has very low risk of optic pathway and other long-term side effects. (See 'Risks/adverse effects' above.)

●We suggest radiation therapy be administered to patients with pituitary adenomas only after surgical and/or medical options have been exhausted (Grade 2C). (See 'Risks/adverse effects' above.)

●We suggest SRS for adenomas that are not close to the optic pathway (at least 3 to 5 mm away) and are smaller than 3 cm in diameter and fractionated radiation therapy for adenomas that are larger than 3 cm and/or closer to the optic pathway (Grade 2B). (See 'Risks/adverse effects' above.)

●For clinically nonfunctioning pituitary adenomas, we suggest either SRS or fractionated radiation therapy, depending upon the size and location of the adenoma. If SRS is chosen, we suggest a dose of 18 Gy (range 14 to 20 Gy) and no more than 8 to 10 Gy to the optic pathway. If fractionated radiation therapy is chosen, we suggest a dose of 45 to 50.4 Gy at 1.8 Gy per fraction and no more than 54 Gy to the optic pathway. The goal of therapy with nonfunctioning pituitary adenomas is tumor growth control. (See 'Clinically nonfunctioning pituitary adenomas' above.)

●For clinically functioning (eg, secretory) pituitary adenomas, we suggest either SRS or fractionated radiation therapy, depending upon the size and location of the adenoma. If SRS is chosen, we suggest a dose of 20 Gy (range 20 to 25 Gy) and no more than 8 to 10 Gy to the optic pathway. If fractionated radiation therapy is chosen, we suggest a dose of 50.4 to 54 Gy at 1.8 Gy per fraction and no more than 54 Gy to the optic pathway. The goal of radiation therapy for functioning pituitary adenomas is both biochemical control, which typically requires higher radiation doses, and tumor growth control. (See 'Clinically functioning pituitary adenomas' above.)

●For patients taking pharmacologic treatment to reduce hormonal secretion by the adenoma, eg, dopamine agonist or somatostatin analog, we suggest discontinuing it for one month prior to and one month following radiation treatment (Grade 2C). (See 'Efficacy and suggested approach' above.)

●For all patients, we recommend counseling on the high risk of subsequent development of hypopituitarism and the importance of lifelong surveillance after treatment. (See 'Risks/adverse effects' above.)

ACKNOWLEDGMENT — We are saddened by the death of Jay Loeffler, MD, who passed away in June 2023. UpToDate acknowledges Dr. Loeffler's past work as an author for this topic.