Radiosurgery and increased mortality: Is there a connection?

This study takes a brief look at radiosurgery and its possible link to increased mortality. It does not distinguish between single-fractionated radiotherapy such as gamma knife and fractionated stereotactic radiotherapy (FSR).

The authors explore four (4) major areas:

• Cerebrovascular disease following pituitary radiotherapy
• Cerebrovascular mortality following pituitary radiotherapy for non-functioning adenomas
• Impact of pituitary radiotherapy on mortality in acromegaly
• Hypopituitarism and excess mortality following pituitary radiotherapy

I am mainly interested in the first and the last in the list above. These impact those with Cushing's who are considering or have undergone radiotherapy.

Cerebrovascular disease is already a risk with Cushing's patients. In Mortality in Patients Treated for Cushing’s Disease Is Increased, Compared with Patients Treated for Nonfunctioning Pituitary Macroadenoma (Dekkers, et al), the authors conclude:

[M]ortality is increased in patients with Cushing’s disease, compared with both NFMA and acromegaly. This implicates that transient exposure to cortisol excess is a major contributor of the increased mortality, even after cure of Cushing’s disease. This observation may also be of relevance for patients treated with exogenous glucocorticoids for nonendocrine diseases.

Cited in the same study, "Causes of death were cardiovascular disease in 23.4%, cerebrovascular disease in 12.8%, malignancy in 19.1%, and infectious diseases in 17% of all patients. " Thus, there is already a link to mortality due to cerebrovascular disease and Cushing's.

The Ayuk/Stewart analysis cited a "study of 331 patients with pituitary adenomas treated with surgery and radiotherapy [where] increasing doses of radiotherapy were associated with increasing risk of cerebral infarction." They go on to admit there is a lot of debate about what caused the cerebrovascular events, with radiation thought to be a cause due to "changes to the cerebral vasculature".

The Dekkers study counters that: "By regression analysis, in a model adjusted for age and gender, radiotherapy and hypopituitarism were not associated with increased mortality risk."

Ayuk and Stewart, when analyzing the data from multiple sources, disagree. Hypopituitarism is common after treatement for pituitary adenomas. They cite several studies which show "over 50% of patients treated with pituitary radiotherapy will develop deficiencies in one or more anterior pituitary hormones over the following decade." They then analyzed numerous studies which "examined mortality in patients with hypopituitarism and which found increased mortality compared with age-matched controls, predominantly due to cerebrovascular and cardiovascular disease."

In two of the studies analyzed, radiotherapy did not seem to attribute to increased mortality. But in another, larger study of over 1000 patients, "treatment with radiotherapy was associated with a significantly increased mortality rate" when comparing patients who had hypopituitarism from radiotherapy with patients who had hypopituitarism from other treatments or due to tumor.

Age may play a part, also:

The authors also reported higher mortality in patients who had been diagnosed at a younger age, with a standardized mortality ratio of 4.87 in the group younger than 20 years, decreasing to 1.0 in those older than 60 years. This is of particular relevance as over half of the radiotherapy-treated patients were younger than 50 years at the time of treatment.

Overall, the data is unclear about the link between radiotherapy and mortality. The authors were also unclear about whether the hypopituitarism was treated with hormone replacements and what significance this may have. I suspect this was partially due to the information available to them from the studies they analyzed.

John Ayuk, Paul M. Stewart (2008). Mortality following pituitary radiotherapy Pituitary, 12 (1), 35-39 DOI: 10.1007/s11102-007-0083-1

Hypopituitarism and Gamma Knife Radiotherapy

Does radiotherapy cause hypotituitarism when treating pituitary adenoma(s)?

Sometimes tumors cause damage to the pituitary gland which results in hypopituitarism and panhypopitituarism. Surgery to remove the tumor(s) can also cause damage to the pituitary which leads to hypopitutiarism. Sometimes, depending on tumor placement and the amount of pituitary removed, the pituitary regains total function. Nothing is cut-and-dry with this due to the numerous factors surrounding tumors and their removal.

This article takes a look at the effect of radiotherapy on the pituitary. Is hypopituitarism a "given" with radiotherapy or can it be avoided? According to the authors, this depends on the total dose, the fraction size of each irradiation, and the time between each fraction.

Since Gamma Knife is a single-fraction radiosurgery, all radiation is delivered in one dose.

Radiation-induced hypopituitarism occurs in a significant number of patients treated for pituitary adenomas with either stereotactic radiosurgery (SRS), which involves a single dose of stereotactic radiotherapy, as well as following fractionated stereotactic radiotherapy (FSRT).

The authors point out the risk is difficult to establish due to the multiple factors involved, which include:

• surgery
• variations in dosages of radiation
• technique used (SFR vs. FSRT)
• accuracy of placement and imaging
• pre-existing hypopituitarism
• lack of consisten protocol for diagnosing hypopituitarism

They also point out hypopituitarism is "more likely to occur following stereotactic irradiation for
secretory adenomas, as higher doses are generally required to achieve hormonal control." This includes gamma knife.

Since hypopitituarism can include multiple hormones, which are the most apt to be affected? Growth hormone (GH) has the greatest vulnerability. "With higher radiation doses (30–50 Gy), however,the frequency of GH insufficiency substantially increases and can be as high as 50–100%."

Patients irradiated for pituitary tumors have an increased risk for gonadotrophin deficiency with the data presenting "severity from subtle subclinical) abnormalities in secretion detected only by
GnRH testing to severe impairment associated with diminished circulating sex hormone levels."

Normal ACTH deficiency "dramatically increases (27–35%) after intensive irradiation [6, 9, 12] and more so (31–60%) in patients with pituitary adenomas [20, 25, 26]." TSH deficiency follows almost identically with patients irradiated for pituitary tumors.

Women tend to develop hyperprolactemia after SRS/GK which tends to normalize over time. The article was not very clear on this and just briefly touched on it. There didn't seem to be much data on it, either.

More on GK later this week.

Ken H. Darzy, Stephen M. Shalet (2008). Hypopituitarism following radiotherapy Pituitary, 12 (1), 40-50 DOI: 10.1007/s11102-008-0088-4

Gamma Knife Radiosurgery...

...A safe alternative for treatment of ACTH-producing pituitary adenomas?

For the next few posts, I'm going to examine the latest research about the use of Gamma Knife (GK) radiosurgery in the treatment of pituitary adenomas, especially ACTH-producing adenomas.

Although GK is called radiosurgery, there is no cutting involved. 201 "beams" of cobalt-60 gamma radiation are focused on the region to be treated. The beams go through the skull in different spots, with each beam too weak to hurt normal tissue. However, when they all come together in the area to be treated, they are then strong enough to destroy the tumor. It is a type of single-fraction radiosurgery.

Another method often used is fractionated stereotactic radiotherapy. The Johns Hopkins' site explains FSR this way:

[With FSR] multiple fractionated doses or fractionated stereotactic radiation can be delivered. The main advantage of fractionation is that it allows higher doses to be delivered to the tumor because of increased tolerance of the surrounding normal tissues to these smaller fractionated doses. In other words, while single-dose stereotactic radiation takes advantage of differences in the pattern of radiation given, fractionated stereotactic radiation takes advantage of not only the pattern, but more importantly of the differing radiosensitivities of normal and surrounding tissues. Another advantage is so-called ”iterative” treatment, meaning the shape and intensity of the treatment plan can be modified during the course of therapy.

Dr. Molitch and Professor Grossman¹, in the March 2009 issue of Pituitary which focuses on radiotherapy for pituitary tumors, introduce the issue as guest editors. In their introduction, they say:

As of yet, there are no adequate studies to conclude whether there is one mode of single-dose radiotherapy that has superior efficacy or safety, and indeed direct comparisons of single-dose vs. fractionated stereotactic radiotherapy (FSR) are all but non-existent.

GK radiosurgery is done in one session. FSR takes multiple sessions spread over a period of time. The head must be in the exact position during each session. For many reasons, including ease, GK has become the preferred method.

In the same issue of Pituitary, Dr. Mary Vance at the University of Virginia² discusses the use of radiation therapy in the treatment of Cushing's disease. According to Dr. Vance, radiation therapy is used "most commonly as adjunctive therapy after unsuccessful pituitary surgery."

Dr. Vance reiterates the fact that GK is "not suitable for a large lesion close to the optic nerves or optic chiasm" and that all radiation therapies do cause loss of pituitary function eventually. She also emphasizes "There are no prospective studies comparing the results among different methods of radiation delivery regarding efficacy, development of new pituitary hormone deficiency or complications."

Points that Dr. Vance makes about any type of radiation therapy:

• Basically used when transsphenoidal surgery doesn't work
• Takes time (months to years) before it works
• Medical therapy (ketoconazole or metyrapone) to lower cortisol may be needed in conjunction with radiation treatment until it works
• Patient needs to be monitored closely for liver problems due to drug therapy and for lower natural production of cortisol

Dr. Vance has a nice summary of the various types of radiation therapy which include gamma knife (GK).

The Gamma knife series of 90 patients treated at the University
of Virginia found that a normal 24 h UFC level occurred in 49 patients (54%) at an average time of 13 months (range 2–67 months). Ten patients (20%) had relapse of Cushing’s with the mean time to relapse of 27 months (range 6–60 months). Seven of these patients underwent a second Gamma knife treatment, three achieved remission. Five of the seven patients (71%) who had a second Gamma knife treatment developed a new visual or 3rd, 4th or 6th cranial nerve deficit. These cranial nerve deficits either resolved (two patients), improved (two patients) or persist(one patient) (New pituitary hormone deficiency developed in 20 patients (22%)

This research also indicates there is no known safe radiation value for second attempts with GK.

The development of cranial nerve deficits and visual loss after a second Gamma knife treatment, in this study and in an another report [14], suggests that the presumed safe radiation dose to the cavernous sinus and optic chiasm and optic nerves is not known. For this reason, and until more definitive information is obtained, a second Gamma knife treatment should probably be avoided.

Dr. Vance points out that although radiation therapy is not perfect, there really is no perfect treatment for Cushing's disease at this time.

More posts on GK as a treatment coming this week.



1. Mark E. Molitch, Ashley B. Grossman (2008). Pituitary radiotherapy Pituitary, 12 (1), 1-2 DOI: 10.1007/s11102-008-0148-9

2. Mary Lee Vance (2008). Cushing’s disease: radiation therapy Pituitary, 12 (1), 11-14 DOI: 10.1007/s11102-008-0117-3